organ systems: blood pressure regulation, potassium, diuretics

this unit talks about the different mechanisms used by the kidney to maintain blood pressure. in contrast to the short term regulation of blood pressure, which occurs in seconds or minutes when the baroreceptors in the aortic and carotid sinuses trigger a sympathetic pathway that increases cardiac output and decreases total peripherial resistance (recall from the vascular regulation lecture), the long term regulation of blood pressure occurs on the order of days to weeks and involves stimulation and inhibition of hormone systems which regulate fluid excretion in the kidney.

two conditions that are subject to regulation by the kidney are introduced: hypervolemia and hypovolemia. hypovolemia is the loss of body fluids via hemorrhage, dehydration, etc.; this is reflected in a decreased blood volume, which is sensed at both the cardiac baroreceptor level and also at the JGA apparatus. the sympathetic nervous response is to constrict the afferent and efferent arterioles (as well as ADH release in extreme cases), while JGA stimulates the renin-angiotensin system, the net effect being increased reabsorption. congestive heart failure or aortic stenosis can incorrectly stimulate a correction for hypovolemia: the decreased blood flow in these conditions will result in the JGA responding as if there is hypovolemia and cause excess reabsorption, leading to systemic edema. hypervolemia is the opposite condition in which there is excess fluid volume (due to fluid or salt intake). the body's response to this is to inhibit the renin-angiotensin system, and activate atrial natriuretic peptides, as well as pressure natriuresis. all three of these responses entail mechanisms that increase excretion and decrease reabsorption.

the next section talks about hypertension, which is essentially a chronically high blood pressure, and what it is caused by. "primary" hypertension seen in 90% of all cases of high blood pressure and usually involves the "blunted pressure natriuresis" phenomenon. pressure natriuresis is normally an increase in the excretion of water and solute in response to increased arterial pressure via a dilation of the vasa recta, which shifts the starling forces in a direction that inhibits reabsorption. excess angiotensin II and salt can oxidatively damage the vasa recta, not allowing it to vasodilate as easily; this means that the pressure natriuresis compensation begins at a higher pressure than usual (displayed a shifting right of the solute excreted vs. arterial pressure curve). secondary hypertension can be caused by a variety of conditions such as renovascular hypertension or renal parenchymal disease, the end result being salt retention and a rightward shifting of the pressure natriuresis curve. in salt-sensitive individuals with hypertension, increasing salt intake can further increase the pressure at which pressure natriuresis begins, due to the damage to the vasa recta and peripheral tissues that occurs in these individuals.

the progression of hypertension can be divided into three phases: phase I is characterized by a persistent excess of angiotensin II and sympathetic activity. phase II is characterized by the chronic vasoconstriction resulting from high angiotensin II, which begins to cause subtle renal injury and an increase in blood pressure/volume. phase III is when the pressure natriuresis occurs, lowering the blood pressure back down to normal, but resulting in a hypertensive kidney.


the next section looks at the regulation of the reabsorption of K+ in the kidney. control over K+ is important because most of the K+ in the body is intracellular, rather than in the extra cellular fluid- thus small changes in intake or excretion of potassium can have large effects. Most of the K+ reabsorption happens in the proximal tubules and is not controlled by hormone or ion levels. However, in the collecting duct, potassium reabsorption can depend on relative ion levels (the alpha-intercalated cells excrete H+ in exchange for K+ in response to a K+ deficiency) or hormone levels (the principal cells have sodium / potassium pumps that are upregulated by aldosterone)

the last section looks at diuretics, which are substances that increase urine output generally by blocking sodium reabsorption in different parts of the nephron, or by increasing the osmolality of the fluid in the lumen of the tubule (and therefore holding the water in the lumen to be excreted). osmotic diuretics such as glucose or sucrose increase osmotic retention in the proximal tubule, and also increase K+ secretion in the distal tubule due to the larger concentration gradient between the lumen and the interstitial space. loop diuretics block solute reabsorption in the thick ascending tubule and therefore osmotically pulls more water into the lumen to be excreted. thiazide is another diuretic that has the same effect on the distal convoluted tubule. caffiene is a diuretic that blocks reabsorption in both the proximal and distal tubule. all of these diuretics mentioned thus far have the potential to induce hypokalemia, a deficiency of potassium, because the hypovolemia that could develop might trigger aldosterone release, which would increase K+ excretion. a "potassium sparing" diuretic is an aldosterone inhibitor, which simply blocks the action of the sodium/potassium pump in the principal cells, leaving sodium in the lumen which increases osmolality and pulls water to be excreted.


