Which ARB drug is better for heart failure therapy? Aldosterone suppression holds the answer

Abstract

The known physiological effect of angiotensin II (AngII) type I receptors (AT₁Rs), synthesis and secretion of the cardiotoxic hormone aldosterone, whose elevation accompanies and aggravates heart failure (HF), is mediated by both G proteins and barrestins (barrs). We recently examined the relative potencies of all the currently used in the clinic AT₁R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of either of these two signaling mediators at the AngII-bound AT₁R and, consequently, at suppression of aldosterone in vitro and in vivo. We also tested the impact of the aldosterone suppression they produce in vivo on the cardiac function of post-myocardial infarction (MI) animals progressing to HF. By using a variety of techniques in cultured cells in vitro, we found that all ARBs are potent inhibitors of G protein activation at the AT₁R but display striking differences in their potency at blocking the second signaling component of aldosterone production in the adrenal cortex, i.e. barrs. Candesartan and valsartan in particular were found the most potent at blocking AngII-induced barr activation at this receptor, translating into excellent efficacies at aldosterone suppression in vitro and in vivo and at post-MI cardiac function and remodeling amelioration. Conversely, irbesartan appears to be largely G protein- inhibitory, as it exhibits very low potency towards barr inhibition. As a result, it is a very weak aldosterone suppressor in vitro and in vivo, and fails to improve cardiac function or adverse remodeling post-MI. These findings will aid pharmacotherapeutic decisions for therapy of post-MI HF and they will also help develop novel and better ARB drugs, with greater efficacy for HF therapy.