Inhibition of voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells by the class Ic antiarrhythmic agent lorcainide

Abstract

Voltage-dependent K+ (Kv) channels play the role of returning the membrane potential to the resting state, thereby maintaining the vascular tone. Here, we used native smooth-muscle cells from rabbit coronary arteries to investigate the inhibitory effect of lorcainide, a class Ic antiarrhythmic agent, on Kv channels. Lorcainide inhibited Kv channels in a concentration-dependent manner with an IC50 of 4.46 ± 0.15 μM and a Hill coefficient of 0.95 ± 0.01. Although application of lorcainide did not change the activation curve, it shifted the inactivation curve toward a more negative potential, implying that lorcainide inhibits Kv channels by changing the channels’ voltage sensors. The recovery time constant from channel inactivation increased in the presence of lorcainide. Furthermore, application of train steps (of 1 or 2 Hz) in the presence of lorcainide progressively augmented the inhibition of Kv currents, implying that lorcainide-induced inhibition of Kv channels is use (state)-dependent. Pretreatment with Kv1.5 or Kv2.1/2.2 inhibitors effectively reduced the amplitude of the Kv current but did not affect the inhibitory effect of lorcainide. Based on these results, we conclude that lorcainide inhibits vascular Kv channels in a concentration and use (state)-dependent manner by changing their inactivation gating properties. Considering the clinical efficacy of lorcainide, and the pathophysiological significance of vascular Kv channels, our findings should be considered when prescribing lorcainide to patients with arrhythmia and vascular disease.