Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart

Abstract

Endothelin (ET) receptor antagonists are cardioprotective during myocardial ischaemia and reperfusion through a nitric oxide (NO)-dependent mechanism. The aim of the present study was to investigate whether the ET receptor antagonist, bosentan, is cardioprotective in atherosclerotic mice. Buffer-perfused hearts from apolipoprotein E/LDL receptor double knockout (KO) and wild-type (WT) mice were subjected to global ischaemia and reperfusion. Following reperfusion, the recovery of rate-pressure product (RPP; left ventricular developed pressure (LVDP) × heart rate) was equally impaired in WT and KO mice given vehicle (34 ± 8 and 29 ± 9%, respectively). The ET A/ET B receptor antagonist bosentan (10 μmoll -1) improved recoveries to 57 ± 10% in WT and to 68 ± 10% in KO mice (P < 0.01). Similar effects were observed for the recovery of left ventricular end-diastolic pressure (LVEDP), developed pressure and dP/dt. Bosentan improved the recovery of coronary flow in both KO and WT mice. Recovery of coronary flow was significantly higher in the KO mice given bosentan (135 ± 15%) than in the WT group (111 ± 12%; P < 0.01). ET-1 (1 nmoll -1) impaired recovery of coronary flow in both WT and KO mice though this effect was more pronounced in the KO mice (P < 0.01). Coronary outflow of NO during reperfusion was enhanced in both KO and WT mice following bosentan administration. The ET A/ET B receptor antagonist bosentan protects the atherosclerotic mouse heart from ischaemia/reperfusion injury. The observation that ET receptor blockade and stimulation have a greater effect on coronary flow in atherosclerotic hearts indicates an increased activation of the ET system in atherosclerotic coronary arteries. © 2005 Nature Publishing Group All rights reserved.