Molecular Pharmacology, Vol 15, 559-580, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Voltage-Dependent and Voltage-Independent Blockade of Acetylcholine Receptors by Local Anesthetics in Electrophorus Electroplaques

¹ Division of Biology, California Institute of Technology, Pasadena, California 91125

This study employs voltage-clamp techniques to survey the action of several local anesthetics on the nicotinic acetylcholine receptor of Electrophorus electroplaques. These drugs partially block the steady-state activation of receptors during bath application of agonist. Certain anesthetics alter the kinetics of voltage-jump relaxations during such application and alter the waveform of neurally-evoked postsynaptic currents. Procaine, tetracaine, and QX-222 act similarly at concentrations of 25-50 µM. When the agonist is carbamylcholine, acetylcholine, or suberyldicholine, the steady-state blockade depends on voltage, with a greater fractional inhibition of agonist-induced currents at more negative membrane potential. Alterations of voltage-jump relaxations are most noticeable with suberyldicholine. Under some conditions, at least two exponential relaxation components are seen; one component is much faster and another much slower than the single component seen in the absence of procaine. In contrast, the percentage blockade by dibucaine and chlorpromazine is about the same at all membrane potentials, and these compounds have little influence on suberyldicholine relaxation kinetics. The uncharged local anesthetic, benzocaine, at a concentration ten times that of the other local anesthetics employed (250 µM), only slightly decreases suberyldicholine-induced currents and has little effect on the relaxation rates. Thus, voltage affects the relative potencies of local anesthetics in blocking agonist-induced currents. At low negative membrane potentials, the potency of the anesthetics parallels their lipid solubiity. At high negative membrane potentials this correlation disappears. The results suggest a dual mode of action for the local anesthetics: an indirect interaction with the lipids surrounding the receptor, and a direct, voltage-dependent interaction with the receptor-channel complex.

Note:
ACKNOWLEDGMENTS This work was supported by National Institutes of Health Grant NS-11756; by a Grant-in-Aid from the Muscular Dystrophy Association, Inc.; by a Muscular Dystrophy Postdoctoral Fellowship to D.D.K.; and by an Alfred P. Sloan Fellowship and N.I.H. Career Development Award NS272 to H.A.L.

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