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Editorial
. 2017 Mar 26;9(3):200-206.
doi: 10.4330/wjc.v9.i3.200.

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

Anastasios Lymperopoulos  1 , Beatrix Aukszi  1
Affiliations
Editorial

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

Anastasios Lymperopoulos et al. World J Cardiol. .

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 Gq/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, Gq/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 II type 1 receptor; Angiotensin receptor blocker; Heart failure; Suppression efficacy; β-arrestin-1.

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Conflict of interest statement

Conflict-of-interest statement: Both authors declare no conflict of interest related to this publication.

Figures

Figure 1
Figure 1
Angiotensin II type 1 receptor and aldosterone production. Schematic representation of the parallel G prt- and βarr1-mediated, AngII-bound AT1R signaling cascades that converge on mitochondrial aldosterone synthesis in adrenocortical zona glomerulosa (AZG) cells. The structure of the proposed AT1R antagonist (2-pentyl-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid)[40], discussed in the text, capable of suppressing both pathways equally well, is also shown (upper left corner). See text for details. G prt: Gq protein; βarr1: β-arrestin1; AngII: Angiotensin II; AT1R: AngII type 1 receptor.
See this image and copyright information in PMC

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