Ketanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes

Ketanserin (KT), an antihypertensive agent, has been shown to prolong action potential duration (APD) and QT interval and to induce torsade de pointes in some patients. We previously suggested that the prolongation of APD could be due to KT inhibition of the fast component of the delayed rectifier current (IKr) in guinea-pig myocytes. However, in other tissue such as human atrium, Purkinje fibers, epicardial cells, and rat ventricular myocytes, the transient outward potassium current (Ito) is one of the major repolarizing currents. We investigated the possibility that KT could also increase APD by blocking Ito. Action potentials and membrane currents were recorded from rat ventricular myocytes known to have a large Ito by using whole-cell patch-clamp techniques. We found that KT (50 mumol/L) significantly prolonged APD at 50% repolarization by 218% (P < .05) and APD at 90% repolarization by 256% (P < .05) with no significant effect on other action potential parameters. Time-dependent Ito and sustained current (ISus) were measured in the presence of 400 nmol/L nisoldipine during depolarizing pulses to 40 mV from a holding potential of -100 mV every 10 seconds. KT resulted in a concentration- and time-dependent inhibition of charge area of Ito evaluated by integration with an EC50 of 8.3 mumol/L. The inhibitory effect of KT (10 mumol/L) was seen at voltages from 0 to 80 mV without any shift of the current-voltage relation of peak Ito. KT did not significantly change activation, inactivation, and reactivating curves of Ito. Kinetic analysis of Ito showed a biexponential fit of inactivation in 80.5% of total tracings studied at voltages between -30 and 80 mV (n = 149, R = .99 +/- .01). The inhibitory effect of KT was more prominent on charge areas of the slow component (Qs) than the fast component (Qf) of Ito (Qf = 33.2 +/- 6.2 s.pA and Qs = 235.5 +/- 7.4 s.pA for the control condition; 12.4 +/- 4.3 and 59.6 +/- 17 s.pA for KT at 40 mV; n = 4). The binding association (k) and dissociation (l) constants at 40 mV were 9.0 +/- 0.9x10(6) M-1.s-1 and 86.6 +/- 0.3 s-1, respectively. KT also blocked ISus in a dose-dependent manner with an EC50 of 11.2 mumol/L and had no significant effect on both the inward rectifier potassium current and the L-type calcium current.(ABSTRACT TRUNCATED AT 400 WORDS)