Summary
The effect of verapamil and felodipine on imipramine-induced cardiac toxicity was assessed in anaesthetized rats. Rats received either infusion of saline (n = 13), or nonhypotensive doses of felodipine (n = 36) or verapamil (n = 36) over 40 minutes. In saline-pretreated rats IV bolus injection of imipramine (10 mg/kg) resulted in severe hypotension, bradycardia, electromechanical dissociation, and death within 3 minutes. Rats pretreated with nonhypotensive doses of felodipine (1, 3, 6, and 10 μg/kg/min) or verapamil (10, 30, 100, and 300 μg/kg/min) survived throughout the experiment, despite an initial fall in blood pressure within the first 5 minutes after imipramine administration. Blood pressure returned to baseline levels within 15 minutes. Intermittent ECG monitoring showed significant prolongation of QRS duration after imipramine in both saline (by 138%) and verapamil-pretreated rats (by 63%), whereas in the rats pretreated with felodipine no prolongation was observed ( + 3%). We conclude that, in our experimental model, felodipine, more than verapamil, protects against the cardiac effects of imipramine intoxication.
Similar content being viewed by others
References
Marchai JB, Forker AD. Cardiovascular effects of tricyclic antidepressant drugs: Therapeutic usage, overdose, and management of complications.Am Heart J 1982;103:401–414.
Nieman JT, Bessen HA, Rothstein RJ, Laks MM. Electrocardiographic criteria for tricyclic antidepressant cardiotoxicity.Am J Cardiol 1986;57:1154–1159.
Boehnert MT, Lovejoy FH. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants.N Engl J Med 1985;313:474–479.
Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Goodman GA, Goodman LS, Rail TW, Murad F, eds.Goodman and Gilman’s The pharmacological basis of therapeutics. New York: MacMillan Publishing, 1985: 413–422.
Rudorfer MV, Potter WZ. Antidepressants. A comparative review of the clinical pharmacology and therapeutic use of the “newer”versus the “older” drugs.Drugs 1989;37:713–738.
Merigian KS, Hedges JR, Kaplan LA, et al. Plasma catecholamines in cyclic antidepressant overdose.Ann Emerg Med 1988;17:403.
Wong RKS, Prince DA. Dendritic mechanisms underlying penicillin-induced epileptiform activity.Science 1979;204: 1228–1231.
Witte OW, Speckmann E, Waiden J. Motor cortical epileptic foci in vivo: Actions of a calcium channel blocker on paroxysmal neuronal depolarizations.Electroenceph Clin Neurophysiol 1987;66:43–55.
Eikenburg DC, Lokhandwala MF. Calcium antagonists and sympathetic neuroeffector function.J Auton Pharmac 1986;6:237–255.
Trouvé R, Nahas G. Ca2+ modulators as antidotes to imipramine and neurotransmitter toxicity.Proc Soc Exp Biol Med 1987;185:498–503.
Boström SL, Ljung B, Mardh S, et al. Interaction of the antihypertensive drug felodipine with calmodulin.Nature 1981;292:777–778.
Frommer DA, Kulig KW, Marx AJ, Rumack B. Tricyclic antidepressant overdose.JAMA 1987;257:521–526.
Kantor SJ, Glassman AH, Bigger JT, et al. The cardiac effects of therapeutic plasma concentrations of imipramine.Am J Psych 1978;135:213–219.
Cauvin C, Loutzenhiser R, Van Breemen C. Mechanisms of calcium antagonist-induced vasodilation.Ann Rev Pharmacol Toxicol 1983;23:373–396.
Cheung WY. Calmodulin plays a pivotal role in cellular regulation.Science 1980;207:19–27.
Choi DW. Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage.Trends Neurol Sci 1988;10:465–469.
Orrenius S, McConkey DJ, Bellomo J, Nicotera P. Role of Ca2+ in toxic cell killing.Trends Pharmacol Sci 1989;10: 281–285.
Eisner DA. The role of intracellular Ca ions in the therapeutic and toxic effects of cardiac glycosides and catecholamines.J Cardiovasc Pharmacol 1986;8:S2-S9.
Neiman CJ. The effects of isoprenaline on Ca2+-dependent oscillations in sheep cardiac Purkinje fibres.J Physiol 1987; 392:451–461.
Sheffield LT. Exercise stress testing. In: Braunwald E, ed.Heart disease. A textbook of cardiovascular medicine. Philadelphia: W.B. Saunders, 1987:253–277.
Opie LH. Calcium channel antagonists part II: Use of comparative properties of the three prototypical calcium antagonists in ischemic heart disease, including recommendations based on an analysis of 41 trials.Cardiovasc Drugs Ther 1988;1:461–491.
Hopkins RJ, Hill TWK. Effects of felodipine on red blood cell deformability.Drugs 1985;29(Suppl 2):42–44.
Godfraind T. Basic mechanisms and classification of calcium entry blockers. In: Godfraind T, Herman AG, Wellens D, eds.Calcium entry blockers in cardiovascular and cerebral & dysfunctions. The Hague: Martinus Nijhoff Publishers, 1984:9–36.
Godfraind T, Govoni S. Increasing complexity revealed in regulation of Ca2+ antagonist receptor.Trends Pharmacol Sci 1989;10:297–301.
Ganong WF. The general and cellular basis of medical physiology. In: Ganong WF, ed.Review of medical physiology. East Norwalk, CT: Prentice-Hall, 1987:1–37.
Lamers JM. The effects of felodipine and bepridil on calcium-stimulated calmodulin binding and calcium pumping ATPase of cardiac sarcolemma before and after removal of endogenous calmodulin.Mol Cell Biochem 1987;78:169–176.
Johnson JD, Andrews CT, Khabbaza EJ, Mills JS. The interaction of felodipine with calcium-binding proteins.J Cardiovasc Pharmacol 1987;10:S53-S59.
Hofmann HP, Raschack M, Unger L. (S)-Emopamil, a novel calcium and serotonin antagonist for the treatment of cerebrovascular disorders.Arzneim-Forsch 1989;39:304–308.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schoors, D.F., Reynaert, H., Huyghens, L. et al. Protective effects of felodipine and verapamil against imipramine-induced lethal cardiac conduction disturbances in the anaesthetized rat. Cardiovasc Drug Ther 5, 489–494 (1991). https://doi.org/10.1007/BF03029774
Issue Date:
DOI: https://doi.org/10.1007/BF03029774