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


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$K_{ATP}$.


  1. Andersson, T. L. and Vinge, E., The efflux of $^{86}Rb$ and [^{3}H$]5-HT from human platelets during continuous perfusion: effects of potassium-induced membrane depolarization and thrombin stimulation. Acta. Physiol. Scand., 141, 421-428 (1991)
  2. Armstrong, S. C., Liu, G. S., Downey, J. M., and Ganote, C. E., Potassium channels and preconditioning of isolated rabbitcardiomyocytes: Effects of glyburide and pinacidil. J. Mol. Cell Cardiol., 27, 1765-1774 (1995)
  3. Atwal, K. S., Grover, G. J., Ahmed, S., Ferrara, F. N., Harper, T. W., Kim, K. S., Sleph, P. G., Dzwonczyk, S., Russell, A. D., Moreland, S., et al., Cardioselective anti-ischemic ATPsensitive potassium channel openers. J. Med. Chem., 36, 3971-3974 (1993)
  4. D'Alonzo, A. J., Grover, G. J., Darbenzio, R. B., Sewter, J. C., Hess, T. A., Dzwonczyk, S., and Sleph, P. G., Hemodynamic and cardiac effects of BMS-180448, a novel $K^{+}$ ATP opener, in anesthetized dogs and isolated rat hearts. Pharmacol., 52, 101-112 (1996)
  5. de Silva, H. A., Carver, J. G., and Aronson, J. K., Pharmacological evidence of calcium-activated and voltage-gated potassium channels in human platelets. Clin. Sci. (Lond), 93, 249-255 (1997)
  6. de Silva, H. A., Aronson, J. K., Grahame-Smith, D. G., Jobst, K. A., and Smith, A. D., Abnormal function of potassium channels in platelets of patients with Alzheimer's disease. Lancet, 352, 1590-1593 (1998)
  7. Edwards, G. and Weston, A. H., Recent advances in potassium channel modulation. Prog. Drug Res., 49, 93-121 (1997)
  8. Garlid, K. D., Paucek, P., Yarov-Yarovoy, V., Sun, X., and Schindler, P. A., The mitochondrial $K_{ATP}$ channel as a receptor for potassium channel openers. J. Biol. Chem., 271, 8796-8799 (1996)
  9. Grover, G. J. and Atwal, K. S., Pharmacologic profile of the selective mitochondrial-$K_{ATP}$ opener BMS-191095 for treatment of acute myocardial ischemia. Cardiovasc. Drug Rev., 20, 121-136 (2002)
  10. Grover, G. J., D'Alonzo, A. J., Hess, T., Sleph, P. G., and Darbenzio, R. B., Glyburide-reversible cardioprotective effect of BMS-180448 is independent of action potential shortening. Cardiovasc. Res., 30, 731-738 (1995)
  11. Grover, G. J., D'Alonzo, A. J., Garlid, K. D., Bajgar, R., Lodge, N. J., Sleph, P. G., Darbenzio, R. B., Hess, T. A., Smith, M. A., Paucek, P., and Atwal, K. S., Pharmacologic characterization of BMS-191095, a mitochondrial $K_{ATP}$ opener with no peripheral vasodilator or cardiac action potential shortening activity. J. Pharmacol. Exp. Ther., 297, 1184-1192 (2001)
  12. Grover, G. J., D'Alonzo, A. J., Darbenzio, R. B., Parham, C. S., Hess, T. A., and Bathala, M. S., In vivo characterization of the mitochondrial selective K(ATP) opener (3R)-trans-4-((4- chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1- benzopyran-6-carbonitril monohydrochloride (BMS-191095): cardioprotective, hemodynamic, and electrophysiological effects. J. Pharmacol. Exp. Ther., 303, 132-140 (2002)
  13. Habazettl, H., Hanusch, P., and Kupatt, C., Effects of endothelium/ leukocytes/platelet interaction on myocardial ischemia-- reperfusion injury. Z. Kardiol., 89(Suppl 9), IX/92-95 (2000)
  14. Jung, Y. S., Moon, C. H., Cho, T. S., Yoo, S. E., and Shin, H. S., Cardioprotective effects of KR-30450, a novel $K^+_(ATP)$ opener, and its major metabolite KR-30818 on isolated rat hearts. Jpn. J. Pharmacol., 76, 65-73 (1998)
  15. Kaeffer, N., Richard, V., Francois, A, Lallemand, F., Henry, J. P., and Thuillez, C., Preconditioning prevents chronic reperfusioninduced coronary endothelial dysfunction in rats. Am. J. Physiol., 271, H842-849 (1996)
  16. Kapural, L., Feinstein, M. B., O'Rourke, F., and Fein, A., Suppression of the delayed rectifier type of voltage gated $K^+$ outward current in megakaryocytes from patients with myelogenous leukemias. Blood, 86, 1043-1055 (1995)
  17. Kapural, L. and Fein, A., Suppression of the voltage-gated $K^+$ current of human megakaryocytes by thrombin and prostacyclin. Biochim. Biophys. Acta., 1355, 331-342 (1997)
