Combined blockade of endothelin‐1 and thromboxane A2 receptors against postischaemic contractile dysfunction in rat hearts

Endothelin-1 (ET-1) may play a role in myocardial ischaemia/reperfusion injury because both the release and vasoconstrictor effect of ET-1 are increased after ischaemia. Since the increased vasoconstrictor effect of ET-1 can be mediated by ET-1-induced release of thromboxane A2 (TXA2), the aim of this study was to test whether combined blockade of ET and TXA2 receptors protects the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion. Bosentan (antagonist for ETA and ETB receptors, 1 μM based on concentration-response curves of ET-1), SQ 30,741 (antagonist of TXA2 receptors, 0.1 μM), or the combination thereof was administered to isolated perfused rat hearts undergoing 15 min of global ischaemia and 60 min of reperfusion. Neither bosentan or SQ 30,741 alone, nor the combination thereof, improved the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischaemia-induced acidosis but this did not translate into a measurable effect on haemodynamic or metabolic variables. Thus, combined blockade of ET and TXA2 receptors does not protect the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding suggests that neither ET-1 nor ET-1-induced release of TXA2 play a major role in the postischaemic recovery of the cardiac contractile function and energy metabolism. British Journal of Pharmacology (2001) 132, 234–240; doi:10.1038/sj.bjp.0703773