---start physio.lec.1.7.97--- a couple of slides to continue from the handout: PaCO2 and PaO2 ventilation is proportional to metabolic rate VENTILATION IS PROPORTIONAL TO METABOLIC RATE!! oxygen consumption, ventilation, and alveolar pCO2 graph. when met rate goes up, ventilation rises IN PROPORTION to metabolic rate. so level of CO2 in alv stays constant, because VENTILATION IS PROPORTIONAL TO METABOLIC RATE. so you can have large ventilatory changes w/o concomitant changes in CO2. so if you are asked, with large ventilation, what is PaCO2 (arterial)? you can't answer. But, if you're told CO2 is high, you can say that ventilation is low. If ventilation is high, you do not know why it is - could be exercise, and CO2 is normal, or could be you have high CO2 causing increased ventilation. so ventilation is occuring, and oxygen is being brought to cells and CO2 is being removed. ventilation is providing for O2/CO2 transport/removal. so O2 and CO2 are involved in control of ventilation. so ventilation does change if you change concentrations of O2, CO2, and H+. the resulting ventilatory change will moderate the changes in the gases. if O2 is low, you increase vent to increase O2. if CO2 is high, you increase vent to blow off more CO2. so, looking at CO2 and concomitantly H+ which is a large factor... when looking at CO2, there are two important curves to consider. One we've had already...that's the PCO2 vs V* curve, relating changes in vent to changes in PCO2. at fixed metabolic rate, as vent goes up, CO2 goes down, nd as vent goes down, CO2 goes up. this is metabolic hyperbola at fixed metabolic rate. as you change metabolic rate, the relationship stays the same, but it's just a different curve eg will shift to right or to left. this is in the handout under alveolar ventilation. now, there's a second graph that is important. that relates %CO2 to V* typical animal: pCO2 of 40, ventilation of 5 then you can put first graph onto second graph.looks like same curve. this is the same metabolic hyperbola. we've just changed the x and y axes. as you breathe increasing amts of CO2, you get a linear increase in ventilation. if you go below normal CO2 you find that ventilation doesn't drop much, it stays constant. if you go below normal 40, ventilation is being driven by something else. and once you get abouve 10-15% CO2 vent doesn't rise as much and can begin to fall. high concentrations of CO2 is an anesthetic gas. then you can do things to manipulate the curve which we didn't do in lab. can change the slope of the curve by changing the oxygen concentration breathed. if you breathe low conc. of O2, what happens to vent ? it increases. if ventilation goes up, what happens to co2? it decreases. so if you breathe high concentrations of O2, and there's no change in met rate, vent will go up, CO2 will drop, and then. this is at low conc. O2, eg at altitude. then, if you give increasing concentrations of CO2 to breathe, ventilation will increase more sharply than it did before. so the combination of high CO2 and low O2 is a very strong stimulus to increase ventilation. when you see high CO2 and low O2 in patients it is due to obstruction/choking/hypoventilation. if you breathe high conc O2, vent will go down, CO2 will go up, and the slope of the line of increased vent due to increased breathing of Co2 goes down. so if O2 is high, you are less sensitive to increased CO2. so oxygen changes this slope, and so do anesthetics. halothane lowers the slope causing decreased increase in vent in response to increased CO2 - at high conc halothane can remove any ventilatory response to increased CO2. other things will move the slope in parallel manner. if you exercise, ther eis no change in sensitivity, but for any given concentration of CO2, you're at higher ventilatory rate. same w/acidosis. alkalosis or sleep will cause lower ventilatory rate at any given concentration of CO2. now based on these studies, people tried to figure out what is stimulus to breathe. they said CO2 is main drive to breathe. RO says not quite. look at it in terms of the BRAIN is the main drive to breathe. this is because the increase in ventilation seen in exercise (20-30x resting) without a change in CO2, so how can CO2 be a drive to breathe? breathing CO2 is a VERY ABNORMAL thing. usually this isn't happening, it only happens in the lab. ever sit in a sauna? if you want to regulate body temp, one way to get rid of heat is to vasodilate. usually, the outside is at a lower temperature than the inside so vasodilation releases heat. sitting in sauna, you vasodilate but you