Skip to main content

Advertisement

SpringerLink
Log in

Antiplatelet Agents Sarpogrelate and Cilostazol Affect Experimentally-induced Ventricular Arrhythmias and Mortality

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Antiplatelet agents, sarpogrelate (SAR), a 5-hydroxy tryptamine 2A receptor antagonist and cilostazol (CIL), a phosphodiesterase-III inhibitor, were observed to be beneficial in attenuating cardiac remodeling and improving cardiac function in congestive heart failure due to myocardial infarction in rats; however, CIL increased ventricular tachycardia and mortality. In order to study the effects of these antiplatelet agents on arrhythmias, Sprague–Dawley rats were pretreated with either SAR or CIL (5 mg/kg/day) for 2 weeks and were then either injected cumulative doses of epinephrine (Epi) or subjected to coronary occlusion. Saline-treated animals served as controls. Electrocardiographic analysis revealed that SAR pretreatment decreased the incidence and severity of ventricular arrhythmias (time of onset of arrhythmias as well as the occurrence of premature ventricular contractions, salvos, tachycardia, and fibrillations), whereas CIL treatment augmented the incidence of cardiac arrhythmias due to both Epi and coronary occlusion. None of the drugs affected the corrected QT interval significantly. Furthermore, the levels of cyclic adenosine monophosphate (cAMP) in left ventricle were markedly higher in CIL-pretreated rats when compared to SAR-pretreated or control rats. It is suggested that an excessive level of cAMP may contribute to increase incidence of ventricular arrhythmias and mortality in animals pretreated with CIL, unlike the SAR-pretreated rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Sorkin, E. M., & Markham, A. (1999). Cilostazol. Drugs and Aging, 14, 63–71. doi:10.2165/00002512-199914010-00005.

    Article  PubMed  CAS  Google Scholar 

  2. Igarashi, M., Okuda, T., Oh-i, T., & Koga, M. (2000). Changes in plasma serotonin concentration and acceleration plethysmograms in patients with Raynaud’s phenomenon after long-term treatment with a 5-HT2 receptor antagonist. Journal of Dermatology, 27, 643–650.

    PubMed  CAS  Google Scholar 

  3. Tsuchikane, E., Fukuhara, A., Kobayashi, T., Kirino, M., Yamasaki, K., Kobayashi, T., et al. (1999). Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. Circulation, 100, 21–26.

    PubMed  CAS  Google Scholar 

  4. Fujita, M., Mizuno, K., Ho, M., Tsukahara, R., Miyamoto, A., Miki, O., et al. (2003). Sarpogrelate treatment reduces restenosis after coronary stenting. American Heart Journal, 145, E16. doi:10.1067/mhj.2003.176.

    Article  PubMed  Google Scholar 

  5. Sharma, S. K., Del Rizzo, D. F., Zahradka, P., Bhangu, S. K., Werner, J. P., Kumamoto, H., et al. (2007). Sarpogrelate inhibits serotonin-induced proliferation of porcine coronary artery smooth muscle cells: Implications for long-term graft potency. Annals of Thoracic Surgery, 7, 1856–1865.

    Google Scholar 

  6. Saini, H. K., Takeda, N., Goyal, R. K., Kumamoto, H., Arneja, A. S., & Dhalla, N. S. (2004). Therapeutic potentials of sarpogrelate in cardiovascular disease. Cardiovascular Drug Reviews, 22, 27–54.

    PubMed  CAS  Google Scholar 

  7. Nagatomo, T., Rashid, M., Abul Muntasir, H., & Komiyama, T. (2004). Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacology and Therapeutics, 104, 59–81. doi:10.1016/j.pharmthera.2004.08.005.

    Article  PubMed  CAS  Google Scholar 

  8. Saini, H. K., Sharma, S. K., Zahradka, P., Kumamoto, H., Takeda, N., & Dhalla, N. S. (2003). Alteration of serotin-induced increase in intracellular calcium in rat aortic smooth muscle cells by sarpogrelate. Canadian Journal of Physiology and Pharmacology, 81, 1056–1063. doi:10.1139/y03-108.

    Article  PubMed  CAS  Google Scholar 

  9. Fan, G., Jiang, Y. P., Lu, Z., Martin, D. W., Kelly, D. J., Zuckerman, J. M., et al. (2005). A transgenic mouse model of heart failure using inducible Galpha q. Journal of Biological Chemistry, 280, 40337–40346. doi:10.1074/jbc.M506810200.

