Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K⁺ channels: Possible mechanism of cardioprotection

Previous studies showed a poor correlation between sarcolemmal K⁺ currents and cardioprotection for ATP-sensitive K⁺ channel (K(ATP)) openers. Diazoxide is a weak cardiac sarcolemmal K(ATP) opener, but it is a potent opener of mitochondrial K(ATP), making it a useful tool for determining the importance of this mitochondrial site. In reconstituted bovine heart K(ATP), diazoxide opened mitochondrial K(ATP) with a K( 1/4 ) of 0.8 μmol/L while being 1000-fold less potent at opening sarcolemmal K(ATP). To compare cardioprotective potency, diazoxide or cromakalim was given to isolated rat hearts subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset of contracture with a similar potency (EC₂₅, 11.0 and 8.8 μmol/L, respectively) and improved postischemic functional recovery in a glibenclamide (glyburide)-reversible manner. In addition, sodium 5- hydroxydecanoic acid completely abolished the protective effect of diazoxide. Whole-myocyte studies showed that diazoxide was significantly less potent than cromakalim in increasing sarcolemmal K⁺ currents. Diazoxide shortened ischemic action potential duration significantly less than cromakalim at equicardioprotective concentrations. We also determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac K(ATP) activity. Cromakalim and diazoxide were both potent activators of K⁺ flux in this preparation (K( 1/4 ) values, 1.1±0.1 and 0.49±0.05 μmol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K⁺ flux through the diazoxide-opened mitochondrial K(ATP). The profile of activity of diazoxide (and perhaps K(ATP) openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial K(ATP).