K _ATP channel

U-89232, a derivative of the ATP-sensitive potassium (K _ATP ) channel opener Cromakalim. Experiments are performed in open-chest pigs subjected to a 60-min occlusion of the left anterior descending coronary artery (LADCA) and to 2 h of reperfusion. Four groups of animals are studied (n=6 each). Animals receive either U-89232, 3 mg/kg i.v. over a 15-min period (U), or Glibenclamide, a selective KATP channel blocker, 1 mg/kg i.v. over a 15-min period (GLI) before the LADCA occlusion. In the GLI+U group, first Glibenclamide (1 mg/kg/15 min) and then U-89232 (3 mg/kg/15 min) are infused before the 60 min of ischemia. Saline-treated animals serve as controls (CON). Hemodynamic parameters are continuously monitored. Regional contractile wall function is quantified with ultrasonic crystals aligned to measure wall thickening. At the end of the protocol, infarct size (IS, as percentage of risk region) is determined by incubating the myocardium with p-nitrobluetetrazolium. With comparable myocardium at risk, infusion of U-89232 before 60 min of LADCA occlusion significantly reduces infarct size (IS, 18.5±3.7%; p<0.001 vs. 63.2±3.3% for the controls), whereas glibenclamide has no effect on infarct size (IS, 69.5±4.4%). The administration of glibenclamide before U-89232 infusion blocks the infarct size-reducing effect of U-89232. At least in a pig model, U-89232 appears to be a cardioselective K ^ATP channel opener, because in the absence of hemodynamic alterations, it exhibits a profound cardioprotective effect, which is fully reversible by blocking K _ATP channels.