Aldosterone

Although leptin is being derived primarily from adipocytes, it is now shown that non adipocyte tissues can be a source of leptin. In fact, gene expression of leptin and its receptors OB-Ra, OB -Rb and OB-Re have been identified in rat heart.46 It is likely that leptin serves an autocrine/paracrine role in regulating cardiac function. Leptin is shown to have a negative inotropic effect and promotes hypertrophy.47, 48 The physiological role of leptin in myocardial ischemia remains unknown. Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis.49 

Plasma leptin levels are increased in patients with acute myocardial infarction and this has been suggested to be detrimental.50 In an experimental model of ischemia and reperfusion, the expression of leptin and its receptors were decreased after ischemia while no change in the leptin efflux in the perfusate was detected. This was suggested to be an adaptive mechanism for increasing clearance of leptin from cardiac tissue.46 

Insulin signaling regulates important metabolic and cardioprotective pathways with potential physiological consequences on cellular response to ischemic stress (reviewed by Abel51 and Hue52). 

Important cardioprotective targets are now recognized to be regulated by the insulin induced intracellular signaling. In fact, insulin induces phosphorylation and inactivation of the proapoptotic protein Bad and activation of the endothelial nitric oxide synthase 

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Mineralocorticoids foUow a mechanistic route similar to that of glucocorticoids, though differing in the proteins expressed. The activated MR-DNA complex promotes the expression of aldosterone-induced proteins (AIPs), which then act to increase conductance of the luminal membrane and concurrently increase pump activity of the basolateral membrane. These actions result from a number of AlP-influenced cellular characteristics,... 

Methylated Glucocorticoids. The preparation of 2a-methyl-9a- uorocortisol has been reported (76). This compound shows enhanced glucocorticoid activity and greatiy enhanced mineralocorticoid activity, so much that it surpasses aldosterone (19) ia sodium-retaining and potassium-excreting potency. Attention was then turned to the preparation of 6-methylated corticoids... 

Studies have shown that aldosterone (19) (112,113) from adrenal extracts was intensely active in the survival and sodium retention assays in the adrenalectomized rat. 

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. 

Hyperaldosteronism is accompanied by elevation of blood pressure (115), and can be treated with an aldosterone antagonist, eg, spironolactone (117) which... 

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

The volume of extracellular fluid is direcdy related to the Na" concentration which is closely controlled by the kidneys. Homeostatic control of Na" concentration depends on the hormone aldosterone. The kidney secretes a proteolytic enzyme, rennin, which is essential in the first of a series of reactions leading to aldosterone. In response to a decrease in plasma volume and Na" concentration, the secretion of rennin stimulates the production of aldosterone resulting in increased sodium retention and increased volume of extracellular fluid (51,55). 

Mineralocorticoids. Aldosterone [6251-69-0] (32), the most potent natural rnineralocorticoid, also possesses a A -3-one group, an oxygen substituent at Clip, and a C17P-2-hydroxyethan-l-one side chain. In addition, the C18 of aldosterone is oxidized to an aldehyde. Mineralocorticoids, particularly aldosterone, act to retain sodium and to prevent the retention of excess potassium. Antimineral ocorticoids have been used therapeutically as diuretics and as agents that regulate blood pressure (63—65). 

It is well accepted that hypertension is a multifactorial disease. Only about 10% of the hypertensive patients have secondary hypertension for which causes, ie, partial coarctation of the renal artery, pheochromacytoma, aldosteronism, hormonal imbalances, etc, are known. The hallmark of hypertension is an abnormally elevated total peripheral resistance. In most patients hypertension produces no serious symptoms particularly in the early phase of the disease. This is why hypertension is called a silent killer. However, prolonged suffering of high arterial blood pressure leads to end organ damage, causing stroke, myocardial infarction, and heart failure, etc. Adequate treatment of hypertension has been proven to decrease the incidence of cardiovascular morbidity and mortaUty and therefore prolong life (176—183). 

Glonidine. Clonidine decreases blood pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance. It activates central a2 adrenoceptors ia the brainstem vasomotor center and produces a prolonged hypotensive response. Clonidine, most efficaciously used concomitantly with a diuretic in long-term treatment, decreases renin and aldosterone secretion. 

Potassium-Sparing Diuretics. Potassium-sparing diuretics act on the aldosterone-sensitive portion of cortical collecting tubules, and partially in the distal convoluted tubules of the nephron. The commonly used potassium-sparing diuretics are triamterene, amiloride, and spironolactone (Table 3). Spironolactone is a competitive aldosterone receptor antagonist, whereas triamterene and amiloride are not (44,45). 

Spironolactone antagonizes the effects of aldosterone by binding at the aldosterone receptor in the cytosol of the late distal tubules and renal collecting ducts. Side effects of spironolactone are gynecomastia, decreased Hbido, and impotency. 

In normal human subjects, ANP infusion for one hour causes increased absolute and fractional sodium excretion, urine flow, GFR, and water clearance (53—55). As shown in many in vitro and in vivo animal studies, ANP achieves this by direct effect on the sodium reabsorption in the inner medullary collecting duct, ie, by reducing vasopressin-dependent free-water and sodium reabsorption leading to diuresis and by indirect effect through increased hemodynamic force upon the kidney. ANP inhibits the release of renin and aldosterone resulting in the decreased plasma renin activity and aldosterone concentration (56,57). 

In an attempt to conserve sodium, the kidney secretes renin increased plasma renin activity increases the release of aldosterone, which regulates the absorption of potassium and leads to kafluresis and hypokalemia. Hypokalemia is responsible in part for decreased glucose intolerance (82). Hyponatremia, postural hypotension, and pre-renal azotemia are considered of tittle consequence. Hypemricemia and hypercalcemia are not unusual, but are not considered harmful. However, hypokalemia, progressive decreased glucose tolerance, and increased semm cholesterol [57-88-5] levels are considered... 

Ascites. Patients with cirrhosis, especially fiver cirrhosis, very often develop ascites, ie, accumulation of fluid in the peritoneal cavity. This is the final event resulting from the hemodynamic disturbances in the systemic and splanchnic circulations that lead to sodium and water retention. When therapy with a low sodium diet fails, the dmg of choice for the treatment of ascites is furosemide, a high ceiling (loop) diuretic, or spironolactone, an aldosterone receptor antagonist/potassium-sparing diuretic. 

Fig. 2 Fluorescence scan of a zl -3-ketosteroid mixture after INH treatment. Aldosterone...

With other acetylenes steric factors may be operative which render the selective reduction somewhat difficult. In the aldosterone intermediates (53) and (54), for instance, selective hydrogenation is obtained only with the 14 -acetylenic ether " (hydroxyl group effect). 

Aldosterone reacts in the lactol form (101) by exchange with acetone ketals to yield the acetonide (102). ... 

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. 

Aldosterone, the most potent of the mineralocorticoids (Figure 25.43), is involved in the regulation of sodium and potassium balances in tissues. Aldosterone increases the kidney s capacity to absorb Na, Cl, and HgO from the glomerular filtrate in the kidney tubules. 

Evidence has been put forward that 6-methoxy-l-methyl-l,2,3,4-tetrahydro-j3-carboline may be a component of animal tissues and may be identical with adrenoglomerulotrophine, a factor controlling aldosterone secretion, which is found in the pineal gland where it occurs together with 5-hydroxytryptamine... 

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