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The Protective Effect of Mitochondrial ATP-Sensitive K+ Channel Opener, Nicorandil, Combined With Na+/Ca2+ Exchange Blocker KB-R7943 on Myocardial Ischemia–Reperfusion Injury in Rat

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Abstract

To study the protective effect of mitochondrial ATP-sensitive K+ channel (mitoKATP channel) opener, nicorandil, combined with Na+/Ca2+ exchange blocker KB-R7943 on myocardial ischemia–reperfusion injury in isolated rat hearts; the isolated rat heart was perfused by modified Langendorff device, after 15-min balanced perfusion, 45-min ischemia (about left and right coronary perfusion flow reduced to 5% of the original irrigation flow), and 2-h reperfusion were performed. Forty Wistar rats were randomly divided into four groups: control group, nicorandil group, KB-R7943 group, and the combination of nicorandil and KB-R7943 group. After 45-min ischemia and then 2-h reperfusion, the myocardial infarct size was 34.31% in control group, 26.35% in nicorandil group, 28.74% in KB-R7943 group, and 19.23% in combination of nicorandil and KB-R7943 group. SOD activity in coronary perfusion fluid was the highest in the combination of nicorandil and KB-R7943 group, and MDA content was the lowest. In the combination drug group compared with the control group, myocardial ultrastructural injury was significantly reduced. The combination of nicorandil and KB-R7943 significantly reduced myocardial infarct size, significantly reduced myocardial ultrastructural damage, could increase coronary perfusion fluid SOD activity, and reduced MDA levels.

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References

  1. Fujita, A., & Kurachi, Y. (2000). Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacology and Therapeutics, 85, 39–53.

    Article  PubMed  CAS  Google Scholar 

  2. Gross, G. J., & Auchampach, J. A. (1992). Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circulation Research, 70(2), 223.

    PubMed  CAS  Google Scholar 

  3. Rajesh, K. G., Sasaguri, S., Suzuki, R., et al. (2004). Ischemic preconditioning prevents reperfusion heart injury in cardiac hypertrophy by activation of mitochondrial KATP channels. International Journal of Cardiology, 96(1), 41.

    Article  PubMed  Google Scholar 

  4. Garlid, K. D., Pauce, K. P., Yarov-Yarovoy, V., et al. (1996). The mitochondrial K+ channel as a receptor for potassium channel openers. Journal of Biological Chemistry, 271, 8796–8799.

    Article  PubMed  CAS  Google Scholar 

  5. Nakai, Y., Horimoto, H., & Mieno, S. (2001). Mitochondrial ATP-sensitive potassium channel plays a dominant role in ischemic preconditioning of rabbit heart. European Surgical Research, 33, 57–63.

    Article  PubMed  CAS  Google Scholar 

  6. Philipson, K. D., Nicoll, D. A., Ottolia, M., et al. (2002). The Na+/Ca2+ exchange molecule: An overview. Annals of the New York Academy of Sciences, 976, 1–10.

    Article  PubMed  CAS  Google Scholar 

  7. Bers, D. M., Barry, W. H., & Despa, S. (2003). Intra cellular Na+ regulation in cardiac myocytes. Cardiovascular Research, 57, 897–912.

    Article  PubMed  CAS  Google Scholar 

  8. Fujioka, Y., Hiroe, K., & Matsuoka, S. (2000). Regulation kinetics of Na+/Ca2+ exchange current in guinea-pig ventricular myocytes. Journal of Physiology, 529, 611–623.

    Article  CAS  Google Scholar 

  9. Lee, C., Dhalla, N. S., Hryshko, L. V., et al. (2005). Therapeutic potential of novel Na+/Ca2+ exchange inhibitors in attenuating ischemia-reperfusion injury. Canadian Journal of Cardiology, 21, 509–516.

    PubMed  CAS  Google Scholar 

  10. Iwamoto, T., Kita, S., & Shigekawa, M. (2002). Functional analysis of Na+/Ca2+ exchanger using novel drugs and genetically engineered mice. Folia Pharmacologica Japonica (Nippon Yakurigaku Zasshi), 120(1), 91P–93P.

    Google Scholar 

  11. Iwamoto, T., Kita, S., Uehara, A., et al. (2001). Structural domains influencing sensitivity to isothiourea derivative inhibitor KB-R7943 in cardiac Na+ /Ca2+ exchanger. Molecular Pharmacology, 59, 524–531.

    PubMed  CAS  Google Scholar 

  12. Elias, C., Lukas, A., Shurraw, S., et al. (2001). Inhibition of Na+/Ca2+ exchange by KB-R7943: Transport mode selectivity and antiarrhythmic consequences. American Journal of Physiology, 281, H1334–H1345.

    PubMed  CAS  Google Scholar 

  13. Ladilov, Y., Haffner, S., Balser-Schafer, C., et al. (1999). Cardioprotective effects of KB-R7943: A novel inhibitor of the reverse mode of Na+/Ca2+ exchanger. American Journal of Physiology, 276, 1868–1876.

    Google Scholar 

  14. Schafer, C., Ladilov, Y., Inserte, J., et al. (2001). Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury. Cardiovascular Research, 51, 241–250.

