Carvedilol blocks the cloned cardiac Kv1.5 channels in a β-adrenergic receptor-independent manner.

Carvedilol, a non-selective β-adrenergic blocker, is widely used for the treatment of angina pectoris and hypertension. We examined the action of carvedilol on cloned Kv1.5 expressed in CHO cells, using the whole-cell patch clamp technique. Carvedilol reduced the peak amplitude of Kv1.5 and accelerated the inactivation rate in a concentration-dependent manner with an IC50 of 2.56 μM. Using a first-order kinetics analysis, we calculated k(+1) = 19.68 μM(-1)s(-1) for the association rate constant, and k(-1) = 44.89 s(-1) for the dissociation rate constant. The apparent K(D) (k(-1)/k(+1)) was 2.28 μM, which is similar to the IC50 value. Other β-adrenergic blockers (alprenolol, oxprenolol and carteolol) had little or no effect on Kv1.5 currents. Carvedilol slowed the deactivation time course, resulting in a tail crossover phenomenon. Carvedilol-induced block was voltage-dependent in the voltage range for channel activation, but voltage-independent in the voltage range for full activation. The voltage dependences for both steady-state activation and inactivation were unchanged by carvedilol. Carvedilol affected Kv1.5 in a use-dependent manner. When stimulation frequencies were increased to quantify a use-dependent block, however, the block by carvedilol was slightly increased with IC50 values of 2.56 μM at 0.1 Hz, 2.38 μM at 1 Hz and 2.03 μM at 2 Hz. Carvedilol also slowed the time course of recovery from inactivation of Kv1.5. These results indicate that carvedilol blocks Kv1.5 in a reversible, concentration-, voltage-, time-, and use-dependent manner, but only at concentrations slightly higher than therapeutic plasma concentrations in humans. These effects are probably relevant to an understanding of the ionic mechanism underlying the antiarrhythmic property of carvedilol.