TAKE IN heat. so body isn't adapted to sauna. [guess it's not adapted to death valley, either.] similarly, we aren't adapted to CO2. gas tanks didn't exist when we were evolving. so...BRAIN sets level of ventilation according to movement signals and something unknown in brain. then if that isn't proportional to metabolism, CO2 may change, and CO2 acts as signal to fine tune ventilation. so when exercising you don't see changes in CO2 unless your ventilation is not appropriate for your metabolic rate. that's how RO looks at it. some people worry about if O2 is more important signal than CO2 but that isn't important. both of them are important under certain circumstances. another important thing to know is - if he tells us this animal has a CO2 that's higher than normal and asks us what the ventilation is, don't think it must be high because CO2 is high. CO2 is a strong drive to breathe, but that doesn't always translate into actual breathing. if there is pulmonary disease, animal may have ENORMOUS drive to breathe, but it is hypoventilating because lungs are shot (like that CF kid on ER last night...) similarly, the drive to get As can not always be converted into As. must be converted byy some mechanism (old exams) into actual As. there's CO2 in blood and CO2 in brain. there are two known areas of CO2 sensors. CO2-H+ central chemoreceptors: are in brain. where in the brain, we don't know, and RO doesn't care. they're in the ventral medulla...MAYBE. what's important is that these receptors are sensitive to extracellular fluid pH. CO2 will set ECF pH, so changes in CO2 will change ECF pH. if you increase [H+] in brain (drop pH - increase CO2), you will increase ventilation. if you increase ventilation, you decrease CO2, so you decrease [H+], and raise pH, and then you can ventilate less. brain uses the lung to control its own pH. neurons like a constant pH. this is set by partial pressure of CO2 and HCO3-. the other receptors are the PERIPHERAL CHEMORECEPTORS. aka carotid body and aortic body. carotid body at bifurcation of internal and external carotid and is sensitve to changes in the CO2 H+ and O2 of blood. the carotid SINUS is a stretch receptor, unrelated to this. carotid body is HIGHLY perfused, and very sensitive to changes in ABG levels. these are neurons that have a certain firing rate. the firing rate changes as CO2 changes. as you raise CO2, firing rate increases if you raise CO2 and lower O2, receptors increase their sensitivity to increased CO2 - so they are very sensitive to choking. animals choke before they ever breathe high CO2. choking is MAJOR drive to breathe. if you give a person 100% oxygen to breathe, ventilation will go down. so there's ordinarily some oxygen drive to breathe, because if you raise oxygen enough you lower ventilation. graph V* vs pO2. as you lower pO2, ventilation stays constant til you get to about 60, then rises. this oxygen response curve is quite complex due to many factors. one of most important factors is the fact that low oxygen is a stimulus to breathe, and as you lower oxygen, you get a stimulus to breathe. decreased O2 causes increased ventilation which decreases CO2 which decreases drive to breathe as you recall. until you get to about 60 these balance out. at 60, drive from low O2 starts to exceed loss of drive due to low CO2. if you keep CO2 constant at 40, you see increase in ventilation whenever you lower O2. combination of low oxygen and high CO2 gives higher drive to ventilate so shape of curve is influenced by receptors and change in CO2 levels. low oxygen causes increased drive to breathe which lowers CO2 which decreases drive to breathe... also due to the amt of oxyHb which changes w/acid base status. when large amts of oxyHb, you have acid blood. this gives poor tissue buffering, brain gets acidotic, and you have increased ventilation again. there is no receptor in brain that responds to low oxygen w/increase in firing that drives ventilation. there are no central O2 receptors. that is ZERO CENTRAL OXYGEN RECEPTORS exist. there are NO CENTRAL OXYGEN RECEPTORS at all. only peripheral chemoreceptors are sensitive to oxygen. aortic and carotid body. NOT AORTIC ARCH AND CAROTID SINUS. the aortic body and carotid body have oxygen sensitivity. also know you have to measure arterial CO2 to assess ventilation. the CAROTID BODY is the major peripheral chemoreceptor. responds to partial pressure of O2 in arterial blood. this organ is VERY highly perfused and can meet all metabolic needs using dissolved O2. it responds to dissolved o2 unless things get really bad. if you