title: Blockade of lysophosphatidylcholine-modified cardiac Na channels by a lidocaine derivative QX-222.
abstract: Single Na channels from rat and rabbit ventricular cells were studied with use of the excised inside-out patch-clamp technique. To investigate local anesthetic interactions with Na channels modified by the ischemic metabolite lysophosphatidylcholine (LPC), the quaternary ammonium lidocaine derivative QX-222 [2-(trimethylamino)-N-(2,6-dimethylphenyl)acetamide] was applied to the cytoplasmic side of patches from untreated cells and from those treated with LPC for approximately 1 h. Single-channel amplitudes and kinetics for unmodified channels were similar to those reported previously for cardiac cells with a single-component, mean-channel open time. LPC-modified channels showed prolonged open channel bursting with a two-component, mean open time, suggesting two open states. Conductance sublevels to the 60-70% level of the main conductance were found in both unmodified and LPC-modified channels and also with and without QX-222 present. QX-222 reversibly shortened the open time of the unmodified channel and for both open times of the LPC-modified channel without decreasing single-channel amplitude. Calculated association rates for QX-222 with the channel were found to be greater for the open states of the modified channel than those for the unmodified channel. Thus the lidocaine analogue QX-222 interacts with and blocks the open state of both unmodified and LPC-modified, cardiac Na channels. The blocking effect on LPC-modified channels would be predicted to be greater both because of the longer dwell time in the high-affinity open states for modified channels and also because of an intrinsically greater association rate in the modified channels.
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Research, Henry Ford Heart and Vascular Institute, Detroit, Michigan 48202-2689, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Undrovinas
authors.forename: J C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
chemical_list: D008244:Lysophosphatidylcholines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C006072:QX-222; D008012:Lidocaine