Hypertension

Question 1

What’s the mechanism of volume overload in heart failure?

Answer 1

CO decreases, we get “effective volume depletion” which stimulates RAAS, and aldo increases salt retention and we get excess volume.
- Also, AngII stimulates release of NE from nerve endings and release of catecholamines from adrenal medulla

Question 2

4 effects of Ang II

Answer 2

1) vasoconstriction, systemic as well as efferent arteriole
2) Enhances release of NE from nerve endings and catecholamines from adrenal medulla
3) growth factor for smooth muscle cells
4) release of aldosterone (^ Na reabsorption)

Question 3

ADH release mechanism

Answer 3

Volume depletion or increased osmolarity –> hypothalamus –> posterior pituitary –> ADH release

Question 4

What plays biggest role in BP maintenance during postural changes?

Answer 4

Sympathetic NS

• -> SNS also triggers renin secretion in juxtaglomerular cells
• -> SNS also causes Na reabs in PCT

Question 5

ANP release?

Answer 5

When right atrial pressure increases, ANP released. This induces diuresis and natriuresis; also potent vaso-relaxer.
- believed to prevent increases in arterial pressure during volume overload.

Question 6

Nitric Oxide

Answer 6

Synthesized from arginine in endothelial cells. Vasodilator. Increases during expansion of ECF (during high salt diet, e.g.) and prevents increases in pressure during volume increase.

Question 7

Pressure natiuresis theory

Answer 7

States that if kidneys are not efficient at excreting salt, then we must increase BP to maintain GFR at a rate that can still excrete sufficient amounts of sodium.
Evidence: kidney transplant switching in mice – BP Follows the kidney
Salt restriction improves! Effective of dietary sodium restriction is most prominent in resistant hypertensives.

Question 8

Thirsty Gene Hypothesis

Answer 8

We have hyperactive RAAS system because our ancestors were on low salt diet and required RAAS and aldo to maintain BP. In our modern diet this becomes problematic because overactive RAAS and ^ aldo even with high salt intake. Thirsty gene theory summary: genes don’t allow you to suppress RAAS as well as others; makes sense 
for ancestors who relied on RAAS to remain normotensive

• -> Inappropriate hyperaldosteronism!
• Adipocytes send cell signals to increase aldosterone

Question 9

Dysfunctional gastro-renal axis theory

Answer 9

Relationship of gastrin and sodium excretion: you eat sodium, and your stomach senses this and goes to the PT cells and tells them to excrete sodium via dopaminwhich inhibits the Na-K-ATPase in the PCT.

Support in research: If you take two rats and infuse gastrin and measure sodium excretion, only normotensive rat can get diuresis and 
natiuresis – means it can respond to gastrin. The hypertensive rat does NOT respond to gastrin, does not get natiuresis.


Question 10

Causes of secondary hypertension

Answer 10

• Hypersecretion of renin (tumor or as a result of renal artery stenosis)
• will see elevated renin, ang II, and aldo

Question 11

Hyperaldosteronism

Answer 11

• will see low K, low renin
• most commonly from aldo secreting tumor in adrenal cortex
• can also see alkalosis because aldo is a potent stimulus of renal K+ and H+ secretion

Question 12

Gluco-corticoid-remideable aldosteronism

Answer 12

Genetic condition where we have chimeric enzyme w/ regulatory region of cortisol (under ACTH control) w/ coding region of aldosterone synthetase. Leads to production of ACTH-stimulated aldosterone, volume expansion and HTN. Administration of cortisol lowers ACTH and reverses HTN.

Question 13

Liddle’s Syndrome (clinical pic + cause)

Answer 13

• clinical pic: looks like hyperaldo but w/ low aldo levels
• Mutation of gene that encodes for Na+ channel in collecting duct; leads to unregulated gain of function and reabsorption. Can treat w/ Na channel blocker like amiloride

Question 14

Neurogenic hypertension

Answer 14

ex: Pheochromocytoma. Tumor in adrenal medulla and SNS chain in chromaffin cells. Pulsatile release of catecholamines.

Question 15

AME

Answer 15

Apparent mineralocorticoid excess (AME) is an autosomal recessive[1] disorder causing hypertension (high blood pressure) and hypokalemia (abnormally low levels of potassium). The condition responds to glucocorticoid treatment. It results from mutations in the HSD11B2 gene, which encodes the kidney isozyme of 11β-hydroxysteroid dehydrogenase type 2. In an unaffected individual, this isozyme inactivates circulating cortisol to the less-active metabolite cortisone. The inactivating mutation leads to elevated local concentrations of cortisol in the kidney. Cortisol at high concentrations can cross-react and activate the mineralocorticoid receptor, leading to aldosterone-like effects in the kidney. This is what causes the hypokalemia, hypertension, and hypernatremia associated with the syndrome.

MIMICKED BY EATING TOO MUCH LICORICE due to Glycyrrhizic acid
- Also cushing’s

Question 16

Conn’s

Answer 16

Primary hyperaldosteronism. Two types of abnormality are seen: a benign tumour of one adrenal, called an adenoma or a general enlargement of both adrenals, called hyperplasia.

• Adenoma treatable by surgery
• Hyperplasia treated by mineralcorticoid agonist

Question 17

Adenoma K+ channel mutation

Answer 17

Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation.

Question 18

Medial fibromuscular dysplasia

Answer 18

“String of beads” on renal arterial angiography. Patients with FMD have abnormal cellular growth in the walls of their medium and large arteries. The arteries may also become narrow (stenosis). Most cases of FMD affect the carotid and renal arteries.

Question 19

Renal artery stenosis

Answer 19

Low flow causes ^ RAAS and Na retention and HTN.

Renin levels can normalize but that does not necessarily rule out renal artery stenosis.

Due to FMD in young people and atherosclerosis in elder.

Question 20

Gitelman syndrome

Answer 20

Looks like pt is abusing thiazide diuretics (loss of function mutation in thiazide sensitive NaCl transporter).

• Auto recessive
• Hypotension
• Hypokalemic metabolic acidosis
• elevated RAAS
• Hypocalciuria

Question 21

Bartter Syndrome

Answer 21

• Loss of function in NKCC2, ROMK or CLCNKB; looks like loop diuretic overdose
• auto recessive
• severe hypotension, early onset
• Hypokalemic met alkalosis
• Elevated RAAS
• hypercalciuria
• massive salt supplementation, usually fatal.