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 (I_Na) 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 I_Na 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 (τ_inac= 0.652 ± 0.020 ms, under control conditions; τ_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 (τ_re= 58.7 ± 1.6 ms, under control conditions; τ_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 I_Na following its binding to the resting state of the channel. Thus, the characteristics of block of I_Na by venlafaxine are different from those usually observed with most tricyclic antidepressants or conventional class I antiarrhythmic drugs.