1/18/05 Tuesday Physiology: Mechanistic Description of Organ Functions 3 Areas Anatomy: form, structure, connections Chemistry: molecular structure, reactions Physical forces: electrical, mechanical, molecular How should we look at body systems? Look at what tissues make up a certain organ system (Table 1.1 summarizes organ systems) 4 Tissue Types (fig 1.2) Neurons/ nerve cells: specialized for nerve impulses that transmit info from sense organs to the brain to muscle Muscle cells: specialized to contract 3 kinds: skeletal, cardiac, smooth (gastrointestinal muscles, muscles in blood vessels) Epithelial: Form the sheets that line your organs, blood vessels, and your whole body (i.e. your skin’s epidermis) Epithelial cells joined by specialized tight junctions that restrict movement of substances between cells (fig 2.26 in text) Protective and controlling functions Protective: Epithelial cell layers form barriers between the body’s internal environment and the external environment Controlling: Cell layers help control the movement of substances since the rate of movement for different substances are determined by what’s in the epithelial lining Connective Tissue that’s made of a scattering of cells suspended in a loose noncellular extracellular matrix Examples Dermis: the layer below the epidermis in skin; made up of fibroblast cells suspended in protein fibers Bone cells suspended in Ca deposits Fat cells in matrix of fat globules Blood cells in blood plasma Cartilage cells in collagen matrix Fig 1.4: Summarizes human body plan Epithelial cell layers form barriers between the body and the external environment Cells of organs do not directly contact the outside environment, but are bathed in interstitial fluid (interbody fluid). Blood cells are bathed in blood plasma. HOMEOSTASIS We can look at body systems from the homeostasis perspective: how are the homeostatic states of different organ systems maintained? Homeostasis: maintaining a constant and optimal internal environment The body is designed to hold all variables in the narrow range at which cells function best—that is, to maintain the optimal levels of various factors Of the many factors requiring exact controls, examples are: Temperature pH Concentrations of CO2, O2, ions (Na, K, Mg, bicarbonate, Ca, etc.), organic nutrients (glucose, amino acids, fatty acids, etc.) Internal organ cells don’t directly contact the external environment, but must exchange material through the blood Oxygenlungs blood body tissues CO2 from tissues blood lungs external environment Thus are the optimal levels of oxygen and CO2 maintained in the internal environment FEEDBACK SYSTEMS Homeostasis is based on NEGATIVE FEEDBACK Negative feedback systems (usually quite complex) help maintain a variable at a constant, optimal level Negative feedback adjusts itself based on input stimuli Examples Your furnace turns up or down depending on the house’s temperature Fig 1.6: the cruise control of a car increases or decreases the amount of gas burned to keep speed constant as you go up and down hills Fig 1.9: Thermoregulation: Thermoreceptors in skin send signals about the outside temp to the hypothalamus, which sends orders via nerves to sweat glands, blood vessels in skin, and skeletal muscles E.g. if Cold outside, your body will increase body heat: sweat glands are turned off (reducing heat loss by evaporation), skin blood vessels constrict (keeping heat in body core), skeletal muscles contract (produce heat through shivering) Stretch reflex Mallet hits knee knee jerks Since you stretch a leg muscle when you hit it, the muscle contracts to maintain muscle length Hormones/ endocrinology: deals with homeostasis POSITIVE FEEDBACK: Only a few examples of positive feedback exist, since there is the danger of runaway reactions Needs a method of termination: either through removal of the stimulus or a breaking response to break the chain Examples Birth: stretching of uterine walls release oxytocin increase strength of contractions more oxytocin released more contractions, etc… Nerve impulses: shutting of ion gates halts the action potential Ovulation: release of the egg COMMUNICATION 2 Mechanisms for Communication (Figure 5.1) Cells may be joined through gap junctions made of specialized proteins (connexons) Cells exchange substances/ electric currents through these junctions Still, direct coupling is less common, and the size of gap junctions is restricted Cells may release something that binds to receptor proteins of another cell and subsequently affects the behavior of that other cell Most common method of communication Production of chemical messenger may affect cells close or distant Autocrine: cell releases substance that affects itself E.g. synapse releases neurotransmitter that affects itself Paracrine: chemical messengers that affect nearby cells Neurotransmitters, hormones, immune factors: affect distant cells Paracrine Communication: examples Histamine: production of hives Antigen applied locally to skin Antigen binds to Ige antibodies attached to Mast cells Mast cells release histamine Stimulates nerve endings (itch) & increases permeability of capillary cells fluid movement into interstitial space swells tissue Nitric Oxide: control of blood flow Low blood oxygen in tissue Endothelial cells lining small blood vessels release NO NO relaxes smooth muscle in vessel walls Blood vessels dilate: blood flow increases more O2 gets to tissue Transmission at a Distance (Fig 5.2): Neurotransmitters: axon of neuron can be several feet long Though neurons are specialized for distance transmission, it can also be considered an example of a special paracrine communication since the signal still travels between the same kinds of cells Hormones: endocrine cells produce released in blood carried through body Neurohormones: nerve cells release these into the blood to be carried through the body E.g. pituitary gland releases growth hormone through axon terminals that connect to the blood vessels Immune factors released into the blood& interstitial fluids to be carried to target organs 2 Main Classes of Chemical Messengers: fat soluble and fat insoluble (more common) Lipid soluble messengers Can pass cell membranes Examples: steroids, sex hormones (testosterone, progestorne, estrogen), adrenal cortex hormones (aldosterone, cortisol type hormones), thyroxin Enters cytoplasm or even the nucleusbinds in a lock and key fit to a receptor to form a complex that then binds to DNA complex increases or decreases the reading of the gene it binds to stimulates or inhibits protein production Lipid insoluble messengers General process Chemical messenger binds to receptor on the cell surface changes structure of receptor protein changes structure of associated G protein G protein releases GDP and takes up GTP G protein dissociates: releases its alpha component alpha component of G protein interacts with a 2nd messenger producing enzyme this enzyme produces a 2nd messenger 2nd messenger activates another enzyme (usually a kinase, a phosphorylating enzyme) kinase phosphorylates a protein (possibly another enzyme) chain continues till a final enzyme (that is ultimately activated or inhibited) affects the function of the whole cell Examples: the cAMP and phosphatidylinositol second messenger systems (Fig 5.17) Thursday Chemical Messengers Recap from last lecture: 2 Main Classes of Chemical Messengers: fat soluble and fat insoluble (more common) Lipid soluble messengers Can pass cell membranes Examples: steroids, sex hormones (testosterone, progestorne, estrogen), adrenal cortex hormones (aldosterone, cortisol type hormones), thyroxin Enters cytoplasm or even the nucleusbinds in a lock and key fit to a receptor to form a complex that then binds to DNA complex increases or decreases the reading of the gene it binds to stimulates or inhibits protein production Lipid insoluble messengers (water-soluble) Ex. Organic molecules, acetylcholine, proteins, peptide hormones General process (Fig 5.16) Chemical messenger (1st messenger) binds to receptor (an integral, or transmembrane, protein) on the cell surface changes structure of receptor protein changes structure of associated G protein G protein releases GDP and takes up GTP G protein dissociates: releases its alpha subunit alpha subunit of G protein interacts with a 2nd messenger producing enzyme (or amplifier enzyme) this enzyme catalyzes the production of a 2nd messenger 2nd messenger activates another enzyme (usually a kinase, a phosphorylating enzyme) protein kinase phosphorylates a protein (possibly another enzyme) chain continues till a final enzyme (that is ultimately activated or inhibited) affects the function of the whole cell Examples: cAMP second messenger system (Fig 5.17a) alpha subunit of G protein activates adenylate cyclase enzyme, which catalyzes the production of cAMP from ATP cAMP (the 2nd messenger) activates protein kinase A 1st messengers in this system include: epinephrine, casopressin, ACTH, and glucagon Very similar is the cGMP second messenger system Guanylate cyclase is the 2nd messenger producing enzyme that catalyzes cGMP from GTP cGMP activates protein kinase G 1st messengers in this system include: atrial natriuretic peptide, endothelins Phosphatidylinositol 2nd messenger system (Fig 5.17b) 2nd messenger producing enzyme Phospholipase C cleaves PIP2 to form 2 second messengers: DAG and IP3 DAG activates protein kinase C IP3 stimulates Ca ion release from the endoplasmic reticulum by binding to Ca channels. The Ca ions (another 2nd messenger) bind to calcium binding proteins (like calmodulin), and the Ca-calmodulin complex activates a kinase 1st messengers in this system include: Angiotensin II, histamine, vasopressin Types of Receptors and Channels A G-protein gated channel (Fig 5.15) G protein directly opens or closes an ion channel G protein gated channels are usually slow: from 100msec- a few sec Since the ligand (a primary messenger) doesn’t bind directly to the channel but works through a G protein, such channels shouldn’t be called ligand-gated channels (as the text says) Fast ligand-gated channels (Fig 5.12a) Ligand binds directly to the channel Channel responds quickly: 5-10 msec 1 messenger affects 1 channel No amplification effect like you might get in 2nd messenger systems Ca2+ ion ligand gated channels (Fig 5.12b) Ca ion influx has many effects Change electrical properties of cell Muscle contraction Secretion As a 2nd messenger, Ca binds with calmodulin to produce a complex that activates a protein kinase Receptors that have both receptor and enzyme properties (Fig 5.13) Ligand binds to receptor enzyme on other side of receptor protein is activated E.g. Tyrosine kinase phosphorylates tyrosine after 1st messenger (such as insulin) binds to it Illustration: Epinephrine Triggers Glucose Release from Liver Cell During stress, the adrenal medulla releases epinephrine, which stimulates the breakdown of glycogen to glucose using a 2nd messenger system Steps: Epinephrine binds to receptor, activating a G protein that activates adenylate cyclase Adenylate cyclase catalyzes ATP cAMP + 2 P cAMP activates protein kinase A (indicated by the + sign), which inturn activates hydrolytic enzymes (that break down glycogen into glucose). At the same time, protein kinase A suppresses (neg sign) the activity of synthetic enzymes, which make glucose into glycogen. cAMP also suppresses Phosphatase, which suppresses hydrolytic enzymes while activating the synthetic enzymes. Thus, by stimulating the breakdown of glycogen into glucose and suppressing the synthesis of glucose into glycogen, the net effect will be an increase of glucose in the cell. Signal Amplification in 2nd Messenger systems (Fig 5.18) Amplification occurs at several levels, resulting in a cascade of rxns 1 receptor activates several G proteins Adenylate cycles can catalyze formation of many cAMPs Each protein kinase can phosphorylate many proteins A huge effect from a few 1st messengers Cell Structure (Fig 2.14) Substances must pass through the plasma membrane to get into the cell’s internal environment Plasma membrane = fluid mosaic, a phospolipid bilayer studded mainly with proteins Table 4.1 shows that there is a major difference in each ion’s concentration in the intra- and extracellular fluids. This shows the cell membrane’s role as a barrier, maintaining the concentration gradients inside and out of the cell. The nerve impulse depends on the Na+ and K+ gradient. [K+] is high inside the cell (140 milliMoles) and low outside of it (4 mM) [Na+] is low inside cell (15 mM) and high outside it (145 mM) [Ca 2+] is low in the intracellular fluid (where it is concentrated in the mitochondria and endoplasmic reticulum) and higher in extracellular fluid (1.8mM) [Cl-] is lower inside the cell (4 mM) and higher outside cell (115mM) [Phosphate, amino acids, ATP, and protein] are higher inside cell [Glucose, HCO3-, and Mg2+] are higher outside the cell Phospholipids (Fig 2.3) Made up of phosphate head with a group (usually choline) attached (polar, hydrophilic) Central glycerol backbone 2 fatty acid tails (nonpolar, hydrophobic) Fig 2.4: the nonpolar tails stick together while the polar heads face water forms bilayers or micelles The Plasma Membrane (Fig 2.15) The PM is essentially a lipid bilayer with cholesterol and proteins embedded in it Types of membrane proteins Integral proteins: have an central section made up of uncharged amino acids that allow them to fit into the lipid region of the PM May be transmembranal (goes through entire PM) or go through only half of the PM (with nonpolar end sticking into the lipid region of the PM) Function as channels, receptors (which often have carbohydrates bonded to them), or enzymes Note: both proteins and lipids can be glycosylated (have a carbohydrate group attached). The attached carbohydrate enhances receptor action. Peripheral proteins: Function as enzymes or are structural (helps anchor structural fibers in the cytosol) Most are on the inner surface of the PM There are 2 ways to get through the PM Diffusion across the lipid bilayer (Fig 4.8): Due to random movement of individual molecules; the distribution of molecules becomes equal throughout the solution over time Requires that the substance be NONPOLAR The rate of diffusion depends on: Magnitude of the concentration gradient: the greater the difference in gradient across the membrane, the greater the rate of diffusion Temperature: higher temps higher rates of diffusion Thickness of membrane: thicker membrane slower rate Surface Area of membrane: greater the SA, the greater the rate Permeability of the membrane for a solute: the greater a substance’s lipid solubility, the faster it goes through the lipid bilayer Oxygen, CO2, fatty acids, & steroid hormones are all nonpolar and diffuse easily across the PM Most substances don’t diffuse across the PM because they are charged (ions) or are too large (e.g. glucose) EXCEPTION: water can diffuse across a lipid bilayer (besides passing through channels) since it’s small size makes up for its charge Osmosis: the diffusion of H2O through a semi-permeable membrane In Fig 4.17, H2O diffuses down its own concentration gradient into the cell if the cell is in pure water; it diffuses out of the cell if the cell is in a sucrose solution more concentrated than the solution inside the cell Osmotic Pressure (pg 122 Toolbox) Osmotic pressure: the pressure needed to stop water from flowing into a more concentrate solution In the figures, the osmotic pressure is read when the piston imposes a hydrostatic pressure enough to stop the influx of water into the solution Figure 4.20 The osmotic pressure of blood plasma is around 300 Osmoles. An IV solution injected into a patient thus needs to be isotonic to blood plasma (isotonic = having no effect on the cells bathed in it) For a dehydrated person, you would administer hypotonic fluid (so water will diffuse into cells) Facilitated diffusion and carrier proteins: Carrier proteins: have binding sites Many variations of carrier proteins: ions may just flow through an open channel without binding sites (e.g. Na+ flows through such steady state channels) Larger molecules and some ions move through carrier proteins In facilitated diffusion, carrier proteins moves molecule only down its concentration gradient (no energy required) Fig 4.11: Binding of glucose change carrier’s structure glucose released into the cell glucose phosphorylated so maintain the chemical concentration gradient that drives glucose into the cell If glucose builds up inside the cell, the carrier would move it outside the cell Note: the carrier protein is open to ONE side at once (facing into or out of the cell as it shifts spontaneously) Active Transport: requires energy to move molecules against their concentration gradient Channels need to be phosphorylated by ATP E.g. The sodium-potassium pump (Fig 4.14) Each cycle moves 3 Na+ out and 2 K+ in Uses primary active transport: directly using ATP to phosphorylate the channel Secondary active transport channels couple 2 flows: the energy from molecule A moving down its concentration gradient is used to power the movement of molecule B up its concentration gradient. E.g. using the influx of Na+ into the cell to power the influx of glucose Tuesday Fig 4.13: transport of ions across a cell membrane through a channel protein Most molecules are too charged or large to diffuse across cell membranes, so they must pass through membrane proteins Steady state channels: ALWAYS OPEN, allows small ions to move through (Na+, K+) Electrochemical concentration gradients determine the direction of motion A charged particle is driven both by concentration and electrical potential differences across the cell membrane Intracellular fluid is relatively negative due to large anions that can’t diffuse out (amino acids, Krebs cycle intermediates, etc. Fig 4.11: transport of glucose by a carrier protein Since glucose is too large for steady state channels, it moves through carrier proteins Carrier proteins: Bidirectional protein, oscillates between being open to the outside and inside of the cell regardless of whether glucose is bound to it or not Facilitated diffusion Always moves glucose down its chemical concentration gradient Glucose’s concentration gradient is always INTO the cell, thanks to phosphorylation of glucose upon its intake so [pure glucose] inside the cell is always low Fig 4.14: Na+ /K+ pump Carrier specialized to move ions against their concentration gradients when coupled with phosphorylation by ATP Requires phosphorylation and the binding of Na+ to shift configuration to facing out; requires dephosphorylation and the binding of K+ to shift configuration inwards Moves 3 Na+ out and 2 K+ in per cycle Keeps [Na+] low in the cell Na+/ K+ pump is a primary active transport system since ATP directly phosphorylates the channel Fig 4.15: Secondary active transport systems Binding sites for 2 molecules: Na+ and glucose or Na+ and H+ Found in intestinal epithelia To move glucose against its concentration gradient, pump uses the inward diffusion of Na+ to power the inward pumping of glucose (cotransport- both molecules move in same direction) or the outward pumping of H+ (countertransport- molecules move in opposite directions) Na+ then pumped back out by Na+/K+ pump Fig 4.23, 2.26: epithelial cells Epithelia: line tissues, control movement of substances into/out of body’s internal environment Apical membrane: faces lumen Basolateral membrane: faces interstitial fluid Tight junction: provide strength to epithelial layers a barrier to the movement of substances across epithelial layer Forms a ring around the epithelial cell: separates the apical from the basolateral membrane and thus allows the apical and basolateral membranes to have different compositions (i.e. different carrier proteins) Fig 4.24: Mechanisms of epithelial solute transport Different carrier proteins in apical and basolateral membranes allows Na+ to be pumped across epithelial cells Apical: steady state channels for Na+ Na+ flows into cell Basolateral: Na+ pumped out There is primary active transport on the basolateral membrane when ATP drives the outward pumping of Na+ by the Na+/ K+ pump There is secondary active transport on the apical membrane when the Na+ influx drives the inward pumping of glucose CYSTIC FIBROSIS Recessive gene Nonfunctional Cl- steady state channels on the apical membrane of epithelia in lungs reduced electrical charge and osmotic gradients reduced secretion of the saline solution that dilutes mucus undiluted mucus clogs the lumen/ passages of the lungs Cl- is the driving force for the secretion of the saline solution. Cl- follows a transcellular pathway through the epithelial cells themselves, pumped across both membranes sets up a negative gradient across the epithelium itself when it diffuses across its steady state channels into the lumen Na+ and H2O follow a paracellular pathway (going around past epithelial cells, in this case, through the unusually loose tight junctions) Na+ attracted by the negative charge in the lumen from the excess Cl- ions, H2O attracted to lumen by osmosis Notice illustration of many concepts: Cl- and K+ have steady state channels, Na+ goes down a electric gradient, H2O goes down its osmotic gradient, the Na+/ K+ pumps showing primary active transport, the Cl- pumps in the basolateral membrane showing secondary active transport. Fig 4.2: Separation of charge across a cell membrane Intercellular fluid of most cells about -70mV relative to the extracellular fluid (more anions on the inside of the cell), but exact number varies in different cells There is only about a .01% difference in charge across cell membranes Fig 8.9: Terminology for changes in cell potentials Hyperpolarization: becoming more negative than at rest Depolarization: getting less negative than at rest Repolarization: returning to resting potential Illustration for how equilibrium potential is reached in an experiment where the semipermeable membrane is permeable only to K+ At time 0 membrane potential is 0 mV (K+ cancel out the Cl-) At time 1 Membrane potential is slightly negative As soon as 1 K+ moves to side 2, an electrical gradient starts to form due to the Cl- being trapped on side 1 forming a relative negative potential on side 1. This draws the positive K+ back to side 1 though its chemical gradient still pushes it to side 2. Equilibrium Membrane Potential= EK Large organic anions: AA, phosphates, Krebs cycle intermediates trapped in cell inside of cell is negative K+ feels a chemical concentration force pushing it to side 2 some K+ flows to side 2 Since the inside of the cell is negative, the positive K+ also feels an electrical force pulling it to side 1 some K+ flows to side 1 When the electrical and chemical concentration forces are balanced, the cell has reached its K+ equilibrium potential Nernst Equation (p 107): calculates the equilibrium membrane potential for a cell E= (RT/zF) ln ([K+]outside/[K+]inside) = the equilibrium membrane potential in a given set of conditions R= gas constant T= temperature z= valence (for Na+, z= 1; for Ca 2+, z= 2, and so forth) F= faraday’s constant At 37 degrees C, for univalent ions (like K+ and Na+), the Nernst equation can be simplified to E = 61 log ([K+]outside/[K+]inside), which comes to -94mV for K+ Fig 8.6 & 8.7 How a cell achieves equilibrium potentials if it were permeable only to K+ or Na+ If the cell were permeable only to K+, it’s equilibrium membrane potential would be about -90mV If the cell were permeable only to Na+, it’s equilibrium membrane potential would be about +60 mV Fig 8.8 K+ is 25x more permeant across its steady state channel than Na+ is across its steady state channels cell’s resting potential of -70 mV is closer to the K+ equilibrium value (-90mV) than Na+’s (+60mV) Equilibrium at -70mV depends on Na+/ K+ carriers that maintain the Na+/K+ gradients at this equilibrium value; also, the trapped anions inside the cell maintain an electrical gradient with the extracellular environment Goldman Equation (p222): describes resting membrane potential Determined by the concentration of K+ and Na+ inside and outside the cell weighted by the permeability of these ions E= 61 log PK[K+]outside + PNa[Na+]o + PCl[Cl-]o PK[K+]inside + PNa[Na+]i + PCl[Cl-]i If you increase the permeability of Na+ more than in the cell’s resting state, Na+ rush into the cell and membrane equilibrium approaches Na+’s equilibrium potential (cell reaches up to +50mV) If you increase the permeability of K+, K+ rush into the cell and membrane equilibrium approaches K+’s equilibrium potential (cell reaches down to -80mV) Fig 8.2 : Neuron structure Neural signals start from sensory receptors dendrites cell body if neuron is sufficiently excited, action potential starts at the axon hillock action potential travels down axon to axon terminal where chemical messengers are released to the next neuron, or to muscle or gland cells Fig 8.13: the action potential Graphs of actions potentials show the change in membrane potential during signal transmission along the neuron. This is the sum of the effects of opening and closing voltage-gated Na+ and K+ channels along the axon Phase 1: opening of Na+ channels membrane potential approaches equilibrium for Na+ (potential reaches +35mV) Phase 2: closing of Na+ channels and opening of slower K+ channels membrane potential approaches equilibrium for K+ (reaches -85mV) Phase 3: hyper-polarization and return to rest Thursday Fig 8.2: Action Potential and Neuron Structure At synapses, chemical messengers diffuse from the axon terminals of the presynaptic cell to the dendrites (usually) of the post-synaptic cell These chemical messenger generate either excitatory or inhibitory potentials, and excess excitatory potentials trigger action potentials Fig 8.16 Excitatory synaptic potential needs to reach the -55 mV threshold (depolarize 15 mV from resting membrane potential of -70mV) to trigger action potential Depolarizing stimulus can be chemical messenger or an artificially injected positive electric current Once the threshold is reached, the action potential intensity is always the same regardless of intensity of stimulus Generation of action potential depends on the opening/closing of voltage-gated ion channels (for Na+, K+, Cl-), which are different from the steady state channels responsible for the resting membrane potential. Fig 8.13 Action potential is 1-2 msec long Phase 1: Depolarizaiton, the rising portion of action potential curve: Once -55mV is reached, Na+ voltage-gated channels fly open positive ions rush into cell depolarization to +35mV The cell reaches +35mV, which is closer to the equilibrium potential for Na+, i.e. 60mV, since the membrane is now more permeable to Na+ than to K+. The opposite is true when the cell is at rest. Phase 2: Repolarization, the falling portion of action potential curve: At The action potential also triggers the opening of voltage-gated K+ channels and the closing of the inactivation gates for the Na+ channels, but these gates open/close slower than the Na+ activation gates open. These processes occur shortly after the Na+ activation gates open, accounting for the repolarization of the axon. Phase 3: Hyperpolarization: since the K+ channels open and close more slowly than the Na+ activation gates, K+ channels remain open after the peak of the action potential, allowing for greater K+ permeability than at rest. Thus, the membrane potential reaches -85mV, which is closer to the equilibrium potential for K+ (-90mV) since the cell is now most permeable to K+. Fig 8.14: a model for the operation of voltage-gated Na+ channels At rest, the Na+ channel’s activation gate is closed and its inactivation gate is open The rising phase of the action potential is due to the activation gate flying open in response to an action potential and thus increasing Na+ permeability The threshold membrane potential also triggers the slower Na+ inactivation gates, which finally close in tandem with the opening of the equally slow K+ channels. The combined effect is repolarization and hyperpolarization. Fig 8.15 Action potentials are all (if you reach threshold) or nothing (if you’re anything short of threshold) Positive feedback loop: depolarization causes some Na+ channels to open Na+ influx depolarizes membrane more more Na+ channels open and more Na+ flow in, etc. shift of about 100mV in the positive direction due to a net increase of about 25x in Na+ permeability Then, Na+ permeability returns to its resting state as Na+ inactivation gates close. Now, K+ permeability increases with the opening of K+ channels Note: only a few ions actually move across the membrane during an action potential You’d need about 1000 action potentials to make a significant change in [K+] or [Na+] if the Na+/K+ pump were absent Fig 8.19: the Local Circuit Theory for Action Potential Propagation Axon hillock: site of initiation of the action potential before it runs down the axon Action potentials do not reverse direction because the cell body usually does not have enough voltage gated proteins to support an action potential In the figure, the yellow section represents the membrane unit supporting the peak of the action potential—this is where Na+ has its highest permeability The Na+ influx in one unit generates a positive current which flows to the next unit of the axon and depolarizes that section to -55mV. Thus, another action potential is initiated at the next membrane unit, and this process continues down the axon. The membrane unit behind the action potential is negative because it is in an after-hyperpolarization phase. Thus, the unit behind the action potential is refractory (unlikely to generate another action potential), and so the action potential won’t go backwards. Fig 8.17a and b: Refractory Periods Absolute refractory period: membrane is unexcitable regardless of the intensity of stimulus Na+ channels have not yet recovered and continue to be blocked for a few msec after the action potential peak Relative refractory period: membrane is able to be excited, but it requires a more intense stimulus to do so because it’s threshold is higher Some Na+ channels have already returned to resting state (so they’re able to be excited again), but K+ channels have not yet closed (making it harder to regenerate an action potential) Refractory periods set an upper limit to the rate a nerve cell can generate action potentials (a few 100 impulses/ sec) Fig 8.5 b and c: Myelinated axons (majority of neurons) Myelin sheath: 100s-1000s of fatty layers wrapped around axons Fatty layers come from oligodentrocye cells (in the central nervous system) or Schwann cells (peripheral nervous system). Nodes of Ranvier: gaps in the myelin sheath where the axon is exposed to the intercellular fluid Voltage-gated ion channels are concentrated here Saltatory conduction: action potential jumps from node to node Fig 8.20: Propagation of action potential in myelinated axons Minimal amount of membrane is actually involved in action potential mechanism (less than 10%) This makes for a 10-fold increase in conduction time because it takes time to actually open and close ion channels. Faster conduction times make for a more efficient nervous system that can respond to stimuli faster (adaptive). Myelination allows the current to flow through the axon without encountering too many ion channels Multiple sclerosis: