|
|
|
|
|
|
|
||
The Journal of General Physiology, Vol 100, 1003-1020, Copyright © 1992 by The Rockefeller University Press
ARTICLES |
GK Wang and SY Wang
Department of Anesthesia Research Laboratories, Harvard Medical School, Boston, Massachusetts 02115.
The inhibitory effects of local anesthetics (LAs) of cocaine and bupivacaine optical isomers on Na+ currents were studied in clonal GH3 cells under whole-cell patch clamp conditions. At holding potential of - 100 mV, all four isomers inhibited peak Na+ currents when the cell was stimulated infrequently. The dose-response curves of this tonic block of peak Na+ currents by (-)/(+) cocaine and (-)/(+) bupivacaine were well fitted by the Langmuir isotherm, suggesting that one LA isomer blocked one Na+ channel. Each pair of isomers showed no greater than a twofold difference in stereoselectivity toward Na+ channels. Additional block of Na+ currents occurred when the cell was stimulated at 2 Hz. This use-dependent block was also observed in all four isomers, which again displayed little stereoselectivity. The voltage dependence of the use-dependent block produced by cocaine isomers did not overlap with the activation of Na+ channels but did overlap with the steady-state inactivation (h infinity), indicating that cocaine can bind directly to the inactivated state of Na+ channels before channel opening. In comparison, the peak batrachotoxin (BTX)-modified Na+ currents were little inhibited by cocaine and bupivacaine isomers. However, the maintained BTX-modified Na+ currents were highly sensitive toward the (- ) form of cocaine and bupivacaine isomers during a prolonged depolarization. As a result, a profound time-dependent block of BTX- modified Na+ currents was evident in the presence of these LA isomers. The estimated values of the equilibrium dissociation constant (KD in micromolar) at +50 mV were 35.8, 661, 7.0, and 222 for (-)/(+) cocaine and (-)/(+) bupivacaine, respectively. Although chloramine-T (CT) also modified the fast inactivation of Na+ channels and gave rise to a maintained Na+ current during a prolonged depolarization, LA isomers showed no greater stereoselectivity in blocking this maintained current than in blocking the normal transient Na+ current. We conclude that (a) cocaine and bupivacaine isomers exhibit only weak stereoselectivity toward the LA receptor in normal and CT-treated Na+ channels, (b) BTX drastically modifies the configuration of the LA binding site so that the LA stereoselectivity of the open Na+ channels is altered by an order of magnitude, and (c) the (-) forms of cocaine and bupivacaine interact strongly with the open state of BTX-modified Na+ channels but only weakly, if at all, with the closed state. The last finding may explain why most LA drugs were reported to be less effective toward BTX- modified Na+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. N. Wright Irreversible Block of Human Heart (hH1) Sodium Channels by the Plant Alkaloid Lappaconitine Mol. Pharmacol., February 1, 2001; 59(2): 183 - 192. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. E. Brau, P. Branitzki, A. Olschewski, W. Vogel, and G. Hempelmann Block of Neuronal Tetrodotoxin-Resistant Na+ Currents by Stereoisomers of Piperidine Local Anesthetics Anesth. Analg., December 1, 2000; 91(6): 1499 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Nau, S.-Y. Wang, G. R. Strichartz, and G. K. Wang Point Mutations at N434 in D1-S6 of {micro}1 Na+ Channels Modulate Binding Affinity and Stereoselectivity of Local Anesthetic Enantiomers Mol. Pharmacol., August 1, 1999; 56(2): 404 - 413. [Abstract] [Full Text]
|
|
|
|
 |
|
 X.-F. Zhang, X.-T. Hu, and F. J. White Whole-Cell Plasticity in Cocaine Withdrawal: Reduced Sodium Currents in Nucleus Accumbens Neurons J. Neurosci., January 1, 1998; 18(1): 488 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
