Hemodynamic and Inotropic Effects of the Endothelin A Antagonist BQ-610 In Vivo

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Abstract
The positive inotropy of endothelin-1 (ET-1) described by in vitro studies is not detectable in vivo because this effect is antagonized by cardiodepressive effects due to ET-induced vasoconstriction with subsequent myocardial ischemia. This vasoconstriction is mainly mediated by ETA receptors. In a previous in vivo study with a selective ETB receptor agonist, we showed that ETB receptors play an important role in the ET-induced positive inotropy. The present in vivo study examined whether selective ETA receptor blockade can unmask the ETB receptor-mediated positive inotropy of endogenous ET-1 by preventing its cardiodepressive effects via ETA receptors. In an open-chest rat model, we compared the acute hemodynamic and inotropic effects of the highly selective ETA receptor antagonist BQ-610 (100 μg/kg) with NaCl controls during and after a 7-min infusion. In addition to measurements in the intact circulation, the effects on myocardial contractility were studied by isovolumic registrations (peak LVSP, peak dP/dtmax), which are independent of peripheral vascular effects. Acute blockade of the ETA receptors by BQ-610 had no effect on blood pressure and heart rate. BQ-610 caused vasodilatation (total peripheral resistance −7.5% vs. control at the end of infusion; pp