Regulation of aldosterone in heart failure and vascular aging: Implications for therapy

Aldosterone mediates a multitude of angiotensin II (AngII)’s effects. Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure (HF), is induced by AngII type 1 receptors (AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupled to Gq/11 proteins. However, it also signals through barrestin-1 (barr1) or-2 (barr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 protein-independent but barr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has come to the light, signifying that AT1R antagonists that block both G proteins and barrs at the AT1R equally well are needed to achieve full suppression of aldosterone. Indeed, although all marketed angiotensin receptor blockers (ARBs, AT1R antagonists or sartans) potently inhibit G protein activation, candesartan and valsartan were found to be the most potent agents at blocking also barr activation. Therefore, these two drugs are portended to be the most effective aldosterone suppressors in vitro and in vivo in post-myocardial infarction (MI) HF animals. Finally, in addition to HF, hypertension, and other cardiovascular diseases, aldosterone is implicated also in arterial aging and associated vascular fibrosis, making it a potential therapeutic target for cardiovascular disease treatment in geriatric patients.