  18. Kawa, K., Voltage-gated calcium and potassium currents in megakaryocytes dissociated from guinea-pig bone marrow. J. Physiol., 431, 187-206 (1990)
  19. Kinoshita, H., Iwahashi, S., Kakutani, T., Mizumoto, K., Iranami, H., and Hatano, Y., The role of endothelium-derived nitric oxide in relaxations to levcromakalim in the rat aorta. Jpn. J. Pharmacol., 81, 362-366 (1999)
  20. Kleiman, N. S., GP IIb/IIIa antagonists. Clinical experience and potential uses in cardiology. Drugs R. D., 1, 361-370 (1999)
  21. Ku, D. D., Coronary vascular reactivity after acute myocardial ischemia. Science, 218, 576-578 (1982)
  22. Laude, K., Beauchamp, P., Thuillez, C., and Richard, V., Endothelial protective effects of preconditioning. Cardiovasc. Res., 55, 466-473 (2002)
  23. Lee, B. H., Seo, H. W., Yoo, S. E., Kim, S. O., Lim, H., and Shin, H. S., Differential action of KR-31378, a novel potassium channel activator, on cardioprotective and hemodynamic effects. Drug Dev. Res., 54, 182-190 (2001)
  24. Li, Y. and Kloner, R. A., Cardioprotective effects of ischaemic preconditioning are not mediated by prostanoids. Cardiovasc. Res., 26, 226-231 (1992)
  25. Maruyama, Y., A patch-clamp study of mammalian platelets and their voltage-gated potassium current. J. Physiol., 391, 467- 485 (1987)
  26. Nakai, Y., Horimoto, H., Mieno, S., and Sasaki, S., Mitochondrial ATP-sensitive potassium channel plays a dominant role in ischemic preconditioning of the rabbit heart. Eur. Surg. Res., 33, 57-63 (2001)
  27. Park, Y. S., Yoo, S. E., Shin, H. S., Jin, Y. R., and Yun, Y. P., Pharmacological characterization of vasorelaxant effects of BMS-180448, a novel cardioselective ATP-sensitive potassium channel opener, in rat aorta. J. Pharmacol. Sci., 92, 218-227 (2003)
  28. Pearson, P. J., Schaff, H. V., and Vanhoutte, P. M., Long-term impairment of endothelium-dependent relaxations to aggregating platelets after reperfusion injury in canine coronary arteries. Circulation, 81, 1921-1927(1990)
  29. Rovnyak, G. C., Ahmed, S. Z., Ding, C. Z., Dzwonczyk, S., Ferrara, F. N., Humphreys, W. G., Grover, G. J., Santafianos, D., Atwal, K. S., Baird, A. J., McLaughlin, L. G., Normandin, D. E., Sleph, P. G., and Traeger, S. C., Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers. 5. Identification of 4-(N-aryl)-substituted benzopyran derivatives with high selectivity. J. Med. Chem., 40, 24-34 (1997)
  30. Seligmann, C., Schimmer, M., Leitsch, T., Bock, A., Simsek, Y., Tschope, C., and Schultheiss, H. P., A thrombocyte-induced myocardial dysfunction in the ischemic and reperfused guinea pig heart is mediated by reactive oxygen species. Free Radic. Biol. Med., 29, 1244-1251 (2000)
  31. Seligmann, C., Simsek, Y., Schimmer, M., Leitsch, T., Bock, A., and Schultheiss, H. P., Human thrombocytes are able to induce a myocardial dysfunction in the ischemic and reperfused guinea pig heart mediated by free radicals-role of the GPIIb/IIIa-blocker tirofiban. Life Sci., 71, 2319-2329 (2002)
  32. Shin, H. S., Seo, H. W., Oh, J. H., and Lee, B. H., Antihypertensive effects of the novel potassium channel activator SKP- 450 and its major metabolites in rats. Arzneimittelforschung, 48, 969-978 (1998a)
  33. Shin, H. S., Seo, H. W., Yoo, S. E., and Lee, B. H., Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310. Pharmacology, 56, 111-124 (1998b)
  34. Teshima, Y., Akao, M., Li, R. A., Chong, T. H., Baumgartner, W. A., Johnston, M. V., and Marban, E., Mitochondrial ATPsensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress. Stroke, 34, 1796-1802 (2003)
  35. Van Benthuysen, K. M., McMurtry, I. F., and Horwitz, L. D., Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro. J. Clin. Invest., 79, 265-274 (1987)
  36. Yellon, D. M., Alkhulaifi, A. M., Browne, E. E., and Pugsley, W.B., Ischaemic preconditioning limits infarct size in the rat heart. Cardiovasc. Res., 26, 983-987 (1992)
  37. Yellon, D. M., Alkhulaifi, A. M., and Pugsley, W. B., Preconditioning the human myocardium. Lancet, 342, 276-277 (1993)