Significance of endothelinB receptors for myocardial contractility and myocardial energy metabolism.
Positive inotropy of endothelin-1 (ET-1), which has already been described in vitro, has not been detected in vivo. Combination with vasodilators has been shown to unmask a positive inotropic effect of ET-1. The ET-induced direct positive inotropy, which seems to be mediated by endothelinB (ETB) receptors, is antagonized in vivo by an indirect negative inotropy due to an ET-induced coronary vasoconstriction via ETA receptors. This study examines the significance of ETB receptors on myocardial contractility and myocardial energy metabolism. The dose-dependent hemodynamic and inotropic effects of the highly specific ETB agonist IRL 1620 (0.4, 1.0, 2.0, 4.0 nmol/kg vs. NaCl controls) were investigated in open-chest rats during and after a 7-min infusion. In addition to measurements in the intact circulation, we examined the myocardial function by isovolumic registrations independent of peripheral vascular effects. Furthermore, the effect of IRL 1620 on myocardial high-energy phosphates was studied. IRL 1620 causes a biphasic pressure response, with an initial decrease followed by a rise (differences of 0.4, 1.0, 2.0 and 4.0 nmol/kg IRL 1620 compared with the controls 5 min after infusion; mean aortic pressure: +37%, +33%, +29%, +20%). IRL 1620 has a positive chronotropic effect (HR: +2%, +14%, +16%, +6%). After an initial vasodilation, IRL 1620 augments the total peripheral resistance: +35%, +31%, +66%, +82%. Because the maximum of the isovolumic left ventricular systolic pressure (+7%, +7%, +12%, +12%) and the corresponding maximum first derivative of the left ventricular pressure (+13%, +14%, +23%, +18%) were increased under IRL 1620, these measurements indicate a positive inotropic effect of IRL 1620 in vivo. Myocardial high-energy phosphates were not changed by IRL 1620. In contrast to nonselective activation of ETA and ETB receptors by ET-1, the selective activation of ETB receptors by IRL 1620 causes a positive inotropy. This discrepancy can be explained by a less pronounced vasoconstriction with absence of myocardial ischemia after ETB receptor activation by IRL 1620.
Beyer
M E
ME
Medizinische Klinik, Abt. III, Eberhard-Karls-Universität, Tübingen, Germany.
Slesak
G
G
Hoffmeister
H M
HM
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D016232:Endothelins / Q000494:pharmacology*; D004734:Energy Metabolism; D006321:Heart / Q000502:physiology*; D006439:Hemodynamics; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000819:agonists / Q000502:physiology*
D000227:Adenine Nucleotides; D016232:Endothelins; D010446:Peptide Fragments; D017466:Receptors, Endothelin; D010725:Phosphocreatine; C074308:sovateltide