Effects of the angiotensin AT(1) receptor blocker candesartan on myocardial ischemic/reperfusion injury

The effect of the insurmountable angiotensin II AT(1) receptor blocker cand esartan on ischemic/reperfusion injury was investigated in isolated rat hea rts and in anesthetized pigs. The possible additive effect of candesartan o n the cardioprotection by a calcium antagonist and a lipid peroxidation inh ibitor was also studied. In Langendorff-perfused rat hearts, candesartan, i n a dose-related manner, improved left ventricular functional recovery and reduced the no-reflow area following global ischemia and reperfusion. A sim ilar degree of cardioprotection by candesartan (10 nM) and an equipotent co ncentration of another AT(1) receptor blocker losartan (3 mu M) was observe d when ischemia was begun immediately after drug pretreatment. When a washo ut 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. I n anesthetized pigs subjected to 45 min of coronary artery occlusion follow ed by 240 min of reperfusion, local coronary venous retroinfusion (0.042, 0 .42, and 4.2 mu M) 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 regio nal myocardial blood flow (microspheres). A combination of candesartan, fel odipine, and the lipid peroxidation inhibitor H290/51 produced a more prono unced infarct limitation than each of these agents alone. In conclusion, ca ndesartan exerts a cardioprotective effect, via a local mechanism within th e 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.