K-ATP channels mediate late preconditioning against infarction produced by monophosphoryl lipid A

The cardioprotective effect of myocardial preconditioning (PC) to reduce infarct size has been shown to last similar to 90 min (early PC), and then a second window of protection (SWOP or late PC) appears 24 h later. Although much work has been done to characterize early PC, little has been done to investigate potential mediators of SWOP. To that end, we have used monophosphoryl lipid A (MLA), a nontoxic endotoxin derivative, to produce SWOP and have examined the role of ATP-sensitive potassium (K-ATP) channels in mediating its cardioprotection. Adult mongrel dogs were given MLA (3, 10, or 35 mu g/kg iv) 24 h before a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion. After reperfusion, the hearts were stained for myocardial infarction with triphenyltetrazolium. MLA produced a dose-dependent reduction in infarct size that was associated with an enhanced shortening of the monophasic action potential duration during early ischemia. To further examine the role of K-ATP channels, animals were treated with MLA (35 mu g/kg) and 24 h later were administered either glibenclamide (0.3 mg/kg iv) or 5-hydroxydecanoate (7.5 mg/kg intracoronary over 20 min), two structurally distinct K-ATP-channel antagonists. Both glibenclamide and 5-hydroxydecanoate abolished the cardioprotection produced by MLA. These results demonstrate that the cardioprotective effect of late PC produced by MLA is dependent on functional K-ATP channels and is the first study to suggest that late PC may be the result of an increased K-ATP current during ischemia.