Effect of combined KATP channel activation and Na+/H+ exchange inhibition on infarct size in rabbits

We tested if combining treatment with cariporide, an Na+/H+ exchange inhibitor, and diazoxide, a mitochondrial ATP-sensitive K+ (K-ATP) channel opener, would reduce myocardial infarct size (IS) to a greater extent than either intervention alone. Four groups of rabbits were studied (n = 10 each): cariporide (0.3 mg/kg), diazoxide (10 mg/kg), both drugs, and saline control, given 15 min before a 30-min coronary artery occlusion and 3 h reperfusion. IS in controls comprised 47 +/- 6% of the risk region. Cariporide reduced IS by 55% compared with control (21 +/- 3%), but diazoxide did not significantly reduce IS compared with controls (37 +/- 6%). Combined treatment resulted in an IS of 18 +/- 5%. Also we determined that diazoxide did not potentiate a subthreshold dose of cariporide nor did a mitochondrial KATP channel blocker, 5-hydroxydecanoate (5-HD), prevent cariporide from reducing IS. Thus cariporide reduced necrosis by 50% in this model, both in the presence and absence of K-ATP channel blockade. There was no significant difference in IS reduction between the group receiving cariporide alone and the group receiving combined treatment. Because the effect of cariporide was not blocked by 5-HD, it is unlikely that K-ATP channels play a role as an end effector in cariporide's mechanism.