Lecture 8 04/07/2009 Basic elements of renal physiology location and structure of kidneys/nephrons blood supply to kidneys and superficial vs. juxtamedullary nephrons the renal corpuscle (components) and tubular system basic physiology of kidney function micturition, i.e. the urination reflex Structures of the renal system; highlighting renal vasculature kidneys bilaterally located, not considered abdominal organs weigh about 120-160 g in a 70 kg individual held by renal capsule, rigid collagen structure that restricts contraction outer cortex and inner medulla renal artery and renal nerves enter, renal veins and ureter exit at renal hilus region, indent in the kidney renal pelvis, extensions called major and minor calyces structural unit called the nephron, about 1 million per kidney arrangement occurs in renal lobules 10-12 lobules in each kidney, formed from renal pyramids with base toward cortex and apex toward calyces pyramidal structure of the kidneys caused by collective arrangement of nephrons that project from outside to inside toward calyces Vascular and tubular structures in the mammalian kidney note proximity of tubular and vascular structures vascular component left or right renal artery gives rise to interlobar artery and veins, which gives rise to arcuate arteries and veins, which lead to interlobular arteries beyond interlobular artery is series of arterioles ? afferent arteriole (upstream), efferent arteriole (downstream); capillary bed between them called glomerular capillaries peritubular capillaries from efferent arteriole, distal to glomerular capillaries, giving kidneys their unique circulatory system renal portal circulation ? two capillary beds arranged in series with one another, supplied by the same upstream arteriole afferent arterioles to capillaries, then to efferent arterioles, then to second set of peritubular capillaries similar capillary system in pituitary gland and liver tubular component where urine is produced Bowman's capsule, beginning element of renal corpuscle (glomerulus) ? gives rise to tubules of nephron, surrounds glomerular capillaries proximal tubule divided into three segments, last of which is straight proximal tubule loop of Henle composed of three components descending thin limb ascending thin limb thick ascending limb final distal tubule when two or more distal tubules from different nephrons meet together, it is called a collecting duct cortical collecting duct outer medullary collecting duct inner medullary collecting duct Structures of the kidney; emphasizing the renal nephron, the functional unit of the mammalian kidney two sets of nephrons cortical (superficial) nephrons ? tubules stay in cortex or outer medulla90% juxtamedullary nephrons ? glomeruli closer to junction of outer medulla and inner cortex, project deeply into medulla almost touching the pelvis, 10% darker color indicates greater osmolality ? least concentrated in cortex (isoosmotic), most concentrated in inner medulla (hyperosmotic) kidneys able to produce more or less concentrated urine Renal circulation kidneys receive 25% of cardiac output (e.g., RBF = 1250 mL/min) ? renal blood flow at Hct of 45%, RPF (renal plasma flow) = 1250 x 0.55 or ~700 mL/min thus, glomerular capillaries are exposed to large volume of blood plasma each minute ? unlikely that 5 mL aliquot will not be exposed to cleansing action of kidney Summary kidneys bilateral, retroperitoneal, cortex/medulla nephron is functional unit; special renal vasculature and tubules glomerulus is the filter; composed of fenestrated glomerular capillaries Comparative structure (function) of renal epithelial cells in different segments of the tubular system proximal tubule located in the cortex transitional epithelial cells causes its shape to change from one tubule to another microvillus border that projects into lumen above dense quantity of mitochondria ? high production of ATP needed to power active transport most of ultrafiltrate gets reabsorbed in proximal tubule (65-70%) via active and passive transport, aquaporins ? absorbs glucose, proteins, water ascending limb of loop of Henle no brushed border, few mitochondria, no reabsorption little energy being used ? mostly passive processes distal tubule cells become complex again more transport actions taking place Pathways for reabsorbing water and solute in the ultrafiltrate ultrafiltrate ? filtered material at Bowman's capsule can be tested by placing microfiltrate into Bowman?s capsule and collecting fluid in that space; concentration would be same as that of plasma in blood protein concentration is different from that in plasma (plasma ? 7 g/dL; much lower in ultrafiltrate) should be 0 protein in the urine ? protein that is in Bowman's capsule gets reabsorbed somewhere in the tubule and does not end up in the urine reabsorptive mechanisms of water and solute two sides for movement of ultrafiltrate transcellular pathway paracellular pathway ? lies between two adjacent epithelial cells, limits size of transport due to gap/tight junction joining the two cells whatever is reabsorbed passes through basolateral membrane, goes through interstitial space, is transported into the blood vessel Estimates of the renal handling of Na+ along the nephron Na+ is main cation in extracellular fluid effective circulating volume ? estimate of how well heart can perfuse all the organs and tissues of the body, including the kidneys; tied directly to extracellular Na+ extracellular Na+ always being lost through filtration and other excretory mechanisms along the nephron at Bowman's capsule, 100% of Na+ filtered is remaining (no reabsorption) convoluted portion of proximal tubule ? 67% of filtered load has been reabsorbed to peritubular capillaries filtered load ? product of the renal arterial plasma concentration of Na+ and the rate of glomerular filtration, i.e., how much Na+ is getting across glomerular capillaries into Bowman's space thick ascending limb of loop of Henle ? 25% of filtered load is remaining most of Na+ is reabsorbed in early part of tubule ? only 3% remaining at collecting duct Summary macroscopic structure of the kidneys renal circulatory system tubular system of the nephron Basic elements of renal physiology what is glomerular filtration and ultrafiltrate what is tubular reabsorption what is tubular secretion what is renal excretion what is clearance; how do the above relate to it Embryologic development and details of the renal corpuscle; i.e., the glomerulus four components glomerular capillaries Bowman's capsule space that lies between glomerular capillaries and wall of Bowman?s capsule extracellular and intracellular glomerular mesangium, supportive cells that support structure and physiology of tubules in the region (analogous to glial cells in nervous system) podocytes, footlike cells that have cell body and toelike projections called primary and secondary pedicels circumscribe glomerular capillary primary pedicels give rise to lateral pedicels lateral pedicels lead to secondary pedicels, which are finer and greater in number intertwine with one another ? beginning of filtration process fenestrated capillaries, walls perforated with window-like structures a few angstroms in diameter allow for transport of molecules but not cellular elements into Bowman's space transport only possible if filtration molecules allow them to pass as well Conservation of mass and urinary excretion only two ways out of the kidney ? venous output and urine output = arterial input arterial input = Px,a * RPFa (plasma concentration of x * renal arterial plasma flow) venous output = Px,v * RPFv (plasma concentration of x * renal venous plasma flow) urine output = Ux * V (concentration of product in urine * rate of flow) Urinary excretion of a solute in the ultrafiltrate is the algebraic sum of its filtered load, tubular reabsorption, and tubular secretion how is the supply of an ultrafiltrate determined? plasma concentration * rate of plasma flow peritubular capillary bed should receive same blood flow as glomerular capillary bed glomerular filtration ? either gets excreted or acted upon by peritubular capillaries amount excreted is function of amount filtered minus amount reabsorbed by peritubular capillaries plus amount secreted back into tubules can be defined quantitatively what does filtered load mean? plasma concentration of x * rate of formation of ultrafiltrate how do Starling forces influence GFR and other functions of the nephron? Experimental techniques used by renal physiologists to study functions of the nephron four techniques free-flow micropuncture technique ? glomerulus products free to flow through tubules and out of the body unimpeded take micropipette, remove segment of renal capsule, find cortical glomerulus, impale proximal tubule sample fluid in proximal tubule, compare contents of sample with contents of renal arterial plasma or systemic plasma anywhere stopped-flow microperfusion technique double lumen pipette ? one lumen has solution, the other has bolus of oil inject bolus of oil to stop the flow of tubular solution, then inject experimental solution if renal tubule contents differ from prepared solution, then something may have been secreted or reabsorbed from tubule continuous microperfusion technique mostly done on mice bolus of oil injected, experimental solution perfuses with nothing additional coming from above vascular pipette impaled into peritubular capillary, which gets another solution make inferences about perfusion of vascular supply and tubule on behavior of epithelial cells isolated perfused tubule ? microrecording of membrane potential put microrecording electrodes in tubule or in tubular epithelial cells record changes in membrane potential that are affected by composition of solution also could be changes effected by the tubule expressing GFR (glomerular filtration rate) Pin ? inulin, glycoprotein that is used for quantifying glomerular filtration rate freely filterable (concentration in plasma and Bowman?s space is the same) neither reabsorbed along tubule nor secreted back into tubule (stays confined within tubule) no known physiological effect on renal function (relatively inert compound) used only in the lab, not clinically known concentration of inulin in proximal tubule 65-70% of water gets reabsorbed, but not inulin ? becomes three times more concentrated (increases to 3 mg/mL) micropipette in tubule, withdraws fluid at known rate ? rate of collection is 10 nL/min collection rate (tubular fluid flow rate) * concentration of inulin in tubular fluid / ? = glomerular filtration rate (= 30 nL/min, 100-120 mL/min for kidney) GFR declines with age; other reduction of GFR indicates renal disease eGFR (estimated) ? generally between 50-100; impossible to calculate without going through previously described tests Summary conservation of mass (solutes in the plasma) and entrance vs. exit from the kidneys glomerular supply of solute vs. filtered load of solute and reabsorption, secretion and excretion experimental techniques: free-flow, stopped-flow, continuous microperfusion, single nephron GFR Lecture 9 04/09/2009 Renal physiology; i.e., the physiology of the renal/urinary system continuing review of renal clearance; special cases the glomerular filtration barrier and variables that determine GFR urinary or micturition reflex (urination) the renin-angiotensin system (RAAA) and maintenance of renal/circulatory homeostasis Renal clearance clearance definition re-emphasized volume of plasma from which a solute X is completely removed by the kidneys looking at excretion of solute in urine, clearance is rate or volume of renal plasma flow that must be delivered to the glomeruli in order to account for that amount that is being excreted RPF = 700 mL/min (both kidneys combined) [Na+] RP = 142 mM @ (0.7 L/min) (142 mmole/L) = 100 mmole/min are delivered to the filtration apparatus (flow rate * concentration) in reality, only 0.14 mmole/min Na+ excreted (vast majority is reabsorbed) assumption: all 0.14 mmole come from a single 1.0 mL of RPF then clearance of sodium, CNa+ = 1.0 mL/min explain 'virtual volume' ? clearance is the virtual volume from which the kidney has removed or cleared a substance per unit time Renal clearance and mass balance of X arterial input of X = venous output of X + urinary output of X (Px,a * RPFa) = [(Px,v * RPFv) + (Ux * V)] (mmole/mL * mL/min) = [(mmole/min * mL/min) + (mmole/mL * mL/min) two ways to transform the above equation to develop concept of clearance, both based on assumption that kidneys clear all of X from incoming volume of renal arterial plasma first way ? replace RPFa with the virtual volume of X, i.e., Cx second way ? assign venous output of X a value of 0 since we assume no X in renal venous plasma classic clearance equation ? Cx = Ux * V/Px,a Factors contributing to the net urinary excretion of a solute X measuring excretion of a solute and comparing it with filtration apparatus either gets reabsorbed in peritubular capillaries, or peritubular capillaries secrete some of solute into tubule reabsorption and secretion by peritubular capillaries can influence secretion and therefore clearance of a solute filtration fraction ? 