Effects of ropivacaine on a potassium channel (hKv1.5) cloned from human ventricle

Abstract

Background: Ropivacaine, a new amide local anesthetic agent chemically related to bupivacaine, is able to induce early after depolarizations in isolated cardiac preparations. The underlying mechanism by which vopivacaine induces this effect has not been explored, but it is likely to involve K+ channel block. Methods: Cloned human cardiac K+ channels (hKvl.5) were stably transfected in Ltk cells, and the effects of ropivacaine on the expressed hKvl.5 currents were assessed using the whole-cell configuration of the patch-clamp technique. Results: Ropivacaine (100 μM) did not modify the initial activation time course of the current, but induced a fast subsequent decline to a lower steady-state current level with a time constant of 12.2 ± 0.6 ms. Ropivacaine inhibited hKvl.5 with an apparent Kp of 80 ± 4 μM. Block displayed an intrinsic voltage-dependence, consistent with an electrical distance for the binding site of 0.153 ± 0.007 (n = 6) (from the cytoplasmic side). Ropivacaine reduced the tail current amplitude recorded at -40 mV, and slowed the deactivation time course, resulting in a 'crossover' phenomenon when control and ropivacaine tail currents were superimposed. Conclusions: These results indicate that: (1) ropivacaine is an open channel blocker of hKvl.5; (2) binding occurs in the internal mouth of the ion pore; and (3) unbinding is required before the channel can close. These effects explain the ropivacaine availability of induction early after depolarizations and could be clinically relevant.