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. 1986 Sep;89(1):137–147. doi: 10.1111/j.1476-5381.1986.tb11129.x

The mechanism of action of the optical enantiomers of verapamil against ischaemia-induced arrhythmias in the conscious rat.

M J Curtis, M J Walker
PMCID: PMC1917029  PMID: 3801768

Abstract

The actions of (-)-verapamil (0.2-6 mg kg-1) and (+)-verapamil (0.4-12 mg kg-1) against arrhythmias induced by coronary artery occlusion were studied in conscious rats. Intravenously administered (-)- and (+)-verapamil dose-dependently reduced ventricular arrhythmias. (-)-Verapamil was consistently 4 times more potent than (+)-verapamil. In the same animals, (-)-verapamil was approximately 4 times more potent than (+)-verapamil for effects on heart rate and blood pressure. Both enantiomers prolonged P-R interval, but had no effect on QRS interval. In separate groups of conscious rats, neither enantiomer influenced the threshold voltage and pulse width required to elicit fibrillo-flutter, or altered the maximum following frequency, during electrical stimulation of the left ventricle. In isolated, paced, Langendorff-perfused ventricles of the rat, both enantiomers dose-dependently reduced contractility, (-)-verapamil being 8-21 times more potent than (+)-verapamil; both absolute and relative potencies were dependent on potassium concentration. These results are compatible with the hypothesis that calcium antagonism in the ischaemic ventricular myocardium is antiarrhythmic during acute myocardial ischaemia.

