CARDIOPROTECTION WITH U-89232 IS NOT REVERSIBLE WITH GLIBENCLAMIDE - EVIDENCE OF A NOVEL ANTIISCHEMIC AGENT DERIVED FROM CROMAKALIM

We have previously reported that cromakalim and U-89232 reduce infarct size in a rabbit model of myocardial ischemia. Because U-89232 appear ed to lack activity in the vasculature, we tested its reversibility wi th glibenclamide. Twenty-eight ketamine-xylazine anesthetized open-che st, New Zealand White rabbits were instrumented for regional coronary occlusion and reperfusion. Study animals received either cromakalim, U -89232 or vehicle. In some animals, glibenclamide was administered. Al l animals were then subjected to ischemia (30 min) and reperfusion (12 0 min), and necrosis was determined using tetrazolium. With comparable hemodynamics and myocardium at risk, infarct size in control animals was 35.5 +/- 4.6% of risk region, and was not different from glibencla mide-treated animals (37.7 +/- 5.8%). Cromakalim alone has been shown to be protective, however when combined with glibenclamide necrosis am ounted to 35.1 +/- 3.8% of the risk region (p = NS vs. control). In co ntrast, U-89232 was protective in the presence of glibenclamide (17.2 +/- 4.9% of the risk region). We conclude that U-89232 produces myopro tection independent of K-ATP channel inhibition, indicating that this compound possesses novel anti-ischemic characteristics.