Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine

Abstract

Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as was eplerenone in subsequent heart failure trials. Neither acts as an aldosterone antagonist in the heart as the cardiac MR are occupied by cortisol, which becomes an aldosterone mimic in conditions of tissue damage. The accepted term “MR antagonist”, (as opposed to “aldosterone antagonist” or, worse, “aldosterone blocker”), should be retained, despite the demonstration that they act not to deny agonist access but as inverse agonists. The prevalence of primary aldosteronism is now recognized as accounting for about 10% of hypertension, with recent evidence suggesting that this figure may be considerably higher: in over two thirds of cases of primary aldosteronism therapy including MR antagonists is standard of care. MR antagonists are safe and vasoprotective in uncomplicated essential hypertension, even in diabetics, and at low doses they also specifically lower blood pressure in patients with so-called resistant hypertension. Nowhere are more than 1% of patients with primary aldosteronism ever diagnosed and specifically treated. Given the higher risk profile in patients with primary aldosteronism than that of age, sex, and blood pressure matched essential hypertension, on public health grounds alone the guidelines for first-line treatment of all hypertension should mandate inclusion of a low-dose MR antagonist.

Impact of Aldosterone on Osteoinductive Signaling and Vascular Calcification

“…Recent studies documented a beneficial effect of aldosterone antagonism [50,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98]. In peritoneal dialysis patients, spironolactone treatment showed protective effects on cardiac function [99].…”

Aldosterone Antagonists. Modern Views on the Mechanism of Action and Effects of Spironolactone

“…Биологическое взаимодействие альдостерона с рецептором опосредуется избирательной экспрессией различных белков, которая зависит от взаимодей-ствия многих транскрипционных и трансляционных ме-ханизмов [10]. Наряду с хорошо известными геномными эффектами альдостерона имеются данные и о неге-номных эффектах, которые проявляются в быстром (в течение нескольких минут) действии альдостерона в со-ответствующих тканях [11].…”

“…Вы-явление указанных дополнительных активаторов син-теза альдостерона послужило доказательной базой, про-ливающей свет на механизмы недостаточного контро-ля уровня альдостерона изолированно ингибиторами АПФ без дополнительного назначения спиронолакто-на. Оно же стало обоснованием целесообразности применения малых доз спиронолактона (25-50 мг/сут) в комбинации с ингибитором АПФ для более полной нейрогуморальной блокады при длительном лечении больных с ХСН [10,15].…”

Indapamide

“…As most vigorously advocated by John Funder, 6 an MRA will almost certainly provide additional cardiovascular protection to whatever type of antihypertensive drug used. In a recent review, he concludes that an MRA should be included in current antihypertensive therapy for all hypertensives with reasonable renal function and normal potassium levels.…”

“…In a recent review, he concludes that an MRA should be included in current antihypertensive therapy for all hypertensives with reasonable renal function and normal potassium levels. 6 The MRA spironolactone is available for $4.00 for 30 tablets but, inexcusably beyond financial avarice, the now generic and less bothersome MRA eplerenone remains costly in the United States, $114 for 30 tablets.…”