EFFECT OF MCI-186 ON POSTISCHEMIC REPERFUSION INJURY IN ISOLATED RAT-HEART

MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) is a newly developed ant ioxidant which has been shown to reduce brain edema in cerebral ischem ia through inhibition of the lipoxygenase pathway of arachidonic acid. However, its effect on myocardial reperfusion injury after prolonged ischemia has not yet been demonstrated. We compared the mode of the ef fect of MCI-186 and recombinant human CuZn superoxide dismutase (rh-SO D) in isolated perfused rat hearts subjected to 60-min ischemia follow ed by 60-min reperfusion. Left ventricular developed pressure (LVDP), necrotic area and the release of creatine phosphokinase (CPK) and endo genous CuZn superoxide dismutase (endoge-SOD) were measured to evaluat e myocardial damage. The decrease in left coronary flow (CBF) was meas ured as an index of the damage of left coronary circulation. MCI-186 ( 17.5 mg/L) was perfused for 10 min in the MCIgroup and rh-SOD (70 mg/L ) was perfused during the reperfusion period in the SOD group starting 5 min prior to reperfusion. The release patterns of CPK and endoge-SO D were analyzed to elucidate the difference in the mode of protection of MCI-186 and rh-SOD. The LVDP remained higher in both MCI and SOD gr oups than that of control (76 +/- 1, 77 +/- 2 and 69 +/- 1% of preisch emic value, respectively). The necrotic area was significantly attenua ted in both MCI and SOD groups compared with that in the control group (16 +/- 1, 14 +/- 1 and 32 +/- 1%, respectively, p<0.05). Total CPK r elease was lower in both MCI and SOD groups than in the control (78 +/ - 7, 100 +/- 2 and 116 +/- 4 x 10(3) units/g myocardium respectively). The decrease in CPK release was more marked in the MCI group than tha t in the SOD group (p<0.05). The reduction in CBF was significantly at tenuated by the treatment with rh-SOD or MCI-186, but the effect was m uch higher in the SOD group than in the MCI group (69 +/- 5, 58 +/- 2, and 48 +/- 2% in SOD, MCI and control groups, respectively). The rele ase pat tem of endoge-SOD was identical to that of CPK and thus this d id not distinguish the mode of effect of MCI-186 from that of rh-SOD. These results indicate that MCI-186 reduces reperfusion injury in isol ated perfused hearts with prolonged ischemia and the effect is more cl osely related to the reduction of myocyte damage than the preservation of the coronary circulation.