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

• Published in: Archives of pharmacal research 2005, 28(1), , pp.61-67
• Main Authors: Cho, Mi-Ra, Park, Jung-Woo, Jung, In-Sang, Yi, Kyu-Yang, Yoo, Sung-Eun, Chung, Hun-Jong, Yun, Yeo-Pyo, Kwon, Suk-Hyung, Shin, Hwa-Sup
• Format: Article
• Language: English
• Subjects: antagonists; cardiomyocytes; cardioprotective effect; dose response; humans; inhibitory concentration 50; ischemia; platelet aggregation; potassium channels; sodium; thrombin; 약학
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/BF02975137

We evaluated the antiplatelet effects of two classes of ATP-sensitive potassium channel openers (KATP openers) on washed human platelets, and the study’s emphasis was on the role of mitochondrial KATP in platelet aggregation. Collagen-induced platelet aggregation was inhibited in a dose dependent manner by lemakalim and SKP-450, which are potent cardio-nonselective KATP openers, and also by cardioselective BMS-180448 and BMS-191095 (IC₅₀: 1,130, >1,500, 305.3 and 63.9 μM, respectively), but a significantly greater potency was noted for the cardioselective KATP openers. The latter two KATP 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 μM 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 μM) or sodium 5-hydroxydecanoate (5-HD, 100 μM), a nonselective and selective mitochondrial KATP antagonist, respectively, at similar magnitudes; this indicates the role of mitochondrial KATP 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 KATP 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 KATP.