Why do we need a selective angiotensin II type 2 receptor agonist?

The renin-angiotensin system has a central role in the regulation of blood pressure and water balance. It is also a main target in the treatment of hypertension. Angiotensin II has 2 major receptors, the type 1 (AT1R) and the type 2 receptor (AT2R), both coupled to G proteins. Adverse vascular remodeling observed in cardiovascular diseases is attributed to AT1R, and a large number of relatively selective AT1R inhibitors are now used in patients. The effects of AT2R are usually presented as counteracting the effects exerted by AT1R. Consequently, some beneficial effects of the AT1R blockers (angiotensin receptor blocker) are commonly attributed to AT2R activation. 1 Beneficial vascular effects of AT2R have now been proven by several studies. For example, AT2R stimulation reduces vascular RhoA/Rho kinase/myosin light chain phosphorylation in angiotensin II and AT1R antagonist valsartan-treated vascular smooth muscle cells in vitro, as well as in the aorta of spontaneously hypertensive rats chronically treated with candesartan. Altogether, previous studies suggest a role for vascular AT2R in blood pressure lowering during chronic AT1R blockade. Similarly, in hypertensive diabetic patients, chronic angiotensin receptor blocker treatment increases AT2R expression level and AT2R-dependent vasodilatation of mesenteric resistance arteries. Nevertheless, in the absence of AT1R inhibition, expression of AT2R varies a lot under physiological and pathophysiological conditions, and the relatively low selectivity of the antagonist PD123319 and the weak specificity of the agonist CGP42112 do not help fully understand the role of AT2R. Thus, its role in most cardiovascular and metabolic disorders remains poorly understood and mainly hypothetical. Consequently, the availability of the first nonpeptide AT2R agonist, compound 21 (C21), was seen as a major breakthrough, as described in a recent review article. Indeed, C21 has protective effects after myocardial infarction and in hypertension-induced end organ damage. In different animal models, AT2Rs also display an anti-inflammatory effect. 1 Nevertheless, there is accumulating evidence that the commonly accepted scheme with a balance between a constrictor effect of AT1R and a dilator effect of AT2R is too simplistic and does not always reflect experimental evidence. The work performed by Verdonk et al, published in this issue of Hypertension, on the AT2R agonist C21 further highlights the complexity of this system, in addition to bringing key information on the mechanism of action of this new drug. Although C21 binds to AT2R with high affinity, this study also shows that C21 induces a puzzling combination of vasodilation and vasoconstriction. Surprisingly, C21mediated vasodilation was independent of AT2R and of the endothelium. Indeed, the authors have shown that C21 has a direct inhibitory effect on calcium influx into smooth muscle cells, thus leading to relaxation. C21 was tested in rat and mouse arteries, as well as human coronary arteries, and C21-dependent vasodilation through calcium entry inhibition was also observed in mice lacking the gene encoding for AT2R. Furthermore, in the isolated perfused heart, C21 induces an initial AT1R-dependent contraction followed by AT2R-independent dilatation. The constrictor effect of AT2R was more pronounced in hypertensive rats, as shown previously. This article brings up 2 major issues requiring further discussion. First, C21-dependent dilatation relies mainly on calcium entry blockade without interfering with the RhoARho-kinase pathway, which has been shown to be inhibited after AT2R stimulation. This finding requires reanalysis of the studies showing protective effects of C21. Indeed, the organ-protective effect of C21 is compatible with the effects of the dihydropyridine calcium channel blockers, that is, reduction of proliferation, inflammation, fibrosis, and vasoconstriction. The authors also show that low doses C21 are needed to selectively block AT2R. Lower doses of C21 might be used after AT1R blockade, which induces a large increase in AT2R expression level. In this condition, lower doses of C21 might be sufficient to more selectively block AT2R. Lower-dose C21 could, thus, be useful in resistant hypertension, although in this case its effect on calcium currents might also be advantageous. Low-dose C21 might also provide additional protection against organ damage in kidney and heart diseases in patients treated with angiotensin receptor blockers. Nevertheless, no data are yet available to support this assumption. It should be noted that more and more patients, not only hypertensive patients, receive angiotensin receptor blockers. In these conditions, a better knowledge of the effect of AT2R stimulation is essential, especially in the different organs affected by cardiovascular diseases. Second, this work further confirms with straightforward experiments The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Integrated Neurovascular and Mitochondrial Biology, Institut National de la Santé et de la Recherche Médicale U1083, Angers, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 6214, Angers, France; University of Angers, Angers, France; University Hospital of Angers, Angers, France. Correspondence to Daniel Henrion, Department of Integrated Neurovascular and Mitochondrial Biology, UMR CNRS 6214-INSERM U1083, University of Angers, 49045 Angers, France. E-mail [email protected] (Hypertension. 2012;60:00-00.) © 2012 American Heart Association, Inc.