    Article  PubMed  CAS  Google Scholar 

  15. Inserte, J., Garcia-Dorado, D., Ruiz-Meana, et al. (2002). Effect of inhibition of Na+/Ca2+ exchanger at the time of myocardial reperfusion on hypercontracture and cell death. Cardiovascular Research, 55, 739–748.

    Article  PubMed  CAS  Google Scholar 

  16. Magee, W. P., Deshmukh, G., Deninno, M. P., et al. (2003). Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943. American Journal of Physiology, 284, H903–H910.

    PubMed  CAS  Google Scholar 

  17. Matsumoto, T., Miura, T., Miki, T., et al. (2002). Blockade of the Na+/Ca2+ exchanger is more efficient than blockade of the Na+–H+ exchanger for protection of the myocardium from lethal reperfusion injury. Cardiovascular Drugs and Therapy, 16, 295–301.

    Article  PubMed  CAS  Google Scholar 

  18. Tsuchida, A., Miura, T., Tanno, M., et al. (2002). Infarct size limitation by nicorandil: Roles of mitochondrial K(ATP) channels, sarcolemmal K(ATP) channels, and protein kinase C. Journal of the American College of Cardiology, 40(8), 1523–1530.

    Article  PubMed  CAS  Google Scholar 

  19. Jia, D., Zheng, X.-W., Qi, G. X., et al. (2000). The influence of KATP channel opener JTV-506 on areas of isolated myocardial infarction in rat. Acta Pharmaceutica Sinica, 35(10), 743–746.

    PubMed  CAS  Google Scholar 

  20. Taira, N. (1987). Similarity and dissimilarity in the mode and mechanism of action between nicorandil and classical nitrates: An overview. Journal of Cardiovascular Pharmacology, 10, S1–S9.

    Article  PubMed  CAS  Google Scholar 

  21. Taira, N. (1989). Nicorandil as a hybrid between nitrates and potassium channel activators. American Journal of Cardiology, 63, 18J–24J.

    Article  PubMed  CAS  Google Scholar 

  22. Krumenacker, M., & Roland, E. (1992). Clinical profile of a nicorandil: An overview of its hemodynamic properties and therapeutic efficacy. Journal of Cardiovascular Pharmacology, 20, S93–S102.

    PubMed  Google Scholar 

  23. Imagawa, J., Baxter, G. F., & Yellon, D. M. (1998). Myocardial Protection afforded by nicorandil and ischemic preconditioning in a rabbit infarct model invivo. Journal of Cardiovascular Pharmacology, 31, 74–79.

    Article  PubMed  CAS  Google Scholar 

  24. Mizumura, T., Nithipatikom, K., & Gross, G. J. (1995). Effects of nicorandil and glyceryl trinitrate on infarct size, adenosine release, and neutrophil infiltration in the dog. Cardiovascular Research, 29, 482–489.

    PubMed  CAS  Google Scholar 

  25. Patel, D. J., Purcell, H. J., & Fox, K. M. (1999). Cardioprotection by opening of the KATP channel in unstable angina: Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil. CESAR 2 investigation. Clinical European Studies in Angina and Revascularization. European Heart Journal, 20, 51–57.

    Article  PubMed  CAS  Google Scholar 

  26. Maxwell, S. R., & Lip, G. Y. (1997). Reperfusion injury: A review of the pathophysiology, clinical manifestations and therapeutic options. International Journal of Cardiology, 58, 95–117.

    Article  PubMed  CAS  Google Scholar 

  27. Gross, G. J., Pieper, G., Farber, N. E., et al. (1989). Effects of nicorandil on coronary circulation and myocardial ischemia. American Journal of Cardiology, 63, 11J–17J.

    Article  PubMed  CAS  Google Scholar 

  28. Lazdunski, M., Frelin, C., & Vigne, P. (1985). The sodium/hydrogen exchange system in cardiac cells; its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. Journal of Molecular and Cellular Cardiology, 17, 1029–1042.

    Article  PubMed  CAS  Google Scholar 

  29. Griffiths, E., & Halestrap, A. P. (1993). Protection by cyclosporine A of ischemia/reperfusion-induced damage in isolated rat hearts. Journal of Molecular and Cellular Cardiology, 25, 1461–1469.

    Article  PubMed  CAS  Google Scholar 

  30. Nakamura, A., Harada, K., Sugimoto, H., et al. (1998). Effects of KB-R7943, a novel Na+/Ca2+ inhibitor, on myocardial ischemia/reperfusion injury. Folia Pharmacologica Japonica (Nippon Yakurigaku Zasshi), 111, 105–115. (Abstr. in English).

    Article  CAS  Google Scholar 

  31. Elmali, N., Esenkaya, I., & Karadag, N. (2007). Effects of resveratrol on skeletal muscle in ischemic-reperfusion injury. Ulusal Travma ve Acil Cerrahi Dergisi, 13, 274–280.

    PubMed  Google Scholar 

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Correspondence to Dalin Jia.

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Jia, D. The Protective Effect of Mitochondrial ATP-Sensitive K+ Channel Opener, Nicorandil, Combined With Na+/Ca2+ Exchange Blocker KB-R7943 on Myocardial Ischemia–Reperfusion Injury in Rat. Cell Biochem Biophys 60, 219–224 (2011). https://doi.org/10.1007/s12013-010-9142-8

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