Bupivacaine inhibits the transient outward K+ current but not the inward rectifier in rat ventricular myocytes.

The effects of bupivacaine on K+ currents in isolated rat ventricular myocytes were examined using the whole-cell patch-clamp technique. Bupivacaine at concentrations greater than 3 microM produced both a reduction in the peak current amplitude and a marked increase in the rate of inactivation of the transient outward current (Ito). Examination of its time course showed that there was no inhibition before the beginning of a depolarizing pulse. However, upon continuous depolarization (i.e., during channel opening) inhibition of Ito developed in an exponential manner, the rate and magnitude of which were dependent on bupivacaine concentration. The IC50 for inhibition of Ito was 22 microM. Bupivacaine had no effect on the voltage-dependence of steady-state inactivation or the rate of recovery from inactivation. The (+)- and (-)-stereoisomers of bupivacaine were equipotent indicating that there is no stereoselectivity to the inhibition of Ito. Increasing the hydrophobicity of the tertiary amine on bupivacaine greatly enhanced its potency. Thus, octylacaine (1-octyl-2',6'-pipecoloxylidide) (C8-N) was 6 times more potent than bupivacaine (C4-N) and 200 times more potent than mepivacaine (C1-N). In contrast to their effects on Ito, bupivacaine (1 mM) and octylacaine (100 microM) failed to produce any block of the inward rectifier K+ current. However, mepivacaine (3 mM) reduced inward rectifier K+ current reversibly by approximately 50%. These results suggest that inhibition of Ito may contribute to bupivacaine-induced cardiotoxicity.