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The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action

  • Ion channels, Receptors and Transporters
  • Published:
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Abstract

Telmisartan is an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma agonist that modulates the renin–angiotensin–aldosterone system. It is used primarily to manage hypertension, diabetic nephropathy, and congestive heart failure. Recent studies have reported that myocardial infarction (MI) has occurred in telmisartan-treated patients. The purpose of the study was to investigate the specific conditions and underlying mechanisms that may result in telmisartan-induced MI. We evaluated the effect of telmisartan on whole hearts, cardiomyocytes, and cardiac sarcolemmal ion channels. Hearts of 8-week-old male Sprague–Dawley rats were perfused with 3, 10, 30, or 100 μM telmisartan or losartan or with normal Tyrode’s solution (control) for 3 h. We found that telmisartan induced myocardial infarction, with an infarct size of 21 % of the total at 30 μM (P < 0.0001) and 63 % of the total area at 100 μM (P < 0.001). Telmisartan also induced cardiac dysfunction (e.g., decreased heart rate, diminished coronary flow, hypercontracture, and arrhythmia). Confocal microscopy demonstrated that 30 μM telmisartan significantly elevated the intracellular Ca2+ level, leading to hypercontracture and cell death. Patch clamp analysis of isolated cardiomyocytes revealed that telmisartan induced Na+ overload by slowing the inactivation of voltage-gated Na+ current (I Na), activating the reverse mode of Na+–Ca2+ exchanger activity, and causing Ca2+ overload. Telmisartan significantly delayed the inactivation of the voltage-gated Na+ channel, causing cytosolic Na+ overload, prolonged action potential duration, and subsequent Ca2+ overload. Above 30 μM, telmisartan may potentially cause cardiac cell death and MI.

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References

  1. Akazawa H, Yabumoto C, Yano M, Kudo-Sakamoto Y, Komuro I (2012) ARB and cardioprotection. Cardiovasc Drugs Ther. doi:10.1007/s10557-012-6392-2

  2. Elias CL, Lukas A, Shurraw S, Scott J, Omelchenko A, Gross GJ, Hnatowich M, Hryshko LV (2001) Inhibition of Na+/Ca2+ exchange by KB-R7943: transport mode selectivity and antiarrhythmic consequences. Am J Physiol Heart Circ Physiol 281(3):H1334–1345

    PubMed  CAS  Google Scholar 

  3. Gaddam KK, Verma A, Thompson M, Amin R, Ventura H (2009) Hypertension and cardiac failure in its various forms. Med Clin N Am 93(3):665–680

    Article  PubMed  Google Scholar 

  4. Goldin AL (2001) Resurgence of sodium channel research. Annu Rev Physiol 63:871–894

    Article  PubMed  CAS  Google Scholar 

  5. Goyal SN, Bharti S, Bhatia J, Nag TC, Ray R, Arya DS (2011) Telmisartan, a dual ARB/partial PPAR-gamma agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes. Diabetes Obes Metab 13(6):533–541

    Article  PubMed  CAS  Google Scholar 

  6. Inserte J, Garcia-Dorado D, Ruiz-Meana M, Padilla F, Barrabés JA, Pina P, Agulló L, Piper HM, Soler-Soler J (2002) Effect of inhibition of Na+/Ca2+ exchanger at the time of myocardial reperfusion on hypercontracture and cell death. Cardiovasc Res 55(4):739–748

    Article  PubMed  CAS  Google Scholar 

  7. Kass RS (2006) Sodium channel inactivation in heart: a novel role of the carboxy-terminal domain. J Cardiovasc Electrophysiol 17(Suppl 1):S21–S25

    Article  PubMed  Google Scholar 

  8. Kass RS, Moss AJ (2003) Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias. J Clin Invest 112(6):810–815

    PubMed  CAS  Google Scholar 

  9. Kim N, Lee Y, Kim H, Joo H, Youm JB, Park WS, Warda M, Cuong DV, Han J (2006) Potential biomarkers for ischemic heart damage identified in mitochondrial proteins by comparative proteomics. Proteomics 6(4):1237–1249

    Article  PubMed  CAS  Google Scholar 

  10. Kuhlkamp V, Mewis C, Bosch R, Seipel L (2003) Delayed sodium channel inactivation mimics long QT syndrome 3. J Cardiovasc Pharmacol 42(1):113–117

    Article  PubMed  Google Scholar 

  11. Kurtz TW (2005) Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta Diabetol 42(Suppl 1):S9–16

    Article  PubMed  CAS  Google Scholar 

  12. Lindau M, Neher E (1988) Patch-clamp techniques for time-resolved capacitance measurements in single cells. Pflugers Arch 411(2):137–146

    Article  PubMed  CAS  Google Scholar 

  13. Maejima Y, Okada H, Haraguchi G, Onai Y, Kosuge H, Suzuki J, Isobe M (2011) Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma. Lab Invest 91(6):932–944

    Article  PubMed  CAS  Google Scholar 

  14. McIntosh R, Lee S, Ghio AJ, Xi J, Zhu M, Shen X, Chanoit G, Zvara DA, Xu Z (2010) The critical role of intracellular zinc in adenosine A(2) receptor activation induced cardioprotection against reperfusion injury. J Mol Cell Cardiol 49(1):41–47

    Article  PubMed  CAS  Google Scholar 

  15. Morgan JP (1991) Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med 325(9):625–632

    Article  PubMed  CAS  Google Scholar 

  16. Nagai N, Noda K, Urano T, Kubota Y, Shinoda H, Koto T, Shinoda K, Inoue M, Shiomi T, Ikeda E, Tsubota K, Suda T, Oike Y, Ishida S (2005) Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Investig Ophthalmol Vis Sci 46(3):1078–1084