immune system attacks myelin sheaths slows down conduction times difficulty with controlling movement, thought processes, etc. Fig 9.2: What happens at a synapse Chemical messenger is synthesized in an axon terminal and packaged in synaptic vesicles Action potential triggers fusion of vesicles with axon terminal membrane Neurotransmitter (NT) flows out binds to receptor on the postsynaptic dendrite receptor opens/closes ion channels NT has short half life so the synapse can respond to the next signal. NT is removed by Enzymatic breakdown A secondary active transporter pumps NT back into the presynaptic cell Diffusion away from the synapse Voltage gated Ca2+ channels at the axon terminal is opened by action potential Ca2+ ions flow in trigger the fusion of vesicles with the terminal membrane exocytosis of NT into synaptic cleft diffusion to postsynaptic membrane opens closes ion channels causes an excitatory or inhibitory potential Fig 9.4a : Excitatory receptors The most common excitatory neurotransmitter is glutamate (amino acid derivative) Upon the binding of a chemical messenger, excitatory receptors usually open for Na+ to flow in AND K+ to flow out. Since the resting membrane is already quite permeable to K+, the opening of excitatory channels make for a greater influx of Na+ than efflux of K+ membrane potential depolarizes from resting -70mV to -60 mV. Fig 12.14 and 12.15: The Neuromuscular Junction Unusually large excitatory synapses at the motor endplates of muscle cells: presynaptic motor neurons here have 100s of NT-laden vesicles vs. the usual couple dozen in other neurons Because the synapse is so large, an action potential is always triggered in the muscle fiber. This allows for precise control of muscle movement So, when Na+/K+ gates open, the synaptic potential produced spreads to the surrounding membrane and triggers and action potential that runs down the whole length of the muscle fiber The excitatory neurotransmitter is acetylcholine (ACh), not glutamate ACh is hydrolyzed by enzymes, and choline undergoes reuptake by presynaptic proteins for more ACh synthesis INHIBITION: nullifying an excitatory potential 3 ways to produce an inhibitory postsynaptic potential (IPSP, as opposed to an excitatory postsynaptic potential, EPSP) Open K+ channels hyperpolarize the cell further from threshold Major inhibitory NT: GABA (amino acid derivative) Fig 9.6: More commonly, inhibition occurs by opening voltage-gated Cl- channels In cells with Cl- transporters that pump Cl- out when the cell is at rest, the Cl- equilibrium potential is -80mV. When a NT induces the opening of Cl- channels, the Cl- influx repolarizes the cell In cells with steady state, Cl- channels, Cl- is in equilibrium with the cell (equilibrium potential of -70 mV). If you open Cl- channels alone, there would be no change in membrane potential since Cl- is already in equilibrium with the cell. However, since excitatory channels are also opened by the action potential, the Cl- influx does have the effect of neutralizing whatever positive ions flow in, reducing the effect of the excitatory synaptic potential. More membrane permeability = cell more leaky for current Fig 9.7: Convergence, in which many presynaptic cells synapse on one postsynaptic cell One neuron receives input from many difference sources Presynaptic neurons release EPSPs or IPSPs (excitatory or inhibitory postsynaptic potentials) increase the positivity or negativity of the area they synapse at on the postsynaptic neuron Depolarization induced by opening postsynaptic ion channels that allow both K+ out and Na+ in; since Na+ influx has the greater effect EPSP Axon hillock: where action potential starts. Separate synapses can be excitatory or inhibitory, but it only matters what the axon hillock feels in total, since the axon hillock initiates the action potential. Fig 8.11 Each depolarization from a single synapse creates only a small depolarization (.1 mV) by the time it reaches the axon hillock because the effect of a depolarization decreases with distance. Mere size of cell body and dendrites creates a large distance from synapseaxon hillock There are leak channels in neural membrane on the way to the axon hillock, so synapses far from the axon hillock have their currents largely depleted by the time it reaches the axon hillock. At the site of the synapse, the depolarization would actually reach 0 mV, but this effect is greatly reduced by the time it reaches the axon hillock. However, there are 100,000s of synapses on a neuron, so when many (25-100) are active at once, summation of many small depolarizations (or hyperpolarizations) action potential (or not) in postsynaptic cell Fig 9.8 Activity of an inhibitory synapse cancels out an excitatory synapse Spatial summation: more than one synapse is active simultaneously different synapses sum their effects Temporal summation: a synapse is active at such a high rate that new incoming action potentials build on the effects of former action potentials that haven’t yet extinguished themselves summation of depolarizations or hyperpolarizations from the same neuron Note: both types of summation require around 50-100 presynaptic terminals being active simultaneously Fig 9.9a: Presynaptic Facilitation: an axoaxonic terminal modulates the amount of neurotransmitter (NT) that another axon terminal releases onto the postsynaptic neuron Axoaxonic synapses represent 50% of the synapses in the nervous system In axoaxonic synapses, the axon terminal of one neuron ends on the axon terminal of another neuron, so the NT released from an axoaxonic terminal influences the amt of NT released from the neuron it synapses with. That is, it doesn’t directly influence the postsynaptic neuron. In the figure, if E releases NT on C just before C’s own action potential reaches C’s axon terminal, E will cause a larger depolarization at C and C will release more NT than normal D is totally independent from E If E fires by itself no effect on X because E’s effects are indirect. Fig 9.9b: Postsynaptic Inhibition In the figure, if you stimulate H just before (0.1sec) F is activated, the NT from H released onto F will hyperpolarize F F’s action potential isn’t as effective in depolarizing F’s terminal F releases less NT onto Y Note the spatial summation for G + F action potential Table 9.1: Major Neurotransmitters Acetylcholine (ACh) Cholinergic receptors/ synapses: use ACh Found at synapses between motor neurons and muscles, neurons and visceral organs, and less commonly between nerve cells (esp. in the brainstem) Decreases cardiac activity Generally, ACh’s effects are opposite those of epinephrine (E) and norepinephrine (NE) Biogenic Amines: from amino acids Catecholamines Tyrosine derivatives Epinephrine (E, or adrenaline); norepinephrine (NE, or noradrenalin); dopamine Control visceral organs; enhance cardiac activity Found in brainstem and brain Serotonin: tryptophane derivative found in brainstem and brain Histamine: found in olfactory system Amino Acids Glutamate: the major excitatory NT in the brain and spinal cord; represents 90% of the excitatory synapses in the brain GABA: the major inhibitory NT in the brain; represents 90% of the inhibitory synapses in the brain Glycine: inhibitory NT in spinal cord Aspartame: minor roles Neuropeptides: peptides of various sizes as NT TRH (thyroid releasing hormone), vasopressin, oxytocin, & insulin function as hormones and NT in the brain and spinal cord Note: thyroxin, which the thyroid gland produces upon arrival of TRH from the pituitary, is lipid soluble, but TRH itself, as with all the NT in this table except nitric oxide, are lipid-insoluble Substance P: major sensory NT; at pressure& pain-sensitive neurons Endogenous opioids: enkephalins & endorphins Binds to pain sites Agonists for morphines: binds to same sites as morphine and so act as natural morphines Found in pain-control circuits in the CNS (central nervous system = brain& spinal cord) Others ATP & ADP as NT Nitric Oxide: a gas and is lipid soluble The only NT in this table that can diffuse through cell membranes activates a 2nd messenger producing enzyme that is in the cytoplasm--guanyl cyclase--which catalyzes the production of GTP the cGMP 2nd messenger Fig 9.3 Fig 9.3a: Ionotropic receptor: one protein is both receptor AND ion channel 2 way ion movement (K+ out, Na+ in) influenced by distribution of charges across the membrane, binding sites along the channel, etc. Opening/closing directly controlled by whether NT binds to its the site on the ionotropic receptor Metabotropic receptor: indirect control of ion channels 3 systems to mediate the opening/closing of ion channels Fig 9.3b: receptor is directly coupled to ion channel through a G protein: NT binds to receptor triggers G protein to release GDP and take up GTP G protein’s alpha subunit dissociates alpha subunit interacts with ion channel ion channel opens/closes Fig 9.3c: 2nd messenger system: G protein 2nd messenger producing enzyme cAMP 2nd messenger produced cAMP binds to site or channel channel opens/ closes Fig 9.4b: 2nd messenger system with kinase: NT binds to receptor G protein 2nd messenger producing enzyme cAMP kinase phosphorylates channel to open/close it All synapses for peptide NT’s are metabotropic Receptors for glutamate, GABA, ACh can be ionotropic or metabotropic Ionotropic receptors: fast (1-2 msec)but transient effects Metabotropic receptors: slow (100s of msec) and long-lasting Benefits: amplification through the 2nd messenger system huge change in cell chemistry Can activate other cellular functions besides opening/closing ion channels since kinase can activate various things A neuron can have both ionotropic and metabotropic AND several different kinds of ionotropic and metabotropic receptors 2 NT Systems Fig 9.10: the ACh system: ACh and other small organic NT are synthesized in the axon terminal. HOWEVER, peptides and proteinaceous NTs are synthesized and packaged in the cell body’s endoplasmic reticulum and golgi apparatus and then transported to the axon terminal Know the sequence of events in fig 9.10 Motor neuron- muscle synapses usually ionotropic because fast responses are required Neuron- visceral organ synapses usually metabotropic receptors In fig: note choline reuptake since choline is too complex to synthesize easily The Neuromuscular junction is such a big synapse that depolarization always produces a huge EPSP and an action potential is always generated (no summation required) Fig 9.11: 2 kinds of ACh receptors Nicotinic receptors: Nicotine acts as an agonist at these receptors (i.e. nicotine binds to receptor sites) Found in muscles, produces large EPSPs due to large muscle synapses Ionotropic channels: open up for both K+ and Na+ Muscarinic receptors: Muscarine is the agonist Metabotropic 2 kinds of muscarinic receptors M1: Produces EPSP In visceral organs ACh binds to M1 receptor G protein 2nd messenger producing enzyme phospolipase C PIP2 is cleaved to IP3 and DAG activates kinases that close K+ channels membrane potential moves toward the Na+ potential excitation muscle contracts M2 Produces IPSP G proteins directly open K+ channels (no 2nd messenger system) hyperpolarization inhibition Found in the heart, where binding of ACh decreases cardiac activity Fig 10.28: Mechanism for Long Term Potentiation (LTP) Glutamate is the major excitatory NT, but its effects depend on what receptor it binds to. Glutamate receptors can be metabotropic or ionotropic. There are 2 kinds of ionotropic glutamate receptors named after their agonists. AMPA receptors: normal ionotropic receptor; glutamate binds channel opens K+ out, Na+ in EPSP in the area of the receptor NMDA receptors: special voltage and ligand dependent (or gated) ionotropic receptors (ligand is the generic name for NT) It is normally blocked by an Mg2+, so glutamate binding alone doesn’t open it The membrane needs to be depolarized to dislodge Mg2+ from the channel. So AMDA receptors open first depolarize membrane Mg2+ in NMDA channels are repelled out by the increasingly positive cell interior NMDA channels open When NMDA receptors are open, they allow Ca2+ ions to move in along with Na+ and K+ movement Ca2+ binds to Ca2+ binding proteins (e.g. calmodulin) complex that acts as a 2nd messenger interact with kinases proteins & channel proteins activated by phosphorylation Order of Events 1 action potential AMPA opens, but by the time it depolarizes the surrounding membrane sufficiently to dislodge Mg2+ from NMDA, there is already no more glutamate in the synapse to bind to NMDA However, if there is continuous stimulation from the presynaptic terminal (around 100 shots/sec), NMDA will have a ready supply of glutamate to stay open after Mg2+ is dislodged [Ca2+] in postsynaptic neuron increases as more NMDAs open and stay open many effects, including more AMPA being incorporated into the membrane more receptors = larger, more sensitive synapse larger EPSP the next time an action potential comes in Ca2+ also produces paracrine, which diffuses across the synapse into the presynaptic terminal and causes more NT to be released Overall: potentiation (repeated high frequency stimulation) strengthens a particular synapse Sensory systems Fig 11.7: Somatosensory receptors: respond to touch/ pressure in skin Have specialized nerve endings which act as energy transducers: mechanical electrical nerve impulse Touch/ pressure senses based on mechanical stimuli that open mechanically gated channels (1 type of stimulus gated channels). Stress to receptor membrane distorts membrane K+ and Na+ channels open Na+ influx overwhelms K+ efflux depolarization Receptor potential spreads to the first Node of Ranvier on the receptor axon if graded potential is enough to bring the node to threshold (-55 mV again) action potential that runs to spinal cord or brainstem If depolarization is not enough to bring the node to threshold no action potential no sensation ENCODING INFORMATION: Receptor needs to encode info about the stimulus intensity, time (duration, change), and location Stimulus Intensity depends on the number of action potentials transmitted to the CNS either through a higher frequency of action potentials or a higher number of receptors all firing action potentials From one receptor: Stronger stimulus more mechanically gated channels open larger receptor potential greater depolarization at the 1st node of Ranvier action potentials are generated more frequently From many receptors: stronger stimulusmore than one receptor is affected more action potentials Fig 11.3: Time frame of stimulus Adaptation: how receptors tend to decrease their sensitivity to a stimulus over time Tonic / Slowly adapting receptors Generates continuous action potentials across the duration of a constant stimulus Tonic receptors show a very small decrease in sensitivity to a stimulus over time Tonic responses are good at encoding information about stimulus duration and average intensity, but are insensitive to vibration/ changing stimuli Phasic / Rapidly adapting receptors Desensitizes quickly, only marks the beginning and the end of a stimulus Phasic responses are good for detecting vibrations and other stimuli with changing intensities Many touch/ pressure receptors are phasic—allows us to feel vibrations Stimulus Location based on receptive fields Receptive field: the area that a receptor responds to (i.e. fires an action potential) when a stimuli (like pressure) is applied to that area. One can extend a particular receptive field on the periphery to the CNS (higher central nervous system) neuron that our particular receptor links to. The smaller the receptive field, the greater the tactile sensitivity The higher the density of receptors, the more overlap in receptive fields, the greater the tactile sensitivity Fig 11.9: the brain can pinpoint location of stimuli better if it occurs in the overlapping region of 2 receptive fields Sensitive lips& fingers have a high density of receptors with small receptive fields, the insensitive back region has few receptors with large receptive fields Fig 11.10: Lateral inhibition Lateral inhibition: enhancing the contrast between weakly and strongly stimulated areas using local inhibitory interneurons that link adjacent receptor neurons In the figure, if you apply stimulus to the center of Y1’s receptive field, you also activate to a limited extent the receptive fields of adjacent neurons X1 and Z1 all 3 neurons fire a number of action potentials proportional to the number of terminals activated Since all of Y1’s terminals are activated but only a few of X1 and Z1’s are activated, Y1 excites more inhibitory interneurons that inhibit the signals from X1 and Z1 to their 2nd order neurons than X1 and Z1 excite to inhibit Y. So, activity in Y triggers the release of inhibitory neurotransmitters onto X and Z net effect is that the signal from Y is amplified by the time the action potentials reach the 2nd order neurons. Thus, the brain is able to detect the stimulus where it is pinpointed: at Y’s receptive field. Table 11.2: Measuring tactile sensitivity using the 2-point discrimination test Using 2 prongs, place them on skin and move the points closer until the person can no longer tell the 2 points apart. The closest distance between the prongs that the person can feel is the 2 point discrimination threshold, a measurement proportional to the density and size of receptive fields on that body part. Labeled lines: each nerve pathway runs to a certain area in the brain; that is, receptors in a certain area always map to neurons in a certain area of the brain Why is pressure to the eye interpreted as light? Though the stimulus is pressure, receptors at the eye links to visual centers that interpret energy at the eye region as light; regardless of what form of energy the original stimulus is, what you experience depends on which neural pathway/ neurons in the brain you activate. Particular neurons will always interpret stimuli as the form of energy they usually detect. So since the neurons linked to eye receptors usually detect light, even pressure stimuli at the eye is interpreted as light. Fig 11.13: Major Types of Somatosensory Receptors: 2 main classes of receptors Class 1: Receptors with morphologically specialized endings Receptors for touch and pressure: some phasic, some tonic Receptor depth associated with sensitivity Superficial receptors: most sensitive, has smallest receptive fields Deep receptors: larger receptive fields because pressure waves spread out as it travels deeper into the skin Class 2: Free Nerve Endings A variety of types with variable sensitivity Large receptive fields due to extensive branching in the dermis (picture shows endings in the epidermis, but this is incorrect) Each ending responds to one kind of stimulus Temperature: separate endings for hot and cold Pain: several kinds of nociceptors (pain receptors) Pressure/ touch Fig 11.6: General Pathway for sensory systems Receptor (1st order neuron) spinal cord or brainstem 2nd order neuron thalamus (the gatekeeper to cerebral cortex for incoming neural activity) 3rd order neuron to cortex Fig 10.6: The spinal cord Fig 10.8: The spinal cord’s structure reflects its function Pathway for sensory systems Sensory receptor spinal nerve dorsal route (includes cell body in the dorsal root ganglion) spinal cord, where the receptor axon terminates at the dorsal horn (part of the central gray matter) Def: ganglion: a collection of neural cell bodies outside the CNS (central nervous system). Def: nuclei: cluster or neural cell bodies inside the brain Gray matter: in center of spinal cord; consists of neural cell bodies, dendrites, and synapses White matter: surrounds gray matter; consists of huge tracts of myelinated axons that run up and down the spinal cord and to& from the brain Ventral horn: gray matter; motor neurons originate here go out ventral root muscle Sensory input follows an afferent route, while motor output follows an efferent route. Fig 10.9: Various tracts Spinalthalamic tracts: carry pain/temp info from free nerve endings to the brain Dorsal tract: carry touch, pressure, vibration info to brain Fig 10.11c: Brain structures Note: hypothalamus and pituitary are involved more in visceral activities, not the sensory system Fig 10.13: The Cerebral Cortex Cerebral cortex: the highest level of the brain 6 layers of nerve cells Folding of the cortex allows a larger surface area to fit inside the skull Cortex is divided based on major folds into specialized lobes Occipital: vision Parietal: somatosensory, some vision Temporal: audition, some vision Frontal: motor activity Fig 10.10a Somatosensory cortex is in the parietal lobe. There are 2 major divisions of pathways that link somatoreceptors to the somatosensory cortex. DIVISION A: Touch/ pressure receptors + some proprioceptors (joint, muscle length) have axons whose main branch doesn’t enter the gray matter but runs up the white matter of the dorsal column medulla (at the medial lemiscus at the base of the skull, dessicate) where the axons cross over to the opposite side of the body thalamus and somatosensory cortex on the side opposite the original stimulus. So if the stimulus came from the Right side of the body, the axons would eventually run to the Left thalamus and the Left somatosensory cortex. Fact: the longest axon known is from a sensory neuron that runs from the back leg of a giraffe to the giraffe’s medulla. DIVISION B Free nerve ending receptors (nociceptors, thermoceptors) enter dorsal horn synapse with spinal neurons that cross to the opposite side of the body in the spinal cord runs up anterior spinothalamic tract thalamus somatosensory cortex. So, crossing over occurs again, but at a lower location (the spinal level) than the pathways for touch/ pressure receptors do. Thus, the 1st order neurons for this pathway need not be as long as those in the pathway division A. Notice the progression from to order neurons and the different places they occur for each tract Doctors can determine the location of damage to the spinal cord by using mapping of these sensory pathways from the body to the spinal cord to the brain. Ex. If the R side of spinal cord is hurt… Applying pain to the R foot sensation, since the free nerve ending pathway crosses over to the L spinal cord below the site of damage Applying pressure to the R foot no sensation because the pressure/ touch pathway runs up the R spinal cord and only crosses over at the medulla that it never reaches Fig 10.14: The primary somatosensory cortex is in the parietal lobe behind the 1st anterior fold Fig 10.15: How topographical mapping helps code spatial localization Stimulate different parts of the body different area in somatosensory cortex stimulated. Nearest neighbor principle: neighboring receptors in periphery are usually carried by neighboring neurons to neighboring regions in the cortex Localizing and identifying stimuli: higher level integration areas in the cortex integrate info from many inputs (shape, pressure, temp, etc.). The area behind the somatosensory cortex processes general info about stimuli (texture, size, curvature, etc.—neurons specialize in the type of stimulus they respond best to). Series of higher and higher association areas finally identify stimuli and decide your response. VISION Fig 11.18 Neural component: retina Optic component concerned with generating a sharp image on the surface of the retina Light passes through cornea aqueous humorpupil (which is a hole in the iris) lens vitreous humor strikes retina Fig 11.27: Optic components of the eye do 2 things Control focus Control the intensity of light entering the eye. Going from dark to light, the pupil contracts to reduce the amt of light entering the eye Under the parasympathetic nervous system’s control, the iris contracts circular muscles. This is called the pupillary constriction reflex. Going from light to dark, the pupil dilates to increase the amt of light entering the eye The PNS directs the iris to relax, increasing pupil size. Note: the sympathetic nervous system directs the radial muscles to contract pupillary dilation. The radial muscles and the sympathetic nervous system have no role in normal control of pupil size; rather, their effects only occur during times of emotional stress. Fig 11.23: Focus of eye depends on a convex lens system Cornea: convex lens, accounts for 70-80% of the eye’s total refractive power, fixed shape Lens: convex lens, accounts for 20-30% of the eye’s total refractive power, adjustable shape Eye changes focus by changing the shape of the lens by contracting certain muscles Lens rounder: focal point moves toward lens Lens flatter: focal point moves away from lens Fig 11.25 So, the degree of roundness of the lens determines the sharpness of focus Cilliary muscles are attached to the lens through connective zonular fibers When the cilliary muscles contract, the zonular fibers are slack lens rounder/ lens convexity increases When the cilliary muscles relax, the zonular fibers are taut lens pulled into a flatter shape It’s the opposite of what you think! Tuesday Fig 11.24 Going from looking at far things (lens flat) to near things (lens convex): scene is out of focus till lens adjusts Accommodation reflex: visual cortex sensitive to image sharpness activates reflex pathway relax cilliary muscles flatter lens image moves from behind retina to the surface of the retina again Accommodation reflex also works when you go from looking at near things to far things: visual cortex activates cilliary muscles to contract lens rounder image move from front of retina back onto focus on the retina Fig 11.26 Nearsighted people: can see near but not far objects Eyeball too long lens system too powerful/ too convex for the eye—i.e. it has too much refractive power bends light so much that it always focuses far objects in front of the retina To decrease lens convexity, put a concave lens in front of the eye focal point moves backwards back onto retina Farsighted people: can see far but not near objects Eyeball shorter than normal lens system not convex enough to focus near objects near objects come into focus behind the retina To increase lens convexity, put a convex lens in front of the eye focal point moves forwards back onto retina So, when the eyeball is the wrong shape, the range of lens curvature within the accommodation reflex is insufficient to focus the image onto the retina. Artificial lenses correct this. Fig 11.28: Anatomy of Retina Light excites photoreceptors excite series of nerve cells in retina ganglion cell axons (which make up the optic nerve) carry signal to visual cortex Notice: light runs through neural network before striking photoreceptors (except in the fovea, where the neural network& blood vessels are moved aside so light can strike cones directly). Thus, the image gets muddied by the time it reaches the photoreceptor layer on the outer surface of the layer. Fig : 11.30: Anatomy of photoreceptors At the base are synaptic terminals that get excited and release NT onto bipolar cells Top of photoreceptors (outer segment)= site of photoexcitation at special folded membrane (disks) jammed with photopigments In rods, main photopigment = rhodopsin. The photopigment in cones (iodopsins) are similar, differing only in small amino acid sequences Fig 11.31: Photoexcitation at the molecular level Light activates rhodopsin the retinal (an aldehyde) inside the rhodopsin (the bigger protein) changes bond structure activates transducin (a G protein) activates phosphodiesterase enzyme which hydrolyzes cGMP into GMP Fig 11.32 b cGMP usually binds Na+ channels in the photoreceptor membrane, keeping Na+ channels open and Na+ flowing in When cGMP is broken down no cGMP to bind Na+ channels Na+ channels close membrane hyperpolarizes Ca+ channels not open NT release drops So, during light stimulation less NT is released. It’s the opposite of what you think! Fig 11.32a In the dark: NT is released continually since nothing breaks down cGMP high cGMP levels many cGMP to bind Na+ channels Na+ channels always open depolarizes cell voltage gated Ca+ channels open NT released Fig 11.33 Cones: have one of 3 iodopsins (similar to rhodopsin in rods) Depending on which iodopsin a cone has--blue, green, or red—that cone will respond best to a certain frequency of light Rods are most sensitive to the green wavelengths too Table 11.4: Cones v Rods Cones: color sensitive, high acuity, high level of light sensitivity (high threshold to illumination) Rods: monochromal, low acuity, sensitive in low levels of light Reasons for cones having a high acuity (& corresponding high light sensitivity) Cones are concentrated in the fovea, the central region of the eye where the retina’s neural network is pulled aside light hits cones in the fovea directly visual acuity up Rods are at the periphery of the retina, where they are covered by the neural network Each cone in the fovea excites its own ganglion cell receptive field of cones are very small visual acuity up In contrast, rods are specialized to gather whatever light there is in dim settings: 1000s of rods feed into one ganglion large receptive fields designed to gather whatever dim light there is. Also, rods have a larger folded membrane area (its outer segment) more membrane to catch each photon of light Fig 11.29: Distribution of rods and cones in the retina Cones concentrated at center of retina (fovea) Rods concentrated at periphery of retina Optic disk: no receptors here because optic nerve goes out here Fig 10.14: Brain Regions Associated with Vision Primary visual cortex the most hind part of occipital lobe Topographic organization: specific points in the visual field map onto specific photoreceptors, which in turn map to specific neurons in the visual cortex High % space in visual cortex devoted to input from the fovea Low % space in visual cortex devoted to input from the periphery As you go up higher and higher orders of neurons, you get different neurons in the visual cortex that are sensitive to either shape, size, color differences, lines, etc. These cells that are specialized to respond to certain images perform the integration to build images In the temporal cortex, you get cells that have increasing specificity to identify specific objects E.g. a neuron fires when you see to a specific face In the parietal cortex, you have cells that have increasing specificity to processing the location and movement of objects. So, a particular neuron would fire when an object is at a specific point in 3D space around us Fig 11.36 The distribution density of air molecules make up sound waves Fig 11.38: Anatomy of the Ear Note the progression of sound waves from the outer middle inner ear Cochlea contains auditory receptors in saline solution. So to get to the receptors, sound waves must pass from air liquid medium, but in the process the waves would lose energy. To overcome this problem, the middle ear amplifies sounds in 2 ways The 3 middle ear bones (hammer, anvil, stirrup): act as levers to amplify the strength of the sound wave as the vibrations travel through them When the stirrup (stapes) vibrates, it passes the vibration onto the oval window, a section of membrane much smaller compared to the tympanic membrane 20-25x amplification of sound just cancels out the loss of sound energy as the sound waves change mediums so enough acoustic energy goes into the cochlea Fig 11.39: Structure of the Inner