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

Abstract

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) Â heart rate) was equally impaired in WT and KO mice given vehicle (3478 and 2979%, respectively). The ET A /ET B receptor antagonist bosentan (10 mmol l À1 ) improved recoveries to 57710% in WT and to 68710% in KO mice (Po0.01). Similar effects were observed for the recovery of left ventricular end-diastolic pressure (LVEDP), developed pressure and dP/dt. 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 (135715%) than in the WT group (111712%; Po0.01). ET-1 (1 nmol l À1 ) impaired recovery of coronary flow in both WT and KO mice though this effect was more pronounced in the KO mice (Po0.01). 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.

An Overview of Experimental Models on Ischemic Heart Diseases

“…When global ischemia develops due to ventricular fibrillation or cardiac arrest, any protective agent is less likely to be used before the onset of damage. There is a prominent lack of experimental procedure showing the onset time of the ischemia or reperfusion prior to the various parameters of interest being monitored (5)(6)(7). However, global ischemia/reperfusion (I/R) reproduces the effects of I/R on the heart when the heart is arrested/restarted during cardiac surgery (8).…”