600 mL/min of renal plasma flow with solute X, good chance that some of solute X will bypass glomerular capillary and simply go straight to venous circulation/peritubular capillaries can be calculated by dividing GFR by renal plasma flow (mL/min) about 20% of solute delivered actually has a chance to get filtered, 80% bypasses Clearance of PAH (CPAH), i.e., estimating renal plasma flow using PAH para-aminophippuric acid (PAH) ? does not exist in the body, must be administered helps to quantify or define secretory mechanisms in the kidney PPAH * RPF = 0.1 mg/min * 600 mL/min = 60 mg/min ultrafiltrate only contains about 10 mg/min rather than 60 excretion of PAH ? 60 mg/min, same amount that was delivered difference between excretion rate and delivery rate must be due to reappearance of PAH from peritubular capillaries back into tubule beyond glomerulus secreted from peritubular capillaries at 50 mg/min comes into contact with basolateral transport mechanism in proximal tubule, pumped back into tubular fluid 60 mg/min divided by 0.1 mg/mL = 600 mL/min (PAH clearance, equal to delivery rate) example of specific case where in a single pass through the kidneys, all of substance X is cleared from the plasma, i.e., clearance of PAH defines renal plasma flow can use quantification of clearance of PAH as estimate of rate of plasma flow going into kidneys (used by clinicians to evaluate renal function) PAH is benchmark for both defining secretion by tubules and quantifying rate of plasma flow cannot be used to estimate GFR because it is secreted Inulin clearance (Ci) and GFR also not endogenous to the body (exogenous compound) glucose polymer found naturally occurring in Jerusalem artichokes another standard for measuring clearance because it has to be administered to body to make measurements list of qualifications that a solute must meet in order for calculation of its clearance rate to be used in estimating GFR must be pretty filterable at glomeruli, cannot be restricted (inulin is small molecule) must not be reabsorbed must not be secreted must be physiologically inert (cannot affect renal circulation in any way, constrict or dilate efferent/afferent arterioles or have any metabolic effect on tubules) cannot be stored by the kidneys in mesangium (can't be stored or metabolized) 120-125 mL/min clearance rate = GFR assume that it is also the rate of glomerular filtration of inulin graphs on slides excretion of inulin directly proportional to plasma concentration of inulin (slope of curve defines the inulin clearance rate, UV/P = 500/4 = 125 mL/min) clearance of inulin is independent of plasma inulin concentration clearance of inulin is independent of urine flow rate both have limitations ? must be administered to body, must perform invasive techniques Estimation of glomerular filtration (eGFR) based on circulating plasma concentrations of creatinine creatinine is metabolic byproduct of creatine phosphate in muscle metabolism rate of excretion of creatinine is relatively constant over long periods of time when individual is healthy and in healthy state, GFR between 120-125, creatinine levels remain constant at 1-1.5 mg/mL muscle mass does not change from day to day; therefore, rate of production of creatinine is relatively constant as well rate of excretion of creatinine matches rate of production from body peripheral blood sample and measure plasma concentration of creatinine to estimate GFR plasma concentration of creatinine would only change if excretion changed, which only changes by problems with filtration Summary clearance redefined clearance based on conservation of mass special case for PAH; i.e., estimate of RPF special case for inulin; i.e., estimate of GFR creatinine used clinically for convenience and relative accuracy Glomerular filtration barrier and factors affecting GFR purpose of the barrier structural components of the barrier starting forces and ultrafiltration molecular charge, size and ultrafiltration Anatomical/morphological detail of renal corpuscle (glomerulus), glomerular capillaries and filtration barrier space between any two adjacent peda cells called filtration slit fenestrated endothelial cell in capillary lumen basement membrane line that connects two adjacent filtration slits ? filtration diaphragm from capillary endothelium to filtration diaphragm ? ultrafiltration barrier all proteins carry negative charge, which is part of barrier (anionic charge) ? repels proteins in arteriole plasma anatomical and electromagnetic barriers to prevent formation of ultrafiltrate and restricts large molecules from getting through Molecular size (radius) and selective permeability of glomerular filtration barrier Na+ < glucose < inulin < myoglobin < plasma albumin relative concentration of solvent in ultrafiltrate compared to plasma further away from 1.0 ? more restricted solute (plasma albumin does not get filtered) smaller than 2 nm in radius is freely filterable; larger than 3-4 nm is restricted plasma albumin and plasma globulins (even larger) most common proteins found in plasma plasma globulins only show up in ultrafiltrate in disease state, with damaged barrier Affect of charge on filterability if ratio is about 1.0, solute is pretty filterable smaller ratio means less filterable anionic dextrans less filterable (curve shifts to left), cationic dextrans more filterable (curve shifts to right) ? charge as a determinant of filterability as size of molecule increases, filterability decreases nephrotoxicity, generic term for renal disease negative charge on filtration barrier is lost in many renal diseases ? more weakened, more solutes get into ultrafiltrate Starling forces and influence of net filtration pressure (PUF) along the length of the glomerular capillary four variables defined inside glomerulus PGC ? glomerular capillary hydrostatic pressure, caused by Pascal's and energy equation, laws of hemodynamics ?GC ? glomerular capillary oncotic (colloid osmotic) pressure, also called plasma oncotic pressure; exerted by plasma proteins, most notably albumin and globulins, should never exceed 6.5-7 g percent, 3.5-4 g percent for albumin, 2.5-3 g percent for globulins PBS ? Bowman's space hydrostatic pressure ?BS ? Bowman's space oncotic pressure hydrostatic pressure favors ultrafiltrate formation, oncotic pressure hinders it only one of three pressures, ?GC, changes along glomerular capillaries PGC at about 50 mmHg ?BS at about 0 mmHg PBS at about 12-15 mmHg ?GC starts at 25 mmHg, ends at 30-33 mmHg (only one to influence balance of Starling forces and therefore ultrafiltrate formation) PUF (ultrafiltration pressure) net ultrafiltration pressure is yellow shaded area of curve indicates that ultrafiltrate formation takes place only at afferent arteriole end, not efferent arteriole end as fluid is filtered from glomerular capillaries, concentration of proteins increases less fluid to dilute same amount of protein, therefore oncotic pressure increases opposing force becomes proportionally more important Influence of selective changes in pre vs. postcapillary resistance on renal blood flow (RBF) and GFR resistances across afferent and efferent arterioles affect flow through glomerular capillaries and therefore volume of fluid that exists in a glomerular capillary efferent arteriole constricted ? rate of flow decreases, therefore volume of fluid in glomerulus progressively increases, therefore glomerular capillary hydrostatic pressure increases, therefore GFR increases afferent arterioles are site of regulation of flow Summary GFR is affected by the makeup of the filtration barrier (endothelium, basement membrane, filtration slits/diaphragm) GFR is affected by the size and charge of solutes (neutral and cations filter more easily than anions) GFR is influenced by Starling forces and pre- and post-capillary resistances Micturition and solute titration curves ureters, bladders and their functions innervation of bladder; storage and voiding of urine summary of filtration, reabsorption, excretion of solute (classic titration curves) Anatomy and electrophysiology of the bladder and ureters in mammals once ultrafiltrate arrives at end of collecting duct before entering major and minor calyces, flows through six segmental compartments via passive flow without being influenced urinary system is relatively sterile system cranberries able to bind to bacteria that causes urinary tract infection, especially in women system of reflexes that eventually expel urine from the bladder smooth muscle cells in walls of ureters have similar action potential as fast-response myocytes in the heart pacemakers exist in calyces, generating action potentials peristaltic contractile waves that move across calyces, pelvis, ureters, bladder wave of contraction driving volume of fluid into storage area landmarks in the bladder body neck triangular structure called trigone with ureteric and urethral orifices, fundus smooth visceral area in bladder that becomes posterior urethra, main sensory site before urination takes place detrusor muscle ? ill-defined layers of muscle that contract as a unit Autonomic and somatic innervation of the urinary bladder (left) and cystometrogram during urination cystometrogram ? measures volume/pressure relationship like a cistern clinician can test for urinary tract function pass catheter through urethra and into bladder; any residual fluid is drained incrementally injects either warm sterile water or 9-10% saline solution, measure pressure in double lumen catheter as bladder fills, first 15 mL is fairly sharp rise in intravesical pressure (bladder is not very compliant during this stage) next 100-300 mL, relatively little rise in pressure (high compliance) ? detrusor muscle has innate ability to sense stress first urge to urinate at about 100-150 mL by 300-400 mL, compliance decreases markedly as volume continues to increase (sense of bladder being full) limited bladder capacity ? above 500 mL is uncomfortable and potentially dangerous hydronephrosis ? acute or chronic, fluid backed up to glomeruli if pressure exceeds 50 mmHg, filtration is shut down and can be lost for good