Differential effects of endothelin-1 on isolated working rat hearts before and after ischaemia and reperfusion

Abstract

Endothelin (ET) may have both detrimental (reduced coronary flow) and beneficial effects (positive inotrope, reduced arrhythmogenesis) following ischaemia. We examined the effects of ET on cardiac function during reperfusion following prolonged hypothermic cardioplegic arrest in a protocol mimicking cardiac transplantation. Isolated working rat hearts were perfused with Krebs buffer to which increasing concentrations of ET-1 or sarafotoxin S6c had been added. Identical experiments were performed after 4h of cardioplegic arrest at 4°C. Under pre-ischaemic conditions ET-1 caused a dose-dependent decrease in cardiac function compared with controls. In contrast, following ischaemia low doses of ET-1 (10-10 M) caused a significant and beneficial increase in cardiac output (109.1% versus 81.3%), dP/dt i.e. the rate of change of pressure with time (94.7% versus 75.6%) and stroke volume (100.3% versus 77.5%) compared with controls (P<0.05). At higher doses of ET-1 there was a detrimental effect on cardiac output, dP/dt and stroke volume similar to that seen prior to ischaemia. Sarafotoxin S6c had no significant effect pre or post ischaemia on any of the parameters measured compared with controls (P = not significant). ET-1 at low concentrations during reperfusion can improve the recovery of cardiac function mediated via ETA receptors. ET may play an important physiological role in the recovery of cardiac function following prolonged ischaemia.