INFARCT SIZE-REDUCING EFFECT OF NICORANDIL IS MEDIATED BY THE K-ATP CHANNEL BUT NOT BY ITS NITRATE-LIKE PROPERTIES IN DOGS

Objective: We wished to determine whether the cardioprotective effect of nicorandil to reduce infarct size is blocked by glibenolamide, a se lective K-ATP channel antagonist, or methylene blue, a nitric oxide (N O)/guanylate cyclase inhibitor, in dogs. The second aim was to determi ne if glyceryl trinitrate produces a cardioprotective effect in the sa me model and to test if this effect is blocked by methylene blue and n ot by glibenclamide. We also determined whether adenosine release from the ischemic-reperfused area is an accurate index of ischemic severit y in the presence of these drugs Methods: Barbiturate-anesthetized dog s were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. In the first three gr oups, either nicorandil (100 mu g/kg bolus + 10 mu g/kg/min), glyceryl trinitrate (10 mu g/kg bolus + 1 mu g/kg/min) or an equivalent volume of saline was given intravenously 15 min before LAD occlusion and con tinued to the time of reperfusion. In the next three groups, glibencla mide (0.3 mg/kg) was administered 15 min before drug infusion. In the final three groups, methylene blur (80 mu M) was given intracoronarily 5 min before nicorandil or glyceryl trinitrate and continued until 15 min following reperfusion. Coronary venous blood sample were collecte d at various times during Ischemia and following reperfusion and the c oncentration of adenosine measured. Results: Nicorandil produced a mar ked reduction in infarct size expressed as a percent of the area at ri sk (NC group, 12.2 +/- 3.2% vs. Control group, 25.7 +/- 4.1%, P < 0.05 ) and this effect was completely abolished by pretreatment with gliben clamide. However, intracoronary administration of methylene blue did n ot block the cardioprotective effect of nicorandil, On the other hand, glyceryl trinitrate also produced a significant reduction in infarct size (GTN group. 13.0 +/- 3.1%) and this effect was reversed by methyl ene blue but not by glibenclamide. Adenosine concentrations in coronar y venous blood were significantly reduced after reperfusion in the gro ups with small infarctions as compared with the Control group. Conclus ions: These results suggest that sit equieffective cardioprotective do ses the infarct size-reducing effect of nicorandil in dogs is mediated via opening oi myocardial K-ATP channels and that the cardioprotectiv e effect of glyceryl trinitrate is most likely to be mediated via acti vation of guanylate cyclase at a site yet to be determined.