can be caused by kidney stones or other chronic illnesses small waves of contractions that continue to rise in amplitude (micturition) until bladder is emptied (voiding) Lecture 10 04/14/09 ADH and renal/circulatory physiology the molecule and its sites of synthesis/storage/release dry mouth, thirst and release of ADH osmotic vs. hemodynamic release of ADH cellular mechanism of action of ADH integrated systems/ADH responses to hypovolemia Reminder of body water compartments, their volumes and osmolalities total body water (42 L) = 0.6 * body weight extracellular fluid (14 L) = 0.2 * body weight interstitial fluid (10.5 L) = ¾ of ECF plasma (3.5 L) = ¼ of ECF interstitial fluid and plasma divided by capillary wall intracellular fluid (28 L) = 0.4 * body weight ECF and ICF divided by cell membrane Effects of adding large loads of water/salt on ECFV and ECFosm ECFV and ICFV should be constant, osmolality in two should remain constant after adding 1.5 L of pure water to ECF early phase ? ECFV expands by 1.5 L (swelling of compartment), osmolality decreases due to dilution with water final phase ? osmolality readjusted, ECFV and ICFV will remain increased until kidneys get rid of excess water (could take up to days) after adding 217.5 millimoles of pure NaCl toECF osmolality of existing water will change early phase ? osmolality of ICF remains constant, of ECF increases final phase ? ECF compartment expands by 0.9 L, ICF compartment shrinks by 0.9 L ICFV determined primarily by ECFosm; most important osmole is sodium, so ECFosm determined by concentration of salt in ECF Interactions between the hypothalamus and posterior pituitary gland in regulating the release of ADH (AVP) as osmolality of ECF spaces increases walls of third ventricle made up of important neuronal structures including hypothalamus and nuclei that make up hypothalamus clusters of neurons; some are osmoreceptors, others are supraoptic neurons that communicate with osmoreceptors and posterior pituitary supraoptic neuron cell bodies are site of synthesis of ADH (arginine vasopressin, AVP) signal from osmoreceptors can incite neurons to release ADH from cell bodies and cause its axonal transport to synaptic junctions via posterior pituitary anteroventral of third ventricle ? AV3V region of hypothalamus, more osmoreceptors that serve to stimulate release of ADH cardiovascular control centers in brainstem communicate with osmoreceptors and supraoptic neurons, as well as other nuclei in the third ventricle which also communicate with osmoreceptors can send signals to osmoreceptors of hypothalamus and can influence their activity therefore, sensory receptors in aortic sinus can influence the osmoreceptors connection between renal function when it comes to balance of fluid volume and osmolality and cardiovascular system, since blood volume is part of ECF blood volume determines adequacy of perfusion of tissues in body PET scans of human subjects made thirsty by intravenous infusion of hypertonic saline maximum thirst due to infusion of NaCl solution reaches osmoreceptor regions red/orange signals are evidence of osmoreceptor activity/response singulate cortex, corpus callosum, lateral ventricles and third ventricle three minutes after drinking all signals are gone water absorbed and transported to those regions rapidly quickly equilibrates hyperosmotic solution Influences of changes in plasma osmolality and blood pressure (or blood volume) on plasma [ADH] osmotic influence on ADH release isoosmotic state (280 osmoles) ? very little ADH released under such conditions 10% increase in osmolality (to 300 osmoles) ? nearly to maximum ADH release hemodynamic influence on ADH release 10% decrease in blood volume does nearly nothing to ADH release 30% or more decrease in blood volume produces ADH response equivalent to corresponding osmotic response (serious hypovolemia) osmolality is much more potent stimulus for changes in ADH than is the circulatory system Mechanism of action of ADH on aquaporin (water) channels (FINISH) transported to kidneys and other tissues specific site of action where it mediates its effects diuresis ? loss of water (most common diuretic, water-losing organ, is kidney) anti-diuresis ? against the loss of water ADH arrives at epithelial cells in tubular system and specifically in cortical and outer and inner medullary collecting ducts (site of action of ADH) important landmarks lumen of tubule apical surface of cell basolateral region of cell circulation (interstitial space) ADH recognizes receptor in basolateral membrane of cortical epithelial cells called V2 receptor (vasopressin 2) vasopressin 1 located on vascular smooth muscle of another organ (different function) binds ADH, coupled to stimulatory G-protein, complex activates adenyl cyclase (?) increases production and concentration of cyclic AMP, which activates protein kinase A, which phosphorylates another protein called aquaporin 2 (AQP2) certain vesicles that are synthesized in nucleus transport aquaporins to apical membrane and insert water channels into membrane cell becomes more permeable to water, water gets reabsorbed from tubule other aquaporins (3 and 4) on basolateral membranes when new steady state has been achieved, then cyclic effect of vesicle and protein synthesis ceases until next stimulus Summary kidneys participate in regulating volume and osmolality of body water compartments much of this regulation depends on degree of disturbances in homeostasis and roles of ADH increased release of ADH = anti-diuresis; reduced release of ADH = water diuresis the above is reflected, in part, by urine volume and urine osmolality (i.e., dilute vs. concentrated urine) JGA, tubuloglomerular feedback and the regulation of RBF and GFR summarize filtration, reabsorption, excretion; solute titration curves what is the JGA (juxtaglomerular apparatus)? what is tubuloglomerular feedback? RAAA and responses to reduced renal arterial perfusion pressure The renal juxtaglomerular apparatus (JGA) and tubuloglomerular feedback renal corpuscle region where afferent arteriole goes into glomerular capillaries and where efferent arteriole leaves glomerular capillaries and where thick ascending limb of loop of Henle (late thick ascending limb) meets with early, convoluted section of proximal tubule comes into close proximity with afferent and efferent arterioles extramesangyum in crotch of afferent/efferent structure glomerular capillaries ? intramesangyum good evidence that all cells communicate in telling structure how to function three mechanisms that activate the system reduction in systemic arterial pressure and carotid sinus baroreceptor stimulus and SNS efferents reduction in local afferent arteriolar perfusion pressure or blood flow, destretch and renin release reduction in filtered load of ultrafiltrate at macula densa of distal TAL/distal tubule (specifically in composition of NaCl) macula densa ? epithelial cells become more columnar, densely packed; communicate with smooth muscle cells in afferent arteriole that are also modified (juxtaglomerular cells, also granular cells because they contain vesicles with NT-like substances) Pressure-flow autoregulation and the inflluence of a decrease in afferent arteriolar perfusion pressure and the RAAA system what happens to JGA when renal arterial blood pressure falls? relative vascular resistance in both afferent and efferent arterioles renal blood flow ? remains pretty constant over range from 60-80 to 160-180 mmHg (autoregulation over wide range of pressures) glomerular filtration rate (GFR) ? also autoregulated; dependent on renal blood flow resistance in afferent arteriole increases proportionately to increase in renal blood flow efferent arteriole constricts, maintaining values like GFR reduction in blood pressure from 80 to 60 or 40 ? GFR and renal blood flow falls, resistance will decrease to accommodate mechanism of action after decline in perfusion pressure of kidneys prorenin released and converted to active proteolytic enzyme called renin (not to be confused with rennin) renin gets in contact with angiotensinogen, large macromolecule; recognizes the C-terminus and clips off a 10 a.a. peptide called angiotensin I (A-I), physiologically inert passes through pulmonary microcirculation capillary bed of lungs, comes into contact with angiotensin-converting enzyme (ACE); converted into angiotensin II (A-II) A-II affects several organs in the body brain ? leads to production of ADH blood vessels ? acts as potent vasoconstrictor in systemic circulation (other naturally-occurring vasoconstrictors include thromboxane, norepinephrine, endothelin) adrenal cortex ? leads to production of aldosterone, a mineralocorticoid which influences salts lead to reduction in excretion of salt and water from the kidneys (retention) protect GFR and renal blood flow How do changes in cardiovascular variables, e.g., effective circulating volume, influence kidney function and homeostasis? effective circulating volume ? measure of adequacy of perfusion of blood to organs granular cells, also high-pressure baroreceptors, sense decrease in ECV and release renin renin cleaves peptide off large molecule and eventually creates A-II, which stimulates release of ADH in the hypothalamus and stimulates the thirst center A-II also causes release of aldosterone in adrenal cortex, leading to reabsorportion of salt and water kidneys will reduce excretion of salt and water, removing the stimulus of decreased effective circulating volume by restoring the system renin-angiotensin system has several effectors/activators, sensor is the granular cells of JGA Summary RAAA system is activated by a reduction in effective circulating volume (i.e., renal perfusion pressure/renal plasma flow) the end result is reduced excretion of salt and water (i.e., retention of these), thus re-expansion of blood volume and perfusion a critical component of the RAAA system is ADH (or AVP); it is released in response to both reduced blood volume and increased interstitial osmolality (the latter is more sensitive) Kidney's role in producing concentrated vs. dilute urine tubular segmental permeability to water gradient of medullary osmolality countercurrent exchange/multiplication role of ADH (AVP, arginine vasopressin) Osmolality in restricted and excess states of body water even though GFR is maintained relatively constant, excretion of urine changes cyclically throughout 24-hour periods, goes up and down in predictable way changes when traveling from east to west, but only if traveling at least three time zones does not change when traveling north to south (within same time zone) urine production lowest in late PM to early AM hours (8-9 PM to 4-5 AM) therefore, greatest rate of urine production occurs in late AM to early PM hours urine flow (rate of excretion of urine) can vary from a few tenths of mL per minute to ten times that volume Lecture 11 04/16/09 The freshman 15: do university dining halls make students overweight and/or obese? abundance of food wide variety of choices take-out late hours personal choices Salivary glands, ptyalin (salivary amylase) and substrate on which it acts restricting caloric intake helps more than other methods of losing weight three ways of looking at gastrointestinal system secretory behavior ? what products GI tract secretes and what those products do motility of the tract ? what mechanical actions the GI tract participates in processes of digestion and absorption phases of GI function sufalic phase of preparing to process a meal ? smells, sounds of pots and pans, etc. can stimulate secretion of saliva oral, gastric, intestinal, colonic phases of function ? once meal reaches those segments of GI tract, what happens salivary glands three pairs in humans ? carotid, submaxillary, sublingual glands first ones to start secreting (salivating) in preparation for a meal one of the main digestive enzymes is ptyalin, a salivary amylase produced by salivary glands ingested carbohydrates that can be partially reduced by ptyalin in the oral cavity amylose amylopectin pectin other plant starches acts between any two glucose monomers does not influence branch point connections Salivary secretions tubules surrounded by cells, secretory in nature many cells secrete different things ? mucin, water, ptyalin, electrolyte, bicarbonate as they are released, they are referred to as primary secretions no one has ever sampled a primary secretion of a salivary gland ? virtually impossible as saliva comes down channels, it is modified by the time it reaches oral cavity, it is referred to as secondary secretion ? different composition common influences on salivary composition flow rate of saliva influences concentration of electrolyte sodium, bicarbonate, potassium, chloride saliva is always hypotonic relative to plasma becomes closer to tonicity of plasma as flow rate of saliva increases ? less time for ductile epithelial cells to reabsorb sodium and chloride as it passes through duct Summary; among others the following are selected functions of chewing (mastication) and saliva aid in speech (oral secretions, speech pathology) 8 x 8 recommendation (eight 8-ounce glasses of water a day) has no scientific basis direct water consumption ? take it from the tap; New York apparently has best-tasting water in the nation indirect water consumption ? from tea, coffee, etc. intrinsic water consumption ? from an apple, orange, etc. disruption of ingested food to produce smaller particles breaking a bolus of food into smaller particles to be digested digestion of food with amylase initiation of the digestion of starch (amylases) regulation of food intake and ingestive behavior Esophageal/gastric journey of ingested meal coordinated actions of swallowing reflex (e.g., speech and breathing) no volitional control over swallowing (same as vomiting) inspiratory neurons inhibited, respiration stops during swallowing epiglottis closes entrance to glottis (trachea) so food will enter esophagus esophageal sphincters, peristaltic waves, receptive relaxation of stomach three other reflexes stimulated reflex inhibition of esophageal sphincter ring of muscle ? to open esophagus lower esophageal sphincter is relaxed so bolus of food can pass it when bolus passes upper esophageal sphincter, initiates peristaltic wave, involving visceral smooth muscle that pushes bolus of food down the esophagus at aboral end of the bolus, wave of relaxation occurs (contraction wave orally to bolus, relaxation wave in front of the bolus downstream) from top to bottom receptive relaxation of stomach in anticipation of a meal entering it secretions and motility of stomach including retropulsion factors influencing storage and emptying of stomach Phases of processing of ingested food: cephalic, oral, esophageal, gastric, small intestinal and colonic supergrains of the world ? rice, maize wheat ? #1 as foundation of world's diet rice is actually #1 in popularity because it is the only thing that will grow in certain places GIT secretory activity begins in the salivary glands/oral cavity and continues aborally to the colon all GIT secretions come, ultimately, from the blood; saliva is an easily accessible body fluid useful for assaying markers of disease, drugs, DNA, etc. whatever volume of food is ingested is matched at least 100% by digestive secretory products, which must also be digested and absorbed ? leads to gastric discomfort due to increased volume 2 L (about 2 kg) of total consumed product per day, including water (direct, indirect, intrinsic) Three functional regions of the stomach CARDIA/fundus secretions: mucus, bicarbonate ion motility: reflux, entry, etc. CORPUS or BODY secretions: IF, pepsinogens, mucus, gastric lipases, H+, bicarbonate ion motility: ?? Secretory functions of the mammalian stomach pacemaker activity in some of the cells of the stomach ? can contract like a pump sagittal view of the stomach ? upper and lower esophageal sphincters antrum ? thickest layer of smooth muscle, greatest capacity to generate force when it contracts from inside to out ? seroso mucosa, musculeris mucosa (contractions determine shape and movement of mucosa), submucosa one layer wraps around tubular structure, other layer runs parallel ? can reduce volume and length of an area gastric pits or crypts (secretory glands) ? walls of each secretory gland composed of several different cell types stem/regenerative cells ? can replace older cells as they are destroyed and recycled parietal cells ? source of acid production, secrete hydrogen ion actively chief cells ? source of production of enzymes that are designed to digest proteins (proteases, peptidases) Secretion of acid by parietal cells (left) and various receptors and signal transduction pathways in the same cell (right) from interstitial side of cell to lumen of the ducts ultimate source of hydrogen ion comes from hydration of CO2 water in interstitial spaces, CO2 in those regions as well under actions of carbonic anhydrase, production of carbonic acid occurs dissociates to hydrogen and bicarbonate ions proton pump (potassium/hydrogen exchanger) ? antiporter, transports ions in opposite directions secretory products that affect proton pump primary secretagogues ? secretory products that have some inhibitory or excitatory effect on other GI products gastrin, a hormone produced by the stomach CCK, another hormone (different types annotated a, b, c) gastrin and CCK phosphorylate proteins and eventually activate antiporter acetylcholine binds to muscarinic receptor, also activates antiporter histamine is common secretagogue, activated by H2, activates protein kinases to activate pump all increase production of acid through some pathway somatostatin and some prostaglandins inhibit such actions by inhibiting AMP (?) to reduce production of acid Direct and indirect pathways by which secretagogues ACh and gastrin stimulate release of parietal hydrogen ions direct pathway - ? indirect pathway - ? gut has its own nervous system called enteric nervous system communicates with autonomic nervous system and motor components of somatic nervous system structures (neurons, cell bodies) confined to wall of the gut vagus nerve can secrete ACh directly on parietal nerve and release H+ mast cells that synthesize and store histamine ? when histamine is released, increased acid production takes place due to stimulation by ACh Acid-resistant protective mucus barrier (left) and control of acid secretion by gastric parietal cells (right) cross-section of lumen of stomach pink represents acid, blue represents base, white is neutral zone large semi-liquid, semi-solid mucosal barrier between cells that line wall of the stomach and cells of the lumen, with two specific functions prevent acid from getting into mucosal lining trap bicarbonate ion so that it doesn't get into the acid pool mucosal gel is several micrometers thick, always present if there is healthy bowel cells that form mucus are destroyed in pathological state lead to death and apoptosis of mucosal cells, cause histamine cycle that is a positive feedback (stimulates release of mast cells, leading to even more acid production with nothing to buffer the acid) #1 cause of erosion of mucosal buffer zone is alcohol consumption begins with localized ulcer (peptide, hydrochloric, or gastric) in local region of stomach wall, treated with proton-pump inhibitors continued alcoholic abuse leads to spread of peptide ulcer eschemia leads to broad destruction of mucosal barrier distension of the stomach by food activates two different reflexes, both cause release of ACh local ENS reflex vagovagal reflex also causes release of GPP GPP acts on a G cell that leads to production of gastrin, which acts on ECL/parietal cells ECL cell causes secretion of histamine, which acts on parietal cell ACh acts on all three ? G cell, ECL cell, and parietal cell pH at about 2.0, most acidic point, right after a meal Summary gastric acid secretion hydrogen ions released by parietal cells combines in lumen of stomach with chloride ions to create HCl under direct and indirect control of PSNS and secretagogues, e.g., gastrin activates digestive proteases in preparation for digestion/absorption of ingested/sluffed proteins Three factors that affect stomach emptying pH of the meal fat content of the meal ? most potent determinant osmolarity of the meal Exocrine slide?? d d d d Exocrine cell types in the pancreatic acinus and intercalated duct common pancreatic duct interlobular duct which branches into intralobular ducts, which branch further into intercalated ducts and end at acinus exocrine pancreas pancreatic acinar cell is the primary cell dense population of rough ER for protein synthesis high concentration of vesicles, indicating release products, secretagogues proteases, lipases, amylases ? enzymes that act on different energy substrates secretory granules released into intercalated ducts and eventually into main pancreatic duct Movement of newly-synthesized proteins through the secretory pathway (left), and mono- vs. biphasic patterns of release of pancreatic amylase in response to secretagogues protein secretory pathway take amino acid and label it with tritium inject labeled a.a. into incubation medium that cell is found in (pulse of radioactivity) sample cells, fix them, measure radioactivity in different parts of protein secretory pathway can tell where protein is, how long it takes for amino acid to get incorporated into a protein originally, 100% found in the rough ER; after 15 minutes, less than 50% (the rest in Golgi vesicles) packaged into lysozymes (autophagic, can destroy vesicles or cell itself) 50% in condensing vacuoles by about 40 minutes reduced in size to Zymogen granules, mostly here after a few hours pharmacology of the compound dose response curve amylase release (%) vs. concentration of secretagogue always some baseline production of secretagogues without stimulation regulated release of secretagogue after excitation of the cell, can be measured GRP, VIP, and CGRP all increase and reach a plateau eventually (monophasic) CCK and carbachol increase steeply and then decrease after a certain point (biphasic) different sensitive receptors for recognizing secretagogues high-affinity ? require very low concentrations; when it is reached, secretion is excited low-affinity ? require much higher concentrations; when it is reached, secretion is inhibited Cyclic release of pancreatic secretions during fed/fasted states interdigestive period ? very low range of secretagogues motility and secretion coordinated 5-20 fold increase during fed state, stays increased for several hours Lecture 12 04/21/09 Key messages from Dietary Guidelines for Americans, 2005 consume a variety of foods where staying within energy needs control intake of calories to manage body weight be physically active every day increase daily intake of fruits and vegetables, whole grains, and non-fat or low-fat milk and milk products if you drink alcoholic beverages do so in moderation Sites of the GIT absorption of nutrients carbohydrates, proteins and lipids early part of duodenum reabsorbs vast majority of energy substrates that are taken into the GI tract (analogous to proximal tubule) entire small intestine available for digestion and absorption of energy substrates calcium, iron and