Ear Cochlea = 3 long tubes: the scala vestibuli, scala media, and scala tympani Scala media: closed tube, contains endolymph fluid which has a high [K+] The 2 other tubes around it contain normal perilymph, which has a high [Na+] Fig 11.40: Pathway of sound waves through the cochlea Vibrations pass through: stapes oval window perilymph in scala vestibuli, simultaneously causing the basilar membrane to move relative to the vestibular membrane scala tympani round window, which absorbs sound waves so there is no echoing Basilar membrane has hair cells with stereocilia (which are really microvilli, not cilia), that extend ito the endolymph. The tectorial membrane lies on top of the microvilli. When the basilar membrane vibrates relative to the tectorial membrane, the microvillli structure is distorted. This causes depolarization NT released onto cochlear nerve Fig 11.41 At the base of the hair cell, NT (glutamate) is released onto the cochlear nerve At the top of the hair cell (on the microvilli) are mechanically gated K+ channels. When the tectorial membrane bends them towards the longer microvilla K+ channels open K+ influx since the endolymph in which the microvilli are bathed has a high [K+] depolarization voltage-gated Ca+ channels open NT released action potential in cochlear nerve signal to auditory parts of brainstem cerebral cortex When the microvilli bend towards the shorter microvilla K+ channels close hyperpolarization less NT released This opening/ closing of K+ create bursts of discharge for each cycle of microvilli bending. Thus, the frequency at which the tectorial membrane hits the microvilli translates into a frequency of action potentials that the brain interprets as sound MOTOR CONTROL Reflex arcs: simple neural pathways; muscle reflexes usually involve one set of muscles being excited and an opposing set of muscles being inhibited simultaneously Fig 10.20: the Flexion/ Withdrawal/ Crossed-extensor Reflex Pain receptors in foot cause sensory neuron to send an action potential interneurons in the spinal cord motor neurons the leg at which the stimulus is detected flexes (contract hamstring) At the same time, an inhibitory motor neuron is activated causes the extensor muscles (quads) to relax At the same time, in the other leg, the hamstrings are inhibited flex & the quads are excited contract Net effect: person draws hurt foot away while keeping their balance Fig 10.19 : Knee Jerk Reflex Muscle spindles excited by stretch when pallet hits kneesensory neuron sends signal to spinal cord where it synapses with a motor neuron leg contracts to oppose the stretching stimulus This is a monosynaptic reflex arc: involves 1 synapse in the spinal cord rapid response Simultaneously, the opposing muscle is relaxed when an inhibitory interneuroun is activated by the sensory neuron from the muscle fibers this interneuron then activates an inhibitory motor neuron that inhibits the hamstring, causing it to relax Thus the inhibition pathway is a disynaptic pathway Thursday Fig 10.14: Control of muscle movement from the top down Central sulcus: separates the parietal (somatosensory, visual) and frontal (motor) cortexes Frontal cortex: where complex movement behaviors are generated Primary motor cortex: electric stimulus applied to different points here activates contraction/relaxation of associated muscles Movement: a result of precisely timed muscle contractions and relaxations Fig 10.15a: Primary motor cortex Wired to motor neurons in the spinal cord Topographic organization; also devotes more tissue to fingers, thumb, lips, and tongue since these body parts require fine and precise movements Remember: the somatosensory cortex also devotes much space to the fingers, mouth, and tongue 3 stages of processing to perform a movement Prefrontal cortex: decides whether to undertake movement; generates the motivation for it Premotor cortex: develops motor program (the sequence of muscle contractions and their timing) Primary motor cortex: executes motor program by activating muscle groups Experiment: looked at brain activity (rate of blood flow in brain regions) during several kinds of motor activity Moving a single finger: the primary motor and somatosensory cortexes were active Doing a complex finger tapping rhythm: the primary motor & somatosensory cortexes; also the premotor cortex was active because a motor program needed to be developed Imagining fingers were tapping without really tapping them: only premotor cortex active Other brain structures involved in movement: the cerebellum & basal ganglia (not basal nuclei like the text says) These structures modulate higher motor areas through corrective adjustments of movement. They do careful calculations to ensure that the motor program is accurate to achieve the desired goal during its development and execution Fig 10.22a: Pyramidal tracts The cerebral cortex is connected to motor neurons in the ventral horn of the spinal cord through several neural tracts Lateral pyramidal tract (corticospinal tract): Continuous axons form a direct and very fast connection from the primary& prefrontal cortexes to motor neurons Note crossover at the medulla: left side of body controls right side of body and vice versa This is the main tract. It deals with sophisticated movements of the distal musculature (mouth, tongue, fingers) Anterior pyramidal tract (ventral corticalspinal tract): Controls postural movements of the axial musculature (muscles of back, hips, etc.) No crossover Fig 10.22b: the Extrapyramidal tracts Many tracts in brainstem Indirect and multiple synapses linking different motor centers Many involved in posture Fig 12.1: The Autonomic Nervous System Somatic nervous system: voluntary movement Autonomic nervous system: visceral movement 2 Divisions of Autonomic NS Sympathetic: active during stressful situations, high levels of physical activity. So for example, it will increase cardiac activity Parasympathetic: active during rest& recovery situations Stimulates digestive activity by increasing contraction of GI walls and increasing secretion Both PNS and SNS consist of 2-neuron-pathways running from the spinal cord or brainstem to effector organs, but differ in anatomy otherwise Note: spinal cord has 4 sections (from head to hip): cervical, thoracic, lumbar, and sacral Sympathetic neurons emerge from the thoracic and part of the lumbar sections of spinal cord Parasympathetic neurons emerge from the cervical and sacral parts From the cervical segment emerge the cranial nerves to the head and the vagus nerve that innervates most of the parasympathetic’s visceral structures (e.g. GI system) From the sacral segment come nerves going to the sex organs, the bladder, and the large intestine Fig 12.7 2 neuron pathway consists of a preganglionic + a postganglionic neuron Different from the somatic nervous system, where motor neurons go directly from the spinal cord to skeletal muscle. Sympathetic NS: Synapses between the pre and postganglionic neurons located in the ganglions of the sympathetic chain or in collateral ganglions. These are cholinergic nicotinic synapses. The postganglionic neuron releases Norepinephrine (NE) EXCEPT for the adrenal medulla, which contains specialized postganglionic cells (chromaffin cells) that release epinephrine (not NE) into the blood (not an effector organ), postganglionic neurons that release epinephrine onto sweat glands Note: NE and E (epinephrine) have similar, though not identical, effects : Postganglionic neurons release acetylcholine (ACh) onto metabotropic muscarinic receptors on effector organs Pre and postganglionic synapses are both close to the effector organ; i.e. the preganglionic neurons are very long and the postganglionic neurons are microscopic. Fig 12.5: Chromaffin cells are postganglionic cells specialized for hormonal secretion Fig 12.9: Postganglionic neurons form multiple varicosities where pulses of NT (ACh or NE) are released onto effector organs Ca2+ channels open as action potential passes through the varicosity on its way down the axon Ca2+ influx triggers NT release Varicosities are spread out wider release of NT across the organ broader effects than the localized synapses we’ve studied before. Thus, smooth muscle does not need NT to enervate each muscle cell (say, in blood vessels), but the NT will diffuse to enough cells to get the job done Fig 9.11 Parasympathetic postganglionic neurons release NT onto muscarinic receptors 2 kinds of muscarinic receptors M1 receptors: excitatory: uses a 2nd messenger system to close K+ channels Na+ effect more dominant depolarization EPSP E.g. M1 receptors found in intestinal muscles M2 receptors: inhibitory: G protein directly couples with K+ channels to open them hyperpolarize Sympathetic receptors When the sympathetic NS is stimulated, NE is released and E is dumped into the blood. 2 classes of receptors for this NE and E: alpha and beta classes and their subclasses Fig 12.8a: Alpha 1: NE binds to receptor G protein 2nd messenger producing enzyme phospholipase C catalyzes PIP2 into DAP and IP3 (2nd messengers) Ca+ levels in cell increase muscle contraction E.g. constriction of blood vessels or intestinal sphincters Fig 12.8b: alpha 2 and beta receptors G protein adenylate cyclase turned on or off Alpha 2: turns off adenylate cyclase changes in ion channel structure inhibition E.g. inhibition of intestinal motion Beta receptors: turns on adenylate cyclase changes in ion channel structure and [Ca2+] in cell Beta 1: strength of cardiac contraction and heart rate up Beta 2: relax muscle, inhibitory action through activating cAMP Different tissues have different relative numbers of the different types of sympathetic receptors, which respond differently to NE and E Alpha 1: responds better to NE Alpha 2: responds to NE and E similarly Beta 1: responds to NE and E similarly Beta 2: responds better to E Table 12.3: Comparing Parasympathetic and (Important table) Most blood vessels only have alpha 1 receptors and respond to sympathetic stimulation only Blood vessels to skeletal muscles, veins, and coronary vessels have both alpha 1 (constriction, NE released directly onto effector organ) and beta 2 receptors (dilatory, E travels through blood from adrenal medulla) For test, know the effects of the parasympathetic NS and sympathetic NS on the heart, blood vessels, and digestive tract Fig 11.15: Referred Pain Referred pain: the site of pain is anterior to the site of the actual pained organ. This mislocation of pain occurs because sensory fibers from pain receptors in the real, pained organ enter the sympathetic chain into the spinal cord at a level much higher than the actual site of the pained organ. The somatosensory cortex of the brain then interprets the location of the pain as coming from the section of the body that’s usually associated with the level of the spinal cord that the sensory fibers from the pained muscle enter. E.g. person with heart problems feels pain in upper arm, person with appendix problems feels pain in the abdomen anterior to it MUSCLE Fig 13.1: Muscle fibers 1 muscle cell = a muscle fiber: Made up of muscle fibrils, the primary contractile units of muscle Multinucleate (from many cells fusing in the embryo) Myofibril: ordered array of thick and thin filaments precise contraction Striated pattern: A band (dark, thick filaments) alternating with I band (light, thin filaments), related to the structure of muscle filaments Take a look at the photomicrograph for this figure to see striations Z line: sites of anchorage for thin filaments Sarcomere: section from one Z line to the next Crossbridge: where thick and thin filaments overlap and interact M Line: proteins that stabilize position of thick filaments H zone: A band region without crossbridges Fig 13.6a: The Sliding Filament Theory of Contraction During contraction: I band and H zone decrease in size while the A band doesn’t change size Thin filaments move to center of sarcomere Fig 13.4: Thin filament structure Thin filaments made out of actin, a protein with binding sites for the myosin that makes up thick filaments 2 strands of F-actin (filamentous actin) are wound together with tropomyosin and troponin, proteins that control contraction Fig 13.5: Thick filament structure 2 myosin molecules bind together tail to tail, then many of these find in a helix with the myosin heads pointed outwards at the Z lines Myosin heads will form the crossbridges Titin: protein that attaches thick filaments to Z lines 2/15/05 Thursday THIS IS THE LAST DAY OF NOTES FOR EXAM I. Fig 13.3: Sarcomere Structure Sarcomere: smallest contractile unit; spans from 1 Z line to the next Fig 13.4: Thin Filaments Actin is made up of a double helix of two F-actin strands. The proteins troponin and tropomyosin control contraction by covering up the myosin binding sites on the actin while the muscle is at rest. Fig 13.5: Thick Filaments Myosin heads contain actin and ATP binding sites, since you need ATP to induce contraction Contraction occurs when the thin filaments are drawn toward the center of the sarcomere by the repeated ratcheting motion of the myosin heads on them Fig 13.7 The Crossbridge Cycle Rigor mortis: the “stiffness of death”: occurs because a dead body has no ATP left to break the actin-myosin crossbridge after the last contraction muscles stuck in rigid position The cycle, starting right after step 3 in the figure After 1 wave of contraction, the myosin is bound to the actin ATP binds to myosin actin released ATP hydrolyzed to ATP + P myosin head cocks from a 45 degree to a 90 degree angle Now that the myosin head structure is favorable to bind actin, it binds actin Binding the actin changes the structure of the myosin head P is released P release changes structure of myosin head head bends forward pulls thin filament to center of sarcomere Fig 13.2: Structure of a skeletal muscle fiber Endplate potential: the very large EPSP that is always produced at the very large motor endplate of a muscle fiber (no summation required for EPSP) Depolarization at the motor end plate induces an action potential that spreads across cell membrane and T tubules T tubules: radial infoldings of the sarcolemma that spreads the action potential deep into the muscle fiber whole cell is depolarized simultaneously inside and out. Since T tubules are continuous with the cell membrane, they contain the same interstitial fluid as is outside the cell Each myofibril is surrounded by a sleeve of sarcoplasmic reticulum (SR), which stores Ca2+ Fig 13.8 Depolarization creates an action potential that runs through the surrounding membrane and T tubules Fig 13.10 As action potential runs down the T tubules, it activates a series of proteins Action potential DHP receptors (voltage sensitive) in the T tubule membranes change structure, which in turn changes the structure of ryanodine receptors in the SR membrane ryanodine receptors open creates channels for Ca2+ to flow out Note: the whole membrane of the muscle fiber can conduct the action potential; there are voltage-gated channels everywhere in the sarcolemma except at the motor endplate (where there is only cholinergic ionotropic receptors that open for both Na+ and K+ simultaneously for local depolarization from -90 mV to -80mV) Fig 13.9 Ca2+ binds troponin troponin shifts structure of tropomyosin exposes myosin binding sites on action Fig 13.16 A contraction lasts much longer than the action potential that initiated it Twitch: a contraction initiated by one action potential Fig 13.13 Isometric twitch: increase of tension without shortening of the muscle Postural muscles do this since they don’t have the anatomical space to shorten a lot Isotonic contraction: muscle shortens till the muscle tension equals the weight of the load Fig 13.18 Muscle has an optimal length to produce a maximum isometric contraction The optimal length of a muscle occurs when there is a max overlap of thick and thin filaments Muscles too short: thin filaments bunch up on each other in the center of the sarcomere and obstruct crossbridge formation Muscles stretched too much: not enough overlap between thick and thin filaments for crossbridges to form Fig 13.14: Isotonic Contraction Rate of shortening depends on the size of load Increase load decreased rate of muscle shortening Max tension = just enough to lift the load Fig 13.19 Each muscle fiber has one motor nerve that innervates it Motor unit: 1 motor nerve + all the muscle fibers it innervates One muscle: has many motor units 2 ways to control the strength of contraction Varying the number of motor units activated Choosing different combinations of motor units. Different motor units can produce either strong rapid contractions or weaker longer contractions. Fig 13.17: Varying the Rate of motor neuron contractions Motor neuron stimulated rapidly tension/ contraction builds on the previous twitch buildup of tension faster contraction and higher intensity of contraction 20-50 stimulations/ sec will give you tetanus, the state of maximum contraction for a muscle. All crossbridges are formed and all actin is uncovered. Fig 13.11: How muscles meet their high demand for ATP Muscle cells need a lot of ATP SR actively pumps Ca2+ back into its lumen after contraction by using ATP Myosin heads need ATP to form crossbridges Na+/K+ pump & other cellular processes also need ATP 3 Major ATP sources 2 pathways that hydrolyze glucose Aerobic environment (O2 present): oxidative phosphorylation Glucose from blood or cell glycogen glycolysis Krebs cycle oxidative phosphorylation 38ATP max/ glucose Fatty acids from blood: beta oxidation: also go through Krebs cycle and oxidative phosphorylation; 30% more efficient than glucose Anaerobic environment (no O2): glycolysis Produces lactate, an acidic compound that inhibits the ATPase on myosin heads Only 2 ATP/ glucose, but rapid pathway Extra ATP stored as creatine phosphate for quick use later Fig 13.24 Fast glycolytic muscle fibers: E.g. eye muscle Derive most ATP from glycolysis Fast strong contractions of limited duration (due to lactate buildup) High concentration of fast myosin ATPases form crossbridges quickly Anaerobic Slow oxidative fibers: E.g. soleus muscle (posture) Derive most ATP from oxidative metabolism Maximum tension is only 10% that of fast glycolytic fibers Long duration of contraction: O2 available to keep supplying ATP Fig 13.25 Fast glycolytic fibers: Larger size stronger contraction Slow oxidative fibers: Smaller size so O2 can diffuse through them easily, but this also makes them have weaker contractions Have high concentration of mitochondria & surrounding blood vessels so they’ll have a ready source of O2 Table 13.1: Properties of Skeletal Muscle Types (some comments) Slow oxidative fibers: Red due to their high concentrations of O2-storing myoglobin Fast glycolytic fibers: low concentration of oxidative enzymes Myosin ATPase activity proportional to the rate of crossbridge formation Muscles have a mix of different types of fibers depending on the nature of the muscle Posture muscles: more slow oxidative fibers Contract for a long time isometrically (little stretching) Muscles that do fast movement: more fast glycolytic muscles: Produce much force but can’t sustain Eye, limbs Tuesday THIS IS THE FIRST DAY OF NOTES FOR EXAM II. ENDOCRINOLOGY Fig 6.1: Primary endocrine system: the primary role of these organs is to secrete hormones Secondary endocrine organs: these organs have another major function; secreting hormones is a secondary function Some glands to point out Master endocrine gland = hypothalamus (in forebrain) Controls pituitary gland, another major endocrine gland Thyroid: body metabolism Adrenal gland: secretes steroid hormones (e.g. cortisol, aldosterone) Pancreas: secretes insulin & glucagon, the 2 major metabolic hormones Table 6.1: IMPORTANT TABLE summarizes endocrine system Fig 5.2: Chemical messengers Hormones: bloodborne messengers Endocrine cells secrete into the blood hormones pervade body affects target cell (cells with the right receptors for the hormone) when it binds to receptors in that cell’s membrane or cytoplasm Include proteins, peptides, amino acids, steroids Neurohormones: neuroendocrine neuron releases these into the blood Target cells are VERY sensitive to hormones: a little hormone big effect Endocrine system, which dumps its messengers into the circulatory system, is slower than nervous system, which releases neurotransmitter directly onto the target cell Fig 5.4 Proteinacous hormones are initially produced in the ER as proteins larger than the final hormone product undergoes cleavage rxns shorter active peptides are packaged into vesicles [Ca2+] rises in hormone producing cell exocytosis of hormone Other functions Fig 5.17 Hormones that bind to receptor proteins in membrane usually activate G proteins and a second messenger system (e.g. the cAMP or the phosphatidylinositol 2nd messenger system) 2nd messenger system triggers different effects in different target cells (different target cells have different receptors, contain different proteins and enzymes, etc.) End result of 2nd messenger system is usually kinases getting activated, and these produce changes in rxns in the cell Other end results include opening/shutting channels, changes in structural proteins, & changes in DNA transcription Fig 5.13 Exception to the usual 2nd messenger activating hormone: INSULIN binds to the enzyme-linked receptor tyrosine kinase on the outside of the cell tyrosine kinase phosphorylates tyrosine on the inside of the cell Fig 5.3 Most hormones are hydrophilic dissolve in blood plasma Examples of hydrophilic hormones are tyrosine (an amino acid) derivatives that include: Catecholamines (from the adrenal medulla): dopamine, epinephrine, norepinephrine (the primary NT in the sympathetic nervous system) Thyroid gland hormones produced from the thyroid gland Thyroxin (tetraiodothyronine, T4): made up of 2 fused tyrosines Triiodothyronine (T3) Unlike the catecholamines, thyroid hormones are LIPID SOLUBLE. Thus, T3 and T4 can diffuse through cell membranes and bind to receptors inside the cell (behave like steroid hormones). Fig 2.6 Steroid Structure: Three 6-membered rings and one 5-membered ring Steroids are derived from a CHOLESTEROL precursor. Cholesterol: a C-27 steroid (contains 27 carbons) Cortisol: C-21 A glucocorticoid, and thus cortisol has the multiple OH groups characteristic of glucocorticoids Produced in adrenal cortex Important in glucose metabolism Aldosterone: C-21 A mineralcorticoid, and thus aldosterone has the aldehyde group characteristic of mineralcorticoids Produced in adrenal cortex Regulates the kidney’s control of K+ and Na+ levels in the blood Estradiol: C-18 Major member of the estrogens, the female hormones Testosterone: C-19 Major member of the androgens, the male hormones Progesterone: C-21 Small differences among the derivatives produce huge differences in their effects. The glucocorticoids and mineralcorticoids differ only in the extra OH groups on the glucocorticoids, and in how the mineralcorticoids have an aldehyde where the glucocorticoids have a methyl group Testosterone and estradiol differ only in that testosterone has one more methyl group Fig 5.5 Complex processes transform cholesterol into its derivatives Cholesterol has 6 C’s lopped off to form progesterone, which undergoes alterations to form cortisol and aldosterone Fig 5.11 Steroid diffuse through cell membranes binds to an intracellular protein hormone-receptor complex diffuses into the nucleus binds to a regulatory protein affects DNA transcription Fig 5.7 Hydrophilic hormones (proteins, peptides) produce a rapid response because the enzymes/ proteins that they activate are already present in the cell they are not blood bound so they can immediately bind to target cells Effect appears in seconds to an hour Steroids produce a slower effect because They have a slow activation process: they are bound to carriers in the blood, and so must disassociate before binding to target cell receptors. Then, it must diffuse through cell membrane, bind to a receptor, diffuse through nuclear envelope, and bind to a final regulatory protein on DNA. It takes time to synthesize new protein from DNA; or, if it inhibits protein production, it takes time to degrade the protein that is already in the cytoplasm Effect takes hours to days to appear Fig 6.2 Hypothalamus is directly associated with pituitary gland The pituitary is made up of the anterior and posterior pituitary (AP and PP), which are really 2 different organs with different functions and embryological origins though they are both controlled by the hypothalamus Hypothalamus is not only the master endocrine gland, but the master controller of the autonomic nervous system and most important visceral systems. Some things the hypothalamus controls Body temperature There is a cooling center and a heating center in the hypothalamus. These neurons get input from nerve cells that monitor the temperature of blood (deep body temp) and thermoreceptors that monitor the temp of the outside environment (surface body temp) Based on these inputs, neurons in the cooling or heating centers are stimulated to cool or heat the body by adjusting sweating, constricting/ dilating surface blood vessels, increasing/ decreasing metabolism Lesions at these centers lab animal can’t control body temp Eating Neurons in the feeding (hunger) / saity (fullness) centers respond to levels of blood glucose/ insulin These neurons also get input from stretch receptors in the stomach/ GI system Lesions in these centers lab animals either starves or overeats since it can’t control its eating Water balance Nerve cells at water balance centers are sensitive to blood osmolarity Get input from receptors for blood pressure & blood volume Lesions at these centers: animal stops drinking or drinks excessively Reproductive functions Fig 6.3 Posterior pituitary (PP) has no hormone producing glands. It is only the release site where hypothalamic hormones are released into the blood Hypothalamic neurons have axons that runs down to the PP and release one of 2 hormones (depending on which hypothalamic nuclei a neuron originated in): Oxytocin: produced in cell body packaged in cesicles transported down axon released from axon terminal diffused through capillary walls into blood ADH (antidiuretic hormone) Also known as vasopressin since it affects blood pressure Reduces urine volume by causing kidneys to retain water Def. “diuresis:” when a lot of dilute urine is released. So, “antidiuresis” describes retaining water to produce a concentrated urine Fig 20.11: ADH flowchart (follow the steps) ADH secretion regulated by blood osmolarity Hypothalamus both secretes ADH and gets neg feedback about it Fig 20.12 ADH secretion also controlled by blood volume and blood pressure: receptors detect when there is higher blood volume and blood pressure due to more fluid being retained tells hypothalamus neg feedback for ADH secretion So, when the osmotic concentration increases (detected by receptors in hypothalamus) AND the blood pressure and blood volume decreases (detected by baroreceptors in major blood vessels) it stimulates ADH secretion ADH system is a neuroendocrine reflex: involves receptors, neural response, effector organ (kidney), neg feedback Fig 22.27: Suckling reflex Oxytocin also involved in birth reflex Stretching of uterus excite mechanoreceptors in uterine walls excite oxytocin producing centers oxytocin released excites contraction of uterine smooth muscle mechanoreceptors stimulated more more oxytocin released positive feedback till birth completed Fig 6.4 Anterior pituitary (AP) produces hormones Hypothalamus produces releasing or inhibiting hormones releases them onto capillary bed at hypothalamus releasing/ inhibiting hormones carried via hypothalamic-pituitary portal vein directly to a 2nd capillary bed in the AP hormones diffuse into the AP excite/ inhibit secretory cells in the AP Fig 6.5 Hypothalamus produces 7 different tropic hormones PRH & PIH (dopamine): stimulate/inhibit release of prolactin by the AP Prolactin production of milk, also breast development during pregnancy Oxytocin: release of milk TRH: stimulate AP to release TSH stimulate thyroid to secrete hormones CRH: stimulate ACTH release by AP control secretion of glucocorticoids GHRH and GHIH (somatostatin): stimulate/inhibit secretion of GH by the AP GH stimulates the liver to secrete somatomedins, which induce bone growth GnRH: stimulate AP to secrete LH and FSH LH: production of estrogen in both sexes, and testosterone in males FSH: development of ovaries; growth of ovum & testes Fig 6.12 Hormonal production is usually controlled by negative feedback Fig 6.6 In more complex hormonal systems, there may be multiple levels of feedback Fig 3.23: Major metabolic pathways Insulin the major metabolic hormone 3 Major storage biomolecules/ energy sources Glycogen: storage form of glucose Protein: storage form of amino acids (AA) Triglycerides: storage form of fatty acids There is a balance of rxn pathways & enzyme that can do reversible rxns, the direction of the rxn based on the body’s hormonal environment Glycogen is stored in muscle and the liver, but is metabolized differently Liver has the enzymes to do both glycogenolysis (breaking down glyocogen)/ gluconeogenesis (making new glucose) when glucose not available and glycogenesis when glucose is plentiful Muscle doesn’t have the enzyme to dephosphorylate glycogen muscle can’t release its stores as glucose into the blood. Thus, muscle glycogen is hydrolyzed to pyruvate (used by the muscle for energy) + lactic acid, which is sent to the liver to be converted to glucose. So, muscle only does glycogenesis from the glucose it takes up, but it doesn’t convert glycogen back to glucose. Glucose is the most important energy source for the body. It goes through aerobic oxidative phosphorylation to produce 38 ATP/ glucose molecule. Fig 3.26: Protein metabolism AA is absorbed by the digestive tract AA taken up by liver and muscle (primarily) protein synthesis Proteolysis: protein is hydrolyzed to AA liver deaminates (removes amine group) organic acids that can be used to synthesize new glucose or that can enter the Krebs cycle Fig 3.25: Triglyceride (fat) metabolism Glycogenesis rxn: Glycerol phosphate (phosphorylated glycerol) + 3 fatty acids triglyceride Glycolysis in cells releases Glycerol liver uses to synthesizes glucose Fatty acids (1) beta-oxidation pathway in body cells, which releases 2.5x more ATP than an equivalent amount of glucose in oxidative phosphorylation; or (2) liver breaks down fatty acids into ketones (4-C chains) and releases those into the blood as an energy source When blood glucose is low, the body needs to generate as much glucose as possible from other molecules because the nervous system is restricted to using glucose as an energy source (it also as a very limited ability to use ketos as energy, but 90% of its energy needs is still glucose.) Fig 3.24: Gluconeogensis Hormones are responsible for inducing the synthesis of glucose from AA, glycerol, and lactate Gluconeogenesis occurs at the liver Fig 6.10: Pancreas is made up of 2 different tissues Majority of pancreas secretes pancreatic exocrine enzymes for digestion into the pancreatic duct, which leads to the small intestine Islets of Langerhans: contain hormone-producing cells Beta cells: secrete insulin Alpha cells: secrete glucagon Delta