Interaction of lidocaine with the cardiac sodium channel: effects of low extracellular pH are consistent with an external blocking site.
Brief extracellular application of millimolar concentrations of lidocaine affected sodium currents recorded in isolated rat ventricular myocytes in two ways: 1) a reduction of the maximum current consistent with a channel blocking action, and 2) a negative shift in the voltage dependence of inactivation consistent with an interaction with the inactivated state of the channel. Both effects occurred very rapidly (<< 1 s). Decreasing extracellular pH to 6.4 increased the potency for channel block (EC50 1.8 +/- 0.2 mM at pH 7.4 and 0.8 +/- 0.1 mM at pH 6.5) and decreased the potency to shift inactivation (V(1/2) shift -42 mV by 1 mM lidocaine at pH 7.4 and -12.6 mV at pH 6.5). Channel block was slightly less at +90 mV compared to -40 mV at either pH (not statistically significant). The increase in potency for block at decreased extracellular pH, while intracellular pH is buffered, and the lack of voltage dependence of block, suggest that the charged form of lidocaine can block the channel by interacting with a site near the extracellular mouth, although alternative explanations are discussed.
Tan
J H
JH
Department of Physiology, University of Adelaide, SA, Australia.
Saint
D A
DA
D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology
D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008012:Lidocaine