Blockade of lysophosphatidylcholine-modified cardiac na channels by
a permanently charged lidocaine derivative qx-222.
Undrovinas, Albertas I., and Jonathan C. Makielski.
Henry Ford Heart and Vascular Institute, Division of Cardiovascular
Medicine, Cardiovascular Research, Detroit, MI 48202-2689, The
University of Wisconsin, Department of Medicine, Section of
Cardiology, Madison, WI 53792
APStracts 3:0074H, 1996.
Single Na channels from rat and rabbit ventricular cells were studied
using 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 one hour. 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 sub
-levels 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.
Received 18 September 1995; accepted in final form 31 January
1996.
APS Manuscript Number H882-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 24 February 96