cells: secrete somatostatin, which regulates the digestive process in the small intestine (in contrast, liver somatostatins inhibit growth hormone (GH) production) F cells: secrete a polypeptide hormone of unknown purpose Metabolism consists of 2 different time periods: the absorptive and postabsorptive states Absorptive state: meal was just consumed Insulin dominates [glucose, AA, fatty acids] high in blood Postabsorptive state: 5-6 hrs after a meal No nutrients are being absorbed from the GI Glucagon & other hormones (epinephrine, cortisol, GH) dominant, insulin levels low Low concentration of nutrients in blood Fig 7.3: Absorptive State NOTE: THE TEXT FIGURES CONTAIN INACCURACIES. REFER TO THE DIAGRAMS ON THE WEBCT SITE FOR THE RIGHT PATHWAYS. Glucose is abundant in blood body cells primarily metabolize glucose Insulin induces glucose transporters to be incorporated into cell membranes so that cells can take up glucose Exceptions: the cells of the liver, the nervous system, exercising muscle, the liver, and pancreatic B cells have glucose receptors that function independently of insulin There is more glucose than is needed to maintain the body’s needs liver and muscle synthesize glycogen from excess glucose 30% glycogen is stored in the liver, 70% in muscle AA are taken up by body cells (primarily muscle) synthesize protein Excess AA are deaminated by the liver and eventually converted to urea, protein, or triglycerides Fatty acids are absorbed from the small intestine adipose tissue uses fatty acids to synthesize and store triglycerides Excess glycerol is taken from liver and also used to synthesize new fat in the adipose tissue Fig 7.5: Factors Affecting Insulin Secretion Positive stimuli for secretion: high blood glucose (the primary stimulus), high concentration of AA and fatty acids in blood, GIP secretion (GI secretes when digestion occurs), parasympathetic NS activity Negative stimuli for secretion: sympathetic NS activity, epinephrine secretion, & a decrease in blood nutrients all inhibit insulin secretion Mechanism of Insulin Secretion from Pancreatic B Cells Low blood glucose: Minimal glucose enters cell Low metabolic rate + minimal ATP Cell membrane potential is at resting level (primarily due to the open ATP-gated K+ channels) Voltage gated Ca2+ channels are closed Pancreatic B Cell High blood glucose: Glucose enters cell High metabolic rate and high ATP level K+ ATP-gated channels close Cell membrane depolarizes Ca2+ voltage-gated channels open Ca2+ influx triggers insulin exocytosis This general mechanism for hormone release applies to other endocrine cells that secrete peptide hormones. However, steroid hormones don’t follow this process because as soon as they are synthesized, they directly diffuse out of steroid hormone-producing cells and into target cells. Peptide hormones, in contrast, are synthesized and stored in vesicles until something triggers their release. Fig 7.5: Effects of Insulin Insulin allows for glucose and AA transporters to be inserted into cell membranes. Thus, insulin required in most cells for glucose and AA to enter the cell Insulin increases the activity of enzymes in anabolic pathways glucose and AA are synthesized into larger biomolecules: glycogen, protein, triglycerides Insulin decreases the activity of catabolic (breakdown) enzymes Diagram of the Absorptive State from Webct There is a direct vascular connection—the hepatic-portal vein—between the small intestine and the liver. AA & small sugars are directly carried to the liver, where they enter pathways in the liver or continue onto the general circulation. From the blood, glucose is taken up by all cells while AA’s are taken up primarily by muscle. Absorption of fat Fat is absorbed from the small intestine as chylomicrons (globules of triglycerides coated with proteins) Chlyomicrons enter the lymphatic system, and then pass into the circulatory system. Thus, all body cells have equal access to fat, in contrast to how the liver gets first priority with AA and glucose. Triglycerides are lipid soluble and so enter all cell membranes Capillary walls contain the enzyme lipoprotein lipase, which breaks down triglycerides in the blood into 2 fatty acids + a monoglyceride The fatty acids diffuse into cells and are converted into triglycerides if alpha-glycerol phosphate (a glucose derivative) is available Fatty acids can also undergo beta-oxidation in cells The monoglyceride enters the liver, where it is used in the synthesis of new triglycerides Very low density lipoproteins (VLDL’s) are released from the liver primarily taken up by adipose tissue with the help of lipoprotein lipase fat cells use to synthesize new triglycerides Protein synthesis in the liver High AA levels in blood most AA’s taken up by muscle, but some AA’s go to liver liver deaminates them urea (secreted in urine) + keto acids. Keto acids are (1) used to synthesize new fatty acids, (2) enter Krebs cycle, (3) used to synthesize glucose in postabsorptive state Excess glucose beyond the set amt of glycogen the body can store is used to synthesize glycerol phosphate and fatty acids Fig 7.4: Postabsorptive State Involves more than one hormone: glucagon (major hormone), epinephrine, cortisol, growth hormone Goal of postabsorptive processes: maintain blood glucose to support the nervous system Other body cells shift to fatty acid oxidation for energy to save glucose for the NS Body draws on energy reserves Glycogen in liver enzymes convert to glucose Glycogen in muscle converted to pyruvate (used by muscle) + lactate (goes to liver for use in gluconeogenesis). Triglycerides undergo lipolysis glycerol (liver uses for gluconeogenesis) + fatty acids (body cells use for beta oxidation) Proteolysis: Muscle tissue gets hydrolyzed AA liver deaminates keto acids intermediate pathways glucose (Note: some very minor deamination also occurs in the kidneys) Note: the text figure has a mistake: AA’s are not usually used by non-nervous tissue for energy. Using proteins for energy is really a last resort process during starvation Diagram of Postabsorptive State from Webct Only liver has the enzymes for gluconeogenesis. Other cells supply the resources for gluconeogenesis: Muscle: source of lactate Fat: source of fatty acids& glycerol When insulin levels are low transporters are unavailable for glucose and AA since cells can’t take up glucose and AA, they are forced to shift to beta oxidation of fats Body taps its energy stores in this order: Glycogen: is readily available for conversion to glucose in liver; it is the immediate 1st source for glucose Glycogen in the muscle is the 2nd source of glucose. Again, muscle doesn’t have the right enzyme for dephosphorlyating glycogen and producing glucose that can be released into the blood. Instead, it must hydrolyze glycogen into pyruvate + lactic acid lactic acid goes to the liver to be used in gluconeogenesis Triglycerides are also a source of glucose. Fatty acids diffuse into cells body cells oxidize. Beta oxidation breaks down fatty acids into 2-C units to be converted into acetyl-CoA Fatty acids are also converted to keto acids by the liver. Proteins are a last resort for energy Fig 7.5 Suppression of insulin causes a shift to the postabsorptive state With less insulin, you remove insulin’s enhancement of anabolic enzymes and suppression of catabolic enzymes; cells lack glucose and AA receptors and so can’t take up glucose and AA’s overall there is less protein and glycogen synthesis Fig 7.6 Glucagon secretion increases in the postabsorptive state Strongest stimulus for glucagon secretion = a drop in blood glucose Sympathetic activity and epinephrine secretion also stimulates glucagon secretion even as it suppresses insulin secretion. Most stimuli for insulin secretion suppress glucagon secretion and vice versa because glucagon and insulin act as antagonists. An exception: [AA] in blood stimulates the secretion of both glucagon and insulin. If you have a high protein diet, you have high blood [AA] but low blood glucose. You need insulin to put in AA transporters in cell membranes, but you also need glucagon to oppose insulin’s suppression of catabolic enzymes and glucagon’s promotion of rxns that turn AA into glucose. Glucagon’s effects are primarily to the LIVER. It has very little effect on adipose tissue (contrary to the text’s diagram). Tuesday Look at the Postabsorptive diagram found on the webct site (https://webct.rutgers.edu) Postabsorptive state: starts 4-5 hrs after last meal Low levels of nutrients (glucose, amino acids) in blood Notable absence of blood [insulin] as much a factor in the shift to the postabsorptive state as the presence of 4 other hormones: glucagon, epinephrine (E), cortisol, and GH Goal of postabsorptive state: ensure adequate levels of blood glucose for the nervous system to function (90-95% of NS metabolic needs are met by glucose exclusively) Other body cells shift to metabolizing fatty acids to save glucose for the NS. Since insulin is absent in the postabsorptive state, most body cells can’t take up glucose to metabolize it anyway Glycogenolysis in liver releases glucose, but in muscle glycogen breakdown leads to pyruvate + lactic acid. The lactic acid goes to the liver to be used in gluconeogenesis (producing new glucose from other molecules, e.g. glycerol, AA, fatty acids) Lipolysis produces 3 fatty acids + glycerol Fatty acids undergo beta oxidation in cells (30% more efficient than glucose oxidation) Glycerol goes to liver to be used in gluconeogenesis Fatty acids go to liver converted to ketones there released into blood as energy source for body and, to a limited extent, the NS Proteolysis: breakdown of AA esp in muscle liver deaminates AA converts to keto acids used in gluconeogenesis Fig 7.6: Glucagon Pancreatic alpha cells secrete glucagon when [glucose] in blood decreases Sympathetic NS activity and E secretion increases [AA] in blood increases In high protein diets, glucagon is secreted to stimulate enzymes involved with gluconeogenesis so that though little glucose is absorbed from the GI tract, blood glucose levels will still be maintained Glucagon’s effects primarily on the liver with the net effect of making the liver release glucose and some effects on fat tissue Stimulates glycogenolysis in liver AND inhibits synthesis of glycogen in liver Stimulates gluconeogenesis and keto production MODERATE effect on fat tissue: induce breakdown of fats NO effect on protein breakdown or synthesis (MISTAKE IN TEXT: last 2 items of what this chart lists as glucagon’s effects on the liver are wrong) 2 Types of Diabetes Juvenile/ Type-1/ Insulin-Dependent Diabetes Immunological destruction of pancreatic beta cells inadequate insulin being produced absence of high levels of insulin to suppress glucagon secretion oversecretion of glucagon since alpha cells are no longer controlled Oversecretion of glucagon + undersecretion of insulin excessive levels of glucose and AA in the blood Remember, usually high levels of blood glucose stimulate insulin release, but since no insulin is released, whatever glucose is in the blood stays in the blood since cells lack the insulin-induced transporters to take up glucose Insulin deficiency Lipolysis up Plasma fatty acids up Ketone synthesis up Plasma ketones up Plasma acidosis up (blood pH decreases & blood becomes more acidic) CNS function, coma, death Blood pressure down Brain blood flow down Plasma volume down Osmotic diuresis up Renal filtration of glucose and ketones up (higher blood [glucose and ketones] more water diffuses into pre-urine solution body loses more water Plasma glucose up Glucose uptake down Glycogenolysis up Gluconeogenesis up Adult/ Type 2/ Non-Insulin-Dependent Diabetes More common type of diabetes: of the 5% population in the with diabetes, 90% have adult diabetes Beta cells are functioning, but body cell glucose transporters (esp for muscle) do not respond to insulin Decrease in number of transporters blood glucose increases blood vessels grow narrow and hard (breakdown of blood vessel walls) decreased circulation esp. in the lower limbs gangrene Other Postabsorptive Hormones (refer back to the Postabsorptive diagram from webct) Fig 6.9: Adrenal Gland Located on top of kidney, has 2 different tissues Adrenal medulla: modified postganglionic neurons, release E (epinephrine) Outer cortex: several layers of cortical tissue secrete steroid hormones, including Glucocorticoids, of which cortisol is the main hormone Produced in the deeper layers of the cortex the superficial layers (zona glomerulosa) produce aldosterone (controls [Na+] and [K+] in blood) Androgens Fig 7.8: Effects and Control of E in metabolism Sympathetic NS controls E release Low blood glucose (or other sources of stress) glucose receptors in hypothalamus excite sympathetic NS sympathetic NS stimulates E release from adrenal medulla Effects of E: glucose and fat metabolism Stimulates glycogenolysis in liver and muscle Fat metabolism produces glycerol, used in gluconeogenesis Primary effects on liver, muscle AND fat tissues (versus glucagon has primary effects only on liver) Net effect: increase levels of blood glucose for the NS and increase levels of blood fatty acids for other cells Fig 7.16: Glucocorticoids Glucocorticoids controlled by ACTH (from pituitary) which is controlled by CRH (from hypothalamus) Note negative feedback effects that cortisol has on pituitary and hypothalamus 2 Levels of Cortisol Release Resting/ Basal level of cortisol release follows a circadian rhythm Early morning burst of cortisol followed by smaller bursts throughout the day Affects adipose tissue, liver, cell transport systems Increases lipolysis & gluconeogenesis (like E and glucagon), and also inhibits glucose and AA transporters to reserve glucose for the NS Surge of Cortisol During Stress: Very little effects on protein metabolism till periods of extended stress/ starvation induces an surge in cortisol release, and high levels of cortisol induces protein breakdown in muscle Fig 7.10: Growth Hormone GH controlled by GHRH and GHIH from hypothalamus, GH released from the anterior pituitary Notice the multiple negative feedback loops Effects on liver: liver increases somatomedin secretion stimulate growth esp. of bone GH release follows a circadian rhythm: GH secretion increases in the middle of sleep and several hrs after a meal Drop in blood glucose and fatty acids and other stressors, and an increase in blood AA, stimulate GH release Metabolic effects of GH: Increase protein synthesis in most tissues (since GH release corresponds with an increase in blood AA levels) Increase lipolysis in fat tissue Suppress glucose reuptake Stimulates AA uptake (E, glucagon, and cortisol don’t do this) Effects on glucose metabolism and lipolysis are similar to the other postabsorptive hormones, but its effects on protein uptake and synthesis are like insulin The Thyroid Hormones Fig 6.8: Thyroid gland Located around trachea; notice the parathyroid glands (whose parathyroid hormone, PTH, regulates blood Ca2+ levels) embedded in the thyroid Thyroid hormones (T3 and T4) are generally active in both the absorptive and postabsorptive states Fig 7.14 Thyroid gland is made up of follicles (single layer of follicular cells surrounding a core of a protein colloid T3 and T4 both contain iodide Follicular cells take up I- ion from blood transport into follicles to use in the synthesis of thyroid hormones I- diffuses across capillaries follicular cells use secondary active transporters (powered by an Na+ gradient) to take up I- I- is oxidized into I2 inside the cell I2 is transported across the membrane facing the lumen of the follicle (using facilitated diffusion) I2 in the colloid core Follicular cells also produce thyroglobulin (TG, a protein made from many tyrosines) and secrete that into the colloid In the colloid, thyroxins (Tyr residues on the TG backbone) are iodinated with one or two I’s into monoiodotyrosine (MIT) or diiodotyrosine (DIT) enzymes do coupling/complexing rxns in which one thyronine is cleaved and joined to an adjacent one to form triiodothyronin (T3) if an MIT combines with a DIT or tetraiodothyronin (T4, if DIT + DIT). So, T3 and T4 are structurally made up of 3 Tyr rings with 3 or 4 I’s TG is endocytosed back into the folliclar cells lysosomes free T3 and T4 from the TG backbone T3 and T4 are released into the blood T3 and T4, unlike other proteinacous hormones, are lipid soluble. Thus, it is bound to carriers in the blood, and then it diffuses into target cells Most thyroid hormone released is in the T4 form. Once T4 enters target cells, it is usually deiodinated into the more active T3 form Fig 7.15 Thyroid hormones have broad effects that are hard to categorize Most of its visible effects are the damaging effects that result from a lack of T3 ad T4 Thyroid hormones affect Development of nervous system Heat production/ ability to control body temp Thyroid hormones increase the number and activity of Na+/K+ pumps, thus they increase ATP use increasing metabolic rate and heat production increase numbers of mitochondria Fig 7.14 Thyroid hormones are controlled by TSH (thyroid stimulating hormone), which binds to receptors on the surface of follicular cells activating a 2nd messenger system activating a kinase activating proteins that stimulate endocytosis of TG TSH releases the stored iodoglobulins in follicles (T3 and T4) TSH also controls thyroid development Notice negative feedback systems involved with TRH Release of thyroid hormones dependent on the presence of the unusual ion I- People without enough dietary iodine T3 and T4 not produced TSH and TRH levels are not inhibited by negative feedback stimulates growth of follicles goiter disease: goiters also develop, but they do because the body produces antibodies that bind to follicular cells and mimic the effects of TSH follicles grow high levels of T3 and T4 Table 7.4: Good summary of metabolic hormones Fig 7.11 Parathyroid hormones control Ca2+ metabolism, which is connected with bone formation Bone structure: Osteocytes, interconnected by gap junctions to each other that allow access to capillaries in the outer surfaces of bone, reside in gaps in the bone. Previously, these cells had formed bone by secreting calcium salts into the organic matrix around themselves Bone is constantly being restructured Osteoblasts (young osteocytes): cells that produce new bone Ostetoclasts: cells that break down bone Fig 20.21 Ca2+ levels are central for heart muscle contraction, release of neurotransmitter, & release of hormones When blood calcium levels drop PTH (parathyroid hormone) released stimulate osteoclasts & inhibit osteoblastsbreakdown of bone blood calcium levels up PTH also stimulates the kidney to increase Ca2+ reabsorption less calcium is lost in urine and more K+ is released in urine. PTH activates the hormonal derivation of Vit D in the kidney Calcitriol, or activated Vit D, increases Ca2+ absorption from pre-urinary fluid and food Fig 20.22 Vitamin D is obtained by sunlight activating a skin steroid or absorption from food Plasma Vit D goes to the liver for the 1st step of activation, then it goes to the kidney for the 2nd stage of activation by PTH Fig 20.20: Summary of the Control of blood Ca2+ Hormones involved: calcitriol, PTH, calcitonin If calcium levels high thyroid C cells produce calcitonin stimulates calcium reuptake into bones by stimulating osteoblasts while inhibiting osteoclasts increase bone growth and decrease blood calcium Thursday Key terms and concepts to look for in today’s lecture Hematocrit: the % of total blood volume composed of cells Blood islands (embryology) Endothelial progenitor cells (EPC): a type of stem cell that the ultimate stem cell, the hemangioblast, differentiates into Erythropoiesis: formation and production of new red blood cells (rbc’s) Erythropoietin (EPO): hormone that stimulates the production of new rbc’s Hemangioblasts: the earliest stem cell Hematopoietic stem cells (HSC): differentiates from hemangioblasts; it itself is the stem cell for blood cells Fig 16.2: The Hematocrit Figure shows a test tube with centrifuged blood The cellular elements suspended in the liquid have been separated into layers In this figure, the hematocrit = 45% of total blood volume since the % volume of red blood cells (rbc’s) is 45% of total blood volume. We use rbc’s to define the hematocrit because rbc’s are the majority of the cellular elements in the blood Blood can take longer to draw if the hematocrit is higher (i.e. there is a greater % of rbc’s in the blood sample). Excess rbc’s in the sample, which make the sample more viscous and thus harder to draw, can be due to People being exposed to high altitudes for a period of time: lack of O2 at high altitudes stimulates the production of more rbcs Polycythemia: condition where there are excess rbc’s Blood being mistakenly taken near a valve in the vein or in the wall of a vein The person being dehydrated: hematocrit gets elevated depending on the degree of dehydration Above the bottom rbc layer is the buffy coat: contains white blood cells (wbc’s), platelets, and larger cells that give rise to platelets (megakaryocytes) Top layer = plasma Distinction between plasma and serum Plasma: what cells are suspended in as they circulate through the vascular system of the body; will CLOT because it contains the blood clotting ingredients in blood (esp. fibrinogen) Serum: plasma WITHOUT blood clotting elements; therefore, it will NOT CLOT You use serum in blood transfusions so it won’t clot in the recipient In hematocrits of people taking anticoagulants, the top layer would be serum, not plasma Table 16.1: The Components of Plasma Water: 90% by weight of blood, 95% by weight of plasma H2O is the aqueous medium in which all other components are either dissolved or suspended Proteins: 3 major classes Albumin: 60% of plasma proteins; responsible for plasma oncotic pressure Globulin: primarily antibodies and transporters Fibrinogen: blood clotting factor Other proteins: enzymes, hormones, etc. Inorganic compounds: waste products of protein/ nitrogen metabolism: urea, uric acid, creatinine Organic compounds: carbohydrates, proteins, lipids, nutrients from diet Electrolytes: Na+, K+, bicarbonate, Ca2+. Cl-, P Plasma is an extracellular fluid, thus the [electrolytes] in plasma is similar to that in the interstitial fluid bathing cells Respiratory gases: dissolved or bound: O2, CO2, etc. Clinical Connections: Anemia (pg 506) Rbc’s are the most common cellular element in plasma Rbc shape: biconcave disks Biconcavity increases the surface area for exchange of gases (uptake of O2, release of CO2) Rbc shape is determined by 2 things Hemoglobin (Hb) is concentrated at the perimeter of the cell Spectrin (a filamentous protein) forms a network structure at the lining of the cell membrane at the perimeter of the cell. This helps hold Hb in place at the perimeter AND gives flexibility to membrane flexibility allows rbc’s to squeeze through capillaries smaller than themselves Mature rbc’s are anucleated (have no nucleus) thus, rbc’s don’t replicate like other somatic body cells. Once the lifetime of an rbc is up, it is destroyed and replaced Table 16.2: Cellular components of blood Blood cells fall into 3 main categories: rbc’s (erythrocytes), wbc’s (leukocytes), and platelets (fragements of megakaryocyte cells) Must understand and be able to convert between common units of volume Microliters: a millionth of a liter Milliliters: a thousandth of a liter; 1 mL = 1 cc (cubic centimeter) Deciliters: a tenth of a liter; 1dL = 100 mL’s Liters: L Rbcs: 5 million rbcs in one microL (mm3) of blood To find out how many Liters of blood you have, take your body weight in kg x .08 (since 8% of your body mass is due to blood volume) There are 2.2 lbs/ kg E.g. a 175 lb person has 86kg x 0.08 = 6.3 L of blood Your heart circulates your total blood volume every minute So, at 5 million rbc’s per microL of blood x each Hb being able to bind 4 O2’s x around 5L blood circulated each minute the circulatory system has a large capacity for O2 delivery Deviations from this concentration of rbc’s given in the chart can result in either Anemia: lack of rbcs Polycythemia: excess rbcs Wbc’s Leucopenia: lack of leukocytes Leukemia: excess leukocytes Excess leukocytes are usually not detrimental (your body produces excess wbc’s whenever you are sick), but chronic elevation of leukocyte levels wbc’s may destroy other cells in your body Platelets: cell fragments involved in hemostasis Hematopoiesis: the formation of blood cells in the body Fig 16.4: Erythropoiesis: the synthesis, lifecycle, and destruction of rbc’s 5 organ systems involved All blood cells are produced in marrow cavities in the shafts of long bones (e.g. humerus, femur). (Limited cell production also occurs in the marrow of flat bones like the pelvis and girdles.) Rbcs produced are released into the circulation for its lifespan of 4 months (120 days) Senescent (old) rbcs are extracted, destroyed, & recycled primarily by the spleen (part of the immune system) Rbc membranes are broken down (hydrolyzed, oxidized etc) Proteinacous rbc contents are released: globin and heme Globin: reduced to amino acids and released to circulation Heme: broken down further into Fe and bilirubin and others released into blood for recycling in the synthesis of new rbs Liver extracts bilirubin and makes bile out of it to help absorb lipids in the diet (e.g. cholesterol) Fe is stored in the liver bound to the protein ferritin; it can be released into the blood bound to the protein transferrin for bone marrows to use in erythropoeisis (rbc synthesis) Hypoxia (lack of O2) stimulates erythropoiesis O2 deprivation at high altitudes stimulates rbc production increases hematocrit Liver produces erythropoietin (EPO is also used to treat cancers) released into blood stimulates production, growth, and development of eryhropoietic stem cells more rbc’s produced Hemoglobin nomenclature Hb: hemoglobin HbA: adult hemoglobin: very different from fetal Hb (HbF) and sickle cell Hb (HbS) HbO2: oxygenated Hb, or oxyhemoglobin HbH: reduced hemoglobin which is likely to be carrying H+, not O2 (may signify something wrong) HbA Has 4 polypeptide chains (2 alpha, 2 beta) Each chain has a Heme moiety/ subgroup attached Each subgroup has a Fe atom either in the +2 or +3 oxidation states +2 state: ferrous iron: state that binds O2 +3 state: ferric iron: poor binder of O2 Conditions with an imbalance of Fe states Drugs can change the oxidation of Fe MetHb anemia: disease where the number of Fe in the +3 state exceeds the number in the +2 state; there is bad Hb in the blood CO: carbon monoxide: has 1000x greater affinity for Fe than O2 if too much CO displaces O2 death Hb undergoes physiological changes as it goes from the arterial to the venous sides of blood flow Fig 16.5: Process of Hematopoeisis (synthesis/ production of blood cells) The text shows the hematopoietic stem cell (HSC) as the primary stem cell, but there is an even earlier precursor: the hemangioblast, when then differentiates into HSC’s and EPC’s (endothelial progenitor cells) Stem Cell Research Embryonic background of hemangioblasts as stem cells Embryo: zygote blastocystmorula The 1st organ system to develop in mammals (in 2-3 weeks at the blastocyst stage) is the cardiovascular system, which must develop first because after 2-3 weeks, the blastocyst/ morula is too large for diffusion to foster further growth and development Hemangioblasts allow the concurrent development of the (1) vascular system to carry blood around, (2) the heart to pump blood, and (3) cells to carry O2 The cardiovascular system is the only way for O2 to be delivered to all the cells in the blastocyst Stem cell research is the wave of the future. In many diseases, the tissue around the heart is destroyed. We have been able to implant stem cells in the afflicted areas of the heart new blood vessels develop (angiogenesis) prolong life of heart 2 branches of stem cells form from the HSC Lymphoid stem cells lymphocytes Myeloid stem cells bone marrow type, hematopoietic tissues Rbcs: anucleated Platelets: anuceated, but have mitochondria, smooth ER, cellular granules, etc. to do protein synthesis Wbc’s: nucleated Basophils and Eosinophils: remain in circulation till they die (after 2-4 weeks) Neutrophils & monocyte/macrophages: in circulation for a few hrs go through vascular walls reside in body tissues (esp the wall of the gut, liver sinuses, spleen) become major factors of the immune system Table 16.3: Leukocytes Wbc’s can be divided into 2 groups according to how they stain Granulocytes (first 3 types of wbc’s in the chart) Have stainable granules Eosinophils: pick up acidic stains Basophils: pick up basic stains Neutrophils: faint stains Agranulocytes: no stainable granules Lymphocytes, monocytes, and macrophages Wbc’s also described as polymorphonuclear since they may have many nuclei Fig 16.6: Hemostasis: maintaining static conditions in the blood Important when there are wounds that cause internal or external bleeding Hemostasis refers to the role that cells (esp platelets) play in protecting the body from the loss of blood volume This system that minimizes blood loss also protects other things associated with blood volume: blood pressure, blood flow Too much blood loss too quickly cardiovascular collapse death Tuesday Key Terms/ Concepts Syncytium Diastolic depolarization (pacemaker potential) Automaticity (autorhythmiticity) Sarcolemma: plasma membrane of a muscle cell Fast v. slow action potentials Hemostasis: maintaining the status quo of blood 3 mechanisms to minimize blood loss during injury Vasoconstriction/ vasospasm Formation of platelet plug Fibrination: formation of a thrombus/ natural blood clot/ fibrin clot STEP 1: Vasoconstriction: the narrowing of the luminal diameter of the blood vessel at the site of injury An immediate response after vessel damage 3 ways to induce vasoconstriction: Neurogenic mechanism: damaged nerves at the injury site by release compounds that cause constriction Surrounding (non-nervous) tissue release chemical metabolites that cause constriction Myogenic response: vascular smooth muscle cells of the vessel wall respond to injury by contracting “Vasocontriction” is the preferred term because it connotes the controlled, purposeful nature of this response, whereas “vasospasm” (used by the textbook) connotes uncontrolled and unpatterned behavior STEP 2: Fig 16.6a: Formation of a platelet plug When a vessel is damaged, the vessel wall and surrounding tissue are also damaged. This induces changes in platelets and 3 steps occur: Adhesion: platelets become adhesive: they stick to area of injury and to each other Aggregation: platelets build up into a plug Formation of platelet plug This process is precipitated and regulated by the release by platelets of compounds derived from arachidonic acid, thromboxane A2 (TXA2) and ADP, which enter a positive feedback loop with each other to make platelets release more TXA2 and ADP. These processes ultimately lead to the formation of the actual blood clot, a process that involves more complicated sequences of events Fig 16.6b: There are around 50 compounds (also called factors) identified as being part of the process of blood’s coagulation or anticoagulation. Many factors are ubiquitous proteins that are always present in circulation, though in their inactive states. Whether blood clots depends