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Development of Newer Calcium Channel Antagonists

Therapeutic Potential of Efonidipine in Preventing Electrical Remodelling during Atrial Fibrillation

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Abstract

Calcium channel antagonists are most frequently prescribed for the treatment of hypertension and the majority specifically inhibit the L-type Ca2+ channel. In order to prevent reflex sympathetic over activity caused by L-type calcium channel antagonists (calcium channel blockers [CCBs]), increasing attention has focused on the blockade of the T-type Ca2+ channel. The T-type Ca2+ channel is found in the kidney and can also appear in the ventricle of the heart when in failure. Therefore, the T-type Ca2+ channel is a possible new target for the treatment of nephropathy and heart failure. In clinical trials, the efficacy and safety of T-type CCBs in hypertension and chronic renal disease have been reported.

It is well known that the T-type Ca2+ channel is present in the adult atrium and plays a role in the cardiac pacemaker, but recent experimental studies suggest that this current also promotes electrical remodelling of the atrium. Using efonidipine, a dual L- and T-type CCB, it has been demonstrated that atrial electrical remodelling can be diminished in dogs. Furthermore, the T-type Ca2+ channel has recently been found in the pulmonary veins, contributing to the pulmonary vein pacemaker activity and triggered activity. A variety of drugs having T-type CCB effects have been shown to be effective in the management of atrial fibrillation, suggesting that this channel may be a novel therapeutic target.

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References

  1. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ 1989 Nov 11; 299(6709): 1187–92

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Ishikawa K, Nakai S, Takenaka T, et al. Short-acting nife-dipine and diltiazem do not reduce the incidence of cardiac events in patients with healed myocardial infarction. Circulation 1997 May 20; 95(10): 2368–73

    PubMed  CAS  Google Scholar 

  3. Grossman E, Messerli FH. Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and blood pressure. Am J Cardiol 1997 Dec 1; 80(11): 1453–8

    PubMed  CAS  Google Scholar 

  4. Staessen JA, Fagard R, Thijs L, et al. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997 Sep 13; 350(9080): 757–64

    PubMed  CAS  Google Scholar 

  5. Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004 Sep 4; 364(9437): 849–57

    PubMed  CAS  Google Scholar 

  6. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005 Sep 10–16; 366(9489): 895–906

    PubMed  Google Scholar 

  7. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: a randomized controlled trial. JAMA 2004 Nov 10; 292(18): 2217–25

    PubMed  CAS  Google Scholar 

  8. Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 2003 Jan; 83(1): 117–61

    PubMed  CAS  Google Scholar 

  9. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII: nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005 Dec; 57(4): 397–409

    PubMed  CAS  Google Scholar 

  10. Hirning LD, Fox AP, McCleskey EW, et al. Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science 1988 Jan 1; 239(4835): 57–61

    PubMed  CAS  Google Scholar 

  11. Furukawa T, Nukada T, Suzuki K, et al. Voltage and pH dependent block of cloned N-type Ca2+ channels by amlodipine. Br J Pharmacol 1997 Jul; 121(6): 1136–40

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Donati L, Buhler FR, Beretta-Piccoli C, et al. Antihypertensive mechanism of amlodipine in essential hypertension: role of pressor reactivity to norepinephrine and angiotensin II. Clin Pharmacol Ther 1992 Jul; 52(1): 50–9

    PubMed  CAS  Google Scholar 

  13. Leenen FH, Fourney A. Comparison of the effects of amlodipine and diltiazem on 24-hour blood pressure, plasma catecholamines, and left ventricular mass. Am J Cardiol 1996 Jul 15; 78(2): 203–7

    PubMed  CAS  Google Scholar 

  14. Furukawa T, Yamakawa T, Midera T, et al. Selectivities of dihydropyridine derivatives in blocking Ca(2+) channel subtypes expressed in Xenopus oocytes. J Pharmacol Exp Ther 1999 Nov; 291(2): 464–73

    PubMed  CAS  Google Scholar 

  15. Takahara A, Sugiyama A, Satoh Y, et al. Cardiovascular effects of an L/N-type Ca2+ channel blocker cilnidipine assessed in the chronic atrioventricular conduction block dogs. J Pharmacol Sci 2004 Oct; 96(2): 219–23

    PubMed  CAS  Google Scholar 

  16. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol 1988; 395: 233–53

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Hüser J, Blatter LA, Lipsius SL. Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells. J Physiol 2000 Apr 15; 524 (Pt 2): 415–22

