MECHANICAL EFFECTS OF ET-1 IN CARDIOMYOCYTES ISOLATED FROM NORMAL ANDHEART-FAILED RABBITS

Endothelin (ET-1) is found at elevated concentrations in the plasma of patients with heart failure and in animal models of cardiomyopathy. T he peptide is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca2+ in cardiomyocytes. The obj ect of this study was to investigate at the cellular level, the action s of ET-1 on contractile function and on Ca2+ currents in heart-failed ventricular myocardium. Male New Zealand White rabbits (8 wks) were t reated with twice weekly injections of epirubicin (4 mg/kg/wk, n=7) or with saline (n=7) for 6 wks, followed by a washout period of 2 wks. V entricular cardiomyocytes were isolated from rabbit hearts using Lange ndorff perfusion with collagenase; contractile function was examined u sing a video microscopy method, and L-type Ca2+ currents were recorded using a whole-cell patch-clamp technique. ET-1 produced a concentrati on-dependent increase in contractile response (% increase from basal v alue) to a maximum at 1 nM ET-1 of 69+/-11% (mean+/-S.D.) in control c ardiomyocytes and 33+/-6% in heart-failed cells. However, there was no significant change in the EC(50) obtained with ET-1 for healthy (0.31 +/-0.1 nM) and for failed cardiomyocytes (0.24+/-0.1 nM). The effects of ET-1 on L-type Ca2+ channels were similar with a peak amplitude at 1 nM ET-1 of -3.26+/-0.8 nA in control cardiomyocytes and -3.32+/-0.9 nA in heart-failed cells. The attenuation of the contractile response to ET-1 in heart-failed cells may reflect a desensitization of ET rece ptors as a consequence of elevated circulating levels of ET and was no t reflected by alteration of transmembrane Ca2+ conductance. It is pro bable, therefore, that multiple signalling pathways are involved in th e actions of ET on ventricular myocardium.