Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

Core Tip

Core tip: The angiotensin II type 1 receptor (AT₁R) endogenously expressed in adrenocortical cells was known for decades to induce aldosterone production via a well-defined G_q protein-mediated signaling pathway. Over the past decade, a number of studies have elucidated another, β-arrestin-1 (βarr1)-dependent signaling cascade, which proceeds in parallel to, and independently of the G_q-mediated one, and also results in aldosterone synthesis and secretion from the adrenal cortex. Importantly, although all of the Food and Drug Administration-approved angiotensin receptor blocker (ARB) drugs (AT₁R antagonists) are very effective at blocking the G_q-mediated pathway, as expected, since they were designed to do so (i.e., to block the G protein signaling of the AT₁R), they seem to display varying efficacies at blocking this new, βarr1-dependent pathway, which translates into significant variation at aldosterone suppression efficacies. In that context, candesartan and valsartan appear the most effective agents at blocking also the βarr1 pathway emanating from the adrenocortical AT₁R, and thus, these two agents may be the best aldosterone suppressors within the ARB drug class.