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

Abstract

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II (AngII). 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 coupling to G_q/11 proteins. However, it can also signal through β-arrestin-1 (βarr1) or -2 (βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, G_q/11 protein-independent but βarr1-dependent signaling pathway emanating from the adrenocortical AT₁R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT₁R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers (ARBs, AT₁R antagonists or sartans) at blocking activation of the two signaling modes (G protein-, and βarr1-dependent) at the AngII-activated AT₁R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT₁R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by AngII and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-“biased” blockers at the human AT₁R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan (and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

Keywords: Adrenal cortex, Adrenocortical zona glomerulosa cell, Aldosterone, Angiotensin receptor blocker, Angiotensin II type 1 receptor, β-arrestin-1, Heart failure, Suppression efficacy

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.