In vivo hemodynamic and inotropic effects of the endothelinB agonist IRL 1620.
The endothelinB (ETB) receptor is involved in endothelin-induced vasoconstriction and appears to play a role in ET-induced positive inotropy. Our previous study could not detect a positive inotropic effect of ET-1 in vivo. To evaluate specifically the effects of the ETB receptor on hemodynamics and inotropy of ET-1 in the intact circulation, we examined in the open-chest rat model the dose-dependent hemodynamic and inotropic effects of the highly specific ETB agonist IRL 1620 (0.4, 1.0, 2.0, and 4.0 nmol/kg vs. NaCl controls) during and after a 7-min infusion. In addition to measurements in the intact circulation, isovolumic recordings (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility independently of peripheral vascular changes. IRL 1620 caused a significant biphasic blood pressure response with an initial fall and a sustained increase, reflecting the vasoactive effects of IRL 1620, with a transient vasorelaxation followed by dose-dependent and long-lasting vasoconstriction. Although IRL 1620 has a positive chronotropic effect the reduction in stroke volume (probably due to the elevated afterload) causes a decrease in cardiac output. Nevertheless, the isovolumic measurements indicate a significant positive inotropic effect of IRL 1620. Therefore, the selective activation of ETB receptors causes a positive inotropic effect, which is also detectable in vivo, as the vasoconstrictor and coronary constrictor effects are less pronounced compared to activation of both ETA and ETB receptors by ET-1.
Beyer
M E
ME
Medizinische Klinik, Abteilung III, Eberhard-Karls-Universität, Tübingen, Germany.
Slesak
G
G
Hoffmeister
H M
HM
D000818:Animals; D016232:Endothelins / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000819:agonists*
D016232:Endothelins; D010446:Peptide Fragments; D017466:Receptors, Endothelin; C074308:sovateltide