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Selected References

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  1. Bayer R., Kalusche D., Kaufmann R., Mannhold R. Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. III. Effects of the optical isomers on transmembrane action potentials. Naunyn Schmiedebergs Arch Pharmacol. 1975;290(1):81–97. doi: 10.1007/BF00499991. [DOI] [PubMed] [Google Scholar]
  2. Bernauer W. Comparative investigation of the effects of metoprolol, propranolol, practolol, and verapamil in the acute phase of experimental myocardial infarction. Klin Wochenschr. 1982 Jan 15;60(2):87–96. doi: 10.1007/BF01716386. [DOI] [PubMed] [Google Scholar]
  3. Bolli R., Fisher D. J., Taylor A. A., Young J. B., Miller R. R. Effect of alpha-adrenergic blockade on arrhythmias induced by acute myocardial ischemia and reperfusion in the dog. J Mol Cell Cardiol. 1984 Dec;16(12):1101–1117. doi: 10.1016/s0022-2828(84)80037-1. [DOI] [PubMed] [Google Scholar]
  4. Botting J. H., Johnston K. M., Macleod B. A., Walker M. J. The effect of modification of sympathetic activity on responses to ligation of a coronary artery in the conscious rat. Br J Pharmacol. 1983 May;79(1):265–271. doi: 10.1111/j.1476-5381.1983.tb10520.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bralet J., Didier J., Moreau D., Opie L. H., Rochette L. Effect of alpha-adrenoceptor antagonists (phentolamine, nicergoline and prazosin) on reperfusion arrhythmias and noradrenaline release in perfused rat heart. Br J Pharmacol. 1985 Jan;84(1):9–18. [PMC free article] [PubMed] [Google Scholar]
  6. Buchanan J. W., Jr, Saito T., Gettes L. S. The effects of antiarrhythmic drugs, stimulation frequency, and potassium-induced resting membrane potential changes on conduction velocity and dV/dtmax in guinea pig myocardium. Circ Res. 1985 May;56(5):696–703. doi: 10.1161/01.res.56.5.696. [DOI] [PubMed] [Google Scholar]
  7. Curtis M. J., Johnston K. M., Macleod B. A., Walker M. J. The actions of felodipine on arrhythmias and other responses to myocardial ischaemia in conscious rats. Eur J Pharmacol. 1985 Nov 5;117(2):169–178. doi: 10.1016/0014-2999(85)90601-6. [DOI] [PubMed] [Google Scholar]
  8. Curtis M. J., MacLeod B. A., Walker M. J. Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat. Br J Pharmacol. 1984 Oct;83(2):373–385. doi: 10.1111/j.1476-5381.1984.tb16497.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Curtis M. J., Macleod B. A., Tabrizchi R., Walker M. J. An improved perfusion apparatus for small animal hearts. J Pharmacol Methods. 1986 Feb;15(1):87–94. doi: 10.1016/0160-5402(86)90008-2. [DOI] [PubMed] [Google Scholar]
  10. Curtis M. J., Macleod B. A., Walker M. J. The effects of ablations in the central nervous system on arrhythmias induced by coronary occlusion in the rat. Br J Pharmacol. 1985 Nov;86(3):663–670. doi: 10.1111/j.1476-5381.1985.tb08943.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dukes I. D., Vaughan Williams E. M. Effects of selective alpha 1-, alpha 2-, beta 1-and beta 2-adrenoceptor stimulation on potentials and contractions in the rabbit heart. J Physiol. 1984 Oct;355:523–546. doi: 10.1113/jphysiol.1984.sp015436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Echizen H., Brecht T., Niedergesäss S., Vogelgesang B., Eichelbaum M. The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans. Am Heart J. 1985 Feb;109(2):210–217. doi: 10.1016/0002-8703(85)90585-x. [DOI] [PubMed] [Google Scholar]
  13. Eichelbaum M., Mikus G., Vogelgesang B. Pharmacokinetics of (+)-, (-)- and (+/-)-verapamil after intravenous administration. Br J Clin Pharmacol. 1984 Apr;17(4):453–458. doi: 10.1111/j.1365-2125.1984.tb02371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Evans R. G., Val-Mejias J. E., Kulevich J., Fischer V. W., Mueller H. S. Evaluation of a rat model for assessing interventions to salvage ischaemic myocardium: effects of ibuprofen and verapamil. Cardiovasc Res. 1985 Mar;19(3):132–138. doi: 10.1093/cvr/19.3.132. [DOI] [PubMed] [Google Scholar]
  15. Fagbemi O., Kane K. A., McDonald F. M., Parratt J. R., Rothaul A. L. The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats. Br J Pharmacol. 1984 Sep;83(1):299–304. doi: 10.1111/j.1476-5381.1984.tb10146.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hirche H., Franz C., Bös L., Bissig R., Lang R., Schramm M. Myocardial extracellular K+ and H+ increase and noradrenaline release as possible cause of early arrhythmias following acute coronary artery occlusion in pigs. J Mol Cell Cardiol. 1980 Jun;12(6):579–593. doi: 10.1016/0022-2828(80)90016-4. [DOI] [PubMed] [Google Scholar]
  17. Johnston K. M., MacLeod B. A., Walker M. J. Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Can J Physiol Pharmacol. 1983 Nov;61(11):1340–1353. doi: 10.1139/y83-193. [DOI] [PubMed] [Google Scholar]
  18. Müller B., Wilsmann K. Effects of the optical isomers of D 600 on cardiovascular parameters and on arrhythmias caused by aconitine and coronary artery ligation in anesthetized rats. J Cardiovasc Pharmacol. 1982 Jul-Aug;4(4):615–621. doi: 10.1097/00005344-198207000-00013. [DOI] [PubMed] [Google Scholar]
  19. Nayler W. G., Horowitz J. D. Calcium antagonists: a new class of drugs. Pharmacol Ther. 1983;20(2):203–262. doi: 10.1016/0163-7258(83)90040-2. [DOI] [PubMed] [Google Scholar]
  20. Raschack M. Relationship of antiarrhythmic to inotropic activity and antiarrhythmic qualities of the optical isomers of verapamil. Naunyn Schmiedebergs Arch Pharmacol. 1976 Sep;294(3):285–291. doi: 10.1007/BF00508397. [DOI] [PubMed] [Google Scholar]
  21. Reuter H. Properties of two inward membrane currents in the heart. Annu Rev Physiol. 1979;41:413–424. doi: 10.1146/annurev.ph.41.030179.002213. [DOI] [PubMed] [Google Scholar]
  22. Sheridan D. J., Penkoske P. A., Sobel B. E., Corr P. B. Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats. J Clin Invest. 1980 Jan;65(1):161–171. doi: 10.1172/JCI109647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Singh B. N., Williams E. M. Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res. 1971 Sep;29(3):286–295. doi: 10.1161/01.res.29.3.286. [DOI] [PubMed] [Google Scholar]
  24. Van Meel J. C., de Jonge A., Kalkman H. O., Wilffert B., Timmermans P. B., van Zwieten P. A. Organic and inorganic calcium antagonists reduce vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1981 Jul;316(4):288–293. doi: 10.1007/BF00501359. [DOI] [PubMed] [Google Scholar]
  25. Vanhoutte P. M. Heterogeneity of postjunctional vascular alpha-adrenoceptors and handling of calcium. J Cardiovasc Pharmacol. 1982;4 (Suppl 1):S91–S96. doi: 10.1097/00005344-198200041-00019. [DOI] [PubMed] [Google Scholar]
  26. Vogelgesang B., Echizen H., Schmidt E., Eichelbaum M. Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique. Br J Clin Pharmacol. 1984 Nov;18(5):733–740. doi: 10.1111/j.1365-2125.1984.tb02536.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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