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

1 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. 2 Buffer‐perfused hearts from apolipoprotein E/LDL receptor double knockout (KO) and wild‐type (WT) mice were subjected to global ischaemia and reperfusion. 3 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  μ mol l −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 d P /d t . 4 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 nmol l −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). 5 Coronary outflow of NO during reperfusion was enhanced in both KO and WT mice following bosentan administration. 6 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.British Journal of Pharmacology (2005) 144 , 860–866. doi: 10.1038/sj.bjp.0706117