Inotropic effects of endothelin-1: interaction with molsidomine and with BQ 610.

-In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ETB receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 microg/kg of the ETA receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: -62%; molsidomine+ET-1: -47%; BQ 610+ET-1: -27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ETA receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ETB receptors.

Effect of endothelin-1 and its combination with adenosine on myocardial contractility and myocardial energy metabolism in vivo.

Contradictory results have been reported about the inotropic effects of the vasoconstrictive peptide endothelin-1 (ET-1). In contrast to in vitro experiments, in vivo studies could not demonstrate a positive inotropy of ET-1. It may be possible, that the direct positive inotropic effect of ET-1 observed in in vitro studies is counterbalanced in vivo by an indirect negative inotropy due to its coronar-constrictive effect. This study examined the hemodynamic and inotropic effects of 2500 ng ET-1/kg without and after pretreatment with the vasodilating nucleoside adenosine (0.5, 2.0, 5.0 mg ADO/kg/min). Data were compared with NaCl controls in open-chest rats during and after a 7-min infusion. Besides measurements in the intact circulation isovolumic measurements were carried out for quantification of myocardial contractility independently of peripheral vascular effects. We further examined the effect of ET-1 and its combination with 2.0 mg ADO/kg/min on myocardial high-energy phosphates (ATP, AMP, ADP, creatine phosphate). ET-1 causes a strong and longlasting vasoconstriction (+ 186% v preinfusion values), which is dose-dependently antagonized in part by ADO (+ 109%, + 136%, + 60%). While the maximum of the isovolumic LVSP (peak LVSP) and the corresponding dP/dtmax (peak dP/dtmax) were unchanged with sole ET-1 (peak LVSP: +5%, peak dP/dtmax: -2%), these indexes of myocardial contractility were increased after pretreatment with ADO (peak LVSP: +11%, +13%, +4%; peak dP/dtmax: +9%, +20%, +10%) indicating a positive inotropic effect of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Hemodynamic and inotropic effects of endothelin-1 in vivo.

Endothelin-1 (ET-1) is known to have strong vasoactive properties. Contradictory results have been reported with regard to its inotropic effects. This study examined the dose-dependent (500, 1000, 2500, 5000 and 10,000 ng ET-1/kg vs. NaCl controls) hemodynamic and inotropic effects of ET-1 in 53 open-chest rats during and after a 7-min infusion. Besides measurements in the intact circulation the myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. A transient ET-1 induced (500, 1000, 2500, 5000 ng ET-1/kg) decrease of the left ventricular systolic pressure (LVSP) and the mean aortic pressure (AoPmean) was followed by a dose-related rise of these pressures (LVSP: -1%, -1%, +8%, +16% vs. preinfusion values; AoPmean: -11%, +9%, +39%, +52%). Heart rate (HR) was not influenced by ET-1. Due to the dose-dependent decrease of the stroke volume (SV) the cardiac output (CO) was reduced (CO: -8%, -23%, -40%, -50%). After an initial vasodilatation ET-1 elevates the total peripheral resistance (TPR: -1%, +49%, +139%, +215%) dose-dependently. 10,000 ng ET-1/kg was a lethal dose resulting in cardiac failure within minutes (low output). Since the maximum of the isovolumic LVSP (peak LVSP) and the corresponding dP/dtmax (peak dP/dtmax) were unchanged under ET-1, the isovolumic measurements do not indicate a positive inotropic effect of ET-1 in vivo in contrast to published results of in vitro experiments. It may be possible that a direct positive inotropic effect of ET-1 observed in in vitro studies is counterbalanced in vivo by an indirect negative inotropic effect due to the coronary-constrictive effect of ET-1.