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

Abstract

We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers (K(ATP) openers) on washed human platelets, and the study's 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-nonselective K(ATP) openers, and also by cardioselective BMS-180448 and BMS-191095 (IC50: 1,130, >1,500, 305.3 and 63.9 microM, respectively), but a significantly greater potency was noted for the cardioselective K(ATP) openers. The latter two K(ATP) openers also inhibited platelet aggregation induced by thrombin, another important blood-borne platelet activator, with similar rank order of potency (IC50: 498.0 and 104.8 microM 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 microM) or sodium 5-hydroxydecanoate (5-HD, 100 microM), 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).

Ethnopharmacological studies on antispasmodic and antiplatelet activities of Ficus carica

“…Based on the medicinal use of Ficus carica as an antiinflammatory remedy and knowing that some K + ATP channel openers possess antiplatelet effect (Cho et al, 2005;Patelunas et al, 1994), Fc.Cr was tested for its possible antiplatelet effect in human platelet-rich plasma against adrenaline and ADP-induced platelet aggregation. Fig.…”

Alternative Targets for Modulators of Mitochondrial Potassium Channels

“…Additionally, BMS191095 was shown to activate neuronal mitoK ATP , regulate neuronal mitochondrial function [ 36 , 37 ], and induce neuroprotection against various insults [ 36 , 38 , 39 ]. It was also shown that BMS191095 and the less-selective BMS180448 inhibited human platelet aggregation; preincubation with both glyburide and 5-HD blocked this effect [ 40 ]. In contrast, the application of BMS191095 protected myoblast C2C12 cells against toxicity induced by the deregulation of calcium homeostasis, and these effects were not reversed by 5-HD [ 41 ].…”

Mitochondrial K+ Transport: Modulation and Functional Consequences

“…This selectivity was decisive to identify mitochondrial channels as mediators of cardiac protection against ischemia reperfusion [ 15 ]. When used at concentrations that activate MitoK ATP , but not CellK ATP , diazoxide protects hearts against damage promoted by ischemia followed by reperfusion, a finding that attracted wide attention to the role of mitochondrial K + homeostasis in tissue protection under myriad of stressful conditions [ 15 , 30 , 31 , 32 ].…”

“…Moreover, pharmacological activators of MitoK ATP can also block excessive production of oxidants in mitochondria, preventing myocadiac ischemic damage. The highly specific MitoK ATP activator BMS-191095 was also shown to additionally act to prevent ischemic damage beyond cardiac cell effects by inhibiting platelet aggregation [ 32 ].…”