questions
1. blood pressure is a measure of how effectively...
2. three factors that are needed to maintain adequate blood pressure...
3. blood volume is regulated by...
4. describe short term regulation of blood pressure.
5. describe long term regulation of blood pressure.
6. what is the timescale for the short term regulation of blood pressure?
7. what is the timescale for the long term regulation of blood pressure?
8. how is blood volume monitored?

9. what is the body's response to hypovolemia?
10. how can congestive heart failure or stenosis of the arteries lead to pulmonary edema?
11. what is the body's response to hypervolemia?
12. what is the difference between the response of the JGA and ANP/pressure natriuresis to hypervolemia?

13. describe what happens when pressure natriuresis is "blunted".
14. most cases of primary hypertension are due to...
15. most cases of secondary hypertension are due to...
16. what occurs in renovascular hypertension?
17. what occurs in salt-sensitive hypertension?
18. how does the pressure natriuresis curve shift in salt sensitive hypertension?
19. describe the two factors that affect the vascular tone of the vasa recta.
20. what effect do angiotensin II and salt have on the vasa recta?
21. what are the two ways in which damage to the vasa recta can augment vasoconstriction?
22. what are some other risk factors for hypertension?

23. what are the characteristics of phase 1 of primary hypertension?
24. what are the characteristics of phase 2 of primary hypertension?
25. what are the characteristics of phase 3 of primary hypertension?

26. what are hypo and hyperkalemia and how does the body respond to these conditions?
27. describe the reabsorption of potassium in the proximal tubules.
28. where is reabsorption of potassium hormonally regulated?
29. what are alpha-intercalated cells and what do they do?
30. what are principal cells and what role do they play in the regulation of reabsorption of potassium?
31. how does excess and deficient K+ affect the principal cells?

32. how do diuretics work?
33. how does heart failure lead to edema?
34. how do osmotic diuretics work?
35. most common treatment of hypertension is...
36. what does thiazide do?
37. describe the mechanism of the treatment of hypertension with thiazide and ACE inhibitor.
38. what do loop diuretics do and what are some examples of them?
39. caffeine causes diuresis by...
40. why is an aldosterone inhibiting diuretic called a potassium sparing diuretic?

answers
1. the vascular system perfuses organs with blood.
2. integrity/strength of vessels, compliance of blood vessels, and adequate blood volume (5L)
3. cardiac output, peripheral resistance,
4. baroreceptors sense changes in mean arterial pressure and adjust cardiac output and total peripheral resistance accordingly.
5. baroreceptors and salt detectors initiate neuroendocrine response that can adjust blood volume (and therefore blood pressure) by altering reabsorption of fluid in kidney.
6. response within seconds and can last for minutes.
7. days to weeks.
8. via baroreceptors in arteries, veins, as well as the juxtaglomerular apparatus.

9. baroreceptors and JGA cells trigger renin / angiotensin system which increases reabsorption, and in severe cases the CNS is triggered to release ADH which also increases reabsorption.
10. both of these conditions lead to a decrease in blood flow to the kidney, which triggers mechanisms that increase reabsorption, increasing fluid volume excessively and causing circulatory congestion and pulmonary edema.
11. inhibiting the RAAS system, production of atrial natriuretic peptides, and stimulating pressure natriuresis.
12. JGA involved mainly in suppressing renin-angiotensin system, which then decreases reabsorption. ANP/pressure natriuresis is more involved in increasing GFR (but still subject to glomerulotubular feedback)

