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Effects of Mibefradil, a T- and L-Type Calcium Channel Blocker, on Cardiac Remodeling in the UM-X7.1 Cardiomyopathic Hamster

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Abstract

Abnormalities of T-type calcium channel function reported to occur in the transition phase to heart failure in the hamster cardiomyopathy may contribute to progression of the disease. We tested the hypothesis that chronic exposure to mibefradil, a selective T-type calcium channel blocker, improves the deleterious cardiac remodeling observed in this condition. In the present study, 40 normal (N) and 40 UM-X7.1 cardiomyopathic hamsters (CMH), aged 180 days, were treated daily by gavage for 21 days with mibefradil (30 mg/Kg). Eight to 10 animals from each group were sacrificed at the end of the treatment period while the remainder were followed for an additional 30 days without treatment (washout period). Hearts were harvested, fixed with 10%-buffered paraformaldehyde and then cut in half down the middle. Several slices were dehydrated, embedded in paraffin and stained with Masson Trichrome. Wall thickness and dilatation index of the left ventricle were estimated by planimetry. Myocardial capillary density was also computed. The greater heart weight/body weight ratio seen in untreated CMH (7.7 ± 0.4 vs 5.5 ± 0.2 in N, p < 0.05) was improved with mibefradil. The dilatation index averaged 0.504 ± 0.04 in N was increased in untreated CMH (0.566 ± 0.03) and ameliorated in mibefradil-treated CMH. The 1-month washout period led to further deterioration of the dilatation index in untreated and mibefradil-treated CMH. Capillary density averaged 10,000 ± 781 per mm2 in hearts from untreated N hamsters and 8,830 ± 795 per mm2 in untreated CMH (p = NS). Chronic exposure to mibefradil resulted in a significant reduction of capillary density in both N and CMH hearts. Following the 1-month washout period, the change in myocardial capillary density associated with mibefradil was no longer detectable. In conclusion, chronic exposure to mibefradil, a T- and L-type calcium channel blocker, exerts opposite effects during the transition phase to heart failure in CMH, improving the deleterious left ventricular remodeling in UM-X7.1 hamsters and reducting myocardial capillary density independently of the disease process.

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References

  1. Osterrieder W, Holck M. In vitro pharmacologic profile of Ro 40-5967, a novel Ca2+channel blocker with potent vasodilator but weak inotropic action. J. Cardiovasc Pharmacol 1989; 13: 754-759.

    Google Scholar 

  2. Orito K, Satoh K, Taira N. Cardiovascular profile of Ro 40-5967, a new non-dihydropyridine calcium antagonist delineated in isolated blood-perfused dog hearts. J Cardiovasc Pharmacol 1993; 22: 293-299.

    Google Scholar 

  3. Karila-Cohen D, Dubois-Randé JL, Giudicelli JF, Berdeaux A. Effects of mibefradil on large and small coronary arteries in conscious dogs: role of the vascular endothelium. J Cardiovasc Pharmacol 1996; 28: 271-277.

    Google Scholar 

  4. Clozel JP, Véniant M, Osterrieder W. The structurally novel Ca2+channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts. Cardiovasc Drugs Ther 1990; 4: 731-736.

    Google Scholar 

  5. Véniant M, Clozel JP, Hess P, Wolfgang R. Ro40-5967, in contrast to diltiazem, does not reduce left ventricular contractility in rats with chronic myocardial infarction. J Cardiovasc Pharmacol 1991; 17: 277-280.

    Google Scholar 

  6. Clozel JP, Banken L, Osterrieder W. Effects of Ro 40-5967, a novel calcium antagonist, on myocardial function during ischemia induced by lowering coronary perfusion pressure in dogs: comparison with verapamil. J Cardiovasc Pharmacol 1989; 14: 713-721.

    Google Scholar 

  7. Roux S, B#x00FC;hler M, Clozel JP. Mechanism of the antiischemic effect of mibefradil, a selective T calcium channel blocker in dogs: comparison with amlodipine. J Cardiovasc Pharmacol 1996; 27: 132-139.

    Google Scholar 

  8. Richard V, Tron C, Blanc T, Thuillez C. Infarct size-limiting properties of Ro 40-5967, a novel nondihydropyridine calcium channel blocker, in anesthetized rats: comparison with verapamil. J Cardiovasc Pharmacol 1995; 22: 552-557.

    Google Scholar 

  9. Vander Heide RS, Schwartz LM, Reimer KA. The novel calcium antagonist Ro 40-5967 limits myocardial infarct size in the dog. Cardiovasc Res 1994; 28: 1526-1532.

