Tags

Type your tag names separated by a space and hit enter

Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents.
Cardiovasc Res. 1999 Dec; 44(3):568-78.CR

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.

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.

Authors+Show Affiliations

Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, University of Leuven, Belgium.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10690289

Citation

Ulens, C, et al. "Norpropoxyphene-induced Cardiotoxicity Is Associated With Changes in Ion-selectivity and Gating of HERG Currents." Cardiovascular Research, vol. 44, no. 3, 1999, pp. 568-78.
Ulens C, Daenens P, Tytgat J. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res. 1999;44(3):568-78.
Ulens, C., Daenens, P., & Tytgat, J. (1999). Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovascular Research, 44(3), 568-78.
Ulens C, Daenens P, Tytgat J. Norpropoxyphene-induced Cardiotoxicity Is Associated With Changes in Ion-selectivity and Gating of HERG Currents. Cardiovasc Res. 1999;44(3):568-78. PubMed PMID: 10690289.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. AU - Ulens,C, AU - Daenens,P, AU - Tytgat,J, PY - 2000/2/26/pubmed PY - 2000/3/18/medline PY - 2000/2/26/entrez SP - 568 EP - 78 JF - Cardiovascular research JO - Cardiovasc Res VL - 44 IS - 3 N2 - 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. 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. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/10690289/Norpropoxyphene_induced_cardiotoxicity_is_associated_with_changes_in_ion_selectivity_and_gating_of_HERG_currents_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/s0008-6363(99)00258-8 DB - PRIME DP - Unbound Medicine ER -