on the balance between the anti- and pro-coagulating elements in the blood We experience injuries all the time: hemorrhagic clotted blood refers to the small red pinpricks our bodies due to the clotted blood from minor injuries In an undamaged vessel, the primary anticoagulants present are prostacyclin (PGI2) and nitric oxide (NO), both of which released by the endothelial cells lining the vessel to prevent platelet aggregation. The endothelium, the innermost lining of the wall of blood vessels, is a very important structure because it is the interface between the circulating blood and the static vessel wall and surrounding tissue. STEP 3: Fig 16.8: Fibrination Fibrination: the formation of the actual blood clot/ thrombus This figure is a schematic of several of the many clotting elements there are There are 2 pathways by which the blood clot can be formed Intrinsic: involves factors/ proteins INSIDE the endothelial barrier Extrinsic: involves things from OUTSIDE the endothelium (connective tissue, underlying smooth muscle of vessel wall, the blade of a knife, etc.) Terminology: a letter “A” at the side of a roman numeral indicates the ACTIVE state of that factor (note that there are active and inactive states for the factors) The conversion from inactive to active states requires some biomolecular event The roman numbers indicate the order in which the clotting factors were historically discovered, not the sequence in which they play a part in clotting. So, lower numerals indicate that those factors were discovered earlier in history, and nothing more. Note the central role of thrombin and all the actions that thrombin mediates. Fig 16.7 Fibrin network entraps red blood cells, platelets, macromolecules (lipoproteins, chylomicrons) When fibrinogen is activated, it forms fibrin monomers that are soluble in the aqueous plasma, but the fibrin doesn’t dissolve away because it rapidly polymerizes into a fibrin net Factor XIII = fibrin activating factor = activates fibrin and allows parallel strands of fibrin to covalently bond to each other, forming a strong fibrin mesh that prepares the way for a blood clot to form Fig 16.6 In this figure, everything from the conversion of Inactive factor X active factor X constitutes the common pathway Both the extrinsic and intrinsic pathways lead to this common pathway Protime: how long it takes for your blood to clot Normal: blood clots in 1-2 min from the time the blood sample is taken. If clottig time is over 3 minutes or under half a minute, the blood has abnormalities in its clotting abilities. INR: international normalized ratio: a comprehensive list of healthy clotting times after incorporating possible influencing factors THE ELECTRICAL PROPERTIES OF THE HEART Many fields to study the heart from: the heart has electrical, mechanical, circulatory, metabolic, and regulatory (endocrine) properties Fig 14.9: The heart This figure of the heart’s anatomy represents the conduction system in mammals Structures to locate: apex of the heart (at the bottom of the ventricles), the R & L atria, the R & L ventricles, the base of the heart (between the atria and ventricles) Fig 14.10: How the wave of electrical depolarization spreads through the heart SA node generates action potential R atrium R & L atria converges at the AV node atrioventricular (interventricular) septum Purkinje fibers (modified muscle fibers, not neurons) carries action potential up ventricles to the base of the heart So, the 1st to depolarize are the tissues adjacent to the SA node The last tissue to depolarize are the tissues at the base of the heart This depolarization pathway ensures The atria contract while the ventricles relax the atria squeeze enough blood into the ventricles to sufficiently fill them The way the depolarization travels from the bottom to the top of the ventricles ventricles eject blood in this direction (from apex to base) Fig 14.8 Syncysium: term means “same tissues” Only the heart has this trait When one cell depolarizes, the whole heart will depolarize almost simultaneously as if its all one cell Gap junctions at intercalated disks between adjacent myofibrils allow for the rapid transmission of current through the cells of the heart. Gap junction structure: 6 connexons (a type of protein) form a hexagonal tube (called a nexus). These nexi form low resistance electrical channels that allow Na+ ions, and thus depolarization, to pass rapidly form one cell to the next Fig 14.11: Action potentials in Pacemaker cells Automaticity (autorhythmiticity): the ability of a cell to generate an action potential in the absence of external stimuli Some cells in the heart automatically fire action potentials. This is a property inherent in pacemaker cells; they don’t depend on any external stimuli (like nerves). In the SA and AV nodes, there are 2 kinds of cells that show automaticity Note the pacemaker potential in the figure. This property gives pacemaker cells their automaticity Pacemaker cells have NO RESTING CELL MEMBRANE POTENTIAL. They depolarize right after repolarization Maximum depolarization: between -70 to -60 mV Action potential has 3 phases Phase 4: slow depolarization/ pacemaker potential/ diastolic depolarization (because this occurs during diastole): the cell depolarizes slowly from maximum depolarization to threshold Phase 0: depolarization section of the action potential Phase 3: repolarization This is the characteristic action potential curve for autorhythmic, slow response cells (mycocytes) in the SA and AV nodes Table 14.1: Shows the phases of the action potential of slow response cells and the channels/ ions responsible for the phases Phase 4: still some uncertain as to what channels or ions are responsible for this state. 2 things seem to occur simultaneously: Funny channels open to let Na+ leak into the cell depolarization T-type Ca2+ channels (T for temporary): open halfway into Phase 4 to let Ca2+ flow into the cell depolarization to threshold Upon reaching threshold, L-type Ca2+ channels (L for long-lasting) open and stay open through the actual action potential. Thus, L-type channels are responsible for the depolarization in Phase 0 Fig 14.12: Morphology of action potential for fast response myocytes Fast response myocytes do not have automaticity Distinguish between the action potentials of fast and slow response myocytes Fast response cells HAVE A RESTING MEMBRANE POTENTIAL (slow response cells don’t) Fast response cells have 5 PHASES (v 3 phases in slow response cells): Phase 4 (rest) Phase 0: depolarization dV/dT = change in voltage/ change in time (msec) = rate of depolarization in fast response cells is MUCH FASTER than in slow response cells Fast response is due to the opening of fast Na+ channels, while depolarization in slow response cells is due to the opening of slower Ca2+ channels Phase 1: slight repolarization Fast response cells show an overshoot (depolarize over 0mV. The text shows slow response cells reaching positive voltages too, but this is WRONG; slow response cells reach 0mV and repolarize). Fast response cells also show reversal potential (which slow response cells don’t): a sharp change back towards negative potentials after its overshoot Phase 2: plateau potential: this is absent in slow response cells Phase 3: repolarization: same as in slow response cells Fig 14.22 If your heart rate is 70 cycles/ min, some cell in the SA node is firing at 70 action potentials/ min. This doesn’t mean that all cells fire at 70 action potentials/ min though; the actual rate of firing for different cells ranges from 30-100 action potentials/ min. So, only a few cells set your actual heart rate. The autonomic nervous system influences the rate of firing in pacemaker cells. Pacemaker cells are also subject to the influence of external stimuli such as nervous input, temperature, drugs, mental states, illness, etc, which work through activating/ suppressing the sympathetic or parasympathetic nervous systems. Review: The parasympathetic and sympathetic NS’s both release the ACh (acetylcholine) as their neurotransmitter (NT) at preganglionic synapses onto nicotinic cholinergic receptors. At postganglionic synapses, the parasympathetic NS releases ACh onto muscarinic cholinergic receptors on the effector organ (in this case, the heart). The sympathetic NS releases norepinephrine (NE) onto beta adrenergic receptors in the heart. Sympathetic neurons emerge from the thoracic-lumbar division of the spinal cord. Parasympathetic neurons emerge from the cranial-sacral section of the spinal cord. Both parasympathetic and sympathetic neurons innervate the heart in specific loci Both parasympathetic neurons (from the vagus nerve) and sympathetic neurons innervate the SA and AV nodal cells The sympathetic NS also innervates myocardiac parenchyma (cardiac muscle cells) and coronary blood vessels in the heart wall, which the parasympathetic NS doesn’t Fig 14.23 NE from sympathetic neurons (and Epinephrine from the adrenal medulla) that innervate the heart bind to beta adrenergic receptors G protein adenylate cyclase changes ATP to cAMP cAMP acts as a 2nd messenger to activate protein kinases protein kinases open funny Na+ and T-type Ca2+ channels in slow response cells Parasympathetic postganglionic cells from the vagus nerve release ACh binds to muscarinic cholinergic receptors stimulatory or inhibitory G protein activated Ca2+ channels close or K+ channels open both lead to hyperpolarization Fig 14.24: Effects of sympathetic and parasympathetic activity on the rate of firing of pacemaker cells In this figure, the peak of the action potential should only reach 0 mV Parasympathetic influence causes the time for the cell to depolarize to threshold to increase while sympathetic influence decreases the time required for the cell to depolarize to threshold in 2 ways Parasympathetic influence decreases the slope of the pacemaker potential section of the curve, while sympathetic influence increases the slope of the pacemaker potential section of the curve Parasympathetic influence causes repolarization to a more negative state than normal, while sympathetic influence causes repolarization to a less negative state than normal The net effect of parasympathetic influence is thus to decrease heart rate while that of sympathetic influence is to increase heart rate Note that the intercycle interval is inversely proportional to the heart rate: a shorter interval faster heart rate; a longer interval slower heart rate Fig 14.12: Refractory periods If you stimulate a myocardiac cell at phase 1 or 2, there will be no response because the cell is refractory to a 2nd stimulus (electrophysiological conditions prevent restimulation) Stimulation at phase 3 may cause response (i.e. firing of another action potential) depending on the strength of the stimulus For nerves and normal muscle cells, the refractory period is about 1-10 msec For the heart, the total refractory period is about 300 msec Effective refractory period refers to the absolute refractory period (from 0-200 msec after the 1st action potential) Relative refractory period (from about 200 msec on): a strong stimulus may induce a 2nd action potential Thursday Correction for notes from : the “base” of the heart refers to the upper, broader end of the heart CONTRACTILE PHYSIOLOGY OF THE HEART (with a focus on the left ventricle) Fig 14.13: Excitation-Contraction (EC) Coupling (also known as electromechanical coupling) Na+, K+, and Ca2+ have important roles in cardiac function No Ca2+ heart becomes acontractile (can’t contract) No Na+ hear becomes inexcitable Modest changes in [K+] heart malfunction (e.g. a 2-3x increase in extracellular [K+] leads to cardiac arrest) This figure shows 2 cells, which can be either slow or fast response cells. An action potential in one cell crosses via a gap junction to the 2nd cell and induces a depolarization, which leads to contraction Steps Na+ ions flow across nexi (gap junction) wave of depolarization passes longitudinally along the sarcolemma and into the cell down T tubules (which are continuous with the sarcolemma) Voltage-dependent opening of L-type Ca2+ channels (these are the types of channels that we find in ventricles, the structure we’re concentrating on) Ca2+ enters the cell in the resting state prior to depolarization down its concentration gradient. At rest, there is a 10,000x difference in [Ca2+] between the intra and extracellular fluids Inside the cell =10-7 mols, or 1/10th of a micromole Outside the cell =1 millimole Calcium induced calcium release: Ca2+ influx from L-type channels are not enough to cause contraction. Rather, these Ca2+ ions bind to Ca2+ receptors on the sarcoplasmic reticulum (SR) and sarcolemma/ T tubules, which opens these new Ca2+ channels release of stored Ca2+ from SR and T tubules into the cytosol This SR Ca2+ sufficiently raises the [cytoplasmic Ca2+] to induce contraction Protein Ca2+ receptors (named after the class of drugs that block them) Dihydropyradine receptors: L-type channels in the sarcolemma Ryanodine receptors: located in the SR Ca+ from the SR binds to troponin conformational change in troponin I (TNI, TI, or inhibitory troponin), which usually covers a tropomyosin element that has myosin binding sites but the conformational change exposes those myosin binding sites crossbridge cycle sarcomere shortens generates force Research going on right now: a small amount of Ca2+ can be released form the SR in gradient fashion. There are dyes that release light when Ca2+ is released; these are called calcium sparks. Relaxation of the sarcomere occurs through 2 ways Ca2+-ATPases in the SR and sarcolemma extract Ca2+ and restore it in the SR or transport it back out of the cell Ca2+-Na+ exchangers (antiports) use energy from Na+ influx to pump Ca2+ out of the cell After relaxation, the cell is ready from another action potential Fig 14.18: EC Coupling leads to mechanical event EC process occurs several times a minute Changes in the EC process brings about the cardiac cycle Phases: there are 6 phases in the cardiac cycle. Generally: systole (systolic phase) is when the myocardium contracts, and diastole is when the cells relax Note when the valves are open or closed Atrioventricular (AV) valves: between atria and ventricles on both the R and L sides of the heart (but we’ll focus on the L heart) Bicuspid (mitral) valve: AV valve in the L heart Mitral valve stenosis: congenital disease affecting the L AV valve Tricuspid valve: AV valve in the R heart Artery valves Aortic valve: b/n L ventricle and the aortic trunk Pulmonary valve: b/n R ventricle and trunk of pulmonary artery When the AV valve opens, the vascular valves are closed and vice versa Timing of valve opening/closing is important because it corresponds with the correct direction of blood flow In the graph: note the pressure changes (green line= ventricular pressure, pink line = atrial pressure) Fig 14.17 The Cardiac Cycle has 6 phases: 3 phases each for systole and diastole Systole Isovolumetric contraction Rapid ejection (emptying) phase Reduced ejection (emptying) phase Diastole Isovolumetric relaxation Rapid filling phase Reduced filling phase Many things in this figure are inaccurate. It is good that they show 6 figures of the heart on the top, but the labeling for the leftmost heart should be “rapid ventricular filling” and that on the right should be “reduced ventricular filling,” and the ejection phase should also be divided into rapid and reduced phases Pressure graph The waveforms of these 3 curves define the 6 phases Note: the aortic pressure represents the systemic pressure. Aortic pressure falls as the ventricle fills because there is no need for it to maintain its high pressures against the ventricle Volume graph shows the change in blood volume in the L ventricle Isovolumetric: same volume There are 2 isovolumetric periods (periods of constant volume): one at about 130mL and one at about 60 mL (note the vertical lines around these phases) At 130mL in the L ventricle: the atrial pressure is slightly > ventricular pressure mitral valve closes because atrial pressure > ventricular pressure no blood flows from atria to ventricle At the same time, the aortic valve does not open till the ventricular pressure is high enough to open it no blood flows out Since both valves around the L ventricle are closed, it is a closed chamber with a constant volume At 60 mL in the L ventricle: When the L Ventricular pressure < aortic pressure aortic valve closes, but the mitral valve doesn’t open till the pressure in L ventricle is lower than that in the L atrium another isovolumetric closed chamber Rapid v reduced filling: Rapid filling: in the 1st few msec of filling, 80% of the blood volume (70mL) is gained by the L ventricle Reduced filling: ventricle gains 10-15mL more blood more slowly after rapid filling In the volume graph, take the tangents of the green curve in the last segment of the graph (after the 60mL isovolumetric phase) right at the beginning and near the end of the phase. You see that the initial slope is greater (rapid filling) than the later slopes (reduced filling). Similarly, you can compare tangents for the rapid and reduced emptying phases. Cardiac cycle rate is about 70 cycles/ min Blood is noncompressible Fig 14.20 End-systemic volume (ESV): residual volume of blood in ventricles after contraction (minimum volume) = 60mL End-diastolic volume (EDV) just before ejection (maximum volume) = 130 mL Stroke volume (SV) = the change in these 2 volumes = 130- 60 = 70 mL This means that with every pump, the heart ejects 70 mL SV x heart rate (HR, or the number of cardiac cycles/ min) = Cardiac Output (CO) The volume of blood that either ventricle ejects / min = the circulating volume of blood in your body = a good indicator of cardiac function Your ventricles contract at 70 cycles/ min x ventricles eject 70mL/ cycle = 4900 mL = your heart pumps 5 L of blood/ min on average (may range from 3L – 7L according to body mass and in response to various interventions, like the autonomic nervous system) Ejection fraction = (end diastolic volume – end systemic volume) / end diastolic volume = SV/ EDV EF is another way to express SV Fig 15.21: Distribution of the volume of blood in the systemic circuit Blood is distributed through several linear arrangements of blood vessels, the heart, and the lungs Most (70%) of our circulating blood volume is in the veins, while about 20% is in the arteries and microcirculation (capillaries). This is due to the phenomenon of compliance. Compliance deals with a vessel’s change in volume over its change in pressure when it holds fluid Complaint vessels (veins) can accommodate a large volume of blood with a small change in pressure; i.e. it’s stretchable Noncompliant vessels (arteries) show a large change in pressure for the same given volume of blood; i.e. it’s nonstretchable Thus, since compliant veins exhibit lower pressures than arteries, veins serve as a storage reservoir for blood for times when the CO needs to be redirected/redistributed During stress, the sympathetic nerves innervating veins release norepinephrine (NE) compliant vessels (veins) contract and become noncompliant this forces blood out of the veins so that it can be shifted to the arties and capillaries and to places where blood is needed During stress, CO can rise from 5 L/min to 30-35L/min (around a 6-fold increase) rapidly by 2 mechanisms Heart rate increases 2-3x in a few seconds Sympathetic nerves active, parasympathetic nerves inactivated Myocardium can contract much more vigorously SV increases from 70mL to 85-90mL/ stroke and the residual volume in the ventricles decrease Redistribution of blood flow during exercise/ crisis The body can identify which tissues need more blood during crises and increase blood flow to those few organ systems important during stress: the heart, the brain, and supporting fight/flight tissues (skeletal muscle, adrenal cortex and medulla, etc.) Blood distribution increases to the: skeletal muscles, heart, and brain (blow flow here in mL increases though the % of blow flow during the stressful state decreases); blood flow to the skin increases when there is prolonged activity (2hrs +) since the skin becomes important for temperature control in the long run (skin is not as important in the short run) Blood distribution to the kidneys, gut/ abdominal organs, and other parts decreases during stress The sympathetic nerves, selectively activated and inactivated, induce a redistribution of blood Sympathetic activation vessel constriction vessel pressure up blood flow up to that area Sympathetic inactivation vessels relax pressure down blood flow decreases in that area and is shifted to other body parts Fig 15.27: Autonomic Control of Cardiovascular Function Autonomic nerves from the brainstem or spinal cord innervate both the heart and blood vessels Changes in autonomic influence could come about by activating either sympathetic or parasympathetic nerves (i.e. vagus nerve), suppressing either, or activating one AND suppressing the other. So, stimulation of the sympathetic nerves to the heart or the suppression of parasympathetic nerves increase HR or contractility or both Focusing on the heart only Positive chronotropic response: increase heart rate (sympathetic dominance) Negative chronotropic response: decrease heart rate (parasympathetic dominance) Positive inotropic response: heart contracts more forcefully ejects blood more vigorously SV up (sympathetic dominance) Negative inotropic response: heart contracts less forcefully / contractility down (parasympathetic dominance) Positive dromotropic response: conduction velocity from the SA to the AV node increases action potentials propagated faster (sympathetic dominance) Negative dromotropic response: conduction velocity from the SA to the AV node decreases (parasympathetic dominance) Fig 14.27 Starling’s law of the heart (Starling’s mechanism of change in SV or CO) Chart plots end-diastolic volume against SV Note: the y axis should be labeled “force (or pressure) development” An increase in end-diastolic volume corresponds with an increase in SV The heart will eject any additional blood it gets from venous return; that is, the heart will contract more vigorously to eject more blood if it gets more blood Thus, when you evaluate the effect of a drug on cardiac contractility, you have to control the end-diastolic volume to prove the change in contractility is due to the drug, not Starling’s law Tuesday THE CIRCULATORY SYSTEM Fig 14.2: The Mammalian Circulatory System The mammalian circulatory system can be divided into 3 parts: systemic, the pulmonary, and lymphatic circulation Pulmonary circulation (to/from lungs): Starts at right ventricle of the heart and ends at the left atrium Systemic circulation (everything except the lungs) Starts at the L ventricle and ends at the R atrium Pressure The systemic circulation is high pressure while the pulmonary is low pressure, though each system has a higher pressure arterial side and a lower pressure venous side. The R ventricle that pumps blood into the pulmonary arteries is only a developmental appendage to the L ventricle. It has a thinner wall and thus less muscle mass to generate force since It has a shorter distance to pump blood: only to the lungs The lungs are a highly compliant (stretchable) spongy tissue, which don’t resist the flow of blood from the R ventricle In contrast, the L ventricle that pumps blood into the systemic circuit has a thicker wall and more muscle mass to generate stronger contractions because It has a longer distance to pump blood: through the whole body except the lungs It pumps blood to non-distensible organs, including The brain, which is not only non-stretchable but is housed in the hard immobile cranium The kidneys, which are capsuled organs (they are surrounded by a rigid fibrous connective tissue such that the kidney’s can’t expand) The purpose of the circulatory system = the exchange of materials between the vascular compartment and the interstitial spaces around the vascular compartment at the capillaries Note where O2 and CO2 are exchanged (at lungs and tissues) and the direction of exchange (lungs = O2 out and CO2 into lungs; tissues = O2 into and CO2 out of cells) High arterial pressure must dissipate before blood gets to capillaries or the capillaries will burst from the force of the blood pressure Pressure at the… Systemic arteries = 100mmHg Pulmonary artery = 25mmHg Systemic veins = 5 mmHg Pulmonary veins = 5mmHg Fig 15.9: The Lymphatic Circulation Lymph = a fluid that is the same as blood plasma except it has a lower [proteins] and virtually no cellular components Function of the lymphatic system Water, ions, and electrolytes are lost on a regular basis during circulatory exchange at the capillaries If the water were allowed to stay in the interstitial spaces around the capillaries, edema (inflammation/ expansion of the interstitial spaces) would result. This swelling would impeded/interfere with the exchange between cells and capillaries. Thus, the lymphatic system is there to remove the excess fluid in the interstitial spaces by the following mechanism. How the lymphatic system maintains fluid homeostasis The lymph system includes end capillaries with a terminal wall located around the capillary beds. Water and solutes in the interstitial fluid diffuse into the lymphatic capillaries There are no pumps in the lymph system, but the movement of surrounding tissues (e.g. contraction and relaxation of muscles) propels the lymph through the lymph vessels. Also, unidirectional valves in the lymph vessels opening in only 1 direction (upwards in the vessels of the lower body, downwards in upper body lymph vessels) to prevent the retrograde flow of lymph Major lymph channels drain into the subclavain veins in the neck which is part of the systemic venous circulation Thus, the lymphatic system maintains circulating blood volume in the systemic circulatory system. This is important because if blood volume drops, the blood pressure drops, and there may be no exchange Lymphatic flow is very slow and a small quantity compared to the systemic circulation Rate of blood flow into systemic arteries = measured in mL/min Rate of flow in lymph vessels = measured in micro L/ min (i.e 1/1000ths of the systemic flow) If you’re stung by a bee and inflammation occurs, the inflamed tissue may compress/ shut lymph vessels such that no lymph can flow the lymph fluid remains at the tissue site and increases inflammation more edema. Most edema, such as in this case, is transitory. In disease states, though, edema can be permanent: certain microorganisms invade the lymph vessels, destroying lymph valves and blocking the vessels such that fluid accumulates in limbs (especially the lower limbs) permanently. Inflammation is essentially edema elfin tyesis from micofloriea Lymph nodes along the lymphatic vessels contain lymphocytes, white blood cells that destroy bacteria in the lymph Fig 14.3: Parallel versus series Blood Flow Red side = arterial flow Blue side = venous flow Parallel flow occurs through most of the different organ systems simultaneously. Capillary beds in parallel each get the same fresh blood from the heart Series flow occurs when 2 capillary beds are in sequence, as from the GI tract to the liver and in the renal portal system (any “portal” system describes 2 capillary beds in series) The set of capillaries that’s downstream in a series system has a different chemical composition than the set before it because the cells at the earlier bed have already modified the blood contents when it does exchange with the blood Note that there is more oxygenated (red) blood at the 2nd capillary bed in the renal portal circuit while the blood that reaches the liver is already completely deoxygenated (blue). This suggests that the kidneys don’t need/ use oxygenated blood as quickly as the gut does The Hepatic Portal system from gut to liver The liver’s main source of blood is from the hepatic portal vein, which comes from the capillary bed at the gut (i.e. the venous blood of the gut). 