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Methadone is associated with a disproportionate risk of sudden death and ventricular tachyarrhythmia despite only modest inhibition of delayed rectifier K⁺ current (I_Kr)_, the principal mechanism of drug‐associated arrhythmia. Congenital defects of inward rectifier K⁺ current (I_K1) have been linked to increased U‐wave amplitude on ECG and fatal arrhythmia. We hypothesized that methadone may also be a potent inhibitor of I_K1, contributing to delayed repolarization and manifesting on surface ECGs as augmented U‐wave integrals.

Using a whole‐cell voltage clamp, methadone inhibited both recombinant and native I_K1 with a half‐maximal inhibitory concentration IC50) of 1.5 μmol/L, similar to that observed for I_Kr block (half‐maximal inhibitory concentration of 2.9 μmol/L). Methadone modestly increased the action potential duration at 90% repolarization and slowed terminal …