    Article  PubMed  CAS  Google Scholar 

  10. Grover, G. J., Sargent, C. A., Dzwonczyk, S., Normandin, D. E., & Antonaccio, M. J. (1993). Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts. Journal of Cardiovascular Pharmacology, 22, 664–672. doi:10.1097/00005344-199310000-00022.

    Article  PubMed  CAS  Google Scholar 

  11. Du, X. J., Anderson, K. E., Jacobsen, A., Woodcock, E. A., & Dart, A. M. (1995). Suppression of ventricular arrhythmias during ischemia-reperfusion by agents inhibiting Ins(1, 4, 5)P3 release. Circulation, 91, 2712–2716.

    PubMed  CAS  Google Scholar 

  12. Shimizu, Y., Minatoguchi, S., Hashimoto, K., Uno, Y., Arai, M., Wang, N., et al. (2002). The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts. Journal of the American College of Cardiology, 40, 1347–1355. doi:10.1016/S0735-1097(02)02158-7.

    Article  PubMed  CAS  Google Scholar 

  13. Zehender, M., Meinertz, T., Hohnloser, S., Geibel, A., Hartung, J., Seiler, K. U., et al. (1989). Incidence and clinical relevance of QT prolongation caused by the new selective serotonin antagonist ketanserin. Multicenter Ketanserin Research Group. The American Journal of Cardiology, 63, 826–832. doi:10.1016/0002-9149(89)90051-9.

    Article  PubMed  CAS  Google Scholar 

  14. Temsah, R. M., Kumamoto, H., Takeda, N., & Dhalla, N. S. (2001). Sarpogrelate diminishes changes in energy stores and ultrastructure of the ischemic-reperfused rat heart. Canadian Journal of Physiology and Pharmacology, 79, 761–767. doi:10.1139/cjpp-79-9-761.

    Article  PubMed  CAS  Google Scholar 

  15. Brasil, D., Temsah, R. M., Kumar, K., Kumamoto, H., Takeda, N., & Dhalla, N. S. (2002). Blockade of 5-HT(2A) receptors by sarpogrelate protects the heart against myocardial infarction in rats. Journal of Cardiovascular Pharmacology and Therapeutics, 7, 53–59. doi:10.1177/107424840200700i108.

    Article  PubMed  CAS  Google Scholar 

  16. Packer, M., Carver, J. R., Rodeheffer, R. J., Ivanhoe, R. J., DiBianco, R., Zeldis, S. M., et al. (1991). Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. New England Journal of Medicine, 325, 1468–1475.

    PubMed  CAS  Google Scholar 

  17. Cohn, J. N., Goldstein, S. O., Greenberg, B. H., Lorell, B. H., Bourge, R. C., Jaski, B. E., et al. (1998). A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. New England Journal of Medicine, 339, 1810–1816.

    Article  PubMed  CAS  Google Scholar 

  18. Trolese-Mongheal, Y., Barthelemy, J., Paire, M., & Duchene-Marullaz, P. (1992). Arrhythmogenic potencies of amrinone and milrinone in unanesthetized dogs with myocardial infarct. General Pharmacology, 23, 95–104. doi:10.1016/0306-3623(92)90054-N.

    PubMed  CAS  Google Scholar 

  19. Wang, S., Cone, J., Fong, M., Yoshitake, M., Kambayashi, Ji., & Liu, Y. (2001). Interplay between inhibition of adenosine uptake and phosphodiesterase type 3 on cardiac function by cilostazol, an agent to treat intermittent claudication. Journal of Cardiovascular Pharmacology, 38, 775–783. doi:10.1097/00005344-200111000-00014.

    Article  PubMed  CAS  Google Scholar 

  20. Gamssari, F., Mahmood, H., Ho, J. S., Villareal, R. P., Liu, B., Rasekh, A., et al. (2002). Rapid ventricular tachycardias associated with cilostazol use. Texas Heart Institute Journal, 29, 140–142.

    PubMed  Google Scholar 

  21. Sanganalmath, S. K., Babick, A. P., Barta, J., Kumamoto, H., Takeda, N., & Dhalla, N. S. (2007). Antiplatelet therapy attenuates subcellular remodeling in congestive heart failure. Journal of Cellular and Molecular Medicine. doi:10.1111/j.1582-4934.2007.00197.

