title: Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents.
abstract: 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 mumol/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 INa but also IK 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 IKr, 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 mumol/l) facilitate HERG currents, while higher drug concentrations block HERG currents (IC50-values of approx. 40 mumol/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, University of Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Ulens
authors.forename: P
authors.initials: P
authors.lastname: Daenens
authors.forename: J
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D011431:Dextropropoxyphene / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D017450:Receptors, Opioid, mu / Q000819:agonists*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014981:Xenopus
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D017450:Receptors, Opioid, mu; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C002756:norpropoxyphene; D011431:Dextropropoxyphene