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Physio Endocrinlogy Quiz 1 > Mineralcorticoids > Flashcards

Mineralcorticoids Flashcards

1
Q

What are the two main mineralocorticoid hormone?

A
  • Aldosterone

* 11-deoxycorticosterone (DOC).

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2
Q

In what tissue is aldosterone produced?

A

• Exclusively in the zona glomerulosa of the adrenal cortex.

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3
Q

In terms of plasma levels, what is higher glucocorticoids or mineral corticoids? What disease develops in the absence of aldosterone?

A

• Although the daily secretion rate of aldosterone is very low, only about 1/100th of that of glucocorticoids, this small amount is essential for life, since in its absence, such as in Addison’s disease, a life-threatening electrolyte imbalance develops.

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4
Q

Explain the Synthesis of Aldosterone.

A

(I did a flow chart for this one. See the long form word doc SBQs or the ppts) Aldosterone is synthesized exclusively in the zona glomerulosa of the adrenal cortex through the action of four enzymes. The first steps of aldosterone synthesis are the same as those that are involved in cortisol synthesis. Cholesterol is converted to pregnenolone, which then undergoes dehydrogenation and isomerization to yield progesterone. Progesterone is converted to 11-deoxycorticosterone through hydroxylation of the 21-carbon atom by a microsomal cytochrome P450 enzyme (P450c21). This compound is further hydroxylated by P450c11 (also called steroid 11ß-hydroxylase or CYP11B) to corticosterone, a glucocorticoid. Corticosterone is then converted through 18-hydroxycorticosterone into aldosterone. Surprisingly, the three terminal steps (i.e., 11ß-hydroxylation, 18-hydroxylation and 18-methyl oxidation) are catalyzed by the same mitochondrial enzyme, aldosterone synthase (or CYP11B2). There are two isoforms of CYP11B enzymes in the adrenal cortex: CYP11B1, which converts 11-deoxycortisol into cortisol, and CYP11B2. This latter isoform is present only in the zona glomerulosa, which is why aldosterone synthesis is restricted to this region.

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5
Q

Where is DOC synthesized?

A

• both the zona glomerulosa and zona fasciculata (mainly in the fasciculate)

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6
Q

How does the activity of DOC compare to aldosterone? At what levels is it produced compared to aldosterone? What is DOCA ?

A
  • The biological activity of DOC is only about 5% of that of aldosterone and it does not play a significant physiological role under normal conditions.
  • It is synthesized in higher quantities than aldosterone
  • Synthetic acetate derivative, DOCA, is a clinically useful and easily available substitute for aldosterone.
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7
Q

What are the normal blood levels of aldsosterone?

A
  • The secretion rate of aldosterone in people on normal sodium diet is between 40 and 200 mg per day, about 1/100th that of cortisol.
  • The normal level of aldosterone in human plasma ranges from 50-150 pg/ml or 150-450 pM, roughly 1/1000th that of cortisol.
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8
Q

What percentage of blood aldosterone is “free”? What is the rest bound to?

A
  • 40% of the circulating aldosterone is free.
  • The rest is weakly bound to proteins, mainly albumin.
  • There is no specific aldosterone-binding protein comparable to corticosteroid binding globulin (CBG).
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9
Q

Since there is no specific aldosterone-binding protein comparable to corticosteroid binding globulin (CBG), how does aldosterone degradation compare to cortisol degradation? Where is aldosterone degraded? What is the half life of aldosterone?

A
  • aldosterone is more rapidly inactivated than endogenous glucocorticoids.
  • Aldosterone is inactivated during one passage through the liver
  • a half-life of less than 30 minutes.
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10
Q

How does liver cirrhosis or severe congestive heart failure affect aldosterone levels?

A

• Patients with liver cirrhosis or severe congestive heart failure often have elevated plasma aldosterone level due to its reduced metabolism by the liver.

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11
Q

What are the two main functions of Aldosterone?

A
  • it regulates the total amount of sodium in the body and the ECFV
  • it regulates potassium homeostasis.
  • The main target site of aldosterone is the kidney, but it also affects sodium excretion by the salivary and sweat glands and the colon. In the kidney, the primary target of aldosterone is the cortical collecting duct.
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12
Q

Explain mineralcorticoid effects on principle cells (Review):

A
  • Aldosterone stimulates the transcription of both ENaC luminal sodium channels and Na/K-ATPase, and also increases the number of active ENaC molecules in the apical cell membrane.
  • Aldosterone also increases potassium secretion from the blood into the tubular lumen.
  • This action is achieved by creating a more favorable electrical driving force for potassium to exit from the cell into the lumen due to the increased sodium reabsorption, which renders the tubular lumen more negative.
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13
Q

What are the effects of aldosterone on hypertension?