85-90% of the blood volume that the liver receives, along with the more important blood contents, get to the liver in through the hepatic portal vein The liver also gets 10-15% of its blood supply from the hepatic artery, which comes from the aorta. However, though the [O2 ] from the hepatic artery is higher than that from the hepatic portal vein, the latter generally gives the liver enough O2 already Only the liver has 2 blood supplies in this way Hemodymanics in the systemic and pulmonary systems Hemodymanics: 3 interconnected variables concerning blood: blood pressure, blood flow (Q), and resistance (R) to blood flow Fig 14.19: Blood flow versus blood pressure In the fig, there is a slow fall to the minimum pressure (the diastolic pressure), while there is a fast rise to the maximum pressure (systolic pressure) Systemic pressure should be as far below 140 mmHg and diastolic pressure below 90mmHg as possible (without becoming too low) Pulse pressure = systolic pressure – diastolic pressure = 120 – 80 = 40mmHg (in this example) The 2 things that determine systemic pressure are Stroke volume (SV) Compliance of arteries that SV is pumped into Compliance: the distensability/ elasticity of vessels The higher the compliance, the lower the systemic pressure (since the vessels can stretch more to accommodate the pressure) Age is the major factor for reduced compliance Maximum compliance occurs at the ages of 18-21 To minimize the loss of compliance, you must have a healthy lifestyle--eat right and exercise Stress reduces compliance The main determinant for diastolic pressure = resistance (R) to blood flow Vessel R up, diastolic pressure up Vessel R down, diastolic pressure down If your arteries are incompliant, a stressful situation may increase your SV (heart exhibits a chronotropic and ionotropic response to stress) a higher SV against vessels with low compliance and high resistance aneurism (blood vessels blow out) Fig 15.1: Gradients of blood pressure drive blood flow Generally, blood pressure up means blood flow up Hydrostatic gradients from a difference in height between the 2 reservoirs determine the flow rate. Increased gradient, increased flow Decreased gradient, decreased flow Fig 15.1 a: So, if delta Pressure = 40mmHg, it drives a flow rate of 20mL/min; i.e. it takes 2 mmHg to force 1 mL water through the conduit Fig 15.1 b: No pressure gradient, no flow Fig 15.1 c: Even if the absolute heights of the water in the reservoirs differ, as long as the delta P between the 2 reservoirs is the same, the corresponding flow rate won’t change Fig 15.2 Blood flow in the body is proportional to pressure differences Mean arterial pressure = 100mmHg while the pressure at the calf is 85mmHg blood flows down its pressure gradient from heart to calf Blood has mass and is thus subject to hydrostatic gravitational forces, which make blood pressure at the feet 200mmHg. However, blood doesn’t backflow from feet to heart because the important gradient is the one between the L ventricle and the R atrium. That is, the overall gradient (100mmHg in arteries v 5mmHg in veins) across the systemic circuit is the one that drives the 5L/min of blood that the heart pumps through the body Hypertension = diastolic pressure > 90mmHg and/or systemic pressure > 140 mmHg Hypotension = diastolic pressure < 70 or 60mmHg and systemic pressure < 90-100 mmHg Hypotension is more rare, and thus it isn’t a clinically significant condition People with hypotension often feel cold because they can’t thermoregulate The danger of hypotension is that a too-low blood pressure results in organs not getting enough blood flow, and that leads to gangrene, ischemia, tissue necrosis (tissue death), etc. Athletes have exercise-induced vasodistension and excerdia Their resting heart rate is a low 45-60 beats/min During exercise, the autonomic nervous system is managed such that at rest, parasympathetic vagus nerve activity is increased and sympathetic discharge is decreased lower heart rate and vasodilation of arterioles blood pressure falls Fig 15.4: Resistance Poiseuille’s Law: blood flow is proportional to pressure gradients Blood flow is directly & indirectly related to the geometry (inner diameter and length) of the vessel The internal diameter of the blood vessel = the main contributor to the vessel’s resistance Arterioles (in the systemic and pulmonary circuits) are THE resistance vessels of the body There is more smooth muscle in arteriole walls than in any other kind of vessel, and these smooth muscle fibers are innervated by sympathetic fibers. Arteriolar smooth muscle responds myogenically to changes in transmural pressure. Transmural pressure is the change in pressure across the wall of the vessel. So, if the pressure inside the vessel is 90 and the pressure from the interstitial fluid surrounding the vessel is 0, then the transmural pressure = PT = 90 – 0 = 90mmHg If P in arteriole increases while outside pressure is constant, then PT increases arteriole responds by constricting to keep flow through the vessel from increasing Fig 15.3 Delta P / (Q x R) = pressure gradient / (rate of flow x resistance) Applies to systemic and pulmonary circulation The greatest pressure gradient is between the beginning and end of arterioles; in other words, there is the greatest drop in pressure across the arterioles In the figure, the pressure falls across the circulatory system, but each segment of blood vessels receives the same volume of blood flow: all 5 L/ min passes through all the arteries, then all the arterioles, then all the capillaries, then all the veins, etc. Thus, blood flow (Q) is constant, and the only changing variable is the pressure gradient Complete formal Poiseuille’s Law: Dot over Q indicates “rate” of flow Blood flow is proportional to delta P x (radius of vessel)4 Blood flow is inversely proportional to the length of the vessel and the viscosity of blood () Thursday Final Lecture on the Cardiovascular (CV) System Starling’s law: the heart adjusts its stroke volume to accommodate whatever volume of fluid is inside it 2 mechanisms of CV control Remote/ Central (Nervous system) regulation of blood pressure (i.e. systemic arterial blood pressure) Local control of blood flow: organs and tissues regulate the amt of blood flow to themselves independently of the nervous system Remote/ Central (Nervous system) regulation of blood pressure When we talk of central regulation, we are referring to short-term/ transient control of blood pressure (there are also long-term regulatory mechanisms that involve fluid/ salt/ water/ diet balance, but we won’t discuss these). Fig 15.26: The major arteries near the heart At the bifurcation where the R and L carotid arteries split into internal and external branches, there are swellings on the internal branch vessel walls: these are the carotid sinuses Carotid sinuses have sensory afferent nerve fibers These fibers are bipolar nerves: axon spreads across the cell body Their sensory nerve endings are baroreceptors (aka pressor receptors), which are a kind of mechanoreceptor that responds to mechanical changes in the blood vessel wall The aortic baroreceptors are located at the bottom of the aortic arch The location of these baroreceptors is strategic: close to the heart so they can determine the change in blood pressure on a beat by beat basis. Though there are baroreceptors in other areas, we will consider the ones at the carotid sinuses and aortic arch only. Fig 15.25: Responses to arterial pressure changes by arterial baroreceptors The baroreceptors do not detect absolute pressure changes, but changes in the degree of stretch of vessel walls Each graph shows a pressure wave pulse and the corresponding action potentials from a single carotid sinus The amount of sensory info relayed from the baroreceptors to the brainstem (via action potential frequencies) varies with arterial pressure Pressure up more stretch in vessel wall freq of baroreceptor action potentials up If the pressure increases but the vessel can’t stretch, there will be no change in the freq of baroreceptor action potentials Sensory nerve fibers of baroreceptors are affected by both dynamic and static components As the wave rises, the freq of action potentials rise dramatically: This is the dynamic rise during periods of rising pressure As the wave reaches a steady peak pressure, the action potential freq stabilize at a steady state this is the static, maintenance component Pathway of baroreceptor action potentials: Pressure in carotid arteries stretches vessel walls baroreceptors detect and send signals via Sinuses (Hering) nerves 9th cranial nerve (glossopharyngeal nerve) brainstem medulla Brainstem has CV control centers (groups of neurons that work together) that regulate the heart and blood vessels to cover all the needs of the CV system Cardiotropic region: neurons there are further divided into… Cardioaccelerator region Cardioinhibitory region Vasomotor center: has 2 subcenters Vasopressor region Vasodepressor region The baroreceptors function in a reflex arc Have all the components of a reflex arc: sensory receptors, sensory afferent verves, integrating centers (medulla), efferent motor nerves from brainstem that project to activators (a.k.a. effector organs) Table 15.4: Activators and Responses of CV Reflex Arcs…an example from the table SA node is an activator of a reflex arc. The SA node has both parasympathetic and sympathetic efferent motor neurons innervating it. If the sympathetic side is more active heart rate up; if the parasympathetic branch (i.e. thru the vagus nerve) is more active HR down. Other effectors or activators include the ventricular myocardium and the smooth muscle in large veins and arterioles. The other examples in this chart are similarly reflexes to changes in blood pressure. Fig 15.29: Baroreceptor mediated response to hemorrhage Hemorrhage: a sudden decrease in blood volume, defined as a 10% or greater loss of blood volume Causes of hemorrhage: accidents, laboratory manipulated, internal bleeding, etc. When giving blood a pint of blood (500mL), for a small person, it is possible that giving blood could activate the baroreceptor reflex since you’re taking more than 10% of that person’s blood volume. The figure shows a control period, then a drop in MAP baroreceptors detect the change leads to a change in several associated variables HR increases due to Sympathetic efferent neurons innervating the SA node becoming more active (Cardioaccelerating center is stimulated) Vagus parasympathetic nerves innervating the SA fire at a lower frequency (Cardiodecelerating cener is inhibited) The SV increases (“SV” really should be replaced by the label “strength of contractility” in the figure) Sympathetic nerves to myocardium increase activity strength of contractility increases SV increases more end diastolic volume of blood is ejected from heart Cardiac output (CO) increases due to increase of HR and SC Total peripheral resistance (TPR) increases: the freq of action potentials to vessel muscles increases vessels contract resistance increases. Increase of HR + SV + TPR MAP (mean arterial pressure) returns to just below normal Opposite effects occur if the blood volume increases Fig 15.30: Reallocation of blood flow to organs that are more vital during a crisis This figure shows the redistribution of CO to the brain and away from the gut during a crisis When MAP falls flow in the gut falls mostly due to the gut arterioles constricting resistance in gut rises blood flow in gut falls The volume of blood that originally went to the gut is taken and relocated to the brain since there is no change in resistance in the brain vessels the brain gets more blood Local Regulation of Blood Flow Regulation of arterial blood pressure is only one means by which blood pressure is maintained under changing conditions—vessel resistance can also change. Through local control of vessel resistance, the body can determine which parts of the body blood should be relocated Light headedness after giving blood due to various factors: standing up right after blood pools at feet due to gravity MAP falls and your head feels light… When MAP is regulated, blood flow and nutrient flow are also affected Fig 15.12: Control of Blood Flow at the Local Level Under all conditions there is a balance between the supply of blood flow to a tissue and that tissue’s demands for O2 and its metabolism—there is a flow-metabolism balance If tissue activity changes, the cells are not in their original baseline state anymore: more O2 is consumed, more CO2 an metabolites accumulate than is carried away by now inadequate blood flow Each tissue communicates to local blood vessels to tell it what amount of blood they need, and they do this independently of the nervous system Active Hyperemia: when there is inadequate blood flow due to increased tissue metabolism. Includes… Exercise hyperemia: for skeletal muscles during exercise Functional hyperemia: the gut in the absorptive state needs more blood to do digestion and absorption How does the vessel know to dilate so there is more blood flow to that area? Vessels sense low O2 and high CO2 Hypoxia (when there is inadequate O2) induces vasodilation. When tissues work and acquire an oxygen debt, they become hypoxic. Hypercarbia or hypercapnia (excess CO2) is a vasodilator. Excess CO2 accumulates in the area till the blood flow increases enough to carry it away. Some of the metabolites produced, when they accumulate in the interstitial fluid, are vasodilators: e.g. excess K+, NO, adenosine. These diffuse to vessel smooth muscle and act as vasodilators till the blood flow increases (takes seconds to minutes). Fig 15.13: Active v Reactive Hyperemia Active & reactive hyperemia both occur in all tissues of the body Note that the first box for the reactive hyperemia chart should say BLOOD FLOW DOWN (not an up arrow) Active hyperemia: an increase in tissue activity makes baseline blood flow there inadequate Reactive Hyperemia: a period of increased blood flow following a period of reduced blood flow, the latter caused by some occlusive intervention (e.g. a hand on the forehead compresses the vessels on the forehead, a clamp on a vessel during surgery, etc.) Compression of vessels metabolite buildup vasodilation occlusive intervention is removed blood pressure forces more blood than necessary for the tissue through the dilated vessels Coronary Blood Flow During Reactive Hyperemia A: Ischemia: lack of blood flow for a time, O2 debt occurs here B: Reactive hyperemia (reflow): excess blood flow into the area lasts about as long as the period of occlusion. So, if ischemia lasted 30 sec, it takes about 30 sec to get the flow back to the baseline 25 mL/min C: Myogenic response: metabolites/ vasodilators are washed away by the reflow vessels will overcontract below the baseline for a short time In thoracic surgery, the heart is isochemic for 45 min and over. The toxins that build up in the isochemic phase get carried to the rest of the heart during the reflow state. Thus, more people die during the reflow state than when the heart is arrested in isochemia. Acetaminophen has CV effects Tuesday Today Lecturer: Norell Spiler Spiler@biology.Rutgers.edu Text: pp 578-585; 601-604; 596-597 (discovery box) April 11th, B137, : scantron pickup for tests I and II RENAL MORPHOLOGY: Topic Outline Kidney and Nephron Renal vasculature and blood supply Micturition and the micturition reflex Kidney failure and dialysis The Urinary System 2 kidneys: form urine (from filtering blood plasma) 2 ureters: transport urine from kidneys to bladder 1 urinary bladder: stores urine 1 urethra: excretes urine from bladder to outside of body Functions of the urinary system Removal of metabolic waste and foreign substances (e.g. urea, uric acid, drugs…) Regulation of the plasma and blood volume (juxtaglomerular apparatus does this) Regulation of the plasma osmolarity ([solutes] in plasma) Regulation of plasma [H+] (long term pH): concerns H+ and bicarbonate The Kidney and Nephron A nephron is the functional unit of the kidney: smallest element capable of performing filtration/ functions Recall sacromere was the functional unit of skeletal muscle There are about 1 million nephrons/ kidney Fig 19.1: Location of kidney Bilateral: 1 kidney on each side of the body Retroperitoneal: behind the abdominal sac Adrenal glands have a superenal (above the kidneys) location Fig 19.2a Aorta renal artery (red oxygenated blood) branches into arterioles renal vein (blue deoxygenated blood) inferior vena cava R atrium Renal cortex: the outer lighter pink layer of the kidney Renal medulla: the inner layer, contains multiple triangular renal pyramids Renal cortex and renal medulla are where urine is formed since these are where the nephrons are located Nephrons drain to common collecting ducts minor calyx major calyx renal pelvis ureter bladder Fig 19.2b: Renal pyramid Fig 19.3 Filtrate: like blood plasma but without the proteins Urine: the remains of the filtrate once it passes through the nephron tubular regions and enters the collecting duct Renal artery branch afferent arteriole glomerulus (glomerular capillaries) large proteins& cells go into efferent arteriole since they can’t cross the membrane of the glomerular capillaries while plasma filters across glomerular capillaries into Bowman’s capsule and enter the renal tubule Renal corpuscle: glomerulus + Bowman’s capsule around it Plasma out of capillaries Bowman’s capsule (opening to renal tubules) becomes filtrate at this point proximal convoluted tubule proximal straight tubule (both the convoluted and straight tubules are referred to as the proximal tubues) descending limb of the Loop of Henle thin ascending limb of the Loop of Henle thick ascending limb of the Loop of Henle distal convoluted tubule collecting duct: filtrate becomes urine once it enters the collecting duct A collecting duct is shared by several nephrons Filtrate is modified in the tubules Secretion from capillaries into tubules Reabsorption from tubules into capillaries Secretion and reabsorption of different molecules/ions are adjusted to the body’s present needs Fig 19.7: The Renal Corpuscle/ Glomerulus Plasma Filtration Renal Functions Filtration: through the glomerulus into Bowman’s capsule Reabsorption: from tubules into capillaries Secretion: from capillaries into tubules Excretion: out collecting duct and eventually the body Fig 19.3: Nephron: plasma filtrate urine (a review of structures) Renal corpuscle (renal glomerulus) Bowman’s capsule: inflow end of renal tubules Glomerulus: tuft of capillaries Site of filtration: movement from capillaries to tubules at the renal corpuscle A.k.a Glomerular Filtration Proximal tubule Proximal convoluted tubule Proximal straight tubule Loop of Henle Descending limb Thin ascending limb Thick ascending limb Distal Convoluted Tubule Connecting Tube Collecting Duct Fig 19.4: 2 kinds of nephrons Cortical nephrons: 80% of all nephrons Located more near the renal cortex Juxtamedullary nephrons: 20% of all nephrons Special function of maintaining the osmotic gradient in renal medulla Loop of Henle of juxtamedullary nephrons are located almost entirely in the renal medulla Both have the same plasma filtration/ urine forming function though they have different locations Fig 19.5: The Juxtamedullary Apparatus (JGA) Structure: JGA is where the distal tubule comes up between the afferent and efferent arterioles Granular cells: modified cells of the afferent arteriole, contain secretory granules with renin Macula densa cells: modified cells of the distal tubule JGA regulates plasma and blood volume Renal Vasculature and Blood Supply Fig 19.6a Kidneys are tiny Combined weight of kidneys = 115-170g (<1% the avg adult body weight) Yet, kidneys get 20% of the combined cardiac output of the body. This is because the kidney gets blood to filter Renal artery… interlobular arteries afferent arteriole glomerulus efferent arteriole peritubular capillaries/ vasa recta interlobular veins … renal vein inferior vena cava Fig 19.6b Blood that exits through efferent arteriole goes into… Peritubular capillaries: capillaries located around the proximal and distal convoluted tubules Vasa recta: capillaries located around the loop of Henle 2 capillary beds in sequence Glomerular capillary bed efferent arteriole peritubular capillary bed Fig 19.21: 4 modifications occur in the renal tubules: filtration, reabsorption, secretion, and excretion Review: plasma urine In each nephron: plasma is filtered from glomerular capillaries proximal convoluted tubule loop of Henle distal convoluted tubule collecting duct Filtrate is modified in renal tubules (reabsorption/ secretion) Fluid from all nephron collecting ducts drain ultimately into renal pelvis and then to the ureter Ureter drains into bladder (urine storage until excretion) Micturition and the Micturition Reflex Micturition = urination Fig 19.21: Urinary bladder Ureters bladder urethra Detrusor muscle: contracts pressure on bladder urinate; involuntary and voluntary control Internal urethral sphincter: involuntary control External urethral sphincter: voluntary control The detrusor muscle contracts AND both sphincters relax for urine to move from bladder through urethra Fig 19.22 As the volume of fluid in bladder increases wall of bladder expandsstretch receptors signals to spinal cord sympathetic NS down, parasympathetic NS up, somatic motor neuron activity down detrusor muscle contracts and both sphincters relax We would increase somatic motor neuron activity and decrease parasympathetic activity to voluntarily control urination Kidney Failure and Dialysis End stage renal disease Glomerular filtration rate is <5% of normal rate Kidney transplant is optimum Dialysis: treatment until a kidney becomes available A necessary form of treatment in patients with end stage renal disease. Often, kidney dialysis is administered in a fixed schedule of ~3 times per week A method of artificially cleaning the blood by running blood counter-currently to dialysis fluid with a selectively permeable membrane between them Hemodialysis Artificial kidney Wastes and excess water pass from the blood through the membrane into the dialysis fluid, which is ten discarded. The cleaned blood is returned to your bloodstream 4-5hrs, 3x per week Catheter takes blood from artery to a dialysis machine As blood moves through the machine, exchange occurs between blood and dialysis fluid through a semipermeable membrane allowing all molecules except blood cells and proteins to diffuse down their electrochemical gradients Dialysate composition can be varied to favor movement of molecules in a particular direction E.g. edema (excess fluid accumulation) dialysate made of a higher solute concentration to favor the movement of water from blood to dialysate Tuesday This is the 1st day of notes for the final. RENAL PHYSIOLOGY I Today: Lecturer: Tyler Rork email@example.com Room: B 219 Nelson Labs Read in text: p585-590; 624-625 Renal Morphology Nephron: basic functional unit of the kidney, filters plasma, 1 million nephrons/ kidney Medulla (inner layer) and cortex (outer layer) Bowman’s capsule: beginning of renal tubules Juxtaglomerular apparatus (JGA): where distal tubules pass b/n efferent and afferent arterioles Peritubular capillaries and vasa recta: blood vessels around the nephron Basic Renal Functions Filtration: flow of protein and cell-free plasma (filtrate) from the glomerular capillaries into Bowman’s capsule Reabsorption: selective transport of molecules from the lumen of the renal tubules to the interstitial fluid outside tubules Secretion: selective transport of molecules from the interstitial fluid outside tubules to the lumen of the renal tubules Excretion: elimination of materials from the body in the form of urine Fig 19.7 At the glomerulus, plasma is filtered into Bowman’s capsule Reabsorption and secretion occur between peritubular capillaries and the renal tubules Excretion: renal tubules collecting ducts minor calyx major calyx renal pelvis ureter bladder urethra elimination from body Fig 19.8 Direction of blood flow: afferent arteriole glomerulus efferent arteriole Podocytes: specialized epithelial cells on the glomerular capillaries Have long foot processes that wrap around the capillary Bowman’s space: space between the glomerulus and the walls of Bowman’s capsule Glomerular membrane: The glomerular filtration barrier has 3 parts Capillary endothelium: may have large gaps (fenestrations) for water and ions to pass Basement membrane: shared by podocytes and capillary endothelial cells Podocyte foot processes Only very small substances (Na, Cl, glucose, water) can pass through all 3 barriers Excluded substances: large proteins, red& white blood cells, platelets. Excluded substances are not found in Bowman’s space Glomerular filtration based on Starling forces: 4 pressures involved Hydrostatic Pressures Glomerular capillary hydrostatic pressure (PGC ) = ~60mmHg Is the blood pressure in the glomerular capillaries Favors filtration since there is positive blood pressure in the glomerulus that tends to push filtrate out of capillaries into Bowman’s space Bowman’s capsule hydrostatic pressure (PBC ) = ~15 mmHg Comes from Bowman’s capsule fluid that just got filtered out Opposes filtration since this pressure tends to push filtrate back into glomerulus Oncotic Pressures Based on osmosis: nonpermeable solutes (i.e. proteins) on one side of a semipermable membrane will draw pure water to itself to balance the osmotic gradient Glomerular capillary oncotic pressure (πGC ) = ~ 29 mmHg Is the oncotic pressure exerted by plasma proteins in glomerular capillaries Opposes filtration since proteins draw water into the capillaries Bowman’s capsule oncotic pressure (πBC ) = ~0mmHg No proteins in Bowman’s space since they can’t cross the glomerular membrane no proteins to create oncotic pressure in Bowman’s space Favors filtration since it at least doesn’t oppose filtration Fig 19.9a: Glomerular Filtration Pressures Forces that favor filtration – forces that oppose filtration = (PGC + πBC ) – (PBC + πGC ) = 60 + 0 – 15 – 29 = 16mmHg Thus, since there is a net positive filtration pressure, there is net filtration Glomerular Filtration Rate (GFR) Is the volume of plasma filtered per unit time (ml/min) Normal GFR = 125 ml/min x 60 min/hr x 24hrs/day = 180 L/day of fluid is filtered Since total plasma volume = 3L, the kidneys filter total body plasma 60 times a day or once every 24 min This large filtration rate allows the kidneys to regulate blood plasma in the body well Fig 19.9b: Filtration Fraction The fraction of renal plasma volume that is filtered Plasma flow rate = 625 ml/min while GFR = 125 ml/min Thus, filtration fraction = 125/625 = 20% Filtration fraction is a measure of the healthiness of kidney function Filtered Load: the quantity of a particular solute that is filtered per unit time (mg/min) Filtered load = GFR x plasma concentration of X X = any given solute E.g. plasma [glucose] = 1 mg/mL If GFR = 125 ml/min, filtered load = 125 ml/min x 1mg/mL = 125 mg glucose/min filtered GFR Regulation Arterial pressure directly affects glomerular capillary pressure, which affects GFR Increase in blood pressure in one vessel increases the blood pressure in vessels downstream from it Since renal vessels are downstream from the arterial system, an increase in Mean Arterial Pressure (MAP)increases PGC increases GFR Large changes in GFR interfere with kidneys’ ability to regulate volume and composition of plasma: need narrow limits for GFR GFR is maintained at a relatively constant level by intrinsic and extrinsic mechanisms over a wide range of conditions Fig 19.10 For MAPs from 80-120 mmHg, the GFR remains constant from internal and extrinsic mechanisms. 3 Intrinsic Mechanisms Myogenic mechanism Based on pressure flow autoregulation principle (that occurs in all arterioles of the body) Smooth muscle of the afferent arteriole are sensitive to stretch of vessel walls As afferent arteriolar pressure rises, the walls of the arteriole stretch, causing smooth muscle contraction and constriction of the arteriole Thus, the pressure in downstream vessels (i.e. glomerular capillaries) decreases, counteracting the initial rise in pressure. Note: pressure will rises only in the area of constriction, but pressures will fall in vessels downstream from the area of constriction The opposite is true of decreased pressures: less blood pressure less vessel stretch afferent arteriole contracts less blood flow increases pressure in glomerular capillaries increases GFR up Fig 19.11a: follow the steps Note: there will be a transient increase in GFR before the myogenic response takes effect When GFR is too high, the kidney’s efficiency decreases since its cell transporters are already saturated Tubuloglomerular feedback Smooth muscle of afferent arteriole is also sensitive to chemical agents Agents are secreted by the macula densa of the distal tubule (part of JGA) Fig 19.5 Macula densa close to the cells of the afferent tubule that it affects Increase in GFR increase in flow of ultrafiltrate ( filtrate with high solute concentrations) in the distal tubule past the macula densa Macula densa is sensitive to stretch, and releases paracrine factors in response These factors stimulate smooth muscle contraction in the afferent arteriole decrease GFR The opposite true for a decrease in GFR Lack of stretch in macula densa macula densa secretes lower levels of paracrine agents less contraction in afferent arteriole GFR increases These regulatory mechanisms occur continuously Mesangial cell contraction (Fig 19.11b) Mesangial cells are modified smooth muscle cells around glomerular capillaries Increase of pressure in glomerular capillaries stretch in mesangial cells In response to stretch, these cells contract Decreases surface area of capillaries available for filtration, thus decreasing GFR This action also constricts the glomerular capillaries somewhat, but mostly they decrease surface area Renin-angiotensin-aldosterone system/ axis (RAAS) Most important regulatory system for the kidney This is an endocrine-like regulatory system for regulation of plasma volume and MAP Serves to decrease urine formation and thus preserve plasma volume while increasing Mean Arterial Pressure Fig 19.5 Recall there are granular cells in the wall of the afferent arteriole These granular cells are responsible for the secretion of renin, a proteolytic enzyme (NOT a hormone) Macula densa cells (of the distal tubule) have osmoreceptors that can detect changes in both Na and Cl concentrations of the tubular fluid besides being sensitive to stretch Crosstalk between granular cells and macula densa facilitates release of renin in response to decreased [Na] and [Cl] So, renin release is stimulated by chemical signals from the macula densa decreased afferent arteriolar pressure (granular cells are directly sensitive to the degree of stretch in afferent arteriole Decreased stretch in the afferent arteriole causes an increase in renin secretion from granular cells Renin release is also stimulated by increased sympathetic activity: there is direct sympathetic innervation to granular cells Fig 20.17: The release of renin When MAP decreases, renin secretion increases since the purpose of renin is to lead to an increase in MAP Fig 20.15: ACE = angiotension converting enzyme Located in capillary endothelial cells, mostly in the pulmonary capillaries Angiotensin II = one of the most powerful vasoconstrictors that the body produces Renin cleaves angiotensinogen angiotensin I ACE acts on angiotensin I angiotensin II Angiotensin causes vasoconstriction MAP up Angiotensin II also acts on the adrenal cortex to secrete aldosterone (a steroid hormone) Aldosterone is released form the adrenal cortex in response to angiotensin II Aldosterone facilitates the reabsorption of Na in the late distal tubule and collecting duct from the renal tubule into the blood Water follows Na down its concentration gradient So, when you increase the osmolarity of interstitial fluid, more water will flow from the renal tubules to the interstitial fluid to the blood Hence, aldosterone facilitates the reabsorption of both Na and water preserve plasma volume Fig 20.16: How angiotensin II increases MAP (skip ADH for now) Thus, RAAS serves to preserve plasma volume and increase MAP This is important in pathophysiological situations such as hemorrhage (Fig 20.23) Fig 20.15: Angiotensin II stimulates reabsorption of water AND vasoconstriction For people with hypertension, use ACE inhibitor drugs, which suppress ACE. If there is less ACE less angiotensin I less angiotensin II less vasoconstriction AND no active reabsorption of Na and water from the distal tubule and collecting ducts MAP down Hemorrhage: excessive bleeding Less blood MAP down since less blood volume When MAP decreases GFR decreases flow of fluid past the macula densa decreases Macula densa senses less Na and Cl tells granular cells to secrete renin Also, the increase in sympathetic activity during hemorrhage stimulates granular cells to secrete renin Renin triggers RAAS increases MAP, preserves plasma volume, and decreases urine formation Thursday RENAL PHYSIOLOGY II Today Lecturer: Tyler Rork firstname.lastname@example.org Room: B 219 Nelson Labs Read in text: pp 590-595, 597-601, 617-623 Test questions come from LECTURES ONLY Basic Renal Principles Review Filtration, reabsorption, secretion, excretion Clearance: the rate at which a substance is excreted Table 19.1 Note that reabsorption rate almost equals the filtration rate, i.e. reabsorption rates are very high. Reabsorption is thus the major process in the renal tubules REABSORPTION Fig 19.13: For reabsorption to occur, the substance must pass through 2 significant barriers Must cross epithelial cells of the renal tubules Must cross capillary endothelium of the peritubular capillaries Tubular epithelial cells have 2 barriers on either side of the cell Apical membrane: faces tubule lumen Basolateral membrane: faces peritubular capillaries Renal tubule epithelial cells have specialized tight junctions no solutes generally pass between cells in large quantities Passive v Active Reabsorption Fig 19.14 Passive reabsorption: occurs via diffusion of a solute down its concentration gradient; requires no energy Active reabsorption: occurs via ATP-mediated pathways on either the apical or basolateral membranes Example from the figure: Y crosses the apical membrane into the cell by passive facilitated diffusion since there is not a great concentration gradient between the lumenal and cellular [Y]. Y crosses the basolateral membrane by active transport since [Y] is greater in the interstitial fluid than in the cell The reabsorption of water is passive