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Research ArticleArticle

Mechanism of Sodium Channel Block by Venlafaxine in Guinea Pig Ventricular Myocytes

Majed Khalifa, Pascal Daleau and and Jacques Turgeon
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 280-284;
Majed Khalifa
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Pascal Daleau
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and Jacques Turgeon
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Abstract

Venlafaxine is a newly introduced antidepressant agent. The drug causes selective inhibition of neuronal reuptake of serotonine and norepinephrine with little effect on other neurotransmitter systems. Cases of seizures, tachycardia, and QRS prolongation have been observed following drug overdose in humans. The clinical manifestations of cardiac toxicity suggest that venlafaxine may exhibit cardiac electrophysiological effects on fast conducting cells. Consequently, studies were undertaken to characterize effects of venlafaxine on the fast inward sodium current (INa) of isolated guinea pig ventricular myocytes. Currents were recorded with the whole-cell configuration of the patch-clamp technique in the presence of Ca2+ and K+ channel blockers. Results obtained demonstrated that venlafaxine inhibits peak INa in a concentration-dependent manner with an estimated IC50 of 8 · 10−6 M. Inhibition was exclusively of a tonic nature and rate-independent. Neither kinetics of inactivation (τinac= 0.652 ± 0.020 ms, under control conditions; τinac= 0.636 ± 0.050, in the presence of 10−5 M venlafaxine; n = 5 cells isolated from five animals) nor kinetics of recovery from inactivation of the sodium channels (τre= 58.7 ± 1.6 ms, under control conditions; τre= 54.4 ± 1.8, in the presence of 10−5 M venlafaxine; n = 10 cells isolated from six animals) were significantly altered by 10−5 M venlafaxine. These observations led us to conclude that venlafaxine blocks INa following its binding to the resting state of the channel. Thus, the characteristics of block of INa by venlafaxine are different from those usually observed with most tricyclic antidepressants or conventional class I antiarrhythmic drugs.

Footnotes

  • Send reprint requests to: Jacques Turgeon, Ph.D., Centre de Recherche, Hôpital Laval, 2725 Chemin Ste-Foy, Sainte-Foy, Quebec, G1V 4G5, PQ, Canada. E-mail: phajtu{at}hermes.ulaval.ca

  • ↵1 This work was supported by a grant from the Medical Research Council of Canada (MT 11876) and by an operating grant from the Heart Stroke Foundation of Canada.

  • ↵2 Recipient of a studentship from the Quebec Heart Institute and the Faculty of Pharmacy, Laval University.

  • ↵3 Recipient of a scholarship (J2) from the Fonds de la Recherche en Santé du Québec.

  • ↵4 Recipient of a scholarship from the Joseph C. Edwards Foundation.

  • Abbreviation:
    INa
    sodium current
    • Received March 15, 1999.
    • Accepted June 15, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Mechanism of Sodium Channel Block by Venlafaxine in Guinea Pig Ventricular Myocytes

Majed Khalifa, Pascal Daleau and and Jacques Turgeon
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 280-284;

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Research ArticleArticle

Mechanism of Sodium Channel Block by Venlafaxine in Guinea Pig Ventricular Myocytes

Majed Khalifa, Pascal Daleau and and Jacques Turgeon
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 280-284;
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