A
  • Since water movement follows passively that of sodium, an increased sodium reabsorption necessarily results in an expansion of ECFV and an increase in blood pressure.
  • Therefore, chronic over-production of aldosterone leads to pathological conditions accompanied by hypertension.
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14
Q

How does aldosterone affect H+ ion excretion (review)?

A
  • aldosterone also enhances the excretion of H+ ions.
  • H+ transport takes place in the minority cell type of the collecting duct, the intercalated cells.
  • Aldosterone has a direct effect on the intercalated cells: it increases the rate of transcription of the H+-ATPase.
  • In addition, the lumen negative voltage created by increased sodium reabsorption in principal cells also stimulates H+ secretion in the collecting duct.
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15
Q

To what extent does the hypthalamo-hypophyseal axis regulate aldosterone?
What are the two main regulators of aldosterone?

A
  • Unlike in the regulation of cortisol secretion, the hypothalamo-hypophyseal axis plays only a minor role in the control of aldosterone secretion.
  • The kidney is not only the major target of aldosterone, but also the primary regulator of aldosterone secretion.
  • The two major regulators of aldosterone secretion are the renin-angiotensin system and plasma K levels, both of which are controlled by the kidney.
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16
Q

Eplain The Renin-Angiotensin System… again… except this time include Agiotensin III and talk about aldosterone secretion.

A
  • Renin ==> angiotensin I, which is biologically inactive ==> angiotensin II via angiotensin converting enzyme or ACE, which is present in endothelial cells and in the blood itself.
  • ACE is the target of a antihypertensive agents, known as ACE inhibitors.
  • Angiotensin II stimulates aldosterone secretion by the zona glomerulosa, and is a potent vasoconstrictor.
  • Angiotensin II is cleaved to angiotensin III that is equipotent with angiotensin II in stimulating aldosterone secretion, but has no vasoconstrictor activity.
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17
Q

What is the cell signaling mechanism of A II and A III to stimulate aldosterone production and secretion?

A
  • on the glomerulosa cell surface receptors.
  • mechanism involves GTP binding proteins ==> activation of phospholipase C ==> inositol triphosphate (IP3) and diacylglycerol (DAG).
  • increase in intra-cellular Ca2+ levels and activation of protein kinase C
  • The final effect of angiotensin II is stimulation of two rate limiting steps in aldosterone biosynthesis: conversion of cholesterol to pregnenolone and the conversion of corticosterone to aldosterone.
18
Q

What are the two rate limiting steps in aldosterone biosynthesis?

A
  • conversion of cholesterol to pregnenolone

* the conversion of corticosterone to aldosterone

19
Q

What is the rate-limiting step in RAAS? What are granular cells? What are extraglomerular mesangial cells? Does the JGA have innervation?

A
  • The rate-limiting step in the formation of angiotensin II is the synthesis of renin. Renin is secreted by a specialized part of the kidney called the juxtaglomerular apparatus.
  • Granular cells in the juxtaglomerular apparatus produce rennin.
  • extraglomerular mesangial cells transmit the signals generated by the macula densa to the granular cells.
  • The juxtaglomerular apparatus is innervated by sympathetic fibers.
20
Q

What are the three major factors that regulate renin production? Explain their principles. (Review)

A
  • renal arterial pressure
  • the amount of sodium arriving to the macula densa
  • sympathetic nerve activity.
  • Factors that decrease renal arterial pressure, such as hemorrhage, dehydration, salt restriction or upright posture, increase renin secretion, and conversely, factors that increase renal arterial pressure, such as vasoconstrictors or supine position, decrease renin secretion.
  • The macula densa responds to changes in sodium concentration within the tubular fluid.
  • Increased sodium load decreases renin secretion, whereas decreased tubular sodium concentration increases renin production.
  • Finally, sympathetic nerves, which innervate the juxtaglomerular cells, increase renin release via a ß-adrenergic, cAMP dependent mechanism.
21
Q

Explain the negative feedback system between potassium and aldosterone (review)

A
  • An increase in plasma potassium concentration increases aldosterone synthesis by a direct action in the adrenal cortex.
  • In turn, aldosterone decreases plasma potassium levels by stimulating its excretion by the kidney.
  • This negative feedback loop is an important regulator of potassium homeostasis.
  • Potassium load in the diet increases aldosterone secretion regardless of the amount of sodium in the diet.
  • Aldosterone secretion is very sensitive to variations of plasma potassium concentrations: changes as small as 0.1 mM can alter aldosterone secretion by about 40%.
22
Q

What is the cell signaling mechanism that K uses to increase aldosterone production and secretion? How is it similar and different from Angio II signaling mechanisms for aldosterone production and secretion?

