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BMS-191095, a Cardioselective Mitochondrial $K_{ATP}$ Opener, Inhibits Human Platelet Aggregation by Opening Mitochondrial $K_{ATP}$ Channels

Cho Mi-Ra    (College of Pharmacy, Chungbuk National University   ); Park Jung-Wook    (Division of Life Science, College of Natural Sciences, Konkuk University   ); Jung In-Sang    (Division of Life Science, College of Natural Sciences, Konkuk University   ); Yi Kyu-Yang    (Medical Science Division, Korea Research Institute of Chemical Technology   ); Yoo Sung-Eun    (Medical Science Division, Korea Research Institute of Chemical Technology   ); Chung Hun-Jong    (Pediatric Department, Chungju Hospital, Konkuk Medical School, Konkuk University   ); Yun Yeo-Pyo    (College of Pharmacy, Chungbuk National University   ); Kwon Suk-Hyung    (Rexgene Biotech Co. Ltd.,   ); Shin Hwa-Sup    (Division of Life Science, College of Natural Sciences, Konkuk University  );
  • 초록

    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 $(IC_{50}\;:\;1,130,\;>\;1,500,\;305.3\;and\;63.9\;{\mu}M,\;respectively)$ , 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 $(IC_{50}\;:\;498.0\;and\;104.8{\mu}M\; for\;BMS-180448\;and\;BMS-191095,\;respectively)$ . The inhibitory effects of BMS-191095 on collagen-induced platelet aggregation were significantly blocked by a 30-min pretreatment of platelets with glyburide $(1{\mu}M)$ or sodium 5-hydroxyde­canoate $(5-HD,\;100{\mu}M)$ , 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 $K_{ATP}$ .


  • 주제어

    Platelet .   BMS-180448 .   BMS-191095 .   Cardioprotection.  

  • 참고문헌 (37)

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