The endothelin A receptor antagonist LU 135252 protects the myocardium from neutrophil injury during ischaemia/reperfusion

Abstract

Objective: Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also a stimulator of polymorphonuclear leukocyte (PMN) aggregation and adhesion. The aim of this study was to investigate whether an ETA receptor antagonist attenuates the PMN-mediated contractile dysfunction following myocardial ischaemia.

Methods: Isolated rat hearts were perfused according to the Langendorff method. The hearts were subjected to global ischaemia and reperfused with buffer solution only, or human PMNs dissolved in rat plasma (HNRP).

Results: In an initial study, the ETA receptor antagonist LU 135252 (1 and 10 mumol/l) or ET-1 (1 and 10 nmol/l) did not significantly affect the recovery of left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), the first derivative of left ventricular pressure (dP/dt) or the rate pressure product (RPP) during reperfusion with buffer solution only compared to a vehicle group. In a second study on hearts reperfused with HNRP, administration of LU 135252 (10 mumol/l) significantly enhanced the recovery of LVDP, dP/dt and RPP in hearts reperfused with HNRP. LVEDP was 20 mmHg lower in hearts given LU 135252 than vehicle in combination with HNRP (P < 0.05). The outflow of PMNs in the coronary effluent during reperfusion was 41 +/- 8% in hearts given LU 135252 compared to 9 +/- 5% in vehicle-treated hearts (P < 0.01). There was a significant correlation between the myocardial functional recovery and the outflow of PMNs. Administration of ET-1 (0.1 and 1 nmol/l) in combination with HNRP resulted in complete loss of contractile function and no outflow of PMNs during reperfusion.

Conclusion: The ETA receptor antagonist LU 135252 protects from ischaemia/reperfusion injury in the isolated rat heart in the presence of PMNs. It is suggested that inhibition of PMN-induced injury during reperfusion is an important cardioprotective action of LU 135252.