Steroids
Glucocorticoid receptor binding was compared in liver cytosol preparations from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats using homologous displacement of [ 3 H]dexamethasone. At 5°C, there was no difference in receptor binding affinity or concentration between strains for dexamethasone, corticosterone or aldosterone. At 37°C, affinity for dexamethasone was lower...
An association between mineralocorticoids and hypertension has been recognized for over 50 years, 1 although the mechanisms involved are not entirely clear. In addition to the hypertension seen in cases of frank mineralocorticoid excess, such as in an aldosterone-producing adenoma, many essential hypertensive patients respond to treatments mitigating mineralocorticoid action, even though...
To elucidate the mechanisms of abnormal steroid production in hyperfunctioning and non-hyperfunctioning adrenal tumors, we examined both the activities and amounts of steroidogenic cytochromes P450 in the tumor and non-tumor portions of these adrenals at the posttranslational (protein) level.Adrenals from 5 patients with primary aldosteronism, 5 with Cushing's syndrome, 1 with deoxycorticosterone...
Pseudohypoaldosteronism (PHA) is characterized by salt-wasting and failure to thrive in the newborn, accompanied by high urinary levels of sodium despite hyponatremia, hyperkalemia and metabolic acidosis, elevation of plasma renin activity, and high plasma aldosterone levels. PHA patients are resistant to mineralocorticoid administration, but their symptoms ameliorate after a period of sodium supplementation,...
Progression to hormone-refractory disease is a common outcome of human prostate cancer. In this study, we have investigated the basis of androgen insensitivity in the human prostate cancer cell line, PC-3, which was derived from a bone metastasis of a hormone-refractory prostate cancer. PC-3 cells with virtually undetectable (PC-3 A R - ) or low (PC-3 A R + ) levels...
In the course of my studies of patients with mineralocorticoid hypertensive disorders, unusual presentations led to unexpected findings, both clinically and in steroid etiologies and regulation. Unique circumstances permitted early studies in defining the autonomy of the aldosterone-producing adenoma. A chance referral brought the index case of 17α-hydroxylase deficiency to the research center....
CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) are steroidogenic enzymes which mediate the final step (11β-hydroxylation) in cortisol synthesis and the final three steps (11β-hydroxylation, 18-hydroxylation, and 18-oxidation) in aldosterone synthesis, respectively. The enzymes share 93% identity in amino acid sequence and are encoded by two structurally similar genes which are located...
19-Noraldosterone, which was recently shown to be synthesized and produced in the human adrenal gland, possesses potent mineralocorticoid and hypertensinogenic activities. 18,19-Dihydroxycorticosterone (18,19-(OH) 2 -B) and 18-hydroxy-19-norcorticosterone (18-OH-19-nor-B), a possible precursor of 19-noraldosterone, have been identified in human urine. These mineralocorticoid hormones are...
11β-hydroxysteroid dehydrogenase (11β-HSD), by converting cortisol and corticosterone to hormonally inactive cortisone and 11-dehydrocorticosterone, respectively, is an important pre-receptor signaling pathway for the renal mineralocorticoid receptor (MR). This receptor has an equal affinity for the glucocorticoids, cortisol and corticosterone, and for the mineralocorticoid, aldosterone. In states...
Glucocorticoids are important in a number of developmental processes in mammals around birth. The pathway of gluconeogenesis is activated in liver shortly after birth due to the combined effects of glucocorticoids and glucagon. We have defined the essential cis-regulatory elements directing hormone-dependent liver-specific expression of the gene for tyrosine aminotransferase, a key gluconeogenic...
Recognition of the pathogenesis of secondary forms of hypertension is often considered the key to appropriate choice of treatment. We here present the results of a prolonged clinical follow-up (from 1 to 20 years) of a large number of patients with mineralocorticoid excess syndromes (MES), including over 100 patients with primary aldosteronism (PA), 3 cases with dexamethasone-suppressible aldoesteronism...
We have previously reported our studies on glucocorticoid (GC) effects on Na + influx in vascular smooth muscle (VSM) cells. We now report a parallel study on the effect of mineralocorticoid (MC) on Na + influx in VSM cells. Unidirectional influx of Na + was measured in cultured cells of rabbit aortic media with 2 2 Na as tracer. Cells were treated with near...
We have previously demonstrated a deficiency of mineralocorticoid receptors in pseudohypoaldosteronism, by radioreceptorassay. We now report findings with an antireceptor antibody derived from the immunogenic region of the receptor. Lymphocytes from normal controls and from two cases of pseudohypoaldosteronism previously shown to lack receptor binding were tested. After the plasma membrane of lymphocytes...
In comparison with the glucocorticoids cortisol and corticosterone, the mineralocorticoid aldosterone is a minority hormone of the mammalian adrenal cortex, and its proper function is dependent upon protective physiological mechanisms. These include a particular site of aldosterone synthesis in zona glomerulosa cells as well as a complex multifactorial control system, which adapts aldosterone production...
11β-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the interconversion of cortisol and cortisone. This activity is postulated to protect the type I (mineralocorticoid) receptor from excessive concentrations of cortisol, allowing aldosterone to function as a mineralocorticoid. An enzyme with 11-HSD activity was isolated from rat liver and the corresponding rat and human cDNA and genomic clones isolated...
Glucocorticoid resistance results from incomplete but apparently generalized inability of glucocorticoids to exert their effects on their target tissues. The condition is associated with compensatory elevation of circulating ACTH and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations...
Mineralocorticoid hormones such as aldosterone modulate cellular ion homeostasis at least in part through the regulation of Na + ,K + -ATPase (NAKA) gene expression. While aldosterone acts at the transcriptional level through its ligand-inducible mineralocorticoid receptor (MR), tissue specific and other transcriptional factors may interact with the MR to modulate this regulatory...
Primary aldosteronism is the commonest cause of potentially curable hypertension when diagnosed in both florid and less florid forms. Genetic screening, so far available only for glucocorticoid-suppressible hyperaldosteronism, permits diagnosis from birth, before any biochemical or clinical abnormalities appear. Biochemical screening using the aldosterone-to-renin ratio permits diagnosis in the...
In view of the hypothetical possibility that the vascular renin-angiotensin system (RAS) might include aldosterone biosynthesis and action in the vasculature, we have undertaken a study to identify aldosterone released into the perfusion circuit from the rat mesenteric artery, and to investigate the effects of an angiotensin converting enzyme inhibition (ACEI) on aldosterone production from the vasculature...
Studies in extrarenal, nonepithelial cells such as human lymphocytes and smooth muscle cells indicate that aldosterone produces not only delayed genomic effects, but also rapid, non-genomic effects on transmembrane electrolyte movements. These non-genomic events involve the immediate activation of the sodium/proton-exchanger of the cell membrane at very low, physiological concentrations of aldosterone...