    PubMed  PubMed Central  Google Scholar 

  18. Ono K, Iijima T. Pathophysiological significance of T-type Ca2+ channels: properties and functional roles of T-type Ca2+ channels in cardiac pacemaking. J Pharmacol Sci 2005 Nov; 99(3): 197–204

    PubMed  CAS  Google Scholar 

  19. Mangoni ME, Traboulsie A, Leoni AL, et al. Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circ Res 2006 Jun 9; 98(11): 1422–30

    PubMed  CAS  Google Scholar 

  20. Chen CC, Lamping KG, Nuno DW, et al. Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science 2003 Nov 21; 302 (5649): 1416–8

    PubMed  CAS  Google Scholar 

  21. Kim D, Song I, Keum S, et al. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. Neuron 2001 Jul 19; 31(1): 35–45

    PubMed  CAS  Google Scholar 

  22. Kim D, Park D, Choi S, et al. Thalamic control of visceral nociception mediated by T-type Ca2+ channels. Science 2003 Oct 3; 302(5642): 117–9

    PubMed  CAS  Google Scholar 

  23. Vitko I, Chen Y, Arias JM, et al. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci 2005 May 11; 25(19): 4844–55

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Levine TB, Bernink PJ, Caspi A, et al. Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial. Circulation 2000 Feb 22; 101(7): 758–64

    PubMed  CAS  Google Scholar 

  25. Gläser S, Steinbach M, Opitz C, et al. Torsades de pointes caused by mibefradil. Eur J Heart Fail 2001 Oct; 3(5): 627–30

    PubMed  Google Scholar 

  26. Masuda Y, Tanaka S. Efonidipine hydrochloride: a new calcium antagonist. Cardiovasc Drug Rev 1994; 12(2): 123–35

    CAS  Google Scholar 

  27. Yamada K, Ishii M, Mizuno Y, et al. Clinical evaluation of the antihypertensive effect of NZ-105 in patients with essential hypertension [in Japanese]. J Clin Exp Med 1992; 161: 275–92

    Google Scholar 

  28. Shinozaki Y, Himori Y, Sano H, et al. Studies on the metabolic fate of NZ-105: absorption, distribution, metabolism and excretion after a single administration to rats. Xenobio Metabol and Dispors 1991; 6: 919–32

    CAS  Google Scholar 

  29. Yamashita T, Masuda Y, Sakai T, et al. NZ-105, a new 1,4-dihydropyridine derivative: correlation between dihydropyridine receptor binding and inhibition of calcium uptake in rabbit aorta. Jpn J Pharmacol 1991 Nov; 57(3): 337–48

    PubMed  CAS  Google Scholar 

  30. Masumiya H, Shijuku T, Tanaka H, et al. Inhibition of myocardial L- and T-type Ca2+ currents by efonidipine: possible mechanism for its chronotropic effect. Eur J Pharmacol 1998 May 22; 349(2–3): 351–7

    PubMed  CAS  Google Scholar 

  31. Masumiya H, Kase J, Tanaka Y, et al. Frequency-dependent blockade of T-type Ca2+ current by efonidipine in cardiomyocytes. Life Sci 2000 Dec 8; 68(3): 345–51

    PubMed  CAS  Google Scholar 

  32. Lee TS, Kaku T, Takebayashi S, et al. Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology 2006; 78(1): 11–20

    PubMed  CAS  Google Scholar 

  33. Furukawa T, Miura R, Honda M, et al. Identification of R(−)-isomer of efonidipine as a selective blocker of T-type Ca2+ channels. Br J Pharmacol 2004 Dec; 143(8): 1050–7

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Tanaka H, Komikado C, Shimada H, et al. The R(−)-enantiomer of efonidipine blocks T-type but not L-type calcium current in guinea pig ventricular myocardium. J Pharmacol Sci 2004 Dec; 96(4): 499–501

    PubMed  CAS  Google Scholar 

  35. Sugano N, Wakino S, Kanda T, et al. T-type calcium channel blockade as a therapeutic strategy against renal injury in rats with subtotal nephrectomy. Kidney Int 2008 Apr; 73(7): 826–34

    PubMed  CAS  Google Scholar 

  36. JATOS Study Group. The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS): protocol, patient characteristics, and blood pressure during the first 12 months. Hypertens Res 2005 Jun; 28(6): 513–20

    Google Scholar 

  37. Oshima T, Ozono R, Yano Y, et al. Beneficial effect of T-type calcium channel blockers on endothelial function in patients with essential hypertension. Hypertens Res 2005 Nov; 28(11): 889–94

