Aldosterone, synthesis

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

Congenital adrenal hyperplasia A rare inherited condition resulting from a deficiency in cortisol and aldosterone synthesis with resulting excess androgen production. The clinical presentation depends on the variant of the condition, but it typically manifests as abnormalities in sexual development and/or adrenal insufficiency. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Angiotensin II stimulates aldosterone synthesis and secretion from the glomerulosa cells of the adrenal cortex. The aldosterone secretion induced by angiotensin II in humans is not accompanied by an increase in glucocorticoid plasma levels. Chronic administration of angiotensin II will maintain elevated aldosterone secretion for several days to weeks unless hypokalemia ensues. 

The 17- and 21-hydroxylase enzymes are associated with microsomes, whereas the ll- -hydroxylase has a mitochondrial origin. Since the last-named enzyme is not detectable in other steroid-producing tissues, the term 11-oxygenated steroids is considered synonymous with adrenal steroids. Aldosterone synthesis involves an essential 18-hydroxylation step catalyzed by P450d8 with corticosterone as the precursor this reaction also takes place within the mitochondria. 

The steroid-inhibiting properties of metyrapone have also been used in the treatment of Cushing s syndrome, and it remains one of the more effective drugs used to treat this syndrome. However, the compensatory rise in corticotrophin levels in response to falling cortisol levels tends to maintain adrenal activity. This requires that glucocorticoids be administered concomitantly to suppress hypothalamic-pituitary activity. Although metyrapone interferes with lip- and 18-hydroxylation reactions and thereby inhibits aldosterone synthesis, it may not cause mineralocorticoid deficiency because of the compensatory increased production of 11-desoxycorticosterone. 

Aldosterone synthesis inhibition. Nicotine, anabasine, and cotinine, in freshly isolated rat adrenal cells at concentrations up to 100 mM, did not inhibit stimulated... 

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. 

Ang II acts directly on the zona glomerulosa of the adrenal cortex to stimulate aldosterone synthesis and release. At higher concentrations, Ang II also stimulates glucocorticoid synthesis. 

Abiraterone is the newest of the steroid synthesis inhibitors to enter clinical trials. It blocks 17a-hydroxylase (P450cl7) and 17,20-lyase (Figure 39-1), and predictably reduces synthesis of cortisol and gonadal steroids in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and has been studied in the treatment of refractory prostate cancer. 

In addition to agents that interfere with aldosterone synthesis (see above), there are steroids that compete with aldosterone for its receptor and decrease its effect peripherally. Progesterone is mildly active in this respect. 

Disorders of 21-hydroxylation account for over 95% of patients with CAH and affect about 1 in 13,000 people. 21-Hydroxylation is catalyzed by P450c21 encoded by a gene CYP21B [95]. The disorder ranges from severe (salt-wasting), when even aldosterone synthesis is prevented, through simple-virilizing, to mild forms, where adequate cortisol is produced. 

Patients with 11/1-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children. There are two human isozymes that are responsible for cortisol and aldosterone synthesis, respectively. The CYP11B1 enzyme (p45011B) converts DOC to corticosterone (B) and 11-deoxycortisol (S or 11-dihydrocortisol) to cortisol (F). It is also capable of 18-hydroxylating DOC but cannot convert to aldosterone. The latter transformation is carried out by CYP11B2 (also known as aldosterone synthase), which encompasses activity for 18-hydroxylation and subsequent 18-oxidation. When CAH is associated with hypertension, deficient lljS-hydroxylase (CYP11B1) is suspected at this time more than ten mutations have been defined in affected individuals [103]. 

In profile analysis, I shows low THAldo and 18-hydroxyTHA (the major 18-hydroxy corticosterone metabolite), but high excretions of THAs and THBs [26, 33]. In II, THAldo is low, the THAs and THBs normal, but 18-OH-THA is often grossly elevated. Representative excretions of several patients with both forms of the disorder are shown in Table 5.3.11. However, it must be emphasized that even if the steroid phenotype appears to have two forms, a single enzyme is responsible for aldosterone synthesis. 

The adrenocorticotrophic hormone ACTH (corticotropin) stimulates the adrenal cortex to secrete the glucocorticoids hydrocortisone (cortisol) and corticosterone, the mineralocorticoid aldosterone, and a number of weakly androgenic substances, as well as a small amount of testosterone. Aldosterone synthesis is also regulated by renin and angiotensin. 

Heparin-induced hypoaldosteronism is well documented, both in patients treated with standard heparin, even at low doses, and in patients treated with low molecular weight heparin (477,478). The most important mechanism of aldosterone inhibition appears to be a reduction in both the number and affinity of angiotensin II receptors in the zona glomerulosa (477). A direct effect of heparin on aldosterone synthesis, with inhibition of conversion of corticosterone to 18-hydroxycorticosterone, has also been suggested. This effect is believed to be responsible for the hyperkalemia that can occur in heparin-treated patients with impaired renal function and particularly in patients on chronic hemodialysis (479), or with diabetes mellitus, or who are taking other potentially hyperkalemic drugs. 

Possibly relevant to the natriuretic activity of SK F 38393 is emerging evidence that dopamine may be a physiological regulator of aldosterone synthesis (28). Dopamine receptors in a particulate fraction of calf adrenal glomerulosa cells have been shown to bind 3H-2-amino-1,2,3,4-tetrahydro-6,7-dihydroxynaptha-lene (3H-ADTN) in a specific (displaceable by 10 pM dopamine) saturable manner (29) (Kj, 0.29 mM maximal binding capacity,... 

Aldosterone Synthesis of pumps Increased gene transcription (through direct interaction of nuclear aldosterone-receptor complex with c/s-regulatory upstream gene element, and/or secondary to elevated Na caused by induction of channel proteins)... 

Trilostane blocks the synthetic path earlier (3p-hydroxysteroid dehydrogenase) and thus also inhibits aldosterone synthesis. 

Cytochromes are used in the conversion of cholesterol to the steroid hormones. These hormones include aldosterone, cortisol, and the sex hormones. Synthesis of aldosterone, for example, CKcurs in the mitochondria of the adrenal cortex. One of the steps in aldosterone synthesis is a hydroxylation that is catalyzed by a complex of adrenodoxin reductase (FAD-containing protein), adrenodoxin (nonheme iron protein), and cytochrome P450 (heme protein). 

ACE-I block the conversion of angiotensin 1 to angiotensin II, which causes vasoconstriction and stimulates the production of aldosterone synthesis. Thus, ACE-1 promote vasodilatation and decrease sodium retention, consequently lowering blood pressure. The inhibition of angiotensin-converting enzymes also blocks the breakdown of bradykinins. The increase in bradykinin level leads to additional vasodilatation effects. However, the increase in bradykinin is also responsible for adverse effects such as cough and angioedema. 

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