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

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Abstract

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.

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Authors and Affiliations

  1. College of Pharmacy, Chungbuk National University, 361-763, Cheongju, Korea

    Mi-Ra Cho & Yeo-Pyo Yun

  2. Division of Life Science, College of Natural Sciences, Konkuk University, 380-701, Chungju, Korea

    Jung-Woo Park, In-Sang Jung & Hwa-Sup Shin

  3. Medical Science Division, Korea Research Institute of Chemical Technology, 305-600, Daejon, Korea

    Kyu-Yang Yi & Sung-Eun Yoo

  4. Pediatric Department, Chungju Hospital, Konkuk Medical School, Konkuk University, 380-701, Chungju, Korea

    Hun-Jong Chung

  5. Rexgene Biotech Co. Ltd., 137-070, Seoul, Korea

    Suk-Hyung Kwon

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  1. Mi-Ra Cho
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  2. Jung-Woo Park
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Correspondence to Hwa-Sup Shin.

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Cho, MR., Park, JW., Jung, IS. et al. BMS-191095, a cardioselective mitochondrial katp opener, inhibits human platelet aggregation by opening mitochondrial katp channels. Arch Pharm Res 28, 61–67 (2005). https://doi.org/10.1007/BF02975137

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  • DOI: https://doi.org/10.1007/BF02975137

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