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*Compound via MeSH
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*CYCLOHEXANOL
*VENLAFAXINE HYDROCHLORIDE

Vol. 291, Issue 1, 280-284, October 1999

Mechanism of Sodium Channel Block by Venlafaxine in Guinea Pig Ventricular Myocytes1

Majed Khalifa2 , Pascal Daleau3 and and Jacques Turgeon4

Quebec Heart Institute, Laval Hospital, Faculty of Pharmacy, Laval University (M.K., J.T.); and Faculty of Medicine, Laval University (P.D., J.T.), Sainte-Foy, Canada

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 (tau inac= 0.652 ± 0.020 ms, under control conditions; tau inac= 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 (tau re= 58.7 ± 1.6 ms, under control conditions; tau re= 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.

0022-3565/99/2911-0280$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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