A
  • Similarly to angiotensin II, potassium also increases intra-cellular Ca2+ concentrations in glomerulosa cells, but through a different mechanism.
  • An increase in plasma potassium leads to depolarization of the cell membrane, which activates voltage-sensitive Ca2+ channels, resulting in an influx of extracellular Ca2+.
  • From here on, the two pathways converge, and both angiotensin II and K stimulate the same steps in aldosterone synthesis, that is, the conversion of cholesterol to pregnenolone and the conversion of corticosterone to aldosterone.
23
Q

What types of receptors are aldosterone receptors? In what cells are they expressed?

A
  • like other steroids, intracellular receptors, which interact with specific regulatory segments on the chromatin and increase the transcription of specific genes.
  • Part of the steroid/thyroid receptor superfamily and are very similar in structure to glucocorticoid receptors.
  • They are present in target tissues such as kidney, colon and sweat gland
  • Also expressed in non-classical mineralocorticoid target cells, such as the heart, vasculature, and the brain (function is not clear). (brain affects salt and thirst appetite)
24
Q

Since mineralocorticoid receptors have high affinity (Kd 0.5-1.0 nM) for aldosterone and cortisol, and cortisol is in much higher plasma levels, how does the body reduce cross-reactivity?

A
  • aldosterone target cells have an enzyme called 11ß-hydroxysteroid dehydrogenase Type 2 (11ß-HSD2) that converts active glucocorticoids (such as cortisol) to their keto form by a dehydrogenation at carbon 11, and the oxidized metabolites (such as cortisone) are biologically inactive because they do not bind to the mineralocorticoid receptor.
  • By lowering the intracellular levels of active glucocorticoids, 11ß-HSD2 protects the mineralocorticoid receptors in target cells from being occupied by glucocorticoids.
25
Q

In what cells/tissues is 11ß-HSD2 expressed? What happens to the non-classical mineralocorticoid target cells with regard to cortisol?

A
  • 11ß-HSD2 is restricted to true aldosterone target cells and organs, such as the collecting duct in the kidney, the colon, sweat and salivary glands.
  • In other tissues, where mineralocorticoid receptors are present but 11ß-HSD2 is not expressed (such as the heart and the hippocampus) do not function as aldosterone targets, but rather bind cortisol and function as high-affinity glucocorticoid receptors.
26
Q

What does 11ß-hydroxysteroid dehydrogenase, called Type 1 do? Where is 11ß-HSD1 expressed? What is the clinical significance of 11ß-HSD1?

A
  • the other isoform of 11ß-hydroxysteroid dehydrogenase, called Type 1, catalyzes the opposite reaction (i.e. reduction), thereby converting inactive cortisone to active cortisol.
  • this enzyme is not expressed in mineralocorticoid target tissues
  • it is mainly expressed in the liver and in adipose tissues.
  • The action of 11ß-HSD1 makes it possible to treat patients with the biologically inactive steroids such as cortisone, which are activated in the liver to cortisol.
27
Q

Recap:
11ß-hydroxysteroid dehydrogenase Type 2 (11ß-HSD2) does what?
11ß-hydroxysteroid dehydrogenase Type 1 (11ß-HSD1) does what?

A
  • 11ß-HSD2 converts active glucocorticoids into inactive forms and protects aldosterone target tissues from overstimulation from cortisol
  • 11ß-HSD1 converting inactive cortisone to active cortisol, is expressed in the LV and adipose tissue, and makes it possible to treat patients with the biologically inactive steroids such as cortisone
28
Q

Why is aldosterone not a substrate for 11ß-HSD2?

A

• Plasma aldosterone is a hemiacetal, where the 11ß-OH group forms a ring with the 18-aldehyde group, and therefore 11ß-HSD2 cannot oxidize the 11ß-OH.

29
Q

What is apparent mineralocorticoid excess syndrome (AME)? What is the cause? What are the symptoms? What is the prognosis?

