Formation of aldosterone

On the basis of other data, several other pathways for aldosterone biosynthesis 

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Aldosterone acts on the late distal tubules and collecting tubule cells by combining with an intracellular receptor which induces the formation of aldosterone induced protein, which promotes Na+ reabsorption and K+ secretion. 

P-450-dependent hydroxylases with NADPH and O2 cofactors. Thus, positions 17, 21 and 11 may be hydroxylated, and the exact order can in fact vary from that shown in Figure 5.114, according to species. It can be seen that production of hydrocortisone from cholesterol actually utilizes cytochrome P-450-dependent enzymes in four of the five steps. The further oxidation of C-18 to an aldehyde via the alcohol allows formation of aldosterone from corticosterone, again involving a P-450 system. 

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II and lower blood pressure by decreasing both the formation of aldosterone formation and the vasoconstrictive action of AH at AT-1 receptors. ACEIs also inhibit the metabolism of bradykinin, and this leads to additional hypotensive effects, because bradykinin is an endogenous vasodilator. Unfortunately, increases in bradykinin are associated with side effects, including cough and angioedema. Losartan, which blocks AT-1 receptors, does not increase bradykinin levels. 

A photochemical partial synthesis of aldosterone (19) made the hormone available on an industrial scale for the first time (114). Corticosterone acetate (51 acetate) is treated with nitrosyl chloride in pyridine at 20°C to yield the 11-nitrite (115). Irradiation of (115) leads to rearrangement with formation of the C g-oxime (116). Removal of the oxime residue with nitrous acid furnishes aldosterone (19) in excellent yield. 

FIGURE 25.43 The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to /3-estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone. 

Angiotensin II is a neurohormone produced primarily in the kidney. It is a potent vasoconstrictor and stimulates the production of aldosterone. Together, angiotensin II and aldosterone increase blood pressure and sodium and water retention (increasing ventricular wall tension), cause endothelial dysfunction, promote blood clot formation, and cause myocardial fibrosis. 

Angiotensin II (Ag II) is a potent stimulus for the secretion of aldosterone. The formation of Ag II occurs by the following process ... 

Potassium secretion is enhanced by aldosterone. As the concentration of K+ ions in the extracellular fluid increases, the secretion of aldosterone from the adrenal cortex also increases. The mechanism of action of aldosterone involves an increase in the activity of the Na+, K+ pump in the basolateral membrane. Furthermore, aldosterone enhances formation of K+ channels in the luminal membrane. 

The answer is a. (Hardman, pp 1482—1483. Katzung, pp 673-674.) Metyrapone inhibits 11-hydroxylation of steroid precursors, which prevents formation of cortisone and cortisol. These precursors are then diverted into aldosterone and androgen production pathways, which explains the adverse effects of hirsutism and edema... 

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

An important transformation in steroid biochemistry is the conversion of pregnenolone into progesterone. Progesterone is a female sex hormone, a progestogen, but this reaction is also involved in the production of corticosteroids such as hydrocortisone and aldosterone. The reaction also occurs in plants, and features in the formation of cardioactive glycosides, such as digitoxin in foxglove. 

Congenital defects in the biosynthesis of steroid hormones can lead to severe developmental disturbances, in the adrenogenital syndrome (AGS), which is relatively common, there is usually a defect in 21-hydroxylase, which is needed for synthesis of cortisol and aldosterone from progesterone. Reduced synthesis of this hormone leads to increased formation of testosterone, resulting in masculin-ization of female fetuses. With early diagnosis, this condition can be avoided by providing the mother with hormone treatment before birth. 

Spironolactone - Spironolactone, a competitive inhibitor of aldosterone, binds to aldosterone receptors of the distal tubule and prevents the formation of a... 

Within the adrenal cortex (the outer portion of the adrenal glands) progesterone is converted into two groups of hormones of which cortisol and aldosterone are representative.263 Two different cytochrome P450 hydroxylases, found in the ER and specific for C-21 and C-17a, respectively, together with a mitochondrial cytochrome P450 specific for C-lip (Eq. 18-55) participate in formation of cortisol.264 Two of the same enzymes together with additional hydroxylases are required to form aldosterone. 

Spironolactone and eplerenone bind to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone. Triamterene and amiloride do not block the aldosterone receptor but instead directly interfere with Na+ entry through the sodium-selective (ENaC) ion channels in the apical membrane of the collecting tubule. Since K+ secretion is coupled... 

The (3-blockers reduce blood pressure primarily by decreasing cardiac output (Figure 19.7). They may also decrease sympathetic outflow from the CNS and inhibit the release of renin from the kidneys, thus decreasing the formation of angiotensin II and secretion of aldosterone. The prototype (3-blocker is propranolol, which acts at both (3i and (32 receptors. Newer agents, such as atenolol and meto-prolol, are selective for [3-i receptors. These agents are commonly used in disease states such as asthma, in which propanolol is contraindicated due to its (32-mediated bronchoconstriction. (See p. 73 for a complete discussion of (3-blockers.)... 

Figure 33-3. Summary of the renin-angiotensin-aldosterone system. Aldosterone secretion is controlled by several factors, including increased K+,ACTH, or angiotensin II.A1-dosterone acts to increase Na+ retention by both the kidney and colon.Aldosterone also promotes renal K+ excretion, which contributes to maintenance of Na+/K+ balance. In the absence of aldosterone, Na+ is lost, K+ is enhanced, the extracellular fluid volume is reduced, and mean arterial pressure and renal perfusion pressure are decreased. As a result, renin secretion is increased, leading to increased formation of angiotensin II, which promotes vasoconstriction and aldosterone secretion.

Figure 26.27. Pathways for the Formation of Progesterone, Cortisol, and Aldosterone.

The ketone groups of aldosterone, corticosterone, and cortisol were derivatized with p-hydrazinobenzoic acid. The resulting carboxylic acid derivatives could be linked to BSA with water-soluble carbodiimide. Aldehydes can be conjugated to proteins directly by Schiff base formation followed by stabilization of the bond by reduction with sodium borohy-dride. Pyridoxal and pyridoxal phosphate are examples of haptens conjugated in this manner. ... 

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