because it follows the osmotic gradient created by the active reabsorption of solutes Reabsorption example: glucose Glucose is freely filtered at the glomerulus Reabsorption of glucose is by secondary active transport via a sodium cotransporter across the apical membrane followed by facilitated diffusion across the basolateral membrane Under normal conditions no glucose is excreted in urine since all tubular glucose is reabsorbed Fig 19.15 Secondary active transport doesn’t directly require ATP to transport substances against their concentration gradients The Na-glucose symporter (a cotransporter) brings both Na and glucose into the cell Na is going down its concentration gradient and glucose goes along for the ride Yet, it does require energy to set up the Na gradient that drives the Na-glucose symporter: the Na-K ATP-ase on the basolateral membrane uses ATP to set up the Na gradient Glucose then does facilitated diffusion out of the basolateral membrane Tubular reabsorption of glucose For all solutes actively reabsorbed, there is a transport maximum (Tm ) Tm occurs due to carrier protein saturation: when [solute] is high enough, all carrier proteins are occupied and higher levels of reabsorption are not possible Solute transport will level off at Tm and any excess solute is excreted So, if all the Na-glucose symports are taken up, excess glucose in the filtrate is excreted Fig 19.16 When you increase the plasma [glucose]… Glucose filtration increases linearly: since glucose is freely filterable, the more glucose there is, the more is filtered Tm of glucose = ~300mg/dL, thus reabsorption levels of glucose level off here As [glucose] continues to rise beyond the Tm , the excretion of glucose rises Glucose transport in diabetes At normal plasma concentrations, all glucose is reabsorbed At concentrations higher than 300mg/dL, glucose exceeds its Tm , thus glucose is excreted in the urine People with diabetes can’t take up blood glucose into cells [glucose] in plasma increases [glucose] in filtrate increases carrier protein saturation during reabsorption increasing levels of glucose is excreted Glucose in the urine is a sign of diabetes Diabetics have kidney failure both because of the higher levels of glucose in the filtrate and because they have higher end MAP’s Clearance The rate at which a substance is excreted A virtual measure of the volume of plasma from which a substance is completely removed or cleared per unit time (ml/min) GFR is also measured in ml/min Clearance = excretion rate of solute X / plasma concentration of solute X Since it is hard to measure the excretion rate, use this formula (MUST KNOW!!!): Clearance = (Ux x V) / Px Ux = urine concentration of X V = volume of urine flow per minute (ml/min) Px = plasma concentration of X Should have Ux and Px in the same units so that they cancel out, leaving the units of ml/min from V Inulin clearance Inulin: A polysaccharide not produced by the body Freely filterable at the glomerulus (like glucose) Is neither secreted nor reabsorbed Injected into the bloodstream in known amounts to estimate GFR The amt of inulin in urine = the amt filtered Thus, inulin is entirely cleared from the volume of plasma filtered; that is, the clearance of inulin = GFR Inulin’s excretion rate = the filtered load, which by definition = GFR x plasma concentration Inulin clearance example Plasma concentration of inulin = 4 mmol/ L Urine flow rate = 2 ml/min Urinary [inulin] = 250 mmol/L Cinulin = (Uinulin x V) / Pinulin Cinulin = (250 mmol/L) x (2 ml/min) / (4mmol/L) Cinulin = 125 ml/min = GFR The mathematics of inulin clearance Excretion rate = filtered load = GFR x Pinulin Thus GFR = excretion rate / plasma concentration, which by definition is clearance So, GFR = Cinulin = (Uinulin x V) / Pinulin Reabsorption & Secretion and Clearance Clearance can be used to determine if there is net reabsorption or net secretion of a certain substance If the clearance of the substance is greater than the GFR, there was net secretion of the substance If the clearance of the substance is less than the GFR, there was net reabsorption of the substance Fig 19.20 Clearance of glucose = 0 mL/min since it is completely reabsorbed In formula, Cglucose = (Uglucose x V) / Pglucose , since Uglucose = 0, Cglucose also = 0 Renal Processing of Na and water Water follows Na down its concentration gradient passively Na is the solute primarily responsible for producing the osmotic gradient that dries water reabsorption; Na is the most prevalent solute in the filtrate Fig 20.4 Apical membrane: Na-glucose symport: secondary active transport into the cell Basolateral membrane: Na/K pump: primary active transport into the interstitial fluid When you transport Na create an osmotic gradient water follows Na out of the renal tubules by osmosis The Osmotic Gradient Created by the differing water permeabilities in the renal tubules The descending limb of the loop of Henle is permeable to water and does not contain specific ion transporters The thick ascending limb of the loop of Henle is impermeable to water and contains ion-specific transporters (for K, Na, Cl) This difference in transport establishes an osmotic gradient in the medullary interstitial fluid Osmolarity increases as you go deeper into the medulla This process involves the vasa recta, which is associated with juxtamedullary nephrons juxtamedullary nephrons establish the osmotic gradient Fig 20.6 Note large difference in osmolarity between the 300 mOsm at the top of the loop of Henle and the 1400 mOsm at the hairpin turn of the loop of Henle Water reabsorption in the late distal tubule and colleting duct Late distal tubule and collecting duct= structures deep in the medulla, where there is an environment of high osmolarity that tends to draw water out of the renal tubules (i.e. reabsorb water) The permeability of water of both the late distal tubule and collecting duct can be varied This variation is adjusted according to the hydration status of the body If the body is hydrated, you decrease the permeability to water of the late distal tubule and collecting duct so water can’t be reabsorbed even in the high osmotic environment more water stays in the urine and is excreted High permeability favors the preservation of plasma water, low permeability favors the excretion of water Fig 20.9a: Excess hydration A state of overhydration (excess water in plasma) late distal tubule and collecting duct = impermeable to water hence urine with low osmolarity and high volume is produced Fig 20.9b: Dehydration A state of dehydration (deficiency of water in plasma) late distal tubule and collecting duct are permeable to water urine with high osmolarity and low volume is produced ADH Antidiuretic hormone (ADH, vasopressin) regulates the permeability of the late distal tubule and collecting duct: its secretion makes them more permeable to water increases water reabsorption ADH secreted out of the posterior pituitary by cells originating in the hypothalamus An increase in osmolarity of extracellular fluid is the signal for ADH release Osmoreceptors in the hypothatlamus monitor the osmolarity of extracellular fluids Also, decreased baroreceptor activity signals for an increase in ADH secretion (low volume and/or pressure of plasma indicates not enough water) ADH secretion water reabsorption up raise plasma volume and pressure Fig 20.16 Angiotensin II stimulates aldosterone secretion Na reabsorption up extracellular fluid osmolarity increases water follows water reabsorption up Angiotensin II also stimulates ADH secretion permeability of late distal tubule and collecting duct to water increases water reabsorption up ADH signals for the synthesis and insertion of aquaporin 2, a protein that acts as a pore for water Aquaporin 2 Stored in the membrane of cytoplasmic vesicles of principal cells (epithelial cells in the distal tubule and collecting duct) Aquaporins are pores that allow the diffusion of water across the apical membrane of principal cells Water then diffuses out of the basolateral membrane by another aquaporin (aquaporin 3), which is always present in the membrane, into peritubular capillaries (in contrast, aquaporin 2 needs ADH to signal for its synthesis and insertion into the apical membrane) Fig 20.10 ADH activates an ADH receptor on principal cells signal for synthesis and insertion of aquaporin 2 into apical membrane Alcohol inhibits AHD secretion no insertion of aquaporin 2 no reabsorption of water dehydration and excessive urination Tuesday Today Lecturer: Dr. Merrill is back Pickup scantrons 4/18 from - at Nelson Labs B137 Final: 70 questions, 45 questions from lectures after Exam II (about 5 questions per lecture), 13-15 questions from Dr. Page, 10-12 questions from Dr. Merrill for before Exam II The Respiratory System: Outline for Today Ventilation of Lungs Determinants of Airflow Pathophysiology of the Lungs Fig 17.8 Ventilation: a mechanical mechanism by which the lungs inflate and deflate Analogy: lungs are like bellows expanding and contracting with air Expansion due to the contraction of thoracic cavity that lungs are in Note pathway of air: down trachea bronchi bronchioles alveoli Important structures Visceral pleuri: epithelial cells on the surface of the lung Parietal pleuri: epithelial cells on the surface of the thoracic cavity (chest wall) These are the 2 membranes that line the intrapleural space between the lungs and the thoracic cavity The intrapleural space is only a potential space: it is not a definable space since the 2 membranes are always in contact, adhered together by a film of aqueous solution that coats the potential space between the 2 membranes. (This aqueous layer comes from the fact that the pleural cells of the membrane do metabolism that produces water, like other cells.) Each lung has its own separate pleural membranes Fig 17.11a Diaphragm Mostly peripheral skeletal muscle, some smooth muscle at its center During inspiration, it contracts, flattens, and descends It is an inspiratory muscle under basal resting conditions, but it can become expiratory during active conditions (i.e. actively expels air) Orientation of ribs: Ribs connect to sternum on the anterior side at a lower orientation Ribs connect to vertebrae on the posterior side at a higher orientation Striated intercostal muscles attach to ribs External/ exterior intercostals: located from the cartilage part of the ribs outwards, inspiratory muscles, medio-lateral orientation Internal/ interior intercostals: located from the cartilage part of the ribs inwards, expiratory muscles, lateral-medio orientation Fig 17.11b: The Respiratory Cycle Due to rib orientation and the way the muscles are attached to them, he way the intercostals contract and relax, and the way the diaphragm changes shape, inhalation causes the thoracic cavity to increase in volume in 3 dimensions: Diaphragm contracts and descends superior-inferior dimension increases Intercostal muscles contract medio-lateral dimension increases Ribs change position anterior-posterior dimension increases Volume is related to pressure: PV relationship drives ventilation Toolbox p 531: Boyle’s Law and the Ideal Gas Law As volume (V) decreases, pressure (P) increases When V decreases, there is less space to accommodate the same # of gas molecules increasing probability that these gas molecules will bump into the sides of a smaller container P increase Boyle’s law: P1 V1 = P2 V2 Ideal gas law: PV = nRT where n = mol of gas, R= universal gas constant, T= absolute temp in K Since the thoracic cavity = a closed system, we can disregard all the variables (since they’re fairly constant) except P and V Fig 17.10: Inspiratory and Expiratory Phases Volume-pressure (VP) laws apply whenever there is airflow There is no airflow at the end of expiration and inspiration Thoracic space changes cyclically according to neurogenic mechanisms A change in V a change in P creates pressure gradients that generate airflow Top graph shows intra-alveolar pressure and bottom graph shows TIDAL volume (change axis label) The following principles apply to both a single alveoli or the whole lung Some important pressures Palv = intra-alveolar pressure Patm = PB = atmospheric or barometric pressure = 760 mmHg at sea level but decreases with elevation ’s law: the total pressure= the sum of partial pressures of the different gases in the mixture So, Patm = PN2 + PO2 + Pinert gases Pressures in the lung are described relative to Patm. We set Patm = 0 as a relative pressure (a reference pressure) The pressure differences between the lung and the atmosphere drives airflow At the end of respiration, Palv = 0 = Patm Inspiration When the alveoli expand, V up and P down Palv = -1 mmHg Though there is no such thing as negative pressures, the negative sign here indicates that pressure in the alveoli is lower than the atmospheric pressure by 1 mmHg Now that there is a pressure gradient, air will flow from the atmosphere into the alveoli down its pressure gradient As the alveoli fills with more air molecules Palv increases back to 0 no pressure gradient airflow stops Expiration = opposite thing happens As alveolar volume decreases, Palv increases to 1mmHg pressure gradient in the opposite direction air flows from alveoli to atmosphere till Palv = 0 again Fig 17.13 Again, Palv = intra-alveolar or pulmonary pressure Patm = PB = atmospheric or barometric pressure Pip = intra-pleural pressure The 2 pressure gradients that drive airflow Patm - Palv = pressure gradient for ventilation Palv – Pip = transpulmonary pressure across lung walls The saline solution in the intrapleural space allows the membranes to slide by each other without coming apart, and so makes the transpulmonary pressure possible Transpulmonary pressure During inspiration, Ptrans = 4-6 mmHg During expiration, Ptrans = 6-4 mmHg Changes in the Ptrans inflates or deflates the alveoli, driving airflow Fig 17.9 Intrapleural pressure = always negative/ subatmospheric in physiological conditions Pnuemothorax: If there is a hole in the thoracic membrane contact between parietal and visceral membranes is disrupted intrapleural pressure equilibriates with Patm Pip = 0 (not negative anymore) lung collapses no ventilation of that lung So, you would seal the pneumothorax asap Fig 17.5 In the alveoli: Type 1 alveolar cell: epithelial cells that make up alveolar walls Type 2 alveolar cell: epithelial cells that produce surfactant Surfactant = a lipid, detergent-like molecule that reduces the surface tension between air and moisture on alveolar walls Alveolar macrophages Respiratory membrane: between alveoli and capillaries Made of alveolar epithelium, basement membrane, capillary endothelium Since its only about 0.2 micrometers thick, it doesn’t hinder gas exchange between alveoli and capillaries Toolbox p 533: ’s Law and Pulmonary Surfactant ’s law: P = 2T/r P= distending pressure: the pressure needed to keep alveoli open T= tension= amt of attraction between air and liquid molecules in alveoli, tends to pull alveoli inwards r = radius of alveoli Ventilation to perfusion ratio (airflow to bloodflow ratio) is usually = 1, but if alveoli collapse, ventilation decreases & blood flow is wasted and this ratio becomes less than 1 In alveoli without surfactant, smaller alveoli need larger distending pressures to prevent it from collapsing this sets up a pressure gradient between smaller and large alveoli air flows from smaller to larger alveoli smaller alveoli collapse the ventilation to perfusion ratio becomes less than 1 Surfactant reduces the amt of pressure needed to keep alveoli open by inserting itself in the water molecules, thus cutting down the forces that attract air to water Diseases caused by problems with surfactant Fetal distress syndrome: Type 2 cells produce inadequate amts of surfactant alveoli collapse Clinical connections p 536: Chronic Obstructive Pulmonary Diseases (COPD) Chronic diseases: emphysema, TB, chronic bronchitis; asthma may be acute too 2 ways to impede airflow Obstruct airways: bronchiolar smooth muscle around bronchioles (the resistance vessels of the lungs, analogous to arterioles) goes into spasms (may constrict due to allergens) restriction of airflow Breakdown of walls of alveoli, terminal bronchioles and/or pulmonary capillaries due to exposure to toxins or other causes emphysema, chronic bronchitis End result is acute chronic respiratory failure due to inadequate ventilation-perfusion ratio hypercarbia (high CO2), hypoxia (low O2), death Fig 17.16: Tests for pulmonary function Spirometery 1 cylinder filled with water, 1 cylinder inside it, 1 cylinder inverted over the inner cylinder Inverted cylinder attached to a recorder Breath out into chamber formed by the cylinders water displaced inverted cylinder rises recorded on paper Fig 17.17 Graph shows time v volume Lung capacity: sum of 2 or more lung volumes Average tidal volume = 500mL/cycle Tidal volume x respiration rate (i.e. # respiratory cycles per minute) = Minute Ventilation = 5L Minute ventilation for the lungs is analogous to Cardiac Ouput for the heart, and both are 5L/min thus, airflow matches blood flow Maximum inspiratory volume = 3.5 L, after a forceful expiration Vital capacity: the maximum amt of air you can move, the volume you breath in after you forcefully exhale till only your residual volume (the 1.2L of air that always stays in the lungs) is left and then inhale as much as you can FEV1: forced expiratory volume in 1 sec: you should be able to forcefully expel 80% of your vital capacity in 1 second, otherwise there is a problem. The purpose of all these measurements for lung volumes and capacities is to quantify your ability to move air versus your age and gender Thursday 2 Ways to Obstruct Airflow: Obstructive v Restrictive Diseases Obstructive Diseases: Chronic Obstructive Pulmonary Diseases (COPD) Emphysema, acute asthma, chronic bronchitis Disease-related breakdown of airway walls, constriction of bronchioles, and/or excessive mucus and other stuff clogging airways Restrictive Diseases Defects in the parenchyma cells in the wall of the lung or cells of the chest wall Skeletal-motor diseases in which there are defects in how the patient can expand the lungs or chest wall Gas Exchange and O2 Transport Fig 17.18: Minute ventilation (Ve ) v Effective Minute Alveolar Ventilation (VA ) Ve = freq (respiratory rate) x tidal volume (Vt ) VA = freq x (Vt – Vd ), where Vd = dead space volume Minute alveolar ventilation is the physiologically important volume Note: there should also be a dot over Ve and VA to indicate these symbols represent measurements in units of time In the figure, the red squares = used air = deoxygenated air that stays in the alveoli. This old air is the about 150mL of residual air that resides in the nasal and oral cavities all the way down to the alveoli. Before old air gets out, fresh air comes in and mixes with the old air, which dilutes the fresh air. Also, during expiration, air getting breathed out pushes fresh air out, again limiting the amt of fresh air the lungs get. So, to find effective ventilation, we take the amt of air breathed in – the residual old air in the airways = Ve – Vd = 500 mL – 150mL = 350 mL Table 17.1 Shows the effect of changing respiratory volume and respiratory rate 1st row shows danger zone values: when Ve is impaired and the respiratory rate rises in response, there is a great reduction in minute alveolar ventilation Toolbox p546: Henry’s Law and Solubility of Gases Gases are soluble in liquid medium according to Temp Physical and chemical properties of gas and media Partial pressure of gas described Note: should memorize some of the important numbers in this lecture Looking at the top boxes in the figure Solubility of O2 when the partial pressure of O2 (PO2) is 100mmHg in alveolar air and the aqueous media is blood plasma = .15mmol dissolved O2 per L of plasma If PO2 doubled to 200mmHg, the solubility of O2 would also double to .3mmol O2/L plasma Looking at the bottom boxes At PCO2 = 100mmHg, the solubility of CO2 in plasma = 3mmol CO2/ L plasma Thus, CO2 is 20x more soluble in plasma than O2 If PCO2 is doubled to 200mmHg, CO2 solubility in plasma would also double to 6 mmol/L plasma Fig 18.2 Why is CO2 more soluble than O2? Physical-chemical properties Respiratory barrier between the alveolar epithelium and capillary endothelium is filled with fat, so since CO2 is more lipid soluble than O2, it can pass both the respiratory barrier and the phospholipid cell membranes much faster than O2 Fig 18.4: Should memorize this figure 2 ways to describe gas distribution in the body Partial pressure of gases Content of gases in solution In the figure, the histograms represent the partial pressures of O2 (PO2 ) and CO2 (PCO2 ) at different parts of the body. The partial pressure of a gas changes depending on the location in the body of the blood or alveolar air you are sampling PO2 in the ambient (atmospheric) air is much greater than PO2 in alveolar air, pulmonary veins, systemic arteries, or tissues there is a pressure gradient for O2 from the atmosphere to body cells, which drives the direction of O2 diffusion from the atmosphere to tissues Only freely dissolved gas molecules generate partial pressure. O2 bound to Hb, carbamino compounds, or other blood proteins can’t exert partial pressures because bound O2 molecules aren’t free to collide Why is PO2 in the atmosphere so much greater than PO2 in the alveoli (and subsequently, the rest of the body)? Dilution of fresh air by dead space air As O2 passes the respiratory membrane on the way from alveoli to the pulmonary capillaries, some O2 gets used by the cells of the respiratory membrane The velocity at which arteriolar blood flows past the alveoli is so fast that there is no equilibriation of O2 between the alveoli and capillaries. That is, there is not as much diffusion of O2 as if the velocity of the pulmonary bloodflow were slower. Partial pressures of CO2 Max PCO2 = 45mmHg in the tissues, and PCO2 is no higher in the rest of the body PCO2 is lower in the lungs Thus, there is a reverse gradient for CO2 from the tissues to the atmosphere that is opposite that for O2, driving the diffusion of CO2 from the body to the atmosphere Note: the only places for exchange for O2 and Co2 is at the capillaries of body tissues and the lungs. Thus, gas partial pressures don’t change along arteries or veins Table 18.1 pH of blood/tissues depends on PCO2 : as PCO2 increases, pH decreases Hypoxia: low O2 Figure 18.1: the Content and Concentration of Gases in the Blood: should memorize this figure More O2 is transported bound in the circulation than is freely dissolved 882mL O2 goes into the alveoli per minute, but most is exhaled back into the atmosphere Only 250mL O2 is transported from the alveoli into pulmonary capillaries per min Tissues also use 250 mL of O2 / min. There is a homeostatically controlled balance between O2 intake and O2 usage 750 mL of O2 per minute carried back to lungs + 250 mL O2 per minute uptake by lungs = 1000 mL O2 delivered to body per minute Note: physiological measurements of O2 consumption is usually in units of dL, or per 100 mL How much blood flow is needed in the lungs per minute for adequate gas exchange was calculated by Adolf Fick. The formula is called the Fick Principle for blood flow. Cells produce 200mL CO2 per minute while using 250mL O2 per minute. The ratio of CO2 production to O2 consumption = the RQ (respiratory quotient). RQ indicates the metabolic rate of the body For people who follow the usual western diet (60-70% carbohydrate, 30% fat, 10% protein), RQ = rate CO2 production/ rate O2 consumption = 200/250 = 0.8 People who have different diet compositions will have different rates of CO2 production and O2 consumption, and thus have different RQ’s High protein/ high fat diets: RQ is closer to 1 since more CO2 is produced Fig 18.2 As O2 diffuses into the pulmonary capillary plasma, it can go into different paths: O2 that remains dissolved in the plasma contributes to PO2 O2 that diffuses into red blood cells can Be dissolved in the cytosol and contribute to PO2 in the RBC Combine with reduced hemoglobin and form oxyhemoglobin (HbO2 ). More than 90% of O2 is carried in the blood as HbO2. Hemoglobin (Hb) is concentrated at the perimeter of the rbc, held there by the cytoskeleton of the rbc. This shortens the distance for O2 to diffuse from the alveoli into the rbc, compared to if Hb were concentrated in the center of the rbc. Why children submerged in frozen lake for up to 45 min survive with little irreversible brain damage? Hypothermia and the diving reflex. Fig 18.8: Hb-O2 dissociation curve The [Hb] in the blood varies by gender (premenopausal women). However, a normal [Hb] for all genders and ages is 12-16 grams /100mL of whole blood A single Hb molecule has 4 polypeptide chains (2 alpha, 2 beta) that can each hold 1 molecule O2 a fully saturated Hb holds 4 O2 molecules The % saturation of Hb indicates how much O2 there is in the blood. % saturation = # of fully saturated Hb (those with 4 O2 bound) / total # Hb The Hb-O2 dissociation curve shows that at physiological PO2 of 100mmHg, Hb is 98% saturated. Under physiological conditions, Hb is never fully saturated. The blood in the systemic veins is still 73% saturated with O2; tissues use only 25% or less of the O2 available from Hb. Thus, there is a large reserve of O2 that can be extracted from Hb if needed. Even at PO2 = 25mmHg (near death), the % saturation of Hb is still about 50%. P50 denotes that partial pressure at which there is 50% saturation, i.e., 25mmHg. The Hb-O2 dissociation curve can be shifted right or left in disease states. Right shift: generally good At any given PO2, there is less O2 bound to Hb than normal tissues have more access to O2 Causes: elevation, higher body temps, higher PCO2 in tissues, lower tissue pH Left shift: bad Causes: CO poisoning (CO replaces O2 in the blood since it has a greater affinity for Hb than O2) Fig 18.5 X axis: length of capillary, also reflects time spent in exchange By the time blood moves through 1/3rd of a pulmonary capillary, it has taken up its maximum level of O2. That is, there is a rapid intake of O2 that drives PO2 in the blood from 40mmHg to 100mmHg very quickly. PCO2 also drops from 46 to 40mmHg very quickly in a short distance; there is a rapid elimination of CO2. Thing to note here is the steep slopes of these graphs When someone goes diving, into space, or mountain climbing, Patm changes from the sea level 760mmHg very rapidly, which causes several potentially lethal disease states (by the time you reach 6000ft altitude): HAPE: high altitude pulmonary edema HACE: high altitude cerebral edema HAMS: high altitude mountain sickness 26000ft and above is called the death zone, since many people die when they’re descending from the summit of mountains at these altitudes. In the graph, Patm = 253 torr and minute ventilation of O2 = 250ml/min The calculated changes in PO2 along the pulmonary capillaries for a climber at rest on the summit of . PO2 in mixed venous blood is 21mmHg and rises slowly along the capillary to reach only 28mmHg at the end. The large PO2 difference of 7 mmHg between alveolar gas and end capillary blood indicates a marked diffusion limitation of O2 transfer. Since less O2 diffuses into blood at high altitudes, people go into hypoxic states if they don’t have an additional supply of O2. People never recover from the neurological damage caused by high altitude hypoxia. Tuesday Gas Exchange and Control of Respiration Fig 18.8: The Hb-O2 dissociation curve Other names for the curve: O2 saturation curve, oxyhemoglobin curve Fig 18.11a: CO2 exchange and transport at the tissues 2 landmark reference points: the tissues and the lungs Tissues: O2 extracted, CO2 added to the blood Cell metabolism releases CO2 interstitial PCO2 (due to dissolved CO2) is greater than that in arteriolar blood CO2 is driven to diffuse into the capillaries Physiology of CO2 exchange and transport: CO2 can go into various paths Some CO2 dissolve into plasma and contribute to PCO2 Some CO2 dissolve into red blood cells’ intrastitial fluid and contribute to PCO2 there Deoxygenated Hb can bind CO2 Hb CO2 (carboxyhemoglobin, carbaminohemoglobin, or carbaminoprotein) Hb binds CO2 at sites different than the ones that it binds O2 at, so it can bind a different number of CO2’s than O2’s (i.e. it can bind more than 4 CO2’s). The fact that the solubility of CO2 is 25x greater than O2 is irrelevant on Hb’s binding affinity with either gas. Most CO2 combines with H2O and, catalyzed by carbonic anhydrase (enzyme), turns into carbonic acid, which then dissociates into H+ and HCO3– (bicarbonate) CO2 + H2O H2CO3 H+ + HCO3- This equilibrium is driven right by the continued diffusion of CO2 into the blood from cells Hb binds to the H+ produced to buffer blood pH Excess HCO3- excess negative charge in the cell antiportal mechanisms in the rbc membrane expel HCO3- in exchange for a smaller amt of Cl- ions through the process of bicarbonate chloride exchange controls the amt of bicarbonate/ negative charge in the cell Fig 18.10: What alters the exchange of gases at the tissues and lungs? pH, PCO2, and temperature Fig 18.10b: Effects of pH Purple line = baseline control conditions: pH 7.4, PCO2 < 46mmHg Effect of pH on O2 exchange Decreasing pH (neutral acidic) decreases Hb’s affinity for O2: curve shifts Right Increasing pH (neutral basic) increases Hb’s affinity for O2: curve shifts Left So, if PO2 = 30mmHg normally corresponds to % saturation = 60%, then under acidic conditions curve shifts R the same PO2 = 30mmHg will correspond to % saturation of only 40% This is fitting because active tissues have a lower pH due to acidic metabolic byproducts Hb has lower affinity for O2 in acidic conditions more O2 released for more active tissues So, R or L shift of Hb-O2 dissociation curve is based on pH of the area that the blood passes. You can also replace the variable pH with the variable PCO2 since PCO2 up [H+] up pH down curve shifts R PCO2 down [H+] down pH up curve shifts L Fig 18.10a: Effects of Temp Temp up Curve shifts R and is depressed Temp down curve shifts L and is elevated This is fitting because active tissues have elevated temps Hb has lower O2 affinity at higher temps release more O2 at heated active tissues where O2 is needed Fig 18.11b: CO2 exchange and transport at the alveoli and pulmonary capillaries Here, rbc’s release CO2 and pick up O2 Veins have elevated PCO2 ( 46mmHg) relative to alveolar air (40mmHg) and ambient air depressed PO2 (40mmHg) relative to alveolar air (100mmHg) and ambient air Hb releases H+ H+ combines with bicarbonate (which was in rbc or is transported back into rbc from the plasma) carbonic acid carbonic anhydrase converts carbonic acid back to CO2 and H2O Again: CO2 + H2O H2CO3 H+ + HCO3- Note: Carbonic anhydrase (CA) only helps this rxn occur faster; it is not necessary for the rxn to occur. Also, CA only catalyzes the interconversion between carbonic acid and CO2 and water; the dissociation of carbonic acid into H+ and bicarbonate occurs by itself and Carboxyhemoglobin unloads CO2 CO2 diffuses out of rbc deoxygenated Hb now picks up O2 Fig 18.9 At the pulmonary capillaries: increase in pH, decrease in PCO2, and decrease in temp curve shifts L at any given PO2 there is a greater % saturation of O2 Hb is in an ideal state to pick up O2: the Hb molecule changes structure to