    Article  Google Scholar 

  17. Nerbonne JM, Kass RS (2005) Molecular physiology of cardiac repolarization. Physiol Rev 85(4):1205–1253

    Article  PubMed  CAS  Google Scholar 

  18. Nilius B (2007) TRP channels in disease. Biochim Biophys Acta 1772(8):805–812

    Article  PubMed  CAS  Google Scholar 

  19. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87(1):165–217

    Article  PubMed  CAS  Google Scholar 

  20. Nilius B, Talavera K, Verkhratsky A (2006) T-type calcium channels: the never ending story. Cell calcium 40(2):81–88

    Article  PubMed  CAS  Google Scholar 

  21. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457–2471

    Article  PubMed  CAS  Google Scholar 

  22. Ruiz-Meana M, Garcia-Dorado D, Hofstaetter B, Piper HM, Soler-Soler J (1999) Propagation of cardiomyocyte hypercontracture by passage of Na(+) through gap junctions. Circ Res 85(3):280–287

    Article  PubMed  CAS  Google Scholar 

  23. Savage DB (2005) PPAR gamma as a metabolic regulator: insights from genomics and pharmacology. Expert Rev Mol Med 7(1):1–16

    Article  PubMed  Google Scholar 

  24. Stangier J, Su CA, Roth W (2000) Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res 28(4):149–167

    PubMed  CAS  Google Scholar 

  25. Strauss MH, Hall AS (2006) Angiotensin receptor blockers may increase risk of myocardial infarction. Circulation 114(8):838–854

    Article  PubMed  Google Scholar 

  26. Sukumaran V, Veeraveedu PT, Gurusamy N, Yamaguchi K, Lakshmanan AP, Ma M, Suzuki K, Kodama M, Watanabe K (2011) Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmune myocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1-7/mas receptor axis. Int J Biol Sci 7(8):1077–1092

    Article  PubMed  CAS  Google Scholar 

  27. Thu VT, Kim HK, le Long T, Lee SR, Hanh TM, Ko TH, Heo HJ, Kim N, Kim SH, Ko KS, Rhee BD, Han J (2012) NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter. Cardiovasc Res 94(2):342–350

    Article  PubMed  CAS  Google Scholar 

  28. Tu D-N, Liao Y-H, Zou A-R, Du Y-M, Run Q, Wang X-P, Li L (2008) Electropharmacological properties of telmisartan in blocking hKv1.5 and HERG potassium channels expressed on Xenopus laevis oocytes. Acta Pharmacol Sin 29(8):913–922

    Article  PubMed  CAS  Google Scholar 

  29. Tytgat J, Vereecke J, Carmeliet E (1990) A combined study of sodium current and T-type calcium current in isolated cardiac cells. Pflugers Arch 417(2):142–148

    Article  PubMed  CAS  Google Scholar 

  30. Ulbricht W (2005) Sodium channel inactivation: molecular determinants and modulation. Physiol Rev 85(4):1271–1301

    Article  PubMed  CAS  Google Scholar 

  31. Ulbricht W, Schmidtmayer J (1981) Modification of sodium channels in myelinated nerve by Anemonia sulcata toxin II. J Physiol (Paris) 77(9):1103–1111

    CAS  Google Scholar 

  32. Viatchenko-Karpinski S, Terentyev D, Jenkins LA, Lutherer LO, Györke S (2005) Synergistic interactions between Ca2+ entries through L-type Ca2+ channels and Na+–Ca2+ exchanger in normal and failing rat heart. J Physiol 567(2):493–504

    Article  PubMed  CAS  Google Scholar 

  33. Yan X, Price RL, Nakayama M, Ito K, Schuldt AJ, Manning WJ, Sanbe A, Borg TK, Robbins J, Lorell BH (2003) Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice. Am J Physiol Heart Circ Physiol 285(5):H2179–2187

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Dr. Kyung Im Cho and Seong-Man Kim for valuable discussions and opinions on the manuscript. This study was supported by Priority Research Centers Program and Basic Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (2010-0020224, 2012007595, and R13-2007-023-00000-0).

Ethical standards

All experimental procedures were reviewed and approved by the Institutional Review Board of Animals, Inje University College of Medicine. Procedures were performed according to the guidelines of the Institutional Review Board on the ethical use of animals.

Conflict of interest

None declared.

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Authors and Affiliations

  1. National Research Laboratory for Mitochondrial Signaling Laboratory, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, 613-735, Korea

    Hyoung Kyu Kim, Jae Boum Youm, Sung Ryul Lee, Se Eun Lim, Sun-Young Lee, Tae Hee Ko, Le Thanh Long, Jung-Hyun Noh, Kyung Soo Ko, Byoung Doo Rhee, Nari Kim & Jin Han

  2. Department of Cellular and Molecular Medicine, Laboratory Ion Channel Research, KU Leuven, Campus Gasthuisberg, Leuven, Belgium

    Bernd Nilius

  3. GE Healthcare Life Sciences, Clinical System U/S, Seoul, Korea

    Du Nam Won

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  1. Hyoung Kyu Kim
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Correspondence to Jin Han.

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Kim, H.K., Youm, J.B., Lee, S.R. et al. The angiotensin receptor blocker and PPAR-γ agonist, telmisartan, delays inactivation of voltage-gated sodium channel in rat heart: novel mechanism of drug action. Pflugers Arch - Eur J Physiol 464, 631–643 (2012). https://doi.org/10.1007/s00424-012-1170-3

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