Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K+ channel

Chromanol 293B and dofetilide are inhibitors of IK_s and IK_r, i.e., of the slow and the rapid component of the delayed rectifier potassium current. The specificity of these drugs was tested by investigating their effects on the delayed rectifier potassium current in vascular smooth muscle, regulating the tone of blood vessels. Using depolarizing step protocols with asymmetrical potassium concentrations (135/4.5 mM K⁺ in pipette/bath), voltage-dependent K⁺ currents (IK_v) of enzymatically dispersed guinea pig portal vein cells were studied in the whole-cell patch-clamp technique. Peak currents were obtained within 20 ms (at +50 mV) after activation. During a 10 s test pulse to +60 mV, these currents exhibited a relatively fast inactivation with time constants of 384 ms (τ_fast) and 4505 ms (τ_slow). Dofetilide was totally ineffective in modulating currents; in contrast, after application of chromanol 293B, a steady-state block of IK_v developed within 135 s. The block was concentration-dependent with an IC₅₀ of 7.4 μM. Chromanol did not produce any shift in the normalized steady-state activation and inactivation curves and the recovery from inactivation was not significantly changed. Chromanol 293B similarly inhibited delayed rectifier K⁺ channels whether in their closed or open state, and produced an “apparent” acceleration of inactivation, i.e., the drug accelerated the faster time constant of inactivation during a 10 s test pulse from 384 ms (control) to 149 ms (100 μM chromanol). In recent studies, chromanol was described as a specific blocker of slowly activating delayed rectifier potassium channels (IK_s) in cardiomyocytes. The results of this study, however, extend the inhibitory spectrum of the drug and demonstrate block of closed and open state delayed rectifier K⁺ currents in portal vein vascular smooth muscle. Such a block could possibly contribute to the generation of portal hypertension. Received: 2 March 2001, Returned for 1. revision: 22 March 2001, 1. Revision received: 9 May 2001, Returned for 2. revision: 16 May 2001, 2. Revision received: 3 August 2001, Accepted: 20 August 2001