look at PO2 and firing rate, as the pO2 drops, firing rate increases in hyperbolic manner just like O2 response curve. if you make animal hypercapnic there's a shift to the right. if there s no central stimulus, if you cut the connection to the CNS from here, animal will have depressed respiration and becomes hypoxic. slide: chemoreceptor activity vsPaO2 - PaO2 decreases cause increases in firing of receptors. but if you change the Hb-carbon monoxide level, there is no increased firing, no increased drive to breathe, because you still have DISSOLVED oxygen in the blood, but you don't have oxyHb forming. you do get increased CO though. this is similar with anemia because the receptor is sensitive to PaO2, not to oxyHb. dissolved O2 stays the same but oxyHb level drops in these situations. -----break---- back to WATER BALANCE: we were talking about osmotic pressure which causes water movement and is kind of like diffusion...the water is moving from an area of low conc. of solute to high conc of solute eg from high conc of water to low conc of water. we talked about diffusion of Na+ but it's similar with any substance.simple diff follows conc.gradient and is unlimited in terms of quantity - eg gradient = limiting factor. the rate of change of sodium ions is dependent solely on concentration gradient in simple diffusion. for carrier mediated diffusion there is an upper limit determined by carrier capacity. when carrier is saturated, rate no longer increases. for active transport, you're limited by supply of ATP. this mechanism works AGAINST The concentration gradient and REQUIRES ENERGY. also we discussed endo/exocytosis - pinching off of membrane. bulk flow/filtration/absorption: method of fluid exchange betw plasma/interstitial spaces. not that important in terms of total exchange of water. we also said that there's an inequality of ions across the plasma and interstitial space because there's anion trapped in plasma space (protein) that can't get out, so the other anions distrbute unequally: gibbs-donnan equilibrium. in system where solutions are separated by semipermeable membrane and a non permeant ion (protein anion) is present on one side, the free diffusible permeable ions will distribute in unequal concentration son the two sides of the membrane. on the side contianing the non-permeant protein anion, the concentrations of the the permeant anions will be less and of the cations will be greater two thermodynamic requirements will be met at equilibrium: there will be electroneutrality on each side of the membrane so on plasma side, the sodium = cl- + protein- and on other, Na+ = Cl- the other requirement is that the product of the concentrations of a pair of permeant anions and cations on one side of themembrane will equal the product of the same pair on the other side. eg [Na+]p[Cl-]p = [Na+]i[Cl-]i donnan ratio: [Cl-]p/[Cl-]i = [Na+]i/[Na+]p say you have 5 Na+ and 5 P- in plasma and 10 Cl- and 10 Na+ in interstitium. at equilibrium you get 5 P- 9 Na+ and 4 Cl- in plasma, and 6 of Na+ and Cl- on other side. see formulae p 8 of handout. at equilibrium; [Na+]p = [Cl-]p + P- [Na+]i = [Cl-]i [Na+]p * [Cl-]p = [Na+]i * [Cl-]i at equilibrium net osmotic pressure causes water to go from interstitium to plasma - more particles in plasma, remember. this is colloid osmotic pressure because it is the protein causing this all. donnan ratio: [Cl-]p/[Cl-]i = 4/6 = .67 [Na+]i/[Na+]p= 6/9 = /67 STARLING HYPOTHESIS for capillary fluid exchange at arteriolar end, intracapillary hydrostatic pressure is 40-45 ; this is the pressure trying to push fluid OUT of the capillary. as you flow down cap, there's a pressure drop. at venule end, hydrostatic pressure is about 10-15 mmHg only. the colloid osmotic pressure due to protein in plasma is constant at -25 to -30 mmHg trying to suck water IN to the capillary, and this is constant along hte capillary. there's also something called Tissue Pressure - tissues squeezing interstitial space, -2 to -5 mmHg trying to force water IN to capillary (some people say it's trying to force water OUT of capillary) but it's not really significant. if you consider all of this, at the arteriolar end there is a 10-15 mmHg net positive pressure forcing fluid OUT into tissues - this is FILTRATION. at venule end, there's a net -10 to -15 mmHg pulling water IN to capillary, and this is absorption, and together they are BULK FLOW. these effects are minimal compared to diffusion but still significant. in muscle of forearm, .003 mL/min/100g tissue. but by diffusion, fluid turns over about 300 times a minute. the