title: Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study.
abstract: The interaction of antiarrhythmic drugs with ion channels is often described within the context of the modulated receptor hypothesis, which explains the action of drugs by proposing that the binding site has a variable affinity for drugs, depending upon whether the channel is closed, open, or inactivated. Lack of direct evidence for altered gating of cardiac Na channels allowed for the suggestion of an alternative model for drug interaction with cardiac channels, which postulated a fixed affinity receptor with access limited by the conformation of the channel (guarded receptor hypothesis). We report measurement of the gating currents of Na channels in canine cardiac Purkinje cells in the absence and presence of QX-222, a quaternary derivative of lidocaine, applied intracellularly, and benzocaine, a neutral local anesthetic. These data demonstrate that the cardiac Na channel behaves as a modulated rather than a guarded receptor in that drug-bound channels gate with altered kinetics. In addition, the results suggest a new interpretation of the modulated receptor hypothesis whereby drug occupancy reduces the overall voltage-dependence of gating, preventing full movement of the voltage sensor.
authors.affiliation: Department of Medicine, University of Chicago, Illinois 60637.
authors.forename: D A
authors.initials: DA
authors.lastname: Hanck
authors.forename: J C
authors.initials: JC
authors.lastname: Makielski
authors.forename: M F
authors.initials: MF
authors.lastname: Sheets
mesh_terms: D000818:Animals; D001566:Benzocaine / Q000494:pharmacology; D004285:Dogs; D004594:Electrophysiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism; D012530:Saxitoxin / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D015222:Sodium Channels; C006072:QX-222; D012530:Saxitoxin; D008012:Lidocaine; D001566:Benzocaine