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.