  22. Sanganalmath, S. K., Barta, J., Kumamoto, H., Takeda, N., & Dhalla, N. S. (2008). Antiplatelet therapy mitigates cardiac remodeling and dysfunction in congestive heart failure due to myocardial infarction. Canadian Journal of Physiology and Pharmacology, 86, 180–189. doi:10.1139/Y08-005.

    Article  PubMed  CAS  Google Scholar 

  23. Podzuweit, T. (1980). Catecholamine-cyclic AMP Ca2+-induced ventricular tachycardia in the intact pig heart. Basic Research in Cardiology, 75, 772–779. doi:10.1007/BF01910455.

    Article  PubMed  CAS  Google Scholar 

  24. Podzuweit, T., Els, D. J., & McCarthy, J. (1981). Cyclic AMP mediated arrhythmias induced in the ischemic pig heart. Basic Research in Cardiology, 78, 443–448. doi:10.1007/BF01908339.

    Article  Google Scholar 

  25. Kirshenbaum, L. A., Gupta, M., Thomas, T. P., & Singal, P. K. (1990). Antioxidant protection against adrenaline-induced arrhythmias in rats with chronic heart hypertrophy. Canadian Journal of Cardiology, 6, 71–74.

    PubMed  CAS  Google Scholar 

  26. Dixon, I. M., Lee, S. L., & Dhalla, N. S. (1990). Nitrendipine binding in congestive heart failure due to myocardial infarction. Circulation Research, 66, 782–788.

    PubMed  CAS  Google Scholar 

  27. Walker, M. J., Curtis, M. J., Hearse, D. J., Campbell, R. W., Janse, M. J., Yellon, D. M., et al. (1998). The Lambeth conventions: Guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion. Cardiovascular Research, 22, 447–455. doi:10.1093/cvr/22.7.447.

    Article  Google Scholar 

  28. Damiano, B. P., & Rosen, M. R. (1984). Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation, 69, 1013–1025.

    PubMed  CAS  Google Scholar 

  29. Wellens, H. J., Brugada, P., & Farre, J. (1984). Ventricular arrhythmias: Mechanisms and actions of antiarrhythmic drugs. American Heart Journal, 107, 1053–1057. doi:10.1016/0002-8703(84)90174-1.

    Article  PubMed  CAS  Google Scholar 

  30. Singh, B. N., & Wadhani, N. (2004). Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs. Journal of Cardiovascular Pharmacology and Therapeutics, 9, S85–S97. doi:10.1177/107424840400900107.

    Article  PubMed  CAS  Google Scholar 

  31. Goldstein, R. A., Geraci, S. A., Gray, E. L., Rinkenberger, R. L., Dougherty, A. H., & Naccarelli, G. V. (1986). Electrophysiologic effects of milrinone in patients with congestive heart failure. American Journal of Cardiology, 57, 624–628. doi:10.1016/0002-9149(86)90847-7.

    Article  PubMed  CAS  Google Scholar 

  32. Lynch, J. J., Jr., Uprichard, A. C., Frye, J. W., Driscoll, E. M., Kitzen, J. M., & Lucchesi, B. R. (1989). Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction. Journal of Cardiovascular Pharmacology, 14, 585–597. doi:10.1097/00005344-198910000-00010.

    Article  PubMed  CAS  Google Scholar 

  33. Piwonka, R. W., Healey, J. F., Canniff, P. C., & Farah, A. E. (1983). Electrophysiological actions of amrinone in dogs with cardiac lesions. Journal of Cardiovascular Pharmacology, 5, 1052–1057. doi:10.1097/00005344-198311000-00021.

    Article  PubMed  CAS  Google Scholar 

  34. Kaumann, A. J., Sanders, L., Brown, A. M., Murray, K. J., & Brown, M. J. (1990). A 5-hydroxytryptamine receptor in human right atrium. British Journal of Pharmacology, 100, 879–885.

    PubMed  CAS  Google Scholar 

  35. Brasil, D. P., Wang, X., Kumar, K., & Dhalla, N. S. (2000). Increased 5-HT, angiotensin II and endothelin 1-induced [Ca2+]i responses in aortic smooth muscle cells due to volume overload: Efficacy of the specific 5-HT2A receptor antagonist sarpogrelate. Latin American Archives of Cardiovascular Science, 1, 54–65.

