Combined blockade of endothelin-1 and thromboxane A(2) receptors against postischaemic contractile dysfunction in rat hearts

1 Endothelin-1 (ET-1) may play a role in myocardial ischaemia/reperfusion i njury because both the release and vasoconstrictor effect of ET-1 are incre ased after ischaemia. Since the increased vasoconstrictor effect of ET-1 ca n be mediated by ET-1-induced release of thromboxane A(2) (TXA(2)), the aim of this study wa to test whether combined blockade of ET and TXA2 receptor s protects the coronary flow, contractile performance, and cardiac energy m etabolism during ischaemia and reperfusion. 2 Bosentan (antagonist for ETA and ETB receptors, 1 muM based on concentrat ion-response curves of ET-1), SQ 30,741 (antagonist of TXA(2) receptors, 0. 1 muM), or the combination thereof was administered to isolated perfused ra t hearts undergoing 15 min of global ischaemia and 60 min of reperfusion. 3 Neither bosentan or SQ 30,741 alone, nor the combination thereof, improve d the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischa emia-induced acidosis but this did not translate into a measurable effect o n haemodynamic or metabolic variables. 4 Thus, combined blockade of ET and TXA(2) receptors does not protect the c oronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding su ggests that neither ET-1 nor ET-1-induced release of TXA(2) play a major ro le in the postischaemic recovery of the cardiac contractile function and en ergy metabolism.