CARDIOPROTECTIVE EFFECT OF DIAZOXIDE AND ITS INTERACTION WITH MITOCHONDRIAL ATP-SENSITIVE K- POSSIBLE MECHANISM OF CARDIOPROTECTION( CHANNELS )

Previous studies showed a poor correlation between sarcolemmal K+ curr ents and cardioprotection for ATP-sensitive K+ channel (K-ATP) openers . Diazoxide is a weak cardiac sarcolemmal K-ATP opener, but it is a po tent opener of mitochondrial K-ATP, making it a useful tool for determ ining the importance of this mitochondrial site. In reconstituted bovi ne heart K-ATP, diazoxide opened mitochondrial K-ATP with a K-1/2 of 0 .8 mu mol/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 ischem ia and 30 minutes of reperfusion. Diazoxide and cromakalim increased t he time to onset of contracture with a similar potency (EC25, 11.0 and 8.8 mu mol/L, respectively) and improved postischemic functional reco very in a glibenclamide (glyburide)-reversible manner. In addition, so dium 5-hydroxydecanoic acid completely abolished the protective effect of diazoxide. Whole-myocyte studies showed that diazoxide was signifi cantly less potent than cromakalim in increasing sarcolemmal K+ curren ts. Diazoxide shortened ischemic action potential duration significant ly less than cromakalim at equicardioprotective concentrations. We als o determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac K-ATP activity. Cromakalim and diazoxide wer e both potent activators of K+ flux in this preparation (K-1/2 values, 1.1+/-0.1 and 0.49+/-0.05 mu mol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+ flux through the diazo xide-opened mitochondrial K-ATP. The profile of activity of diazoxide (and perhaps K-ATP openers in general) suggests that they protect isch emic hearts in a manner that is consistent with an interaction with mi tochondrial K-ATP.