Hemodynamic and inotropic effects of the endothelin A antagonist BQ-610 in vivo.
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 micrograms/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; p < 0.01) with a consecutive increase in stroke volume (+15.3%; p < 0.01), cardiac output (+15.4%; p < 0.001), and ejection fraction (+10.4%; p < 0.01). The isovolumic measurements indicated a significant positive inotropic effect of BQ-610 (peak LVSP + 4.2%, p < 0.01; peak dP/dtmax + 5.5%, p < 0.01). Therefore, selective ETA receptor blockade by BQ-610 improves the hemodynamics in the intact circulation by causing a reduction in afterload and an increase in myocardial contractility. The positive inotropic effect of BQ-610 may be mediated by the positive inotropy of endogenous ET-1 via ETB receptors after selective ETA receptor blockade.
Beyer
M E
ME
Medical Department III, Eberhard-Karls-University, Tübingen, Germany.
Slesak
G
G
Brehm
B R
BR
Hoffmeister
H M
HM
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D044022:Receptor, Endothelin A; C087220:BQ 610