Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spironolactone administration (50 mg/kg/day for 3 days) to make guinea pigs decreased cortisol production by adrenal slices in vitro. Adrenal microsomal and mitochondrial cytochrome P-450 levels were also decreased after treatment with spironolactone. The decline in adrenal cytochrome P-450 content was accompanied by decreases in microsomal 21-hydroxylase and mitochondrial cholesterol side-chain cleavage and 11beta-hydroxylase activities. Activities of other adrenal enzymes, such as delta4-hydrogenase and NADPH-cytochrome c reductase, were unaffected by spironolactone treatment. Cortisone administration to guinea pigs failed to mimic the effects of spironolactone on adrenal function, which indicates specificity of spironolactone action and excludes inhibition of adrenocorticotropin secretion as a mode of action. Addition of spironolactone to isolated adrenal mitochondria or microsomes produced type I spectral changes with spectral dissociation constants similar to those for endogenous steroid substrates. Spironolactone, in vitro, inhibited 11beta- but not 21-hydroxylase activity. The results indicate that spironolactone administration diminishes the activity of adrenal mitochondrial as well as microsomal cytochrome P-450-containing enzymes, resulting in a fall in corticosteroid output.
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PMID:Mechanism of action of spironolactone on adrenocortical function in guinea pigs. 97 70

Among 436 patients with hypertension unrelated to any renal lesion, renovascular damage, pheochromocytoma, Cushing's syndrome or hyperthyroidism, 15 patients had low plasma renin activity (PRA) and elevated plasma aldosterone concentrations in the upright position and resultant high aldosterone/PRA ratios: 8 with aldosterone-producing adenoma (APA; group 1) and 7 with idiopathic hyperaldosteronism (IHA; group 2). Thirty-nine patients had suppressed PRA in the presence of normal plasma aldosterone levels and moderately elevated aldosterone/PRA ratios (group 3). Thirty of them had elevated plasma 11-deoxycorticosterone (DOC) and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) concentrations (group 3a) and 9 of them had normal levels of those mineralocorticoids (group 3b). The rest of them (382 patients) had low aldosterone/PRA ratios (group 4). Adrenal scintigraphy with dexamethasone pretreatment revealed [13I]-cholesterol accumulation not only in patients with APA (unilateral) or IHA (bilateral), but also in patients of group 3a (bilateral). In patients in groups 3a and 3b adrenal size (especially thickness), as measured by computed tomography (CT scan), was enlarged, as in patients with IHA (group 2), and was significantly greater than in patients of group 4 (p less than 0.001). Spironolactone reduced blood pressure in all tested patients of group 3a, and the removal of adrenal tumor or hyperplastic tissue normalized blood pressure in patients of groups 1, 2 and 3a. Excised adrenal glands exhibited cortical hyperplasia with or without nodular hyperplasia in patients of group 3a. Good agreement was found between the actual size of the excised tissue and the measurement obtained by CT scan. Since beta-endorphin and beta-lipotropin were depressed in patients of group 3a, it is suggested that an unknown pituitary substance stimulates the adrenal cortex to release too large amounts of DOC and 18-OH-DOC and inappropriate secretion of aldosterone.
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PMID:Inappropriate elevation of the aldosterone/plasma renin activity ratio in hypertensive patients with increases of 11-deoxycorticosterone and 18-hydroxy-11-deoxycorticosterone: a subtype of essential hypertension? 207 Mar 75

Angiotensin converting enzyme (ACE) inhibitor therapy in conjunction with loop diuretics and, possibly, digoxin, is associated with a relatively high incidence of recurrent heart failure and death. Even high doses of ACE inhibitors may not completely suppress the renin-angiotensin-aldosterone system; aldosterone "escape' may occur through non-angiotensin II dependent mechanisms involving corticotropin, atrial natriuretic peptide, serum potassium, and deficient high-density lipoprotein cholesterol concentrations. Addition of spironolactone (an aldosterone receptor blocker) to an ACE inhibitor regimen causes marked diuresis and symptomatic improvement. The Randomized Aldactone Evaluation Study (RALES) was organized to explore the role of combination therapy with spironolactone in patients with heart failure. Patients with New York Heart Association Functional Class II-IV heart failure and left ventricular ejection fractions < or = 40% who were on regimens comprising an ACE inhibitor, loop diuretic, and, possibly, digoxin were randomized to receive placebo or spironolactone in doses of 12.5, 25, 50, or 75 mg per day. Eve at the lowest dose of spironolactone, a significant decrease in plasma N-terminal pro-atrial natriuretic peptide occurred, with concomitant increase in concentrations of plasma renin and urinary aldosterone. As prophylaxis for heart failure, a daily dose of 25 mg of spironolactone and monitoring of serum potassium concentrations are recommended; symptomatic therapy in refractory or severe heart failure may require doses as high as 100 mg b.i.d. The RALES Mortality Trial will follow up 1400 similar patients for 3 years to determine the effect of the addition of spironolactone on combined mortality and hospitalization for heart failure.
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PMID:ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). 868 55