A
  • congenital 11ß-HSD2 deficiency
  • In this syndrome aldosterone and renin levels are low, but all the symptoms of hyperaldosteronism are present, because deficient enzyme activity in the kidney leads to high intracellular cortisol which leads to unregulated constant activation of the mineralocorticoid receptors
  • patients retain large amounts of Na, their ECFV increases which leads to severe hypertension
  • the patients become seriously hypokalemic due to abnormally high K secretion in the collecting duct.
  • Due to deficient 11ß-HSD2 activity in the kidney, the urine cortisol-to-cortisone ratio, which is normally 1:1, is significantly elevated to ~12 to 14 : 1
  • The congenital form of AME is a very severe disease, most patients die before reaching adulthood.
  • A milder, acquired form of AME occurs in patients due to excessive ingestion of licorice, which is an inhibitor of the enzyme 11ß-HSD2.
30
Q

How does licorice (glycyrrhizic acid) mimic apparent mineralocorticoid excess syndrome?

A

• A milder, acquired form of AME occurs in patients due to excessive ingestion of licorice, which is an inhibitor of the enzyme 11ß-HSD2.

31
Q

What are mineralocorticoid receptor antagonists?
Name two.
What are they used to treat?

A
  • Competitive inhibitors.
  • Spironolactone and Eplerenone
  • used in the clinic to mitigate the conditions of diseases with abnormally high aldosterone production (such as Conn syndrome) or those of AME
32
Q

In heart failure, (not sure what this slide was)

1) if the patient has “Rales” which medication is used?
2) If the patient has “Ephesus” which medication is used?

A
  • 1) Spironolactone

* 2) Eplerenone

33
Q

What is Addison’s disease? What are its symptoms?

A
  • Hypoaldosteronism
  • Primary adrenal insufficiency
  • due to destruction of the adrenal gland
  • symptoms are consequences of glucocorticoid and mineralocorticoid deficiency.
  • Hypoaldosteronism is associated with decreased ECFV, hypotension and high serum potassium (hyperkalemia) which can lead to cardiac arrhythmias.
  • Continued ECF loss ultimately leads to cardiovascular collapse and death.
34
Q

What are causes and symptoms of ISOLATED MINERALOCORTICOID DEFICIENCY?

A

(a) acquired hyporeninemic
cause: low renin production
(b) inherited enzyme defect
of aldosterone synthase

SYMPTOMS:
•	hyperkalemia
•	low plasma renin and aldosterone
•	cardiac arrhythmia
•	muscle weakness
35
Q

What is PSEUDOHYPOALDOSTERONISM?

A

rare

- infancy 
- salt-wasting
- plasma aldo NORMAL
- Na+ channel or MR defect
36
Q

What are symptoms and causes of hyperaldosteronism 1?

A 
–Symptoms:
•hypertension
•hypo K
•high aldosterone
•low PRA (plasma renin)

•PRIMARY
–cause:
•adrenal adenoma
•bilateral adrenal hyperplasia (conn disease)

37
Q

What are symptoms and causes of hyperaldosteronism 2?

A 
•SECONDARY
–diseases with edema
•congestive heart failure
•cirrhosis
•nephrotic syndrome
–Cause:
•Effective blood volume ↓
•Renin ↑
•Angiotensin II ↑
Aldosterone ↑
38
Q

What is Hyperaldosteronism (Conn’s Syndrome, and AME)

A
  • Hypertension (Na retention)
  • Hypokalemia (K secretion and also causes muscle weakness)
  • metabolic alkalosis (H secretion)
  • slight impairment of urine concentrating ability.
  • Potassium depletion also causes muscle weakness.
39
Q

What are causes of excess aldosterone?

A
  • autonomous adrenocortical tumor (primary aldosteronism or Conn’s syndrome
  • or can be due to abnormal activation of the renin-angiotensin system leading to hyperplasia of the zona glomerulosa (secondary aldosteronism).
40
Q

What is Amiloride? What is spirolactone?

A
  • Amiloride is an ENaC inhibitor

* Spirolactone is a competitive inhibitor of the mineralcorticoid receptor

41
Q

What are non-renal affects of aldosterone:

A
  • Main effect: ↑ reabsorption of Na+
  • Colon: importance in neonates
  • Sweat glands: importance in hot climate, after strenuous exercise
  • Taste buds & brain: tasting salt, salt appetite
42
Q

Example: ADMISSION VALUES OF A PATIENT WITH APPARENT MINERALOCORTICOID EXCESS (AME)

A

PATIENT NORMAL

Blood pressure 235/125 <100 150-500

Physio Endocrinlogy Quiz 1 (6 decks)

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