Effects of endothelin-1 and IRL 1620 on myocardial contractility and myocardial energy metabolism.
In contrast to in vitro studies, experiments in intact animals could not detect a positive inotropic effect of endothelin-1 (ET-1). We presumed that the ET-induced direct positive inotropy is antagonized in vivo by an indirect cardiodepressant effect due to a mainly ETA-mediated and ET-induced coronary constriction, with consequent myocardial ischemia. To confirm this hypothesis we examined in thoracotomized rats the effects of a nonselective activation of ETA and ETB receptors by 1 nmol/kg ET-1 with and without the vasodilator adenosine (2.0 mg/kg/min), and the effects of a selective activation of ETB receptors by the ETB agonist IRL 1620 (2 nmol/kg) on myocardial contractility and energy metabolism (ATP, ADP, AMP). In addition to recordings in the intact circulation, isovolumic measurements (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility. ET-1 had no positive inotropic effect (peak dP/dtmax -2% vs. control, n.s.) due to a marked vasoconstriction with a consequent fall in the myocardial ATP content (-17%; p < 0.01). Adenosine antagonized the ET-induced vasoconstriction in part, normalized myocardial energy metabolism (ATP -7%), and thus unmasked the positive inotropic effect of ET-1 (peak dP/dtmax +20%; p < 0.01). Selective activation of ETB receptors by IRL 1620 had only a small vasoconstrictor effect, which did not produce myocardial ischemia (ATP + 10%; n.s.) and thus caused a positive inotropic effect in vivo (peak dP/dtmax +22%; p < 0.01). The positive inotropic effect of ET-1 is not detectable in vivo as its marked, mainly ETA-mediated, vaso- and coronary constriction causes myocardial ischemia that thus produces an indirect negative inotropic effect.
Beyer
M E
ME
Medizinische Klinik, Abteilung III, Eberhard-Karls-Universität, Tübingen, Germany.
Slesak
G
G
Nerz
S
S
Kazmaier
S
S
Hoffmeister
H M
HM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016232:Endothelins / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; 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; D000255:Adenosine Triphosphate