folate (folic acid) most ions and minerals get absorbed in early part of duodenum all the way to late ileum has strong role in digestion of these substances bile acids recycling of bile acids takes place bile acids and salts important in processing of lipids once they have participated in digestion of lipids, bile acids are recirculated into terminal portions of small intestine goes to descending colon, transported through circulation back to gallbladder, re-released during same meal enterohepatic circulation of bile can be recirculated up to three times during reabsorption of a single meal cobalamin (vitamin B12) reabsorbed only in ileum important in erythropoeisis, so crucial that this part of GI tract is healthy General patterns of digestion and absorption five general patterns no digestion simplest form of digestion deals with single monomer, glucose molecule directly delivered to tissues luminal hydrolysis of polymer to monomer occurs somewhere in small intestine small protein (pentapeptide in this case, five a.a. joined by peptide bonds) gets digested by proteases released into duodenum, converted from pentapeptide into individual a.a. individual a.a. transferred across mucosal wall and delivered into circulation brush border or mucosal digestion at brush border of enterocyte mucosal epithelial cell that has protein enzyme that is integral part of apical border of that cell good example is table sugar, a disaccharide ? one monomer of glucose and one monomer of fructose sucrose recognized by sucrase (enzyme), which specifically hydrolyzes bond to create glucose and fructose transported by different mechanisms into circulation intracellular or cytosolic hydrolysis small peptide (tripeptide in this case) can be absorbed intact into enterocyte once inside enterocyte, comes in contact with protease or enzyme that can break it down into individual a.a. a.a. get transported into interstitial space in the blood lipid (luminal hydrolysis followed by intracellular resynthesis) remain in stomach for longer period of time triglyceride ? backbone glycerol molecule attached to fatty acid chains (can be short, medium, or long chain fatty acids) #1 source of dietary fat is triglyceride ? therefore, circulating triglyceride concentration value just as important as total cholesterol value triglyceride concentration also contributes to other fat-related vascular disease broken down into glycerol and fatty acids in lumen in the gut transported to enterocyte, then get recombined into triglyceride in cytosol and get absorbed in that form, although as part of larger component (lipoprotein) Carbohydrates, brief description starch (plant polysaccharide, 45-60% CHO diet) amylose (straight chains of alpha-1,4 linkages) amylopectin (branched, macromolecule, alpha-1,4- and alpha-1,6 linkages) disaccharides (30-40% CHO diet) sucrose (table sugar) lactose (milk sugar) dietary fiber (cellulose, lignins, pectins) soluble (fruits, vegetables) insoluble (wheat, lentils, beans, related food products) more important to know because they contain more alpha-1,6 than alpha-1,4 linkages are not available to be broken down by amylases large fraction of these fibers pass through the gut and get into the colon colon is home of many bacteria called commensal bacteria once in the colon, insoluble fibers able to retain water because they bind ions (usually hydrated) ? more insoluble fibers makes it less likely for people to develop colon cancer colon cancer starts with constipation, leads to polyps and other symptoms try to apply these foods to one's diet about 12 g in average woman, 17 g in average man ? about one-half to one-third of what we should be getting connie is the coolest kid i know =) Alpha-1,4 and alpha-1,6 carbon (glucose) bonds defined Effects of GIT luminal alpha-amylase on complex carbohydrates in lumen, amylase starts to cleave parts of straight chains out of complex carbohydrates creates products like maltose, maltotriose, and alpha-limit dextrins Mucosal brush border carbohydrate enzymes (Table 29.2) simplest are lactase and sucrase for lactose and sucrose, respectively most complex is isomaltase which can break down both alpha-1,4 and alpha-1,6 linkages, even in alpha-limit dextrins Digestion of carbohydrates to monosaccharides digestion of starch in the lumen red signs: points in amylose-amylopectin chain that enzyme cannot hydrolyze three main products maltose (disaccharide) maltotriose (trisaccharide) alpha-limit dextrins not only is amylase unable to break bonds at a branch in the chain, but it is also unable to break bonds in adjacent glucose molecules moreover, it cannot break terminal hydrocarbon bonds luminal brush border wide variety of enzymes available to digest substrates lactase sucrase piggybacked onto isomaltase glucoamylase all three products can get broken down by brush border enzymes to individual glucose monomers or galactose and glucose even alpha-limit dextrins and trisaccharides get broken down into individual monomers glucose and galactose use a sodium symporter to get absorbed into the cell use the same transporter, sodium-glucose transporter 1 each of the monomers eventually gets through cell and into the circulation Effects of lactose intolerance (lactase deficiency) on plasma level of glu/lact and H2 in expired air top panel shows normal person lactose is blue, glucose is red person drinks volume of glucose or lactose-containing solution physician takes blood samples each hour blood glucose should rise and come back to steady state within 3-4 hours to confirm, several hours later physician collects volumes of expired air beginning at about 5 hours measure volume of H2 in breath ? calculate how much should be in the expired air bottom panel shows lactase deficiency typical rise in lactose is not seen (small bump) whopping production of H2 gas seen a few hours later lactase enzyme that does not convert lactose to component monomers bacteria in the colon can convert lactose to monomers, so increased H2 is seen Summary of carbohydrate digestion/absorption (assimilation) begins with amylases in mouth and stomach continues in duodenal lumen and at duodenal brush border co-transported with Na+ across apical membrane (SGLT-1) other apical transporters for fructose (e.g., GLUT5) basolateral uptake by GLUT2 (GLUT5 for fructose?); driven by Na+/K+-ATPase at basolateral membrane main source of calories in diets of Westerners Protein digestion and absorption in the mammalian GIT more complex than for carbohydrates four phases (stomach, duodenum, brush border, enterocyte) central role for pancreatic proteases dietary roles of essential vs. non-essential amino acids Fate of dietary protein as it exits the stomach and enters the duodenum pancreas specializes in producing four classes of proteins amylases for carbohydrates lipases for fats or lipids proteases for proteins nucleases for nucleic acids like DNA among some of the proteases are trypsinogen, procarboxypeptidase, others all released into duodenum in inactive form (pro-proteases) do not become effective proteases until they are in the lumen of te gut along brush border is enterokinase, an important enzyme cleaves off trypsin from trypsinogen trypsin can then activate the rest of the enzymes exopeptidase and endopeptidase classes ? work at terminals or interior of proteins, respectively, to break peptide bonds hydrolytically Actions of luminal, brush border, and cytosolic oligopeptides ? a few monomers of peptides joined together in linear fashion gets converted into tetrapeptide by one of many peptidases tetrapeptide then converted into tripeptide, which have one of two fates can be broken down into dipeptide can be transported with proton symporter into cell as intact tripeptide individual a.a. transported into cell di- and tripeptides absorbed as intact oligomers inside enterocyte, di- and tripeptides can come into contact with dipeptidases and tripeptidases and get broken down into individual a.a. Amino acids and their classification (neutral, basic, acidic; essential and non-essential) neutral (carry no charge) aliphatic ? gly, ala, val, leu, ile aromatic ? tyr, phe, try hydroxyl ? ser, thr sulfur ? cys, met imino ? pro, hydroxypro basic (carry cationic charge) arg, lys, his acidic (carry anionic charge) glu, gln, asp, asn essential ? must come from the diet, since they cannot be synthesized in the body non-essential ? can be synthesized in the body, usually from carbohydrates Both enterocytes and specialized M cells can absorb whole, intact proteins (e.g., antigens) infants up to 6 months can absorb all proteins intact, do not need brush border enzymes mother transfers passive immunity to newborn, antigens and antibodies are absorbed through milk adults do absorb some intact proteins two types of transport mechanisms for intact proteins M cells in wall of small intestine any epithelial mucosal cell very small percentage (10%) and very small quantity of proteins are delivered intact some proteins can be put in vesicles and transferred to mucosal component of immune system part of immune system comes from transport of intact antigens and antibodies end up in lymphocytes, can be immediate source of defense against infection Malabsorption of neutral (left) and cationic (basic) amino acids in heritable diseases Hartnup disease ? a.a. transporter is missing for L-phenylalanine cystinuria ? a.a. transporter is missing for L-arginine small peptide versions administered to allow absorption of those a.a. Lecture 13 04/23/09 Digestion and transport of fats and lipids most complex of all energy substrates principles of water insolubility and emulsification resynthesis within cytosol of enterocytes basolateral transport into lymphatic circulation lacteals/enterohepatic recirculation of bile salts Digestion and absorption of lipid (exogenous/endogenous fats) some digestion of fat in stomach, but minimal because as solid particles of ingested meal turn into semi-liquid state, triglycerides (98% of fat that we ingest) rise to top of chyme and settle there as a layer triglycerides have little chance to be exposed to gastric lipases released by the stomach, since lipases are suspended in aqueous phase and are unavailable to lipids large fat globules (visible to the naked eye, several mm in diameter) some emulsification occurs in the stomach anterograde peristaltic wave generated by top of stomach and simultaneous retrograde wave generated by anterum (bottom of stomach) collide head-on causes mixture and churning of the chyme for that moment, exposes fat and lipid to gastric lipases, contact them by chance happens to a small fraction of individual lipid products triglyceride is a glycerol molecule, three carbon chain each of those carbons is attached to a fatty acid chain fatty acid chains can be short, medium, or long chain fatty acids some nonesterified fats, free cholesterol, other kinds of lipids released from stomach into early duodenum hormones get released, stimulate pancreas and gallbladder to release their contents gallbladder releases primarily bile salts; biliary secretion also contains free cholesterol, some remnants of triglycerides pancreas releases copious amounts of pancreatic lipases ? produced in excess of their need bile salts and lipases needed to emulsify fat globules emulsification bile salts are amphipathic, have hydrophobic and hydrophilic domain lipophilic domain adheres to and projects into fat globule hydrophilic domain extends into aqueous phase, or lumen of the gut allows bile salt to begin acting with pancreatic lipases to break down fat globule into smaller elements, including micelles occurs from beginning of duodenum into mid