favor O2 uptake Fig 18.12 As PCO2 rises over a physiological range, the total amt of CO2 carried by the blood increases If PO2 decreases (occurs as the red cell leaves tissues) from 100 to 40 mmHg, there is an upward shift in this curve such that at any PCO2, blood has a greater capacity to carry CO2 So, you should know the relative PCO2 and PO2 at different locations in the body and know why Venous blood has a greater capacity to transport CO2 than arterial blood Arteriolar blood has a greater capacity to transport O2 than venous blood The effect of temp, pH, and PCO2 is different for O2 and CO2. Also, either gas will affect the binding of the other gas to Hb A pH drop in the muscles during exercise is usually restored by homeostatic mechanisms. However, muscle death can occur if the change in pH is too drastic or too prolonged Fig 18.13 Haldane effect: influence of PO2 on the exchange of CO2 Bohr effect: influence of PCO2 and/or H+ on the exchange of O2 Fig 18.15: Central/ neurogenic/ remote control of respiration The brainstem (midbrain, pons, medulla) contains respiratory control centers Def of “centers:” areas where there are masses of like-behaving neurons Pontine respiratory group: similar-behaving neurons that influence respiratory patterns Medulla has even more centers Dorsal respiratory group (DRG): bilateral orientation Ventral respiratory group (VRG) Studies that decerebrate animals (i.e. severing the brainstem from everything above it) find that such animals still have normal respiration and heartbeat patterns. This suggests that the brainstem has centers responsible for heartbeat and respiration; that is, control over heartbeat and respiration are below the level of the cerebral cortex. Fig 18.16 The freq of action potentials in inspiratory motor neurons, which connect to external intercostal muscles (the muscles of inspiration) show an upwards ramp/ slope. There is an increase in freq of these action potentials during inspiration, then a sudden stop of action potentials during expiration for 5-6sec, and then the cycle repeats. The rhythmic centrally-mediated cycle begins in the 2-3rd trimester of pregnancy. Though the fetus doesn’t really breath yet, the electrical rhythm generator for respiration has already developed Fig 18.14: Passive (Quiet) v Active Breathing This information is taken from the phrenic nerve, the primary motor nerve to the diaphragm The external intercostal muscles are for inspiration, the internal intercostal muscles are for expiration Passive breathing is so termed because the expiratory nerves/muscles are not active during normal, “passive” breathing. That is, during quiet breathing, only the inspiratory muscles are active. During active breathing, the nerves& muscles of inspiration and expiration are more active or become active. There is also a greater degree of change in lung volume. Fig 18.17 Note that higher level brain centers (cerebrum, cerebellum) also influence the medulla The DRG and the VRG generate breathing Central pattern generator: here, inspiratory and expiratory neurons in the medulla communicate with each other; they don’t only communicate with peripheral neurons Scientists speculate that inspiratory neurons are rhythmically terminated by activation of expiratory neurons Fig 18.18 Peripheral chemoreceptors: located outside the CNS Chemoreceptors in the carotid bodies (located at the carotid bifurcation, same as baroreceptors for blood pressure) send sensory afferent info to the respiratory control centers. Chemoreceptors here are the most sensitive and thus the most important Chemoreceptors in the aortic bodes are also sensory nerve endings that respond to changing chemical compositions of their environment, but are less sensitive and thus less important. All peripheral chemorepctors respond to changes in PCO2, PO2, and pH. A decrease in PO2, a decrease in pH, and an increase in PCO2 are the 3 stimuli that activate these receptors. Fig 18.20 Central chemoreceptors: located in the CNS (specifically the brainstem) Central chemoreceptors are sensitive to pH only Capillary endothelium at the brain have tight junctions that don’t allow H+, bicarbonate, or other charged particles to enter the cerebrospinal fluid Thus, pH in the cerebrospinal fluid changes when CO2 diffuses in and forms carbonic acid, which dissociates into H+ and bicarbonate. Central chemoreceptors respond to the H+ produced here Fig 18.19 These graphs may represent minute ventilation or alveolar ventilation Fig 18.19 a: Hypoxia stimulates ventilation At high altitudes, PO2 decreases and respiratory rate increases by 5-6x A normal breathing rate of 12 cycles/min 75-100 cycles/min to make up for the decreased PO2 respiratory rate exceeds heart rate Fig 18.19b: Hypercarbia stimulates ventilation If you increase PCO2 2x, respiratory rate increases 5-6x A modest decrease in PO2 and a modest increase in PCO2 supraadditive effect in increased ventilation (an effect greater than the sum of the 2 individual effects) Hyperventilation: reduced partial pressure of CO2 in alveolar air (PCO2 <40mmHg) May or may not be accompanied by a change in PO2 or respiratory rate Hypoventilation: increased partial pressure of CO2 in alveolar air CO2, not O2, is the important physiologically regulated variable. All homeostatic mechanisms are geared to maintain arteriolar PCO2. Note that when PCO2 decreases, pH also increases, thus CO2 regulation relates to pH regulation. Thursday THE GI SYSTEM I Table 21.1: The GI System Organs and Functions Theme: Energy balance- the consumption and expenditure of calories Fig 21.1 Major functions of the GI tract: Digestion Absorption Secretion Motility: material can move in the oral to aboral (mouth to anus) direction or the reverse direction System structure: the main GI tract and its accessory organs (liver, pancreas, gallbladder, etc.) Note how the nutrients pass from the GI tract to blood to tissues Fig 21.3 Shows a general cross section of the gut that can apply from the esophagus to the rectum Serosal side: outside the gut wall Mucosal side: lumen of the gut Absorption occurs in the direction from the mucosal to the serosal side There is a separate enteric nervous system that controls contractions of smooth muscle in the gut wall and communicates with the autonomic NS to coordinate all functions of the GI tract Layers Mucosa Muscularis mucosa: specialized muscle that regulates the movements of the mucosa Submucosa Muscularis externa Circular muscle layer regulates the diameter of GI lumen Longitudinal muscle layer regulates the length of the gut Serosa There are also glands, blood vessels, and enterocytes (epithelial cells of the mucosal epithelium) associated with the GI tract Mucal glands: generalized secretory glands located at the underside of the tongue and throughout the GI system that secret mucus, which… Aids digestion Lubricates the oral cavity and gut wall so materials pass through easily Aids in vocalization and speech Fig 21.9 The salivary glands are paired and bilateral to each other. The major glands are the Right and Left… Parotid glands Sublingual glands Sumbmandibular, or submaxillary glands Control and Regulation of the Gut 3 Phases Affecting Secretory Behavior Cephalic: the sight, smell, or sound of food causes a change in secretory and GI muscle behavior (e.g. salivation at the smell of food) Gastric Intestinal The presence of food in the stomach and intestine influences the behavior of the GI tract Fig 21.8 Primary secretion: implies that there is a non-primary secretion later on. Indeed, the primary secretion is modified by the epithelial cells of the duct. Thus, we have not been able to collect true primary secretion, only the modified secretion. Note: secretions are generally aqueous solutions Bloodflow influences gland activity The volume of flow affects the composition of saliva. If the primary secretion has lots of NaOH, but the bloodflow past these cells is slow, then more NaOH will diffuse into the blood and less salts will be present in the saliva. Whether the body is in the absorptive or postabsorptive state influences secretory rates and the composition of the secretions Various physiological states alter secretory function Consciousness v unconsciousness Hypo v hyperthermia (temperature factor) The GI tract is controlled by reflexes from the time you swallow to defecation. The Swallowing Reflex The trachea is covered by the epiglottis, which reflexively closes when you swallow prevents choking and inspiration while swallowing. But since people do choke, this reflex is not foolproof Besides closing the epiglottis, this reflex also relaxes the upper esophageal sphincter long enough for food to pass, closes this sphincter, and then relaxes the lower esophageal sphincter for food to pass into the stomach. Fig 21.4 The stomach is a secretory organ, with secretions coming from the mucosa. The esophagus is secretory too, but its secretions are not as important. The main function of the esophagus is to transmit the bolus of food from mouth to stomach The mucosa of the stomach has gastric pits (gastric crypts) facing the lumen that number about 100 per mm2, making each pit 10 micrometers wide at the most. The cells of the gastric pits Parietal cells: secrete HCl, also called gastric or peptic acid Chief cells: secrete pepsinogen, a class of protein proteases that cleave peptide bonds in adjacent amino acids protein digestion starts in the stomach Neck cells: secrete an alkaline (basic) aqueous medium AND a mucilaginous material called mucin or mucus the mixture temporarily coats the gastric lining to prevent gastric acid from digesting the stomach Though this alkaline material does cancel out the HCl from the parietal cells somewhat, it doesn’t interfere with digestion since: the neck cells secrete their material quickly and it coats the stomach lining quickly, so the only time the HCl gets neutralized is when it touches the stomach lining. Ulcers are caused by overproduction of acid, underproduction of mucin, or abuses to the stomach. Esophageal cancer is on the rise. People who use their voice too much are especially at risk. Fig 21.5 The small intestine has 3 functionally distinct parts: the duodenum, the jejunum, and the ileum. The small intestine wall has the same generalized layers of the GI tract: the mucosa, submucosa, the muscularis externa, and externa; the figure should also have depicted the muscularis mucosa. The small intestine lumen is made of numerous crypts of Lieberkuhn. Each crypt has the means for absorbed nutrients to be carried away, each crypt containing… A lacteal: a branch of a major lymph duct that projects into the crypt An arterial blood supply The epithelial cells on the surface of the crypts have a microvilli brush border. The crypts and the brush borders on them increase the surface area of the small intestine to maximize the exposure of small intestine enzymes (released by the epithelial cells or bound to the brush border) to the contents of the small intestine Fig 21.10 The pancreas has endocrine and exocrine functions Endocrine: B cells produce insulin and A cells produce glucagon at the islets of Langerhans Exocrine glands in the pancreas have epithelial cells that secrete 2 major GI products Enzymes: lipases (digest lipids) and proteases (digest proteins) Bicarbonate to buffer acid chyme that enters the duodenum from the stomach The gallbladder: stores and concentrates bile salts and bile pigments from the liver. Bile salts help digest fat and bile pigments color the fecus The contents of the gallbladder and the pancreas enter the duodenum at the same site Get the USDA Dietary Guidelines for 2005 Fig 21.12 Salivary amylase (ptylin) is an enzyme that begins the hydrolysis of carbohydrates in the mouth before the acidity of the stomach inactivates it. The figure shows plant starch in the oral cavity being cleaved by ptylin into small disaccharides (maltose, sucrose, lactose) and limit dextrins. Limit dextrins are branch points of 3-9 sugar monomers. Salivary amylase can’t digest a these branch points or on terminal sugars; it only attacks the interior of a molecule. Enzymes on the microvilli of the duodenum then digest disaccharides into monosaccharides, since the gut only absorbs monomers. E.g. maltase digests maltose into 2 glucoses Fig 21.14 Shows the proteolytic activity of the gastric secretory cells Pepsinogen is stored in zymogen granules (inactive state) till their release HCl partially activates pepsinogen partially activated pepsinogen then fully activates pepsiongen into pepsin pepsin cleaves the interior of protein molecules into smaller peptide chains brush border enzymes of the duodenum then hydrolyze these chains to amino acids A list of secretory products not mentioned so far (for a more complete listing, refer to Medical Physiology by Boron and Bulpaep, published by Sanders, 1st ed 2003, p 40-41) Salivary glands: bicarbonate and electrolytes Stomach: Intrinsic factor: necessary for the digestion/ uptake of Vitamin B12, which is involved in erythropoesis and other processes Gastrin: hormone: chemoreceptors detect protein in the diet stimulate production of gastrin by the stomach gastrin stimulates HCl production Pancreas Lipases to break down lipids Proteolytic enzymes Trypsinogen Chymotrypsinogen Duodenum Secretin: a hormone that stimulates the pancreas to release bicarbonate; thus, secretin is an antagonist to gastrin Motulin: a hormone that augments the motility of the GI tract (peristaltic movements and others) Enteric neurons: secrete various neurotransmitter-like hormones, including VIP (vasoactive intestinal peptide), which has a regulating function on GI blood flow, which in turn affects absorption, digestion, and secretion Tuesday Today: Nutrition and Digestion of Carbohydrates and Lipids Today’s average young adult/teen/child drinks 55 gal of soft drinks/yr. This is equal to 62lb of added sugars (mostly sucrose and fructose disaccharides) per year. If you only cut soda intake alone, you could lose a lot of weight. Fig 21.13: Digestion and Absorption of Maltose Maltase: an enzyme bound to the microvilli surface that turns maltose disaccharides into 2 glucose monomers (which is absorbable) An adjacent cotransporter to the maltase enzyme has binding sites for glucose and Na. When both sites are filled, it actively transports both molecules into the cell. This cotransporter needs ATP energy (from when the ATPase in the basolateral membrane hydrolyzes ATP) since the [sugars] in the cell is already high—it thus transports glucose inside against its concentration gradient. Glucose leaves the enterocyte through facilitated diffusion in the basolateral membrane interstitial fluid capillary portal vein liver Clinical Connections: Lactose Intolerance (p 662) Lactase is a membrane-bound enzyme in the small intestine that digests lactose (milk sugar found in dairy products) into glucose + galactose so they can be absorbed into enterocytes by the Na-sugar cotransporter. From a few yrs of age to adulthood, this enzyme becomes deficient in many people such that 50% the people in the world are lactose intolerant. Lactose intolerant people can’t digest lactose disaccharides, so when they eat dairy they get bloating, flatulence, and diarrhea that leads to the loss of electrolytes and fluid and eventually malnourishment Such people should either try to avoid dairy or take synthetic lactase products to partially compensate for their lactase deficiency. Also, there are now dairy products that are made with little or no lactose. Fat Metabolism Fig 21.17 Some people say human bodies were not designed to take in fatty diets, but this isn’t true since our bodies do have all the enzymes and mechanisms for transport required in fat metabolism. The problem is that modern diets have too much fat. Fat digestion is more complicated and troublesome than carb or protein metabolism. Fat is the last to leave the stomach because (1) it rises to the top of the chyme in the stomach and (2) it is the least digested so far Fat takes longer to digest overall because it takes time for the pancreas and liver to produce the enzymes and bile (respectively) to digest fat Fat is released to the duodenum in globules which can be up to 1-2mm (visible size). These nonpolar fat globules don’t dissociate in the aqueous chyme, thus bile salts are needed to break down fat globules Bile salts Bile salts are synthesized by the liver stored and concentrated in the gallbladder released into the duodenum with pancreatic secretions during the absorptive state Bile salts are amphipathic: they have hydrophilic and lipophilic parts. The lipophilic parts interact with the fat globules and pull them apart into more manageable size globules in the aqueous solution increase surface area of fat globules so that there is more contact between lipases (enzymes that break down fat) and the inner contents of the fat globules (cholesterol esters, phospholipids, triglycerides) Triglycerides are the #1 component of lipids in American diets. When you get your blood lipid content screened, they look for your cholesterol and triglyceride levels Emulsification: the process of breaking down large fat globules into manageable size globules Fig 21.18 The intestinal lumen can be divided into 2 sections Bulk phase of the chyme/meal: the main area of the lumen Unstirred layer: the area of the lumen right against the microvilli During digestion, the duodenum becomes filled with 3 classes of pancreatic enzymes that break down lipids Pancreatic lipase: works mostly on triglycerides, releases free fatty acids from fat globules to leave mono or diglycerides Cholesterol ester hydrolase: works primarily on cholesteryl esters: frees fatty acids from cholesteryl esters to produce free fatty acids and cholesterol Phospholipase A2 : breaks off free fatty acids from phospholipids groups The net effect of these 3 classes of enzymes = increase [free fatty acids], [cholesterol], and [some phospholipids] into the bulk phase of the lumenal solution Micelles act as transporters to get the end products of lipid digestion into the unstirred layer and then the microvilli’s transporter proteins for monoglycerides, fatty acids, and cholesterol. Micelles are in equilibrium with the solution. Thus, as more products of fat digestion are absorbed and their concentration in the lumen decreases, the micelles dissociate. Fig 21.20 Monoglycerides, free fatty acids, and cholesterol are absorbed into microvilli reassembled into triglycerides in the smooth endoplasmic reticulum of enterocytes golgi apparatus in these cells add lipoproteins to the triglycerides masses of triglycerides and protein form chylomicrons apo(lipo)proteins are added to the chylomicrons to facilitate their exocytosis from the cell interstitial fluid lacteal Chylomicrons are macromolecules that are too large to diffuse between the endothelial cells of capillaries, thus they go through the more porous lacteals lymph circulation systemic circulation tissues. Note: fats don’t go through the liver first like proteins or carbohydrates! Conclusion of fat metabolism: it is difficult for our bodies to process dietary fat. Fig 21.19: The enterohepatic circulation Bile salts are conserved and preserved Enterohepatic circulation: bile salts circulate from enterocytes to liver After performing emulsification in the duodenum, bile salts are reabsorbed in the ileum of the small intestine portal hepatic circulation liver, where bile salts are reconstituted released to biliary system released back to duodenum for another round of emulsification This cycle occurs 3-4 times during one absorptive state (circulates for 3-5 hrs) Some bile salts are lost in the feces, but the majority is reabsorbed If bile salts aren’t needed (little fat content in the meal), they are stored and concentrated in the gallbladder Discovery box p 669 Observe the apolipoproteins on the figure of the chylomicron There are 6 classes of lipoproteins Chylomicrons: When chylomicrons pass through the capillaries of skeletal muscle and adipose tissue, they meet up with lipoprotein lipase (an enzyme located on the endothelial cells of the capillary), which partially metabolizes chylomicrons—they extract some lipid content from the chylomicrons. Chylomicrons leave as chylomicron remnants, the 2nd class of lipoprotein. VLDL: very low density lipoproteins IDL: internal density lipoproteins LDL: low density lipoproteins HDL: high density lipoproteins The national cholesterol education program has calculated healthy ranges for blood cholesterol and triglycerides based on age, gender, body mass, etc. If your total blood cholesterol is 200-239 mg/dL: borderline high risk ( for CV death) Greater or equal to 240 mg/dL: high risk for early death from a cardiovascular (CV) disease Other risk factors for CV disease besides high cholesterol: smoking, family history of CV disease, obesity Some people have hypercholesteremia or hyperlipidemia, a genetic disease for high blood fat (have 300-1000mg cholesterol/dL) 25% of young people are in the high risk category without knowing it. The national average for blood cholesterol for high school seniors is 155 mg/dL, but this tends to increase by the college years due to alcohol, the freshman 15, and a more sedentary lifestyle. A healthier diet and more exercise will reduce cholesterol levels. Some graphs The average woman eats 10-12 g fiber/day and the average man eats 15-17g fiber per day. We should eat at least 3x that amt; there is no upper limit to the amt of fiber that you can eat. Good sources of fiber are whole grains and legumes. Thursday Gametogenesis Spermatogenesis Oogenesis Fig 22.2: Differentiation and Development of Genders There are actually 3 categories of gender Genetic sex (of embryo): XX or XY Physiologic sex Phenotypic sex From fertilization to the 8th week, only the genetic gender exists; you can’t tell gender physiologically yet. The developing embryo is bipotential (can potentially develop male or female reproductive organs) The embryo starts out with both male and female primordial tissues around undifferentiated gonads Male primordial tissues make up the Wolffian ductal system Female primordial tissues make up the Mullerian ductal system The Y chromosome determines with tissues develop phenotypic male should develop by week 8 Fig 22.3: Fertilization sex determination sex differentiation The srY gene (sex-determining region of the Y chromosome) on the Y chromosome codes for testis-determining factor (TDF) TDF induces the primitive gonads to differentiate into male testes testes produce 2 hormonal products: Androgens: esp. testosterone: promotes the development of the Wolffian ductal system (internal and external) development of male reproductive system MIS: Mullerian inhibiting substance Also known as Mullerian inhibiting hormone or antiMullierian hormone Inhibits the development and promotes regression of the Mullerian ductal system If there is no Y chromosome present no srY gene no TDF no testes female reproductive organs develop by default By week 11-12, the Wolffian ducts regress in the lack of testosterone AND the Mullerian ducts are free to develop in the absence of MIS Fig 22.5: The testes Fig 22.5a: Structures Epididymus: contains the vas deferens Seminiferous tubules: site of spermatogenesis, where developing sperm cells and semen are released into efferent ductules and then into the vas deferens Fig 22.5b: 3 cell types at the seminiferous tubules Sertoli cells: make up the wall of the seminiferous tubules Interstitial cells of Leydig (or Leydig cells) Developing spermatids/ spermatozoa Fig 22.5b The testis/sertoli-blood barrier: a basement membrane that separates the Sertoli and seminiferous tubules from the interstitial space and blood Analogous to the blood-brain barrier Fig 22.8 Note the tight junctions between the Sertoli cells Basal compartment of the seminiferous tubule: located above the tight junctions Lumenal/central/ablumenl compartment of the seminiferous tubules: located below the tight junctions The differentiation, meiosis, & mitosis of a primordial germ cell occurs several weeks after fertilization in both genders In males: Stem cell primitive/primordial germ cells primordial germ cells do fast mitosis fill basal compartment primitive germ cells forced through tight junctions differentiate into primary spermatocytes 1st meiotic division 2 secondary spermatocytes meiosis 2 4 spermatids change in morphology (develop tail, head, etc) 4 spermatozoa Primitive germ cells arise early after conception. In contrast, everything from meiosis I down in the figure occurs from puberty In the male, note the ratio: 1 primary spermatocyte 4 spermatozoa Fig 22.6 Gametogenesis is under feedback control via hormonal regulation: involves the hypothalamus, anterior pituitary, and the testes The hypothalamus releases GnRH at puberty in a cyclic, pulsatile fashion for both sexes gonadacytes in the anterior pituitary secrete LH and FSH into systemic circulation FSH binds to receptors on Sertoli cells LH binds to receptors on interstitial cells of Leydig stimulate the production of androgens (esp. testosterone) testosterone activates Sertoli cells promote spermatogenesis and the production of inhibin by Sertoli cells as well as other various effects Inhibin acts as negative feedback on the anterior pituitary for FSH secretion Testosterone acts as negative feedback on the anterior pituitary (short loop) and the hypothalamus (long loop) inhibit LH production Fig 22.13b: The Ovarian cycle and Oogenesis (development of female gamete) Oocyte: egg Oogonia: primitive oocyte The female reproductive cycle is really 3 different cycles that take place in the ovary, uterine wall, and other locations. The cycles are: Ovarian cycle Uterine cycle Menstrual cycle For the 1st several weeks after conception: stem cells oocytes, which do multiple mitotic divisions by the 1st trimester, the maximum number of oocytes that the female will have has been produced The female embryo now has 5-10million primitive oocytes at birth, there will only be 1 million oocytes at puberty, there will be around 400,000 oocytes number continues to decrease through her life only 350-400 oocytes have the potential to become offspring (most oocytes are wasted) Note the difference for males, who retain the ability to produce germ cells: males can produce 5-6million mature sperm per gram of gonadal tissue through much of their lives Ovarian cycle really has 3 phases (not just the 2 shown) Follicular phase Ovulatory phase: the 24-36hrs between the follicular and luteal phases Luteal phase Fig 22.13b Primordial/ Primitive follicle: the spherical structure that the egg develops in At day 14: the mature follicle dislodges the oocyte (ovulation) the rest of the cycle depends on whether the egg gets fertilized and implanted or not The follicle changes appearance, morphology, and function during the course of the cycle. After ovulation, it changes into the corpus luteum, which may disintegrate (if no fertilization) or stay as an endocrine structure (if egg gets fertilized) The primitive follicle starts out with 1 layer of granulosa cells around the oocyte At day 1-2 of the follicular phase, a few (10-20) follicles get special preference only these follicles continue to develop, the other follicles decompose and are reabsorbed by the ovaries in the process of atresia (the breakdown of developing follicles) Antrum: a fluid filled cavity Preantral follicles Antral follicles: larger than preantral follicles due to their having developed an antrum The oocyte is surrounded by a protective zona pellucida, which is secreted by the increasing numbers of granulosa cells Theca cells: differentiated from the granulosa cells. While granulosa cells produce estrogen and respond to FSH, theca cells produce androgens and respond to LH. The follicle takes the androgens synthesized by non-granulosa cells that diffuse into them and convert these androgens to estrogen Day 10: only 1 preantral follicle is selected becomes the dominant follicle, the only one the continues to develop into a Graafian follicle; all the others undergo atresia The antral cavity enlarges and surrounds the oocyte the oocyte eventually breaks off from the wall and floats in the antrum Day 14: the Graafian follicle merges with ovary wall (under the control of LH and other hormones) wall of follicle is digested antrum fluid is released, carrying the egg into the oviduct egg proceeds toward uterus Fig 22.15: The Menstrual Cycle and its Hormonal Changes Menstrual cycle has 3 phases Menstruation/ Menstrual phase: 3-5 days Proliferation phase: follicles increase in size, granulosa cells become more secretory Secretory phase: continued and increasing secretion LH and FSH plasma levels peak during ovulation For the 1st 14 days (in the ovarian cycle), LH levels are fairly stable Day 9-10: LH levels start to rise day 14: LH surge: the single most important cause of ovulation Rising estrogen levels cause the LH surge. Estrogen levels are fairly constant for most of the follicular phase, but as granulosa cells increase in number, they secrete more net estrogen estrogen goes into a positive feedback loop at the anterior pituitary, which produces LH LH surge Again, changes in progesterone and estrogen, LH, and FSH levels in the luteal phase (after day 14) depends on whether fertilization occurs or not Fig 22.14: The Uterine Cycle 4-5 days after menstruation, the endometrium lining of the uterus is at its thinnest. When it lost its blood supply, there as apoptosis (cell death), tissue necrosis, and a sloughing off of the endometrium. Now, new endometrium develops in the preovulatory phase. Also, the myometrium (the muscle layer under the endometrium, NOT SHOWN IN FIGURE) develops too From day 5 onwards, there is Angiogenesis: new blood vessels develop increase in blood flow Endometrial hyperemia Secretory glands mature and develop with the increased blood supply secrete more products that promote protein synthesis, etc. By the 20th day of the uterine and ovarian cycle, the endometrium is thickened and ready for implantation Fig 22.20a: Uterine/ Fallopian/ Ovarian Tubes or Ducts The oviducts are also called the uterine horns Within 24 hrs of ovulation, the egg is fertilized in the 1st third of the oviduct The fertilized egg undergoes rapid changes: zygote undergoes cleavage morula blastocyst implantation on day 5-6 afterwards READ up on the processes of FERTILIZATION, IMPLANTATION, and PLACENTATION (development of placenta) in your text Males v Female Gametogenesis The ovum is fully mature by the time it leaves the ovary, while the sperm cell develops until it contacts the ovum and then undergoes changes that make it fully mature. Thus, the sperm cell needs the ovum to reach full maturity, but the reverse isn’t true. Granulosa cells and Sertoli cells both surround oocytes or spermatozoa (respectively) and provide nutritional, endocrine, and physical support. Table 22.1: Sertoli v Granulosa cells: read over this chart All reproductive hormones begin with cholesterol, which is converted to progesterols progesterone male hormones female hormones. Chemically, both genders depend on each other. The avg age for menarche (1st menstruation) is decreasing (from 15-12 over the last century), meaning that the female reproductive life is increasing (i.e. from menarche to menopause). However, male fertility is on the decline, by as much as 50% in the last half century.