BMS-191095, a cardioselective mitochondrial K-ATP opener, inhibits human platelet aggregation by opening mitochondrial K-ATP channels

We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers (K-ATP openers) on washed human platelets. and the studys emphasis was on the role of mitochondrial K-ATP in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nons-elective K-ATP openers, and also by cardioselective BMS-180448 and BMS-191093 (IC50; 1,130, >1,500, 305.3 and 63.9 muM, respectively), but a significantly greater potency was noted for the cardioselective KATp openers. The latter two K-ATP openers also inhibited platelet ag induced by thrombin, another important blood-borne platelet activator, with similar rank order of, potency (IC50: 498.0 and 104.8 muM for BMS-180448 and BMS-191095. respectively). The inhibitory effects of BMS-191095 on collagen-induced platelet aggregation were significantly blocked by a 30-min pretreatment of platelets with glyburide (1 muM) or sodium 5-hydiroxydecanoate (5-HD, 100 muM), a nonselective and selective mitochondrial K-ATP antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial K-ATP in the antiplatelet activity of BMS-191095. However, glyburide and 5-HD had no effect when they were added to the platelet cuvette immediately prior to the addition of BMS-191095. These findings indicate that cardioselective mitochondrial K-ATP openers like BMS-191095 are able to exert cardioprotective effects in cardiac ischemia/reperfusion injury via dual mechanisms directed at the inhibition of platelet aggregation and the protection of cardiomyocytes, and both these mechanisms are mediated by mitochondrial K-ATP.