jejunum ? by end of jejunum, most of lipid has been broken down and absorbed The digestive breakdown of emulsion droplets to micelles emulsion droplets consist of two components, a central core that is lipid-rich that contains primarily triglycerides, diglycerides, and cholesterol with fatty acid attached to it surrounding core are several layers of additional lipids that have been formed in lipid bilayers surface layers include fatty acid soaps (liquefied, partially solidified), monoglycerides, phospholipids, free cholesterol, bile salts as bile salts and pancreatic lipases begin to break down fats, part of it pinches off and forms a vesicle ? same outer layers and same content of lipid inside the core as in emulsion droplet smaller in size than liquid droplet, processed even further to produce smaller products multilamellar vesicle has phospholipid bilayer, like emulsion droplet number of corresponding vesicles increases ? increased surface area (size and number) available to pancreatic lipases and bile salts to do their work as layers get digested, free product diffuses out toward surface and takes place of digestive products in vesicle, get broken down ? number of layers decrease mixed micelle is transport vehicle that takes much of the lipid still in its membrane as well as free lipids in the core, delivers them from axial stream of the gut toward the enterocyte or mucosal membrane Micellar transport of emulsified lipid products to the surface of the enterocyte apical membrane micelles are of two different kinds, both are transport vehicles that take fats toward gut wall mixed micelle bile salt micelle at least three, maybe four, barriers that mixed micelle or bile salt micelle must pass through to get lipids to enterocyte aqueous phase (bulk phase), lumen of the gut ? slightly alkaline gelatinous mucus-containing material that prevents H+ from getting in acid microclimate disequilibrium zone (unstirred layer) ? immediately adjacent to the enterocyte, stationary (doesn't get moved) apex of the enterocyte itself all lipids in state of equilibrium in the bulk phase concentration of lipid in micelle is greater than the outside ? encourages release of free fatty acid into unstirred layer, free to enter the enterocyte as free fatty acid leaves micelle, concentration is reduced, triglycerides and diglycerides get digested to replace the layers that are leaving absorption of the fats takes place by three possible routes free fatty acids are polar (charged) hydrocarbon chains, carrying net negative charge; come into contact with sodium-proton exchanger, proton binds to free fatty acid and makes it a nonionic species, allowing it to pass through the phospholipid bilayer physical movement of wall of the gut and churning actions of bulk phase (mechanical activity) can thrust long or medium chain fatty acids through the cell membrane ? encourages further digestion and absorption into the enterocyte fatty acid transport proteins pick up short chain fatty acids and transfer them into the enterocyte Re-esterification of digested lipids by the enterocyte, i.e., formation of chylomicrons and lipoproteins release of product and transfer into the cell glycerol, short and medium chain fatty acids can diffuse into the cell and be transferred into interstitium and delivered to general systemic circulation for vast majority of fat in our diet, it must go through reprocessing and finally get released in basolateral membrane in quite different form enter smooth ER, get reassembled into form of triglyceride, stored in form of vesicle inside smooth ER in rough ER, APO proteins being synthesized ? released from rough ER and are taken up by smooth ER, inserted into membrane of stored vesicles containing triglycerides some additional processing, vesicles transferred to Golgi apparatus, converted into chylomicrons ? first member of class of proteins and lipids called lipoproteins vesicular membrane fuses with basolateral membrane of enterocyte, chylomicron released into interstitium ? too large to pass through pores of fenestrated capillaries enter lacteals instead, terminal lymphatic capillaries that originate in the microvilli of enterocytes in the gut fingerlike projections that project between two adjacent cells in microvillus which have large gaps in endothelial cells chylomicrons can pass through via diffusion lacteals carry them from gut wall into mainstream lymphatic channels of the body, including thoracic duct fat gets dumped into systemic circulation in subclavean veins near the neck lipoproteins ? six classes chylomicrons chylomicron remnants (modified by enzymes) very low-density lipoproteins (VLDLs) ? not many of these intermediate-density lipoproteins (IDLs) low-density lipoproteins (LDLs) high-density lipoproteins (HDLs) Summary during lipid meal, fat droplets are emptied from the stomach into the duodenum biliary and pancreatic secretions enhance and sustain the process of emulsification of fat droplets (reduced size, increased number) lipid monomers and mixed micelles/bile salt micelles delivered to enterocyte emulsion-like products resynthesized inside enterocyte chylomicrons and VLDLs delivered to circulation Blood lipids and heart disease are directly related (e.g., hyperlipidemias) 155 mg/dL (plasma cholesterol levels upon HS graduation) 200-239 mg/dL (borderline high; > 240 mg/dL is high risk) become aware also of your triglyceride, LDL and HDL levels; change them if necessary college sedate, party lifestyle (poor nutrition, excess alcohol, et. al.) contributes to risk of early heart disease? become proactive; change the above; take care of your hearts and marvelous bodies Lecture 14 04/28/09 Metabolism = sum of all chemical reactions in the body total of all chemical changes that occur in the body anabolism: energy-reducing process where small molecules are joined to form larger molecules catabolism: energy-releasing process where large molecules are broken down to smaller molecules energy in carbohydrates, lipids, proteins is used to produced ATP through oxidation-reduction reactions each day there is a need for energy to sustain cells with ATP, to provide brain with glucose ? energy needs are dependent upon activity goal is to meet the body's need for energy (ATP) Anabolic and catabolic reactions ATP production ? energy released during catabolism can be used to synthesize ATP anabolism ? result in the synthesis of the molecules necessary for life catabolism ? ingested food is source of molecules used in catabolic reactions ATP breakdown ? energy released from breakdown of ATP used during anabolism to synthesize other molecules and to provide energy for cellular processes like active transport and muscle contraction Anaerobic respiration breakdown of glucose in absence of oxygen ? produces 2 molecules of lactic acid and 2 molecules of ATP reason for anaerobic respiration still existing as a mechanism is for fight-or-flight situations, when we need energy fast because our life is in danger if there is an option, aerobic respiration is always preferred ? 36 ATP vs. 2 ATP for each molecule of glucose if we need to do any movement in a fast way to escape in fight-or-flight situations, then anaerobic pathways are very important phases ? glycolysis, lactic acid formation Cori cycle ? process of converting lactic acid to glucose Aerobic respiration breakdown of glucose in presence of oxygen to produce carbon dioxide, water, 38 ATP molecules ? most of ATP molecules to sustain life are produced this way phases ? glycolysis, acetyl-CoA formation, citric acid cycle, electron-transport chain three stages digestion in GI tract lumen anabolism and formation of catabolic intermediate within tissue cells oxidative breakdown in mitochondria of tissue cells glucose present in the blood, excess glucose in storage in liver, muscles, fat all pathways come to acetyl-CoA and can enter Krebs cycle if you eat an expensive diet of just protein, there is no storage for protein ? used for tissue growth and repair; in adults mostly used to produce hormones and for tissue repair storage of glycogen in liver and muscle for carbohydrates energy storage in adipose tissue Metabolic pathways involved in cellular respiration glycolysis ? glucose to pyruvic acid Krebs cycle ? pyruvic acid to chemical energy electron transport chain and oxidative phosphorylation ? creation of ATP all glucose that enters muscle is phosphatated ? will be transformed into energy (glycogen or through cellular respiration), will not be released by that cell anymore due to lack of dephosphatase liver is key organ for all transformation ? can transform and store glycogen glucose from liver glycogen can directly contribute to blood glucose levels ? can be directly released to the blood, reestablishing glucose levels when we are not eating different mechanisms exist in the muscles interactions between different types of foods in our diet body is always looking to provide glucose to the brain in starvation states, muscles are degraded, amino acids are broken down to produce glucose to supply the brain gluconeogenesis ? transformation of amino acids into glucose excess glucose converted into fat via lipogenesis glucose pool used to increase glucose in the blood for metabolism in body tissues Metabolic states absorptive state ? period immediately after eating when nutrients absorbed through intestinal wall into circulatory and lymphatic systems (about four hours after each meal) postabsorptive state ? occurs late in morning, afternoon, night after absorptive state is concluded blood glucose levels maintained by conversion of other molecules to glucose since levels tend to go down about 5 hours after eating liver as main station for metabolic activities dependent upon person's eating habits 80-120 mg/100 mL ? normal range of blood glucose levels Interconversion of nutrient molecules glycogenesis ? excess glucose used to form glycogen lipogenesis ? when glycogen stores filled, glucose and amino acids used to synthesize lipids glycogenolysis ? breakdown of glycogen to glucose gluconeogenesis ? formation of glucose from amino acids and glycerol Role of liver in metabolism several roles in digestion detoxifies drugs and alcohol degrades hormones produces cholesterol, blood proteins (albumin and clotting proteins) plays a central role in metabolism Metabolic functions of the liver glycogenesis glucose molecules are converted to glycogen glycogen molecules are stored in the liver glycogenolysis glucose is released from the liver after conversion from glycogen gluconeogenesis glucose is produced from fats and proteins The endocrine system has primary responsibility for metabolic regulation absorptive vs. postabsorptive anabolic vs. catabolic insulin vs. glucagon (and others) hour-to-hour regulation of energy metabolism depends mainly on the ratio of insulin to glucagon insulin not needed by liver and brain ? needed everywhere else diabetes is the lack of insulin and the excess of blood glucose glucagon created by alpha cells, insulin by beta cells Regulation of energy metabolism system of anabolic and catabolic pathways pathways used depend on ATP availability hormones that regulate metabolism insulin glucagon cortisol ? activates all pathways to increase glucose in the bloodstream during stress, we need more energy increased glucose provides needed energy in stressful situations epinephrine ? activates increase of blood glucose The absorptive state (postprandial period) events during this period nutrients enter blood stimulates release of insulin inhibits release of glucagon energy metabolism in liver, adipose tissue, skeletal muscle affected most ATP produced provided