13. blunted pressure natriuresis can be caused by damage to the vasa recta that reduces its ability to synthesize NO. this leads to higher blood pressures required to produce the same vasodilation, effectively reducing excretion and shifting the pressure natriuresis curve (sodium excretion vs. blood pressure) to the right.
14. high blood pressure, and blunted pressure natriuresis.
15. renal diseases that result in salt retention such as renal parenchymal disease, renovascular disease, pheochromocytoma, cushing syndrome.
16. hardening of the renal arteries decreases renal blood flow, eliciting the RAAS system and secretion of angiotensin II which constricts the arteries and shifts the pressure natriuresis curve to the right.
17. increased salt intake in salt-sensitive individuals causes short term increases in blood pressure.
18. the curve shifts to the right and the slope decreases.
19. angiotensin II released by local vessels and tubules cause pericytes around vasa recta to constrict by increasing intracellular levels of Ca2+. NO produced by thick ascending loop causes pericytes to relax.
20. creating reactive oxygen species that damage vasa recta via oxidative stress.
21. by exacerbating RAAS vasoconstriction and inhibiting vasodilation by NO, prostaglandins, dopamine.
22. genetics, age, obesity, insulin resistance

23. persistent excess angiotensin II and sympathetic nervous activity.
24. chronic vasoconstriction due to the angiotensin/NO balance lead to subtle renal injury which leads to sodium retention and increased blood volume/pressure.
25. pressure natriuresis curve shifts to the right; blood pressure rises and salt excretion increases.

26. hypokalemia is a deficiency of potassium which causes muscle weakness and twitches, and is compensated by increased K+ reabsorption. hyperkalemia is excess potassium which causes cardiac arrhythmias and excitability; compensated by increased K+ secretion.
27. 67% of potassium is reabsorbed in proximal tubules, 20% in thick ascending limbs. neither of these areas are regulated by hormone or ion levels.
28. in the distal tubule and collecting duct
29. cells in the collecting duct that actively reabsorb K+ via a K+/H+ ATPase pump.
30. principal cells make up 90% of the collecting duct epithelium and contain ATPase pumps that exchange K+ for Na+. aldosterone can upregulate these pumps, which increases Na+ and therefore water reabsorption, as well as increasing K+ excretion.
31. in K+ excess, ATPase pumps in principal cells are upregulated to increase excretion of K+. in K+ deficiency, aldosterone release is inhibited, causing more K+ to be retained within the body.

32. by inhibiting sodium reabsorptions at different points along the nephritic tubule.
33. heart failure causes a drop in arterial pressure which via the RAAS system induces higher fluid reabsorption in the kidney, causing a higher venous pressure. higher venous hydrostatic pressure causes fluid to leak out into the extracellular space, causing edema.
34. solutes such as glucose, sucrose, mannitol, corn silk, are filtered but not reabsorbed, leading to a higher solute concentration in the tubule and thus less reabsorption of water.
35. thiazide diuretics and ACE inhibitor
36. inhibits Na,Cl reabsorption in distal tubules leading to more water excretion
37. thiazide blocks the Na,Cl reabsorption in the distal tubules, leading to more water excretion. this could in theory produce a hypovolumic state, which would trigger aldosterone release and therefore K+ excretion. thus ACE inhibitors are used to block the formation of angiotensin II and counter K+ secretion.
38. loop diuretics block reabsorption of Na, Cl, K in the ascending loop of henle and thus increase water excretion. examples are: Lasix, ethacrynic acid, bumetanide.
39. inhibiting Na+ reabsorption from proximal and distal tubules.
40. it inhibits aldosterone release, which increases Na+ excretion in the water and retains more K+.

11.08.08 organ systems: vascular physiology and hemodynamics part 1

this was a long introduction to the more intricate details of blood flow dynamics. the beginning of the lecture introduced the larger structures of the circulatory system: the major arteries and aortas: the aortic arch, which branches into the braciocephalic, left common carotid, and left subclavian, with the braciocephalic branching off into the right subclavian and right common carotid. the thoracic aorta, which has intercostal, brachial, and esophageal branches. finally, the abdominal aorta, which has a visceral branch that is divided into the renal, suprarenal, and the GI branch, as well as a common iliac and femoral artery. other details of larger architecture: the right pulmonary artery goes underneath the aortic arch. the ligamentum arteriosum is the vestigial remains of the ductus arteriosum in the developing heart, which shunted blood from the pulmonary artery directly to the aorta, past the non-functioning lungs. the superior vena cava is a combination of the right and left brachiocephalic veins, which are each a convergence of the right and left internal jugular and subclavian veins.