    Google Scholar 

  36. Lukas, A., & Ferrier, G. R. (1988). Electrophysiological effects of amrinone and milrinone in an isolated canine cardiac tissue model of ischemia and reperfusion. Journal of Pharmacology and Experimental Therapeutics, 244, 348–354.

    PubMed  CAS  Google Scholar 

  37. Packer, M., Medina, N., & Yushak, M. (1984). Failure of low doses of amrinone to produce sustained hemodynamic improvement in patients with severe chronic congestive heart failure. American Journal of Cardiology, 54, 1025–1029. doi:10.1016/S0002-9149(84)80138-1.

    Article  PubMed  CAS  Google Scholar 

  38. Pflugfelder, P. W., O’Neill, B. J., Ogilvie, R. I., Beanlands, D. S., Tanser, P. H., Tihal, H., et al. (1991). A Canadian multicentre study of a 48 h infusion of milrinone in patients with severe heart failure. Canadian Journal of Cardiology, 7, 5–10.

    PubMed  CAS  Google Scholar 

  39. Cheng, J. W. (1999). Cilostazol. Heart Disease, 1, 182–186.

    PubMed  CAS  Google Scholar 

  40. Schror, K. (2002). The pharmacology of cilostazol. Diabetes, Obesity and Metabolism, 4, S14–S19. doi:10.1046/j.1463-1326.2002.0040s2s14.x.

    Article  PubMed  CAS  Google Scholar 

  41. Shakur, Y., Fong, M., Hensley, J., Cone, J., Movsesian, M. A., Kambayashi, J., et al. (2002). Comparison of the effects of cilostazol and milrinone on cAMP-PDE activity, intracellular cAMP and calcium in the heart. Cardiovascular Drugs and Therapy, 16, 417–427. doi:10.1023/A:1022186402442.

    Article  PubMed  CAS  Google Scholar 

  42. Van de Water, A., Xhonneux, R., Reneman, R. S., & Janssen, P. A. (1992). Cardiac and hemodynamic effects of intravenous R80122, a new phosphodiesterase III inhibitor, in a canine model of myocardial ischemia and heart failure. Journal of Cardiovascular Pharmacology, 20, 18–24. doi:10.1097/00005344-199207000-00004.

    Article  PubMed  Google Scholar 

  43. Matsui, K., Kiyosue, T., Wang, J. C., Dohi, K., & Arita, M. (1999). Effects of pimobendan on the L-type Ca2+ current and developed tension in guinea-pig ventricular myocytes and papillary muscle: comparison with IBMX, milrinone, and cilostazol. Cardiovascular Drugs and Therapy, 13, 105–113. doi:10.1023/A:1007779908346.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work reported in this study was supported by a grant from the Canadian Institutes for Health Research (CIHR). J.B. was supported by the TACTICS program in association with CIHR and the Heart and Stroke Foundation of Canada. SAR was kindly supplied by Mitsubishi Pharma Corporation, Osaka, Japan, whereas CIL was obtained from Otusuka America Pharmaceutical Inc., Rockville, MD, USA.

Author information

Authors and Affiliations

  1. Faculty of Medicine, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba, 351 Tache Avenue, Winnipeg, MB, Canada, R2H 2A6

    Judit Barta, Santosh K. Sanganalmath, Hideo Kumamoto & Naranjan S. Dhalla

  2. Department of Internal Medicine, Aoto Hospital, Jikei University School of Medicine, Tokyo, Japan

    Nobuakira Takeda

  3. Faculty of Medicine, Institute of Cardiology, University of Debrecen, Debrecen, Hungary

    István Édes

Authors
  1. Judit Barta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Santosh K. Sanganalmath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideo Kumamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuakira Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. István Édes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naranjan S. Dhalla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naranjan S. Dhalla.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barta, J., Sanganalmath, S.K., Kumamoto, H. et al. Antiplatelet Agents Sarpogrelate and Cilostazol Affect Experimentally-induced Ventricular Arrhythmias and Mortality. Cardiovasc Toxicol 8, 127–135 (2008). https://doi.org/10.1007/s12012-008-9019-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-008-9019-x

Key words

Search

Navigation