by glycolysis, citric acid cycle, electron transport chain anabolic pathways amino acids used for protein synthesis excess amino acids converted into fatty acids insulin stimulates uptake of fatty acids into adipose tissue promotion of energy storage via anabolic pathways The postabsorptive state four hours after intake insulin levels decrease glucagon increases blood glucose decreases fatty acids and glycogen mobilized Pathways of the absorptive state absorptive state follows a meal anabolic ? protein synthesis, glycogenesis, lipogenesis uptake of glucose by liver excess glucose and amino acids stored as fat Pathways of the postabsorptive state stored nutrients mobilized for use, with special emphasis on assuring glucose supply for the heart and brain preferential oxidation of fatty acids (and ketone bodies) catabolic ? protein hydrolysis, glycogenolysis, lipolysis liver is source of glucose via glycogenolysis and gluconeogenesis Endocrine pancreas islets of Langerhans clusters of cells scattered among the acini endocrine portion of the pancreas alpha cells secrete glucagon in response to low plasma glucose beta cells secrete insulin in response to high plasma glucose Mechanism of insulin secretion low blood glucose minimal glucose enters cell low metabolic rate and minimal ATP Em is at resting level voltage-gated Ca2+ channel closed KATP channel is open high blood glucose glucose enters cell high metabolic rate and high ATP level ATP binding closes KATP channel Em depolarizes, opening voltage-gated Ca2+ channel Ca2+ influx triggers insulin exocytosis occurs in pancreatic beta cell catecholamine activates alpha cells, increasing the production of glucagon, which activates pathways to increase blood glucose ? sometimes stimulated by stressful situations Absorptive vs. postabsorptive, anabolic vs. catabolic, high insulin vs. low insulin absorptive, anabolic, high insulin involve storage of nutrients, including amino acids to proteins, glucose to glycogen, alpha-glycerol phosphate and fatty acids in most cells, glucose is used for energy in the liver, glucose is converted into glycogen and fat postabsorptive, catabolic, low insulin involve degradation of proteins, triglycerides, and glycogen in most cells, fatty acids and ketones are used for energy in the liver, pyruvate, lactate, glycerol, and amino acids are used to form glucose increase in plasma insulin leads to absorptive state events decrease in plasma insulin leads to post-absorptive state events Pancreatic islets of Langerhans insulin produced by beta cells increased levels during absorptive state mainly affects muscle, adipose, and liver glucagon produced by alpha cells increased levels during post-absorptive state Actions of insulin all are anabolic pathways most tissues increased glucose uptake, except in brain, liver, and exercising muscle increased amino acid uptake increased protein synthesis decreased protein breakdown adipose tissue increase in fatty acid and triglyceride synthesis decrease in lipolysis liver and muscle increase in glycogen synthesis decrease in glycogenolysis liver increase in fatty acid and triglyceride synthesis decrease in gluconeogenesis Regulation of insulin secretion stimuli for creation of beta cells in pancreas increase in plasma glucose increase in plasma amino acids increase in glucose-dependent insulinotropic peptide (GIP) secretion increase in parasympathetic activity decrease in sympathetic activity decrease in epinephrine secretion Translocation of glucose transporters in skeletal muscle and adipose cells Regulation of blood glucose by insulin and glucagon insulin regulation increase in plasma glucose leads to creation of beta cells in pancreas insulin secretion increases most tissues ? increased glucose uptake into cells liver and muscle ? increased glycogen synthesis, decreased glycogenolysis liver ? decreased gluconeogenesis leads to decrease in plasma glucose, which is a negative feedback system that removes stimulus of increased plasma glucose glucagon regulation decrease in plasma glucose lads to creation of alpha cells in pancreas glucagon secretion increases liver ? increase in gluconeogenesis, increase in glycogenolysis, leads to increase in plasma glucose adipose tissue ? increase in lipolysis, leads to increase in plasma fatty acids (glucose spared from being used for energy?) increase in plasma glucose is negative feedback system to remove stimulus of decreased plasma glucose Regulation of glucagon secretion stimuli for creation of alpha cells in pancreas decrease in plasma glucose increase in plasma amino acids increase in sympathetic activity increase in epinephrine secretion leads to increase in glucagon secretion Effects of glucagon alpha cells in pancreas leads to increase in glucagon secretion liver increase in glycogenolysis decrease in glycogen synthesis increase in gluconeogenesis increase in ketone synthesis increase in protein breakdown decrease in protein synthesis adipose tissue increase in lipolysis decrease in triglyceride synthesis Counter-regulatory hormones hypoglycemic - insulin hyperglycemic glucagon epinephrine cortisol growth hormone ANS action ? sympathetic nerves Metabolic control by sympathetic nervous system decrease in plasma glucose alerts glucose receptors in central nervous system increase in sympathetic activity alerts adrenal medulla to increase epinephrine secretion liver ? increase in glycogenolysis and gluconeogenesis leads to increase in plasma glucose, a negative feedback system that removes stimulus of decreased plasma glucose muscle ? increase in glycogenolysis adipose tissue ? increase in lipolysis leads to increase in plasma plasma fatty acids and glycerol Energy balance energy input ? food energy input ? metabolic pool in body ? energy storage energy output ? internal work ? thermal energy (heat), external work both types of work come from metabolic pool in body external work consists of any kind of movement internal work consists of energy expenditures necessary to stay alive thermal energy helps maintain body temperature loss of water and increase in lipids based on first law of thermodynamics energy input = energy output (work) energy stored as glycogen and fat work = transport, mechanical, chemical unit of measure ? kilocalorie (Calorie) raise 1 L of water by 1 degree Celsius calorie = raise 1 gram of water by 1 degree Celsius basal metabolic rate (BMR) in kcal/day Metabolic rate total amount of energy produced and used by body per unit of time components basal metabolic rate ? energy used at rest, 60% of metabolic rate thermic effect of food ? energy used to digest and absorb food, 10% muscular activity ? energy used for muscle contraction, 30% Body energy balance energy intake = total energy output (heat + work + energy storage) energy intake is liberated during food oxidation energy output heat is usually about 60% storage energy is in the form of fat or glycogen Weight control: energy consumed versus energy expended basal metabolic rate influencing factors: genetics, rate, gender, body composition, stress, food intake energy balance and body weight caloric content: fat = 9 Calories, proteins and sugars = 4 Calories excess intake leads to increased storage (weight) physical activity uses calories (150 Calories/mile walked or jogged) Body mass index an indicator of obesity-related health risk BMI = weight (lbs) * 700 / height (inches)2 BMI greater than or equal to 27 indicates health risk Obesity trends among US adults between 1985 and 2007 obesity: having a very high amount of body fat in relation to lean body mass, or body mass index (BMI) of 30 or higher BMI: a measure of an adult?s weight in relation to his or her height, specifically the adult?s weight in kilograms divided by the square of his or her height in meters Maintaining weight caloric input must equal caloric use calories burned depends upon activity level, age, height and build Appetite hunger and satiety are regulated by complex interactions among multiple brain centers hormones sensory and motor pathways Regulation of food intake body weight is usually relatively stable ? energy intake and output remain about equal mechanisms that may regulate food intake levels of nutrients in the blood hormones body temperature psychological factors Role of hormones in appetite regulation hormones from GI cholecystokinin ? suppressant ghrelin ? stimulant PYY ? suppressant adipocytes (fat cells) secrete hormones (leptin) that regulate appetite and body weight genetic defect leading to no creation of leptin when treated with leptin, boy lost great deal of weight from age 3.5 to age 8 cells in gut and placenta also make leptin circulates in blood and acts on different tissue including hypothalamus, skeletal muscle, and liver is a protein for which a DNA sequence has been determined and found on the genome Ghrelin newly discovered peptide hormone secreted mainly by cells of the stomach lining directly stimulates the appetite control center makes you feel hungry Metabolic rate and body heat production basal metabolic rate (BMR) ? amount of heat produced by the body per unit of time at rest factors that influence BMR surface area ? small body usually has higher BMR gender ? males tend to have higher BMR Lecture 15 04/30/09 Integrative physiology of exercise cardiorespiratory and metabolic variables genetic factor sex, age environmental factors: altitude, temperature, humidity, hour, etc. anthropometric factors: weight, height, body surface area, etc. disease (any disease, even the flu) psychological factors (nervousness, anxiety) physical training eating habits: type of food, quantity conditions related to exercise alone isometric, dynamic, combined exercise quantity of muscle tissue (+) or (-) work body position type, intensity, duration, equipment, etc. Learning objectives overview of how major systems are involved in the metabolism for skeletal muscle contraction how the extreme activities of exercise disrupt homeostasis focus on how the circulatory and respiratory systems integrate their responses to exercise demands how exercise impacts health Basic physiology how does the body work during exercise? heart and lung muscles metabolic energy basis of physical training heart and lung adaptation muscle adaptation metabolic and blood adaptation nutrients How to make ATP ATP available in cells ? immediate energy source ATP produced by anaerobic metabolism ? short-term energy source ATP produced by oxidation (aerobic metabolism) ? long-term energy source ATP in muscle ? a limited supply body stores 80-100 g (3.5 oz.), enough for only seconds of energy ATP resynthesis is important Energy for skeletal muscle contraction ATP and ADP phosphocreatine anaerobic pathway aerobic pathway Aerobic energy release from food energy released from food serves to phosphorylate ADP to ATP Integration of metabolism: in muscle contraction glucose never leaves the muscle, used as a source of energy to produce ATP or stored in glycogen CO2 constantly being produced as a byproduct three stages glucose comes from liver glycogen or dietary intake fatty acids can only be used in aerobic metabolism lactic acid from anaerobic metabolism can be converted to glucose by the liver Sustaining muscle contractions: ATP sources/time phosphocreatine ? short bursts at maximal effort anaerobic ? intermediate duration at intense effort aerobic ? long duration at reduced effort Hormonal regulation of energy source for ATP production body reserves ? glucose 2000 and FAAs 70,000 kcal exercise intensity glucose fatty acids metabolic shifts ? glucagon, cortisol, epinephrine/norepinephrine, GH, insulin Energy source for ATP production varies