Significance of the endothelin ET_A receptor in the haemodynamic and inotropic effects of endothelin-1 in rats

The main aim of the present study was to investigate the direct inotropic effects of stimulation of the endothelin (ET) receptor ET_A under in vivo conditions. It is well known that ET_A receptor stimulation causes pronounced vasoconstriction. The ET-1-induced coronary vasoconstriction may lead to myocardial ischaemia and, consequently, to cardiodepressor effects that may mask the direct positive inotropic effect of ET_A receptor stimulation. Thus, in the present study, steps were taken to avoid this possibility. In anaesthetized open-chest rats the haemodynamic and inotropic effects of ET_A receptor stimulation were studied by monitoring responses evoked by ET-1 (1 nmol/kg of body weight) after ET_B receptor blockade with BQ 788 (0.5 μmol/kg of body weight); these responses were compared with saline controls (after ET_B receptor blockade). To avoid vasoconstrictor effects induced by ET_A receptor stimulation, additional experiments were performed in the presence of the vasodilator adenosine (2.0 mg·kg⁻¹ of body weight·min⁻¹). Myocardial function was also examined during aortic clamping so as to circumvent the effect of changes in afterload. We studied further the effect of ET_A receptor stimulation on myocardial energy metabolism. ET_A receptor stimulation reduced cardiac output (−49% compared with control), raised total peripheral resistance (+173%) and reduced myocardial ATP content (−23%). Aortic clamping did not reveal a positive inotropic effect of ET_A receptor stimulation. Furthermore, even though adenosine attenuated the decrease in cardiac output (−21%), the increase of total peripheral resistance (+48%) and prevented the fall of myocardial ATP content (+6%), this did not unmask a positive inotropic effect of ET_A receptor stimulation. Thus we conclude that ET_A receptor stimulation causes vasoconstriction and myocardial ischaemia, but has no positive inotropic effects in rats.