Negative inotropic effect of selective AT 2 receptor stimulation and its modulation by the endocardial endothelium

Abstract

Angiotensin II is an octapeptide whose effects are mediated by two types of receptors. AT 1 receptors are responsible for the vasoconstrictor, positive inotropic and growth promoting properties, while AT 2 receptors have been linked to vasodilator and anti-mitogenic properties. In this study we investigated the effects of selective AT 2 receptor stimulation on myocardial contractility and lusitropy. Effects of selective AT 2 receptor activation were evaluated in rabbit right papillary muscles ( n = 96) by adding increasing concentrations of H-9395, an AT 2 receptor agonist, alone or in presence of a selective AT 1 receptor antagonist (ZD-7155), or alternatively, by adding increasing concentrations of angiotensin II in presence of ZD-7155. In the latter conditions, selective AT 2 receptor activation was also performed in presence of NG-nitro- l-Arginine, indomethacin, proadifen, hydroxocobalamin, apamin plus charybdotoxin, Hoe-140 or PD-123,319, as well as, after endocardial endothelium removal. Selective AT 2 stimulation induced a negative inotropic and lusitropic effect in the first three protocols. This effect was completely abolished after selective removal of the endocardial endothelium and blunted in presence of Hoe-140, hydroxocobalamin, apamin plus charybdotoxin and PD-123,319, but maintained in presence of NG-nitro- l-Arginine, indomethacin or proadifen. Selective AT 2 receptor stimulation induces a negative inotropic and lusitropic effect, which is modulated by endocardial endothelium and mediated by bradykinin B 2 receptors through NO release and calcium dependent potassium channels activation. Such findings may help to better understand the therapeutic effects of selective AT 1 antagonists, which are increasingly used for treating cardiovascular diseases.