due to several factors ? age, gender, genetics, amount of muscle mass glucose becomes more important energy source as exercise becomes more intense fat is used at rest, becomes less important energy source for ATP production when exercise becomes more intense Homeostatic balancing of exercise: controlled disruption feed forward reflexes anticipate increased demand heart and lungs protective reflexes stretch damage increased temperature ? sweating, increased peripheral blood flow, redistribution blood pressure is relatively constant Cardiovascular response to exercise areas in the brain that coordinate cardiovascular and respiratory systems exercise is a voluntary action ? therefore, it requires activation from motor cortex and association cortex also requires use of vision, hearing to prepare us for the action many pathways come from higher levels in the brain activation of our heart ? increase in heart rate (very important variable to explain for changes in the body during exercise state) secretion of catecholamines during exercise, activated by sympathetic system of autonomic nervous system ? adrenergic activation similar to that during fight-or-flight nervous system activates the heart to increase heart rate, cardiac output, stroke volume amount of blood received by tissues changes during exercise state Cardiovascular response to exercise cardiac output increases from 5 to 35 L/min heart rate increase about 2-3 times blood distribution distribution to muscles increases to 88% of all blood decrease in distribution to all other tissues besides brain Resting heart rate averages 60 to 80 bpm, can range from 28 bpm to above 100 bpm tends to decrease with age and with increased cardiovascular fitness affected by environmental conditions such as altitude and temperature Heart rate during exercise heart rate increases in proportion to exercise intensity maximum heart rate near the point of exhaustion once approached, it starts leveling off highest heart rate achieved during maximal effort to the point of exhaustion decreases about 1 beat per year following 15 years of age 220 ? age = predicted maximal heart rate Heart rate and intensity advantages and disadvantages to using a treadmill obese people should not use the treadmill ? have to carry their body weight, so there is an overload of work elderly should also not use the treadmill young people are able to use the treadmill because they do not need the extra stability Change in heart rate during exercise as exercise begins, parasympathetic nervous system withdraws influence, leading to increase in heart rate sympathetic nervous system stimulates heart, leading to increase in heart rate adrenal gland secretes catecholamines propanolol blocks sympathetic nervous system ? leads to plateau in heart rate atropine blocks parasympathetic nervous system ? leads to greater increase in heart rate Heart rate during exercise calculate maximum heart rate by subtracting your age from 220 <60% of maximum heart rate ? non-training zone 60-70% of maximum heart rate ? training in aerobic zone will be able to do prolonged exercise prolonged and continuous exercise in this zone leads to weight loss 70-85% of maximum heart rate ? standard training zone allows for increase in endurance and maximum oxygen consumption maximal cardiovascular workout >85% of maximum heart rate ? anaerobic zone cannot stay in this zone for too long bursts of this training can increase lactate tolerance and high intensity work output Heart rate and training red-line zone ? 90-100% MHR (maximal heart rate) anaerobic threshold zone ? 80-90% MHR aerobic zone ? 70-80% MHR weight management zone ? 60-70% MHR healthy heart zone ? 50-60% MHR Stroke volume may increase with increasing rates of work up to intensities of 40% to 60% of maximum may continue to increase up through maximal exercise intensity, generally in highly trained athletes depends on position of body during exercise athletes that only do lifting have hypertrophy ? muscle wall increases, but toward the chamber, so chamber volume decreases Cardiac cycle systole ? diastole cardiac output (Q) = stroke volume (SV) * heart rate (HR) Stroke volume in cyclists relationship between heart rate and stroke volume trained people ? heart rate increase accompanied by increase in stroke volume untrained people ? heart rate increases without increase in stroke volume stroke volume increases as people start doing training Frank Starling mechanism ? more blood in the ventricle causes it to stretch more and contract with more force increased ventricular contractility (without end-diastolic volume increases) decreased total peripheral resistance due to increased vasodilation of blood vessels to active muscles Cardiac output resting value is approximately 5.0 L/min increases directly with increasing exercise intensity to between 20 to 40 L/min the magnitude of increase varies with body size and endurance conditioning when exercise intensity exceeds 40% to 60%, further increases in Q are more a result of increases in HR than SV since SV tends to plateau at higher work rates cardiac output increases at greater exercise intensity, plateaus at Qmax trained athletes can continue to work out for longer because of increased cardiac output Changes in heart rate, stroke volume, and cardiac output heart rate increases with increased exercise intensity stroke volume stays somewhat constant ? run > jog > lie > stand cardiac output similar for lying and standing but increases dramatically to jog and to run look at graphs and table on slide Cardiac output during exercise look at graphs of relative and absolute distribution of cardiac output during exercise Magnitude and distribution of the cardiac output at rest and during moderate exercise Exercise effects on cardiovascular system increased cardiac output, decreased total peripheral resistance increased blood flow to working tissues decreased blood flow to non-working tissues Homeostatic balancing of exercise: controlled disruption during exercise, TPR (total peripheral resistance) goes down because of vasodilation TPR reliant upon blood vessels ? blood flow to area increases with vasodilation, less resistance mean arterial blood pressure rises slightly despite drop in resistance systolic blood pressure goes up more than the diastolic blood pressure Gas transport Changes in arteriovenous oxygen how much air we put inside of our body (respiratory frequency) capacity of muscle to expand the lung cavity level of hemoglobin dissociation of O2 and CO2 ? binding and release pressure gradient of O2 and CO2 affects transport and exchange Oxygen content resting conditions ? 4-5 mL O2/100 mL blood absorbed in the capillaries maximal exercise ? 15 mL O2/100 mL blood absorbed in the capillaries more oxygen being consumed for aerobic respiration diffusion of O2 is higher because of increased demand Oxygen transport capacity TO2 = CaO2 * Q (cardiac output) rest ? males 20 mL O2/min * 50 dL = 1000 mL O2/min exercise ? 20 mL O2/min * 250 dL = 5000 mL O2/min Chemoreceptors central ? predominate regulator peripheral ? carotid and aortic bodies sensitive to PaO2, PaCO2, and pH primary regulator of breath-to-breath VE is PaCO2 Ventilatory regulation resting beginning of exercise, primarily under neural control ventilatory ?fine tuning? primarily controlled by peripheral CO2 chemoreceptors cessation of exercise, loss of neural stimulation continued stimulation of peripheral chemoreceptors during remaining recovery Respiratory ventilation: exercise-induced hyperventilation feed forward reflex: central nervous system feedback reflexes motor sensors joint movement muscle contraction chemo sensors O2 and CO2 levels synchronized with cardiac output plasma: [O2], [CO2], and pH ventilation also goes up because inspiratory muscles are activated arterial pH goes down during exercise ? slight acidosis, athletes can better support acidosis that occurs during exercise What limits VO2max? capacity of uptake/consumption of oxygen indirect calorimetry ? best method is to measure VO2max to estimate amount of work done direct calorimetry would be to measure the heat produced through movement, but very difficult to do this Oxygen consumption: factors sustaining or limiting exercise O2 consumption increases with increased exercise (measure with VO2max) limiting factors O2 ? cell availability, O2 deficit O2 ? transport to mitochondria, cell, blood, or lung Oxygen uptake during exercise oxygen uptake ? use of oxygen by the cells for aerobic metabolism VO2 ? mL O2/kg/min VO2max = max O2 uptake possible by individual quantification of aerobic capacity VO2max VO2max ? max oxygen uptake further increases in exercise intensity (further energy requirement) results in NO increase in VO2 additional energy is produced via anaerobic glycolysis the average young untrained male will have a VO2max of approximately 3.5 L/min and 45 mL/kg/min the average young untrained female will have a VO2max of approximately 2.0 L/min and 38 mL/kg/min VO2 absolute VO2 max male ? 3.0 and 6.0 L/min female ? 2.5 and 4.5 L/min this absolute value does not take into account differences in body size relative VO2max expressed in mL/min/kg 4.0 L/min and 75 kg ? relative VO2max = 4000/75, or 53.3 mL/min/kg Blood lactate threshold point at which lactate begins to dramatically increase in the bloodstream (55% VO2max) fatigue increases exponentially caused by increase in anaerobic metabolism ? lactate production VO2peak can be measured, but it will probably never reach actual VO2max ventilatory threshold ? point at which production of CO2 exceeds offer of O2 position of regression line changes leads to accumulation of CO2 in the body alternative approach instead of measuring blood lactate threshold Effect of training on blood lactate/lactate threshold study of the breaking point in the regression line of blood lactate vs. percent of VO2max some researchers prefer to measure blood lactate, others prefer to measure ventilation Ventilatory threshold bicarbonate buffers H+ above LT, blood pH decreases VE and VCO2 response to exercise intensity similar to blood La response H+ stimulates VE VE and VCO2 breakpoints sometimes used to indicate LT Health advantages of regular exercise: quality of life decrease in cardiovascular disease risks ? heart attack, stroke, high blood pressure decrease in blood pressure decrease in LDL and triglycerides increase in HDL, decrease in risk for diabetes blood glucose level decrease in obesity decreased stress association increased immune function moderate exercise enhances immunity, but strenuous exercise is a form of stress that depresses immunity Recovery recovery oxygen uptake VO2 stays high after exercise replenish ATP-CP reload hemoglobin supply elevated energy needs to cardiovascular system lactic acid removal (heavy exercise) Cori cycle reconversion in muscle cell ? lactate to pyruvate to glucose few seconds to a few hours light activity accelerates recovery increased blood flow to muscle, liver, and heart all can oxidize lactate for energy Summary exercise challenges a range of many systems involve in metabolism to produce maximal energy from various nutrient sources phosphocreatine most quickly produces ATP for muscle contraction while anaerobic glycolysis is intermediate aerobic ATP production is needed for endurance exercise ventilation and cardiac rate and output undergo huge changes which are anticipated by feed forward reflexes and protected by other reflexes to keep BP and temperature in homeostasis exercise reduces risk factors in many common health problems ? heart disease, obesity, diabetes, and stress
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