importance of this mechanism is obvious, though, in the glomerulus. finsih up by talking about changes between extra and intracellular compartments three things to remember; 1. since ions and water move freely across capillary endothelium, the plasma and interstitial spaces behave as a SINGLE EXTRACELLULAR COMPARTMENT (eg ignore gibbs donnan) 2. WATER moves freely across cell membranes, but they are functionally IMPERMEABLE TO SODIUM IONS 3. WHEN SALT or WATER are added or removed to/from the extracellular space, WATER MOVES to PRESERVE OSMOTIC BALANCE. DILUTION EQUATION: Quantity = Concentration * Volume normals total body water C = 300 mOsm/L ; Q = 12600; V = 42 intracellular space C = 300 V = 23 extracellular space C = 300 V = 19 (can solve for Q easily) what would be osmolarity and compartment volumes if you drink a liter of water- adding one liter to extracellular space? this changes total body osmolarity- reduces it, dilutes it out. Q = CV if osmolarity of extracellular space decreases, osmolarity of intracellular space will decrease until the two are equal think of this. C = Q/V 300 mOsm/L * 42L -------------- = 293 mOsm/L in both ECF and ICF 43 L (added one) V = Q/C (EXTRACELLULAR VOLUME) 300 * 19 L ----------- = 19.45 L - a shift of .45L to extracellular space 293 mOsm/L remember, salt can't move...water moves. p 10 handout: urine output and mOsm/L of total body vs time. this shows that a liter of water does cause this change. urine output then goes up, raising osmolarity, until kidneys clear that liter of water, bringing osmolarity back to normal. now, what if we add SALT to extracellular space? We're adding 486 mEq solute - like drinking a pint of seawater (3% salt) what happens to volume of EC space? will go up. IC space? goes down. look at this again. calculating Q = 300 mOsm/L * 42 L + 486 mOsm added Q/42 L (a pint being insignificant) resut C = 311.6 mOsm/L is the new osmolarity now, looking at intracellular volume V = Q/C V = 300*42 (this is normal Q)/311.6 (new osmol.) = 22.1 L --> a loss of .9 physiologically, this will make you feel thirsty. you will drink enough water to dilute this back to 300 mOsm/L - which will be 1.6 L water. so drinking sea water shrinks IC space. also, kidney can only clear about 2% saline, and sea water is 3%, so you never clear it, and you keep shrinking your IC space until you die. [now he's going off on the primordial soup theory and the osmolarity of THAT sea vs TODAY's see (obviously pr.soup was more dilute) and i'm totally amused that this is even an issue :)] what happens if you drink isotonic 0.9% NaCl? not much. osmolarity will not change, nothing will drive water movement, so you just expand the extracellular space not the intracellular space. that's why you give it. now what happens if you REMOVE say 486 mOsm of solute from ECspace? eg, using dialysis or something. i'm guessing you shrink the EC space, myself. osmolarity relies on thirst and kidney to be maintained. we can drink water, and our kidneys can modify excretion of salt and water. so thirst is brought about by losses of water or gains in sodium. and the kidney has osmolar regulation and volume regulation, depending on what has to change to initiate the mechanism. so for OSMOLAR regulation you regulate exretion of water, stim by hypotonic ECF stimulating receptors causing ADH release from p.pituitary, which acts on kidney to induce water retention/reduced water output. VOLUME reg involves aldosterone and ADH and changes in glom.filtration rate and release of Atrial Naturetic peptide. renin release which generates ATI and II which acts an adrenal to release aldosterone. Ald acts on kidney to increase sodium reabsorption. ADH system is triggered by pressure sensors in L atrium. this triggers ADH release and ACTH release which causes aldosterone release. changein glom filt. rate due to changes in osmotic pressure eg starling mechanism favoring movement of water INTO plasma space (increases filtration). last p handout has nice flow chart for review. ----break--- Renal Physiology, Dr Bovee x 2057 GUYTON textbook of Med Physiology ch 26-30 are useful<--handout figs from here. BOVEE Canine Nephrology ch 3 -10. <--handout figures from here. kidney has multiple functions: excretory, regulatory, metabolic, endocrine. two MAJOR functions are to excrete metabolic end products via urine, and to control concentration of solutes in body fluids. partial list of normal fx: renal circulations glom ultrafiltration transpport of multiple solutes renal acidification mechanisms vasopressin and urinary concentrating mechanisms. renal