TY - JOUR T1 - Mechanism of Sodium Channel Block by Venlafaxine in Guinea Pig Ventricular Myocytes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 280 LP - 284 VL - 291 IS - 1 AU - Majed Khalifa AU - Pascal Daleau AU - and Jacques Turgeon Y1 - 1999/10/01 UR - http://jpet.aspetjournals.org/content/291/1/280.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -