D-Aldosterone

This is communication No. 28. For No. 27 see H. Kohler, R, H. Hesse, and M. M. Pechet, The Metabolism of d-Aldosterone Metabolic Pathway, Isolation, Characterization, and Synthesis, in preparation for submission to J. Biol. Chem. 

Weber KT, Villarreal D. Aldosterone and antialdosterone therapy in congestive heart failure. Am J Cardiol 1993 71 (suppl)3A-11 A. 

Marver D. Aldosterone action in target epithelia. Vitam Florm 1980 38 55-117. 

The first successful use of a microbial stage to separate a racemic mixture was described by Vischer, Schmldlln, and Wettstein (V-1055) who prepared natural ([Pg.73]

The first glimpse into species differences regarding the biosynthesis of pregnane derivatives was afforded by Bush (1953), who demonstrated that various species differed in their adrenal secretion of cortisol and corticosterone. Interesting species differences have been observed by Idler and co-workers in fish. Thus, the Elasmo-branchii alone were found to possess la-hydroxycorticosterone in their blood stream and the responsible corticosterone la-hydroxylase in their interrenal tissue (Idler et al., 1969). la-Hydroxycorticosterone had approximately 80% of the sodium transport activity across the isolated toad bladder exhibited by d-aldosterone (Grimm et al., 1969). 

Although MR also binds glucocorticoids, its main ligand in classical mineralocorticoid target tissues such as kidney and colon is aldosterone ( d 1.3 nM). This can be granted to the ability of 11 (3-hydioxysteroid dehydrogenase type II (11 (3-HSD II) to convert active cortisol into its inactive metabolite cortisone in these tissues. Since aldosterone is no substrate for this enzyme it can readily bind to MR, leading to exclusive occupation of the receptor by aldosterone. In contrast, no such mechanism exists in brain and presumably... 

Although the kidneys are not considered endocrine glands per se, they are involved in hormone production. Erythropoietin is a peptide hormone that stimulates red blood cell production in bone marrow. Its primary source is the kidneys. Erythropoietin is secreted in response to renal hypoxia. Chronic renal disease may impair the secretion of erythropoietin, leading to development of anemia. The kidneys also produce enzymes. The enzyme renin is part of the renin-angiotensin-aldosterone system. As will be discussed, these substances play an important role in the regulation of plasma volume and therefore blood pressure. Other renal enzymes are needed for the conversion of vitamin D into its active form, 1,25-d i hyd ro xyv itamin D3, which is involved with calcium balance. 

In the colon, semifluid material entering from the small bowel is thickened by absorption of water and salts (from about 1000 to 150 mL/d). If, due to the action of an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be incurred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone (p. Ltillmann, Color Atlas of Pharmacology... 

Addison s disease), both cortisol and aldosterone must be replaced when ACTH production is deficient (secondary AC insufficiency), cortisol alone needs to be replaced. Cortisol is effective when given orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by 5- to 10-fold. Aldosterone is poorly effective via the oral route instead, the mineralocorticoid fludrocortisone (0.1 mg/d) is given. 

NT27 6 Skowronski, R. J., and D. Feldman. Inhibition of aldosterone synthesis in rat adrenal cells by nicotine and related NT286 constituents of tobacco smoke. Endocrinology 1994 134(5) 2171-2177. 

It has also been found that low doses of eplerenone (25-50 mg/d) may interfere with some of the fibrotic and inflammatory effects of aldosterone. By doing so, it can reduce the progression of albuminuria in diabetic patients. More important is that eplerenone has been found to reduce myocardial perfusion defects after myocardial infarction. In one clinical study, eplerenone reduced mortality rate by 15% (compared with placebo) in patients with mild to moderate heart failure after myocardial infarction. 

Aldosterone is secreted at the rate of 100-200 mcg/d in normal individuals with a moderate dietary salt intake. The plasma level in men (resting supine) is about 0.007 mcg/dL. The half-life of aldosterone injected in tracer quantities is 15-20 minutes, and it does not appear to... 

DOC, which also serves as a precursor of aldosterone (Figure 39-1), is normally secreted in amounts of about 200 mcg/d. Its half-life when injected into the human circulation is about 70 minutes. Preliminary estimates of its concentration in plasma are approximately 0.03 mcg/dL. The control of its secretion differs from that of aldosterone in that the secretion of DOC is primarily under the control of ACTH. Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not increase DOC secretion. The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia with reduced P450cll or P450cl7 activity. 

Eplerenone, another aldosterone antagonist, is approved for the treatment of hypertension (see Chapters 11 and 15). This aldosterone receptor antagonist is somewhat more selective than spironolactone and has no reported effects on androgen receptors. The standard dosage in hypertension is 50-100 mg/d. The most common toxicity is hyperkalemia but this is usually mild. 

Spironolactone, a competitive inhibitor of aldosterone (see Chapter 15), also competes with dihydrotestosterone for the androgen receptors in target tissues. It also reduces 17a-hydroxylase activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50-200 mg/d in the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, or cyproterone in this condition. 

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