handling of anion and cation including uric acid excretion vasoactive peptides arachidonic acid metabolites renal clearance of peptides we're going to have a general discussion of renal physiology in all species. they are very similar and he will tell us of any major differences. we have TONS of info from dog, rat, man. there's very little known about farm animals, we just assume they're similar. [THAT'S great. hmmph.] No farm animal renal physiologists exist. kidney is complex organ which interacts w/many other organs and understanding it is critical to understanding many diseases and diagnostic tests. STRUCTURAL FUNCTIONAL relationships in kidney structure and function are closely related. structures in close proximity are close to each other for a very good reason. we should consider kidney not as "That bean shaped organ" but as a group of nephrons, that's why kidney study is NEPHROLOGY. the discussion will begin with the blood vessels. kidney is very unusual in terms of blood supply. slide: cortex w/glomeruli and fine fibrillary arteriolar and venular circulation. the organization of the vasculature - first you havve the outer portion labeled C for cortex, then you have outer and inner medulla see fig 3-2 p 2 of handout. the large vessels are arcuate artery and vein. the nephrons are located in the cortex, you can see the glomeruli and proximal tubules and the tubules descending down. so, cortex/outer medulla/inner medulla/papilla. note: a few juxtamedullary glomeruli exist and fewer still are actually in the outer medulla, but most are in cortex. two kinds of nephrons: cortical population - 75-80%: from capsule down to about 3/4 way through cortex. has relatively short tubular segments - prox tubule entirely within cortex, loop of henle descends and returns to distal tubule...then there are juxtamedullary nephrons which are larger than the cortical nephrons, and which have a different anatomy to their tubules. they hae very LONG tubules and the limbs of henle go all the way down through inner medulla to papillae. this are the nephrons that allow concentration of urine. fig 1-12: structure of nephron. you can see the nephron has 6 types of tubular cells (oversimplification). look at the vasculature coming into the glomerulus - at top is afferent arteriole leading in and efferent going out. then you have glom. capillary, and then tubule begins. first you have proximal tubule: cell with very dense brush border and dense intracellular structure. major workhorses. transport lg volumes of solute and water out of the filtrate, remove it from potential urine and return it to interstitial space. next, at end of prox tubule, you are in the vasa recta, and the cells are less sophisticated, less brush border, less dense organelle situation. but these cells absorb a lot of bicarb and/or [something i missed] then, cells lining loop of Henle - these are flatter, squamoid cells. don't do major active transport - more involved in passive transport. these cells are related to concentrating capacity of kidney and are less important wrt major fx of kidney. next, thick ascending limb cell: present in first part of distal tubule. more sophisticated, involved in special transport system for na+ and Cl-. then, you pass the afferent and efferent arteriole and there are tubular cells passing by right next to these arterioles. these epi cells actually become attached to afferent arteriole, and have ability to send signals to afferent arteriole based on urine content - causing dilation or constriction. these are the juxtaglomerular apparatus cells of the macula densa. then the urine leaves distal tubule and enters collecting duct. collecting duct is active transport site - electrolytes and water regulated here. kidney recieves a VERY large quantity of blood flow. it's trying to conserve solute so it isn't lost into urine. at same time, allows some stuff to be excreted - waste products. so this is the regulatory fx of kidney. to go to regulatory state effectively, kidney has series of hormones it uses, from kidney itself and from other sites. blood flow: kidney gets 20% of CO - more than any other organ on a flow per gram basis except some other weird endocrine thng. this is set up this way due to phylogenetic development...we're descended from marine animals living in saline environment - ended up with system that needed huge flow to maintain homeostasis - because it's so ineffecient. now, the kidney regulates its solute in close correlation to blood coming to it. special consideration of flow through various compartments of vasculature, glomerular