Differential effects of bupivacaine on cardiac K channels: role of channel inactivation and subunit composition in drug-channel interaction.

INTRODUCTION: We examined the effects of a nonspecific ion channel blocker, bupivacaine, on K channels encoded by hERG, rKv1.4, rKv4.3, and hKvLQT1 along with hIsK. Their native counterparts in the heart are important for the function of I(Kr), I(to) and I(Ks) and, thus, play an important role in repolarization. METHODS AND
RESULTS: To elucidate the mechanisms and sites of bupivacaine's actions, we correlated the voltage and time dependencies of drug effects with those of channel gating. We also studied the effects of altering the C-type (hERG) or N-type (rKv1.4) inactivation process or the subunit composition (hKvLQT1 with or without hIsK) on bupivacaine's actions. The results suggest that, except for hKvLQT1 co-expressed with hIsK, bupivacaine binding occurred at depolarized voltages coinciding with channel activation. With hKvLQT1 co-expressed with hIsK, bupivacaine bound preferentially at negative voltages when channels were in the closed state, and unbound at depolarized voltages when channels opened. The C-type inactivation of hERG enhanced, whereas the N-type inactivation of rKv1.4 hindered, bupivacaine's effects.
CONCLUSION: We propose that bupivacaine's actions on these K channels can be described as a nonspecific pore blockade in the inner mouth region. However, the apparent binding affinity and voltage dependence of binding can be differentially influenced by the inactivation processes occurring at two ends of the pore (C-type inactivation at the outer end and N-type inactivation at the inner end), or by the interaction between hIsK and hKvLQT1 subunits.