title: Inhibition of HERG channels by the local anaesthetic articaine.
abstract: OBJECTIVE
  Articaine is an amide local anaesthetic widely used in dentistry. Human ether-a-go-go-related gene (HERG) potassium channels constitute potential targets involved in cardiotoxic side-effects of various pharmacological agents including amide local anaesthetics. The aim of this study was to determine the sensitivity of HERG channels to the inhibitory action of articaine and to further evaluate the effect of the mutations Y652A and F656A in the putative drug-binding region of HERG on the sensitivity for articaine.
  
  
  METHODS
  We examined the inhibition of wild-type and mutant HERG channels, transiently expressed in Chinese hamster ovary cells by articaine. Whole cell patch-clamp recordings were performed at room temperature.
  
  
  RESULTS
  Inhibition of HERG wild-type and HERG Y652A channels by articaine was concentration dependent and reversible. The concentration-response data were described by Hill functions (wild type: IC50 = 224 +/- 6 micromol L-1, Hill coefficient h = 1.17 +/- 0.03, n = 23; Y652A: IC50 = 360 +/- 48 micromol L-1, h = 0.93 +/- 0.08, n = 26). The mutation Y5652A decreased the sensitivity by factor 1.6. The mutation F656A decreased inhibition of inward tail currents by 300 micromol L-1 articaine in 100 mmol extracellular K+ 3-fold.
  
  
  CONCLUSIONS
  Our results indicate that the local anaesthetic articaine does not inhibit HERG channels at clinically relevant concentrations. Articaine may therefore constitute a safer alternative for local and regional anaesthesia. The aromatic amino acid F656 rather than Y652 in the S6 region might play a role in interaction of the drug with the channel.
authors.affiliation: University Medical Center Hamburg-Eppendorf, Department of Anaesthesiology, Martinistrasse 52, 20251 Hamburg, Germany.
authors.forename: C C
authors.initials: CC
authors.lastname: Siebrands
authors.forename: P
authors.initials: P
authors.lastname: Friederich
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002355:Carticaine / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D009154:Mutation; D018408:Patch-Clamp Techniques / Q000379:methods; D010649:Phenylalanine / Q000235:genetics / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D014162:Transfection; D014443:Tyrosine / Q000235:genetics / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D014443:Tyrosine; D010649:Phenylalanine; D002355:Carticaine