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 Ca(2+) and K(+) channel blockers. Results obtained 
demonstrated that venlafaxine inhibits peak I(Na) in a concentration-dependent 
manner with an estimated IC(50) 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 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.