    PubMed  CAS  Google Scholar 

  38. Andreasen D, Jensen BL, Hansen PB, et al. The alpha(1G)-subunit of a voltage-dependent Ca(2+) channel is localized in rat distal nephron and collecting duct. Am J Physiol Renal Physiol 2000 Dec; 279(6): F997–1005

    PubMed  CAS  Google Scholar 

  39. Hansen PB, Jensen BL, Andreasen D, et al. Differential expression of T- and L-type voltage-dependent calcium channels in renal resistance vessels. Circ Res 2001 Sep 28; 89(7): 630–8

    PubMed  CAS  Google Scholar 

  40. Hayashi K, Nagahama T, Oka K, et al. Disparate effects of calcium antagonists on renal microcirculation. Hypertens Res 1996 Mar 1; 19(1): 31–6

    PubMed  CAS  Google Scholar 

  41. Hayashi K, Wakino S, Sugano N, et al. Ca2+ channel subtypes and pharmacology in the kidney. Circ Res 2007 Feb 16; 100(3): 342–53

    PubMed  CAS  Google Scholar 

  42. Fujiwara K, Kanno Y, Hayashi K, et al. Renal protective effects of efonidipine in partially nephrectomized spontaneously hypertensive rats. Clin Exp Hypertens 1998 Apr; 20(3): 295–312

    PubMed  CAS  Google Scholar 

  43. Hayashi K, Kumagai H, Saruta T. Effect of efonidipine and ACE inhibitors on proteinuria in human hypertension with renal impairment. Am J Hypertens 2003 Feb; 16(2): 116–22

    PubMed  CAS  Google Scholar 

  44. Hayashi K, Ozawa Y, Fujiwara K, et al. Role of actions of calcium antagonists on efferent arterioles: with special references to glomerular hypertension. Am J Nephrol 2003 Jul–Aug; 23(4): 229–44

    PubMed  CAS  Google Scholar 

  45. Sen L, Smith TW. T-type Ca2+ channels are abnormal in genetically determined cardiomyopathic hamster hearts. Circ Res 1994 Jul; 75(1): 149–55

    PubMed  CAS  Google Scholar 

  46. Martinez ML, Heredia MP, Delgado C. Expression of T-type Ca(2+) channels in ventricular cells from hypertrophied rat hearts. J Mol Cell Cardiol 1999 Sep; 31(9): 1617–25

    PubMed  CAS  Google Scholar 

  47. Nuss HB, Houser SR. T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res 1993 Oct; 73(4): 777–82

    PubMed  CAS  Google Scholar 

  48. Villame J, Massicotte J, Jasmin G, et al. Effects of mibefradil, a T- and L-type calcium channel blocker, on cardiac remodeling in the UM-X7.1 cardiomyopathic hamster. Cardiovasc Drugs Ther 2001 Jan; 15(1): 41–8

    PubMed  CAS  Google Scholar 

  49. Mulder P, Richard V, Compagnon P, et al. Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure. J Am Coll Cardiol 1997 Feb; 29(2): 416–21

    PubMed  CAS  Google Scholar 

  50. Ito H, Hirata Y, Adachi S, et al. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993 Jul; 92(1): 398–403

    PubMed  PubMed Central  CAS  Google Scholar 

  51. Izumi T, Kihara Y, Sarai N, et al. Reinduction of T-type calcium channels by endothelin-1 in failing hearts in vivo and in adult rat ventricular myocytes in vitro. Circulation 2003 Nov 18; 108(20): 2530–5

    PubMed  CAS  Google Scholar 

  52. Lalevee N, Rebsamen MC, Barrere-Lemaire S, et al. Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes. Cardiovasc Res 2005 Aug 1; 67(2): 216–24

    PubMed  CAS  Google Scholar 

  53. Hoglund C, Cifkova R, Mimran A, et al. A comparison of the effects of mibefradil and atenolol on regression of left ventricular hypertrophy in hypertensive patients. Cardiology 1998 May; 89(4): 263–70

    PubMed  CAS  Google Scholar 

  54. Tzivoni D, Kadr H, Braat S, et al. Efficacy of mibefradil compared with amlodipine in suppressing exercise-induced and daily silent ischemia: results of a multicenter, placebo-controlled trial. Circulation 1997 Oct 21; 96(8): 2557–64

    PubMed  CAS  Google Scholar 

  55. Leuranguer V, Monteil A, Bourinet E, et al. T-type calcium currents in rat cardiomyocytes during postnatal development: contribution to hormone secretion. Am J Physiol Heart Circ Physiol 2000 Nov; 279(5): H2540–8

