LIMITATION OF MYOCARDIAL INFARCT SIZE BY NICORANDIL AFTER SUSTAINED ISCHEMIA IN PIGS

Nicorandil is a compound with hybrid properties of nitrates and adenosine triphosphate (ATP)-sensitive potassium channel (K-ATP) opening. The effects of nicorandil and isosorbide dinitrate (ISDN) were investigated in a model of 60-min coronary occlusion/180-min reperfusion in open chest pigs. Three groups of 10 pigs were randomly assessed to receive saline or equihypotensive doses of nicorandil or ISDN. Drug infusion was started at 30 min of ischemia and continued throughout reperfusion. Area at risk (AAR) and infarcted area (IA) were assessed by monastral blue dye-triphenyltetrazolium dual staining technique and calculated by planimetry. Myeloperoxidase concentration (MPO) in the nonischemic area and in the IA was assessed as an index of presence of neutrophils. Measurements of reduced glutathione (GSH), oxidized glutathione (GSSG), lipofuscine, and malondialdehyde were performed on coronary vein blood as indexes of oxidative stress. IA, as a percentage of AAR, was 78 +/- 10% after saline, 61 +/- 12% after N (p < 0.05 vs. saline), and 69 +/- 14% after ISDN (not significant vs. saline). Cardiac output and left ventricular dP/dt were depressed during coronary occlusion in all groups and their recovery during reperfusion was earlier in the microrandil group. In the saline group, MPO was increased in the IA compared to the nonischemic area (78 +/- 63 vs. 21 +/- 21 mu g/mg prot, p = 0.02). In the ISDN group and in the nicorandil group, the increase of MPO concentration in the IA compared to the nonischemic area was not statistically significant (44 +/- 27 vs. 25 +/- 20 mu g/mg prot, p = 0.09 and 43 +/- 39 vs. 34 +/- 51 mu g/mg prot, p = 0.47, respectively). No differences were observed on the indexes of oxidative stress among groups. Thus, nicorandil, administered after a prolonged period of coronary occlusion, reduced IA and improved the recovery of hemodynamics during the course of reperfusion compared to saline and ISDN. Nicorandil and ISDN tended to reduce neutrophils infiltration in IA. The mechanism of the protective effect of nicorandil is elusive and may be related to a direct activation of myocardial K-ATP channels and/or to the antineutrophil activity.