Abstract 10263: Biased Agonism/Antagonism of Sartans and Angiotensin II Analogs for Angiotensin II Type 1 Receptor-Induced, β-Arrestin--Dependent Aldosterone Production in Heart Failure
We recently showed that activation of β-arrestin-1 (βarr1) by the angiotensin II (AngII) type 1 receptor (AT1R) mediates AngII-induced aldosterone production in vitro and physiologically in vivo. Herein, we investigated the relative potency of various AT1R antagonist drugs (sartans) at inhibiting βarr vs. G-protein activation and hence aldosterone production. Additionally, we tested novel AngII “biased” agonist (i.e. that only stimulate βarrs and not G-proteins) analogs at stimulating βarr activity and aldosterone production. Finally, we tested plasma aldosterone levels after treatment with these agents and the impact on cardiac function of post-myocardial infarction (MI) rats.
Methods: For in vitro studies, the adrenocortical H295R cell line was used, whereas for in vivo studies, post-MI rats overexpressing βarr1 in their adrenals received 7-day-long treatments with the agents of interest.
Results: Candesartan and valsartan were the most potent βarr activation and βarr-mediated aldosterone production inhibitors in vitro, as well as the most “biased” antagonists for βarr vs. G-protein inhibition. Conversely, losartan and irbesartan were the least potent and the least “biased”, respectively. Consistent with these in vivo, candesartan and valsartan, contrary to irbesartan, caused significant plasma aldosterone reductions in post-MI rats. Accordingly, cardiac ejection fraction (EF) and contractility were significantly augmented in candesartan- and valsartan-treated rats (EF: 41.1±1% and 40±1% respectively, vs. 35±0.3% for saline-treated), but further deteriorated in irbesartan-treated post-MI rats (EF: 32±1%, n=7 rats/group). Finally, we report on a novel AT1R biased agonist, CORET ([Sar1,Cys(Et)5,Leu8]-AngII), which is far more potent at stimulating βarr than SII, the standard AT1R biased agonist. CORET elicits far higher aldosterone levels than SII, significantly worsening cardiac function post-MI in vivo.
Conclusions: Candesartan and valsartan are the most potent sartans at lowering aldosterone in vitro and in vivo after MI, thus improving cardiac function in heart failure progression. Losartan and irbesartan appear the least potent sartans at doing so. CORET is a novel, very potent AT1R biased agonist for βarr activation.
- © 2010 by American Heart Association, Inc.