Norporpoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents

Objective: Norpropoxyphene (NP) is a major metabolite of propoxyphene (P), a relatively weak mu-opioid receptor agonist. Toxic blood concentrations ranging from 3 to 180 mu mol/l have been reported and the accumulation of NP in cardiac tissue leads to naloxone-insensitive cardiotoxicity. Since several lines of evidence suggest that not only block of I-Na but also I-K block may contribute to the non-opioid cardiotoxic effects of P and NP, we investigated the effects of P and NP on HERG channels. HERG presumably encodes I-Kr, the rapidly-activating delayed rectifier K+ current, which is known to have an important role in initiating repolarization of action potentials in cardiac myocytes. Methods: Using the 2-microelectrode voltage clamp technique we investigated the interaction of P and NP with HERG channels, expressed in Xenopus oocytes. Results: Our experiments show that low drug concentrations (5 mu mol/l) facilitate HERO currents, while higher drug concentrations block HERG currents (IC50-values of approx. 40 mu mol/l) and dramatically shift the reversal potential to a more positive value because of a 30-fold increased Na+-permeability. P and NP also alter gating of HERG channels by slowing down channel activation and accelerating channel deactivation kinetics. The mutant S631C nullifies the effect of P and NP on the channel's K+-selectivity. Conclusion: P and NP show a complex and unique drug-channel interaction, which includes altering ion-selectivity and gating. Site-directed mutagenesis suggests that an interaction with S631 contributes to the drug-induced disruption of K+-selectivity. No specific role of the minK subunit in the HERG block mechanism could be determined. (C) 1999 Elsevier Science B.V. All rights reserved.