Although regarded as a benign condition, simple hypertrichosis may be very disturbing to a child cosmetically. An abnormality in androgen metabolism has been implied in the etiology of simple hypertrichosis recently. This study was undertaken to investigate the effect of spironolactone therapy for its antiandrogenic property in 12 prepubertal girls with hypertrichosis with no underlying etiology. The girls, with a mean age of 6.9 (1.2) years, had normal height and bone age. Basal hormone levels and adrenocorticotropin stimulation test results were in the normal ranges. Pelvic and adrenal ultrasound did not reveal pathology. Total and medullary hair width were measured from hair taken from preauricular, anterior midthigh, distal and proximal forearm areas. Spironolactone was started at an oral dose of 25 and increased to 100 mg x m(-2) x day(-1) twice daily for 1 year. Total hair width decreased significantly in the preauricular and anterior midthigh regions up to 6-9 months of treatment. Medullary hair width, which was affected by therapy to a greater extent, decreased significantly in all regions up to 6 months. Both total and medullary hair width showed a tendency to increase afterwards. No side effects were encountered. Spironolactone may be used in the treatment of simple hypertrichosis; however, more data are needed to clarify the efficacy and safety of anti-androgen therapy in hypertrichosis.
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PMID:Spironolactone therapy in hypertrichosis. 898 Jan 64

Traditionally, the role of aldosterone in heart failure was thought to be a result of its effects on epithelial cells where it induces sodium reabsorption and potassium excretion with subsequent haemodynamic effects from intravascular volume expansion. On this basis, spironolactone, a non-selective aldosterone antagonist, has been used for the treatment of congestive heart failure to block aldosterone-mediated effects in epithelial cells. The Randomized Aldactone Evaluation Study (RALES), in which spironolactone was added to existing therapy in patients with heart failure, showed a significant reduction in morbidity and mortality. These results suggest that the role of aldosterone in the pathophysiology of cardiovascular disease may be more complex than previously recognised. There now is extensive experimental and growing clinical evidence for an important physiological role for aldosterone in the pathology of cardiac and renal disease. Classical effects of aldosterone are mediated via its nuclear receptor. Novel non-epithelial effects of aldosterone are mediated via a second messenger system, which involves activation of the sodium/hydrogen antiporter. These effects of aldosterone have been demonstrated in the kidney, vascular smooth muscle cell and leukocytes, and in the regulation of rapid corticotropin suppression. It has been hypothesised that cardiac damage induced by aldosterone is independent of the presence of hypertension. In support of this, experimental evidence demonstrates that cardiovascular damage induced by aldosterone can be prevented by administration of a selective mineralocorticoid receptor antagonist. These findings suggest the dissociation between cardiovascular lesions and high blood pressure, and highlight the importance of aldosterone in the pathological changes.
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PMID:Rationale for the use of aldosterone antagonists in congestive heart failure. 1192 27

Effects of alterations in stress hormones and their actions were investigated on alcohol preference, by intraperitoneal administration of RU38486 (a Type II glucocorticoid receptor antagonist, also given by the intracerebroventricular route), spironolactone (a Type I glucocorticoid receptor antagonist), metyrapone (a corticosterone synthesis inhibitor), corticosterone, adrenocorticotropin (ACTH1-39), or intracerebroventricular injection of corticotropin releasing factor (CRF) or a CRF antagonist (alpha-helical CRF9-41). Intracerebroventricular or intraperitoneal administration of RU38486 did not alter the alcohol consumption of mice with high preference for alcohol, or, on first administration, the intake of those with low alcohol preference. When given by repeated intraperitoneal injection however this drug prevented the increase in alcohol consumption seen in "low preference" mice after 3 weeks vehicle injections. Spironolactone did not alter alcohol preference when given by intracerebroventricular or intraperitoneal routes. Repeated, but not single, administration of metyrapone reduced alcohol preference in both high and low preference animals and prevented the increase from low alcohol preference caused by repeated vehicle injections. ACTH1-39 or corticosterone administered by single or repeated intraperitoneal injection, or CRF given i.c.v., did not alter alcohol preference, but the CRF antagonist, alpha-helical CRF9-41, caused a transient increase from low alcohol preference. Blood corticosterone concentrations prior to preference measurements did not correlate with the alcohol preference of the mice. The results indicate that delayed consequences of corticosterone acting on Type II glucocorticoid receptors may be involved in the increases in alcohol preference after injection stress. They also suggest that central actions of CRF may influence the low alcohol consumption of the low alcohol-preferring mice.
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PMID:The hypothalamopituitary-adrenal axis and alcohol preference. 1632 17