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 a s described in in vitro experiments. ET-induced direct positive inotropy, w hich seems to be mediated by ETB receptors, may be antagonized in vivo by a n indirect cardiodepressive effect owing to an ET-induced coronary vasocons triction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabo lism with the effects of I nmol/kg ET-I after pretreatment with 5 mg/kg mol sidomine or with 100 mu g/kg of the ETA receptor antagonist BQ 610. We inve stigated 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 ef fects. We also studied the effect of ET-1 on myocardial high-energy phospha tes. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced red uction 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 vaso constriction. The increase of isovolumic peak first derivative of left vent ricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) aft er pretreatment with molsidomine or BQ 610 indicates that these drugs unmas k the positive inotropy of ET-1. ET-induced myocardial ischemia was abolish ed 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 prevent ing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 s eems to be mediated by ETB receptors.