capillaries, and peritubular caps. there's one renal artery and you have branching and then you have arcuate arteries branching into lobular arteries and then into afferent arterioles goign to glomeruli. # of glomeruli depends on size of animal. if kidney is going to get this huge bloodflow needs regulatory mechanism. fig 1-12 shows breakdown of vessels as they enter and leave kidney. you have your two populations of nephrons, and you can see that the cortical ones are shorter. the juxtamedullary ones are longer, going all the way to papillae. you can see the density of peritubular capillaries representing the venous portion of the nephron, which are available to reabsorb the large quantities of solute and water after they're resorbed by tubule. they are wrapped around most active tubular sites: eg proximal and distal tubule, and ascending limb of henle.if you lookat slide you can see efferent arteriole comes out of glomerulus, then peirces down into outer and inner medulla, but it does'nt go as just one vessel. for juxtamedullary gloms, there's a special thing called VASA RECTA: peritubular capillaries which wrap around and do something i missed 'cause some LUSER answered the phone, the bundles turn into veins and go back up into the large vein that lies next to the arcuate vein which returns blood to renal veina nd central circulation. so as you go down the vasa recta, there's a lower and lower blood flow. so there's a lack of density of vessels in inner medulla and papilla. so there's very low flow in deeper part of kidney, 'cause vessels are very small. those vessels are responsible for special type of transport process allowing us to concentrate our urine. back on p 3 we talked about the two pops of nephrons: one other thing. the cortical population is highly regulated and we say they are highly AUTOREGULATED, having inherent ability to change their tone to control amt of blood flow to them. the juxtamedullary nephrons are POORLY AUTOREGULATED and not as able to vasoconstrict. sometimes we wish they could. we talked about low flow through vasa recta. now hydrostatic pressure fig 4.2 as it changes from aorta through vascular compartments of kidney and then exits as renal venous blood. this pressure is generated by CO and tone of vasculature in general throughout body. we begin w/pressure of about 100 mmHg (normal in about all species)(these are all MEAN pressures) at the afferent arteriole. the kidney has a special way of regulating this, not influenced by CO, plasma volume, or general vascular tone in body. needs to regulate its own blood flow since it's so high. as soon as you get into afferent arteriole there is considerable vascular tone there, and pressure is reduced, and slow is blunted, so that by the time you get to glomerular capillary you're down to near 60 (handout says 40?). then, crossing glom cap, you lose another 3 to 6 mmHg. you can consider the glom caps as part of the arterial side, and efferent is "venous" side, though not really. at efferent side there's a rapid drop in pressure due to tone and volume of fluid. the peritubular capillaries have a relatively low pressure of 15-20 mmHg and are stable, you don't change across them. then you get to venule/arcuate vein and pressure drops a bit more, and then a bit more into renal vein (to about 10). pressure is major driving force w/in kidney. hydrostatic pressure changes in specific anatomic sites. see fig 4-31 for pressure labelled anatomical diagram. note smooth muscle cells present at end of afferent and beginning of efferent arterioles. what about pressure in nephron? that's also hydrostatic pressure: CO vs resistance.. 18 mmHg inside lumen of nephron (low compared to cap) stays same til distal tubule, ends up about 10, then bottoms out at zero. why so low? epithelial system, no tone, and ureter/bladder very low pressure system. function of peritubular capillaries. we've already said that these peritubular capillaries are important for reabsorption, but there's another force inside them, and another force inside all this vasculature and that's the ONCOTIC pressure, a pressure generated by concentration of serum proteins present inside the lumen of the vasculature. a small amt may also be in lumen of nephron, and may be in interstitium. oncotic pressure is very impt to ability of capillaries to suck in the fluid reabsorbed by tubules. so...hydrostatic pressure and oncotic pressure important and oppose each other. difference bet two determinse rate of flow of fluid in and out of peritubular capillary and other tubules and stuff. ---end---