ARB DRUGS AND ALDOSTERONE IN HEART FAILURE: THE ADRENALBETA-ARRESTIN1 CONNECTION

Morris Auditorium

Objective. To examine the relative potencies of all the currently used in the clinic AT1R antagonist drugs (angiotensin receptor blockers, ARBs) at preventing activation of the signaling mediators G proteins and beta-arrestins, thereby suppressing aldosterone production. Background. The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion is mediated by either Gq/11 proteins or beta-arrestin1, both of which can couple to its type 1 receptors (AT1Rs), present in adrenocortical zona glomerulosa (AZG) cell membranes. Methods. We measured beta- arrestin1 activation by the AT1R bound to different drugs in AZG cells in vitro. We also measured aldosterone production in response to the various drugs in these cells, as well as circulating aldosterone levels in experimental rats having heart failure (HF) and treated in vivo with ARBs. Results. While all ARBs are potent inhibitors of G protein activation, candesartan and valsartan are the most potent at blocking AngII-induced beta-arrestin1 activation, translating into excellent efficacies at aldosterone suppression in AZG cells. Conversely, irbesartan and losartan are the least potent beta-arrestin inhibitors and aldosterone suppressors. As a result, in vivo, candesartan and valsartan are the most potent aldosterone suppressors in HF animals improving cardiac function, whereas irbesartan and losartan appear ineffective at combating HF-related hyperaldosteronism in vivo. Conclusion. Candesartan and valsartan may be the most appropriate agents of the ARB drug class to use in HF treatment. Grants. 1) American Heart Association (AHA #09SDG2010138, National Center) 2) Nova Southeastern University’s President’s Faculty Research and Development Grant (PFRDG) NSU #335320