    Google Scholar 

  10. Nuss HB, Houser SR. T-type Ca2+current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res 1993; 73: 777-782.

    Google Scholar 

  11. Martinez ML, Hereda MP, Delgado C. Expression of T-type Ca2+channels in ventricular cells from hypertrophied rat hearts. J Mol Cell Cardiol 1999; 31: 1617-1625.

    Google Scholar 

  12. Glass MG, Fuleihan F, Liao R, et al. Differences in cardioprotective efficacy of adrenergic receptor antagonists and Ca++channel antagonists in an animal model of dilated cardiomyopathy. Circ Res 1993; 73: 1077-1089.

    Google Scholar 

  13. Watanabe M, Kawagushi H, Onozuka H, et al. Chronic effects of enalapril and amlodipine on cardiac remodeling in cardiomyopathic hamster hearts. J Cardiovasc Pharmacol 1998; 32: 248-259.

    Google Scholar 

  14. Clozel JP, Osterrieder W, Kleinbloesen CH, et al. Ro40-5967: a new nondihydropyridine calcium antagonist. Cardiovasc Drugs Rev 1991; 9: 4-17.

    Google Scholar 

  15. Vacher E, Richer C, Fornes P, Clozel JP, Giudicelli JF. Mibefradil, a selective calcium T-channel blocker, in strokeprone spontaneously hypertensive rats. J Cardiovasc Pharmacol 1996; 27: 686-694.

    Google Scholar 

  16. Jasmin G, Proschek L. Calcium and myocardial cell injury. An appraisal in the cardiomyopathic hamster. Can J Physiol Pharmacol 1984; 62: 891-898.

    Google Scholar 

  17. Gosselin H, Qi X, Rouleau J-L. Correlation between cardiac remodeling, function, and myocardial contractility in rat hearts 5 weeks after myocardial infarction. Can J Physiol Pharmacol 1997; 76: 53-62.

    Google Scholar 

  18. Bishop SP, Powell PC, Hasebe N, et al. Coronary vascular morphology in pressure-overload left ventricular hypertrophy. J Mol Cell Cardiol 1996; 28: 141-154.

    Google Scholar 

  19. Jasmin G, Proschek L. Hereditary polymyopathy and cardiomyopathy in the Syrian hamster. I. Progression of heart and skeletal muscle lesions in the UM-X7.1 line. Muscle and Nerve 1982; 5: 20-25.

    Google Scholar 

  20. Sole MJ, Lo C-M, Laird CW, Sonnenblick EH, Wurtman RJ. Norepinephrine turnover in the heart and spleen of the cardiomyopathic Syrian hamster. Circ Res 1975; 37: 855-862.

    Google Scholar 

  21. Factor SM, Minase T, Cho S, Dominitz R, Sonnenblick EH. Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cause of focal myocardial necrosis. Circulation 1982; 66: 342-354.

    Google Scholar 

  22. Hano O, Lakatta EG. Diminished tolerance of prehypertrophic cardiomyopathic Syrian hamster hearts to Ca2+ stress. Circ Res 1991; 69: 123-133.

    Google Scholar 

  23. Roberds SL, Ervasti JM, Anderson RD, Ohlendieck K, Kahl SD, Zoloto D. Disruption of the dystrophin-glycoprotein complex in the cardiomyopathic hamster. J Biol Chem 1993; 268: 11496-11499.

    Google Scholar 

  24. Stefenelli T, Wu ST, Parmley WW, Mason DT, Wikman-Coffelt J. Influence of positive inotropic agents on intracellular calcium transients. Part II. Cardiomyopathic hamsters. Am Heart J 1989; 118: 1228-1236.

    Google Scholar 

  25. Buser PT, Wu SY, Parmley WW, Jasmin G, Wikman-Coffelt J. Distinct modulation of myocardial performance, energy metabolism, and [Ca2+]i transients by positive inotropic drugs in normal and severely failing hamster hearts. Cardiovasc Drugs Ther 1995; 9: 151-157.

    Google Scholar 

  26. Fontaine ER, Viau S, Jasmin G, Dumont L. Effects of phosphoramidon, BQ788, and BQ123 on coronary and cardiac dysfunctions of the failing hamster heart. J Cardiovasc Pharmacol 1998; 32: 12-20.

    Google Scholar 

  27. Billman GE, Hamlin RL. The effects of mibefradil, a novel calcium channel antagonist, on ventricular arrhythmias induced by myocardial ischemia and programmed electrical stimulation. J Pharmacol Exp Ther 1996; 277: 1517-1526.

