Long term regulation of blood pressure

Question 1

Overview of HTN

Answer 1

• A failure of renal compensation, based on hereditary and environmental factors
• BP is a function of ECFV and RAAS/SNS
• Kidneys have a physiologic role in maintaining pressure natriuresis
• Kidneys set the BP for the body by adjusting Na and ECFV

Question 2

Pressure natriuresis (short term regulation of BP) 1

Answer 2

• High arterial pressure signals for NaCl excretion
• Increased arterial pressure means less NaCl reabsorption in the PT (as a % of NaCl in PT- there is more of it)
• Leads to more NaCl delivery to MD which leads to TGF
• TGF will maintain a steady GFR despite this rise in arterial pressure, to bring Na filtration back to normal

Question 3

Pressure natriuresis (short term regulation of BP) 2

Answer 3

• On top of this there is a natriuretic response, which is decreasing Na reabsorption in PT to increase Na and volume excretion
• This is done by removing Na channels from the apical membrane of PT cells
• This decreases Na reabsorption and normalizes BP by decreasing effective circulating volume

Question 4

Long term regulation of BP

Answer 4

• The long term regulation of BP is to control ECFV above that which is needed to maintain CO/perfusion but below that which will cause damage to CVS/kidneys
• Kidneys will control baseline BP by regulating ECFV, which is based on dietary Na intake
• A higher level of Na would cause an increase in ECFV, but the kidneys promote Na and H2O excretion to normalize ECFV
• However this is at the expense of BP, since the BP baseline will increase as dietary Na increases even though ISF isn’t increases
• Thus the BP set point is increased w/ increase in Na intake

Question 5

Na/K ratio

Answer 5

• HTN is less likely to affect those w/ a low Na/K ratio

- HTN depends on low K, not just those w/ high Na intake

Question 6

When pressure natriuresis cannot decrease BP

Answer 6

• Usually due to a problem w/ increased aldosterone secretion (tumor)
• With this example, the increased aldo leads to increased Na reabsorption in the CCD
• This will increase the ECFV and BP, so pressure natriuresis will go into effect
• The Na reabsorption in PT will decrease and since this is proximal to the site of action of aldo there will be a reduction in the ECFV, leading to a slightly normalized BP
• The BP will stay elevated since the baseline Na has been raised (changes BP set point at which Na intake = Na output)
• The problem gets corrected everywhere (not just PT, also TAL and DT) except the site of the problem (CCD)

Question 7

Genetic diseases leading to sustained hypotension

Answer 7

• Na wasting d/o
• Gitelmans: LOF mutation in NCC in DT leads to hypotension and accompanying hypokalemia and alkalosis
• Bartters: LOF mutations in NKCC, apical K, or basolateral Cl (anything that decreases Na reabsorption in TAL), also leads to hypotension, hypokalemia, and alkalosis
• Pseudohypoaldosteronism (PHA): either due to LOF mutation of mineralcorticoid receptor or LOF mutation of ENaC (both lead to hypotension w/ hyperkalemia and acidosis)

Question 8

Genetic diseases leading to sustained hypertension 1

Answer 8

• Hyperaldosteronism or pseudohyperaldosteronism (mutations leading to activation of NCC)
• LOF mutations of 11BOHSD can lead to pseudohyperaldo (excess licorice consumption will do the same)
• Liddles: mutation in ENaC causes prolonged/excessive channel retention and Na reabsorption in CC
• MR mutations that allow binding of progesterone (appears during pregnancy)

Question 9

Genetic diseases leading to sustained hypertension 2

Answer 9

• Renovascular HTN: renal artery stenosis of a kidney causes RAAS activation from that kidney but leads to unregulated Na reabsorption from both kidneys and increases BP (goldbatt HTN)
• Renin-secreting tumor or elevated levels of angiotensinogen
• Gordons: mutations in WNK/SPAK leads to constitutive activation of NCC
• Calcineurin inhibitors prevent inactivation of NCC

Question 10

Overview of aldo producing tumor

Answer 10

• Increases Na reabsorption thru ENaC in CCD, leads to increase in ECFV and BP
• This is detected by increased atrial stretch which decreases SNS activity to kidney and increases ANP synthesis and release
• ANP will decrease IMCD Na reabsorption, and decrease RAAS/ADH release
• Increased MAP leads to increased renal perfusion pressure and thus decrease in RAAS and stimulation of pressure natriuresis
• Together these work by correcting the situation by reducing Na reabsorption everywhere in the nephron except in the CCD (where the problem lies)
• BP stays elevated since baseline Na has gone up, but new equilibrium established for Na in = Na out