The effect of the insurmountable angiotensin II AT1 receptor blocker candesartan on ischemic/reperfusion injury was investigated in isolated rat hearts and in anesthetized pigs. The possible additive effect of candesartan on the cardioprotection by a calcium antagonist and a lipid peroxidation inhibitor was also studied. In Langendorff-perfused rat hearts, candesartan, in a dose-related manner, improved left ventricular functional recovery and reduced the no-reflow area following global ischemia and reperfusion. A similar degree of cardioprotection by candesartan (10 nM) and an equipotent concentration of another AT1 receptor blocker losartan (3 microM) was observed when ischemia was begun immediately after drug pretreatment. When a washout period was implemented between pretreatment and ischemia, the protective effect of candesartan, but not that of losartan, remained, suggesting that candesartan may provide a more efficient cardioprotection than losartan. In anesthetized pigs subjected to 45 min of coronary artery occlusion followed by 240 min of reperfusion, local coronary venous retroinfusion (0.042, 0.42, and 4.2 microM) of candesartan starting just before reperfusion improved, in a dose-related manner, the recovery of myocardial segment shortening (sonomicrometer) and reduced infarct size without persistent effect on regional myocardial blood flow (microspheres). A combination of candesartan, felodipine, and the lipid peroxidation inhibitor H290/51 produced a more pronounced infarct limitation than each of these agents alone. In conclusion, candesartan exerts a cardioprotective effect, via a local mechanism within the ischemic myocardium. A combination of drugs with different pharmacologic profiles may provide a better cardioprotection in the setting of myocardial ischemic/reperfusion compared with each individual compound.