    Google Scholar 

  28. Figulla HR, Vetterlein F, Glaubitz M, Kreuzer H. Inhomogenous capillary flow and its prevention by verapamil and hydralazine in the cardiomyopathic Syrian hamster. Circulation 1987; 76: 208-216.

    Google Scholar 

  29. Conway RS, Natelson BH, Chen WH, Ting W. Enhanced coronary vasoconstriction in the Syrian myopathic hamster supports the microvascular spasm hypothesis. Cardiovasc Res 1994; 28: 320-324.

    Google Scholar 

  30. Küng CF, Tschudi MR, Noll G, Clozel JP, Lüscher TF. Differential effects of the calcium antagonist mibefradil in epicardial and intramyocardial coronary arteries. J Cardiovasc Pharmacol 1995; 26: 312-318.

    Google Scholar 

  31. Mehrke G, Zong XG, Flockerzi V, Hofmann F. The Ca2+channel blocker Ro 40-5967 blocks differently T-type and L-type Ca2+channels. J Pharmacol Exp Ther 1994; 271: 1483-1488.

    Google Scholar 

  32. Mirsha SK, Hermsmeyer K. Selective inhibition of Ttype Ca2+channels by Ro 40-5967. Circ Res 1994; 75: 144-148.

    Google Scholar 

  33. Sen L, Smith TW. T-Type Ca2+channels are abnormal in genetically determined cardiomyopathic hamster hearts. Circ Res 1994; 75: 149-155.

    Google Scholar 

  34. Mulder P, Richard V, Compagnon P, et al. Increased survival after long-term treatment with miberfradil, a selective T-channel calcium antagonist, in heart failure. J Am Coll Cardiol 1997; 29: 416-421.

    Google Scholar 

  35. Veniant M, Clozel J-P, Heudes D, Banken L, Menard J. Effects of Ro 40-5967, a new calcium antagonist, and enalapril on cardiac remodeling in renal hypertensive rats. J Cardiovasc Pharmacol 1993; 21: 544-551.

    Google Scholar 

  36. Höglund 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; 89: 270-283.

    Google Scholar 

  37. Martina B, Lotz W, Frach B, Bart T, Battegay EJ. The effects of mibefradil and enalapril on 24-hour blood pressure control and left ventricular mass in patients with mild to moderate hypertension: double-blind, randomized trial. J Cardiovasc Pharmacol 1999; 33: 647-651.

    Google Scholar 

  38. Ruskoaho H, Savolainen ER. Effects of long-term verapamil treatment on blood pressure, cardiac hypertrophy and collagen metabolism in spontaneously hypertensive rats. Cardiovasc Res 1985; 19: 355-362.

    Google Scholar 

  39. Motz W, Strauer BE. Left ventricular function and collagen content after regression of hypertensive hypertrophy. Hypertension 1989; 13: 43-50.

    Google Scholar 

  40. Kyselovic J, Morel N, Wibo M, Godfraind T. Prevention of salt-dependent cardiac remodeling and enhanced gene expression in stroke-prone hypertensive rats by the longacting calcium blocker lacidipine. J Hypertens 1998; 16: 1515-1522.

    Google Scholar 

  41. Turek Z, Kubat K, Kazda S, Hoofd L, Rakusan K. Improved myocardial capillarisation in spontaneously hypertensive rats treated with nifedipine. Cardiovasc Res 1987; 21: 725-729.

    Google Scholar 

  42. Kobayashi N, Kobayashi K, Kouno K, Yagi S, Matsuoka H. Effect of benidipine on microvascular remodeling and coronary flow reserve in two-kidney, one clip Goldblatt hypertension. J Hyperten 1997; 15: 1285-1294.

    Google Scholar 

  43. Kumamoto H, Okamoto H, Watanabe M, Onozuka H, Yoneya K, Nakagawa I, Chiloa S, Watanabe S, Mikami T, Abe K, Kitabatake A. Beneficial effects of myocardial angiogenesis on cardiac remodeling process by amlodipine and MCI-154. Am J Physiol 1999; 276: H1117-H1123.

    Google Scholar 

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Authors and Affiliations

  1. Département de pharmacologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada

    Johanne Villame, Julie Massicotte & Louis Dumont

  2. Département de biochimie, Unité associée, INRA-Université de Bourgogne, Dijon, France

    Johanne Villame

  3. Département de pathologie et biologie cellulaire, Faculté de médecine, Université de Montréal, Montréal, QC, Canada

    Gaëtan Jasmin

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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 15, 41–48 (2001). https://doi.org/10.1023/A:1011158717901

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