we then zoom in and look at the smaller architecture of arteries, arterioles, capillaries, veins and venules. arteries have three layers, a tunica intima which has endothelium, sub endothelial CT, and an internal elastic lamina. tunica media is the middle layer with smooth muscle and external elastic lamina. tunica adventitia is the outermost layer, with fibrocollagen. arterioles have extensive smooth muscle (which, as it is explained later, helps create a large resistance which causes the largest pressure drop in the circulatory system), running 1-5 layers deep in the tunica media with less fibrous tissue in the tunica intima and adventitia. capillaries are described as the place for nutrient exchange, either through the membrane for lipid soluble solutes such as gas, or through the extensive pore network for water soluble solutes. veins and venules have thinner walls and less elastin, allowing them to function as a reservoir for the blood, containing up to 64% of the circulating blood.

then we shift to blood flow dynamics and begin with a simple equation describing blood flow: Q=P/R. blood flow equals pressure gradient divided by vascular resistance. blood flow is essentially cardiac output, which is stroke volume times heart rate, and is regulated by neural and endocrine systems. resistance is related to vascular resistance and is regulated by metabolic and neurohumoral systems. pressure is described as an "emergent property" which arises from the interaction of flow and resistance. which seems like just a fancy way of saying P=Q*R. pressure difference is then defined as Paorta-Pvenacava, but since Pvenacava is negligible, P=Paorta. we later find out that Paorta is essentially mean arterial pressure (the formal definition / estimation of which is diastolic pressure plus 1/3 of the difference between systolic and diastolic pressure). thus the most useful, applicable form of this flow equation seems to be (cardiac output) = (mean arterial pressure) / (vascular resistance)

several more terms are introduced in the discussion of blood flow. resistance is elucidated in the poiseuille equation as being proportional to the viscosity of the blood and length of the vessel while being inversely proportional to the radius^4. velocity is the measure of flow taking into account surface area; it can also be described as the speed at which the blood flows along the length of the vessel (as opposed to the flow, which does not account for this). capillaries have the greatest total surface area, making the velocity of blood drop considerably, allowing time for nutrient exchange. viscosity is used as a segue into the idea of laminar flow, which occurs as a result of blood/blood friction and also blood/vessel wall friction, causing the velocity to be greatest in the center of the vessel. finally, turbulence is described as proportional to the reynold's number, which is proportional to diameter of the vessel, density of blood, and velocity, and inversely proportional to the viscosity.

there are a few different aspects of blood pressure that are looked at in this last section. the first is the act of taking blood pressures via a sphygmanometer, which can measure systolic and diastolic pressure by listening for the pressure at which the korotkow sound appears, which represents the turbulence caused by the systolic pressure briefly opening up the occluded brachial artery. the diastolic pressure can then be determined when the korotkow sounds disappear, since the artery will be continuously open when diastolic pressure is slightly greater than the pressure of the cuff. the second is the idea of the two different types of blood pressure on the microscopic level: pressure that arises from blood/blood interaction, going along the length of the vessel, is described as perfusion pressure and is related to kinetic energy. the blood pressure that arises from blood/vessel wall interaction is called transmural pressure and is related to potential energy (in this case stored as pressure in the arteries).

the next aspect of pressure that is looked at is the pulse pressure, which is defined as the difference between the systolic and diastolic pressures, and as such is directly related to both stroke volume and compliance. we learn that in healthy circulation, there is a certain level of compliance in the aortas which allows for some of the stroke volume to be effectively "stored" in the arteries during systole, and the pressure created from this storage allows blood to flow in the capillaries even during diastole. in contrast, in arterial dysfunction involving low compliance, the stroke volume translates directly into the capillaries, not allowing for any additional flow during diastole. this is displayed graphically on the pressure vs. stroke volume graph, in which compliance is a line with a positive slope; where decreased compliance increases the slope of the compliance line, thereby increasing systolic pressure and reducing diastolic pressure. finally, three pathologies relating to pulse pressure are described: artherioscerlosis is a disease in which the arteries have lower compliance, causing higher systolic pressure and therefore larger pulse pressure. hypothyroidism and aortic stenosis are both diseases in which the stroke volume is reduced, which also leads to an reduced pulse pressure.