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)
  • Published : 2005.01.01

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 $(IC_{50}\;:\;1,130,\;>\;1,500,\;305.3\;and\;63.9\;{\mu}M,\;respectively)$, 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$K_{ATP}$.

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