The K-ATP channel blocker HMR 1883 does not abolish the benefit of ischemic preconditioning on myocardial infarct mass in anesthetized rabbits

Previous experimental studies showed that the benefit of ischemic precondit ioning (IPC) is abolished by K-ATP channel blockade with glibenclamide. How ever, the newly discovered K-ATP channel blocker HMR 1883 (1-[[5-[2-(5-chlo ro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-methylthiourea) shows marke d antifibrillatory activity in the dose range of 3 mg/kg to 10 mg/kg i.v. i n various experimental models without affecting blood glucose levels. In or der to investigate in a head to head comparison glibenclamide and HMR 1883 with respect to their influence on TPC, experiments were performed in rabbi ts with ischemia-reperfusion using myocardial infarct mass as final read ou t. Male New Zealand White rabbits (2.6-3.0 kg) were subjected to 30-min occlus ion of a branch of the left descending coronary artery (LAD) followed by 2- h reperfusion. For IPC experiments the LAD was additionally occluded for tw o periods of 5 min, each followed by 10-min reperfusion, before the long-te rm ischemia. Infarct mass was evaluated by TTC staining and expressed as a percentage of area at risk. Rabbits (n=7/group) were randomly selected to r eceive (i.v.) saline vehicle 5 min prior to the 30-min occlusion period in infarct studies without IPC or to receive glibenclamide (0.3 mg/kg) or HMR 1883 (3 mg/kg) in IPC experiments, these substances being given 5 min prior to the first preconditioning or 5 min prior to the long-term ischemia of 3 0 min. Myocardial risk mass as a percentage of left ventricular mass did no t differ between groups. The same was true for the ratio of left ventricula r mass to 100 g body weight. Myocardial infarct mass as a percentage of the area at risk in the saline vehicle group without IPC was 41+/-3%. Whereas glibenclamide significantly increased infarct mass (from 41+/-3% to 55+/-4% ), HMR 1883 did not affect it. IPC reduced infarct mass from 41+/-3% to 21/-4% (P<0.05 vs, control without IPC). Glibenclamide given prior to IPC or prior to the long-term ischemia totally abolished the IPC effect (42+/-2% a nd 55+/-4%, respectively; P<0.05 vs. control). In contrast, HMR 1883 under the same conditions did not affect infarct size when given prior to IPC or prior to the long-term ischemia (21+/-3% and 26+/-2%, respectively). The mo nophasic action potential duration (MAP(50)) was reduced from 103+/-3 ms un der normoxic conditions to 82+/-2 ms, 5 min after ischemia in the absence o f drugs. This ischemia-induced shortening of the MAP was prevented by both HMR 1883 (MAPS, 103+/-3 ms) and glibenclamide (MAP(50) 106+/-3 ms). In conclusion, although both K-ATP channel blockers prevented ischemia-indu ced shortening of MAP, HMR 1883 did not abolish the beneficial effects of L PC on myocardial infarct mass in rabbits, whereas glibenclamide totally rev ersed this cardioprotective effect of LPC. This suggests that the sarcolemm al ATP-sensitive potassium channels are not involved in the mechanism of IP C.