The opioid methadone induces a local anaesthetic-like inhibition of the cardiac Na super(+) channel, Na sub(v)1.5

Background and Purpose Treatment with methadone is associated with severe cardiac arrhythmias, a side effect that seems to result from an inhibition of cardiac hERG K super(+) channels. However, several other opioids are inhibitors of voltage-gated Na super(+) channels. Considering the common assumption that an inhibition of the cardiac Na super(+) channel Na sub(v)1.5, is the primary mechanism for local anaesthetic (LA)-induced cardiotoxicity, we hypothesized that methadone has LA-like properties leading to a modulation of Na sub(v)1.5 channels. Experimental Approach The whole-cell patch clamp technique was applied to investigate the effects of methadone on wild-type and mutant human Na sub(v)1.5 channels expressed in HEK293 cells. A homology model of human Na sub(v)1.5 channels was used to perform automated ligand-docking studies. Key Results Methadone inhibited Na sub(v)1.5 channels in a state-dependent manner, that is, tonic block was stronger with inactivated channels than with resting channels and a use-dependent block at 10Hz. Methadone induced a concentration-dependent shift of the voltage dependency of both fast and slow inactivation towards more hyperpolarized potentials, and impaired recovery from fast and slow inactivation. The LA-insensitive mutants N406K and F1760A exhibited reduced tonic and use-dependent block by methadone, and docking predictions positioned methadone in a cavity that was delimited by the residue F1760. Dextromethadone and levomethadone induced discrete stereo-selective effects on Na sub(v)1.5 channels. Conclusions and Implications Methadone interacted with the LA-binding site to inhibit Na sub(v)1.5 channels. Our data suggest that these channels are a hitherto unrecognized molecular component contributing to cardiac arrhythmias induced by methadone.