    PubMed  CAS  Google Scholar 

  56. Gaborit N, Le Bouter S, Szuts V, et al. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol 2007 Jul 15; 582 (Pt 2): 675–93

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995 Oct 1; 92(7): 1954–68

    PubMed  CAS  Google Scholar 

  58. Yue L, Melnyk P, Gaspo R, et al. Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ Res 1999 Apr 16; 84(7): 776–84

    PubMed  CAS  Google Scholar 

  59. Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res 1997 Oct; 81(4): 512–25

    PubMed  CAS  Google Scholar 

  60. Sun H, Chartier D, Leblanc N, et al. Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes. Cardiovasc Res 2001 Mar; 49(4): 751–61

    PubMed  CAS  Google Scholar 

  61. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997 Apr 1; 95(7): 1945–53

    PubMed  CAS  Google Scholar 

  62. Ramanna H, Elvan A, Wittkampf FH, et al. Increased dispersion and shortened refractoriness caused by verapamil in chronic atrial fibrillation. J Am Coll Cardiol 2001 Apr; 37(5): 1403–7

    PubMed  CAS  Google Scholar 

  63. Lee SH, Yu WC, Cheng JJ, et al. Effect of verapamil on long-term tachycardia-induced atrial electrical remodeling. Circulation 2000 Jan 18; 101(2): 200–6

    PubMed  CAS  Google Scholar 

  64. Fareh S, Benardeau A, Thibault B, et al. The T-type Ca2+ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs. Circulation 1999 Nov 23; 100(21): 2191–7

    PubMed  CAS  Google Scholar 

  65. Fareh S, Benardeau A, Nattel S. Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs. Cardiovasc Res 2001 Mar; 49(4): 762–70

    PubMed  CAS  Google Scholar 

  66. Ohashi N, Mitamura H, Tanimoto K, et al. A comparison between calcium channel blocking drugs with different potencies for T- and L-type channels in preventing atrial electrical remodeling. J Cardiovasc Pharmacol 2004 Sep; 44(3): 386–92

    PubMed  CAS  Google Scholar 

  67. Chen YC, Chen SA, Chen YJ, et al. T-type calcium current in electrical activity of cardiomyocytes isolated from rabbit pulmonary vein. J Cardiovasc Electrophysiol 2004 May; 15(5): 567–71

    PubMed  Google Scholar 

  68. Yamashita N, Kaku T, Uchino T, et al. Short- and long-term amiodarone treatments regulate Cav3.2 low-voltage-activated T-type Ca2+ channel through distinct mechanisms. Mol Pharmacol 2006 May; 69(5):1684–91

    PubMed  CAS  Google Scholar 

  69. Shinagawa K, Shiroshita-Takeshita A, Schram G, et al. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation 2003 Mar 18; 107(10): 1440–6

    PubMed  CAS  Google Scholar 

  70. Cohen CJ, Spires S, Van Skiver D. Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol 1992 Oct; 100(4): 703–28

    PubMed  CAS  Google Scholar 

  71. Fujiki A, Tsuneda T, Sugao M, et al. Usefulness and safety of bepridil in converting persistent atrial fibrillation to sinus rhythm. Am J Cardiol 2003 Aug 15; 92(4): 472–5

    PubMed  CAS  Google Scholar 

  72. Sato D, Niwano S, Imaki R, et al. Bepridil inhibits subacute phase of atrial electrical remodeling in canine rapid atrial stimulation model. Circ J 2006 Feb; 70(2): 206–13

    PubMed  CAS  Google Scholar 

  73. Uchino T, Lee TS, Kaku T, et al. Voltage-dependent and frequency-independent inhibition of recombinant Cav3.2 T-type Ca2+ channel by bepridil. Pharmacology 2005 Jul; 74(4): 174–81

    PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Dr Shunichiro Miyoshi for his valuable advice. No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Cardiology Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan

    Narutaka Ohashi & Satoshi Ogawa

  2. Saiseikai Central Hospital, Tokyo, Japan

    Hideo Mitamura

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  1. Narutaka Ohashi
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  2. Hideo Mitamura
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  3. Satoshi Ogawa
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Correspondence to Narutaka Ohashi.

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Ohashi, N., Mitamura, H. & Ogawa, S. Development of Newer Calcium Channel Antagonists. Drugs 69, 21–30 (2009). https://doi.org/10.2165/00003495-200969010-00002

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