Summary
The ionic mechanism of action of a spin-labeled local anesthetic (SLA), 2-[N-methyl-N-(2,2,6,6-tetramethylpiperidinooxyl)]-ethyl 4-ethoxylbenzoate, was studied by means of voltage clamp technique with squid giant axons in comparison with the parent compound without spin label moiety, 2-(N,N-dimethyl)ethyl 4-ethoxylbenzoate (GS-01). Like other local anesthetics, they suppressed both sodium and potassium conductance increases. However, three remarkable differences have been noted between SLA and GS-01: (1) SLA is more effective than GS-01 in suppressing the sodium and potassium conductance increases; (2) SLA induces a potassium inactivation, whereas GS-01 is lacking this ability; (3) SLA has no effect on the time to peak sodium current, whereas GS-01 prolongs it. GS-01 resembles procaine with respect to (2) and (3) above. SLA will become a useful probe for the study of the molecular mechanism of local anesthetic action and of ionic channel function.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Armstrong, C.M. 1969. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons.J. Gen. Physiol. 54: 553
Armstrong, C.M. 1971. Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons.J. Gen. Physiol. 58: 413
Blaustein, M.P. 1968. Action of certain tropine esters on voltage-clamped lobster axon.J. Gen. Physiol. 51: 309
Blaustein, M.P., Goldman, D.E. 1966. Competitive action of calcium and procaine on lobster axon. A study of mechanism of action of certain local anesthetics.J. Gen. Physiol. 49: 1049
Frazier, D.T., Narahashi, T., Yamada, M. 1970. The site of action and active form of local anesthetics. II. Experiments with quaternary compounds.J. Pharmacol. Exp. Ther. 171: 45
Gargiulo, R.J., Giotta, G.J., Wang, H.H. 1973. Spin labeled analogs of local anesthetics.J. Med. Chem. 16: 707
Giotta, G.J., Gargiulo, R.J., Wang, H.H. 1973. Binding of spin-labeled local anesthetics to lobster nerves.J. Membrane Biol. 13: 233
Jost, P., Waggoner, A., Griffith, O.H. 1971. Spin-labeling and membrane structure.In: Structure and Function of Biological Membranes. L. Rothfield, editor. p. 83. Academic Press Inc., New York
McConnell, H.M., McFarland, B.G. 1970. Physics and chemistry of spin labels.Quart. Rev. Biophys. 3: 91
McConnell, H.M., Wright, K.L., McFarland, B.G. 1972. The fraction of the lipid in a biological membrane that is in a fluid state: A spin label assay.Biochem. Biophys. Res. Commun. 47: 273
Narahashi, T., Anderson, N.C. 1967. Mechanism of excitation block by the insecticide allethrin applied externally and internally to squid giant axons.Toxicol. Appl. Pharmacol. 10: 529
Narahashi, T., Frazier, D.T. 1971. Site of action and active form of local anesthetics.In: Neurosciences Research. S. Ehrenpreis and O.C. Solnitzky, editors. Vol. 4, p. 65. Academic Press, New York and London
Narahashi, T., Frazier, D.T. 1975. Site of action and active form of procaine in squid giant axons.J. Pharmacol. Exp. Ther. 194: 506
Narahashi, T., Frazier, D.T., Moore, J.W. 1972. Comparison of tertiary and quaternary amine local anesthetics in their ability to depress membrane ionic conductances.J. Neurobiol. 3: 267
Narahashi, T., Frazier, D.T., Yamada, M. 1970. The site of action and active form of local anesthetics. I. Theory and pH experiments with tertiary compounds.J. Pharmacol. Exp. Ther. 171: 32
Narahashi, T., Moore, J.W., Poston, R.N. 1969. Anesthetic blocking of nerve membrane conductanes by internal and external application.J. Neurobiol. 1: 3
Ohta, M., Narahashi, T. 1973. Sparteine interaction with nerve membrane potassium conductance.J. Pharmacol. Exp. Ther. 187: 47
Ohta, M., Narahashi, T., Keeler, R.F. 1973. Effects of veratrum alkaloids on membrane potential and conductance of squid and crayfish axons.J. Pharmacol. Exp. Ther. 184: 143
Rosen, G.M. 1974. Use of sodium cyanoborohydride in the preparation of biologically active nitroxides.J. Med. Chem. 7: 358
Rosen, G.M., Ehrenpreis, S. 1972. Physical and pharmacological properties of a series of ultra-long-acting local anesthetics and neuromuscular blocking agents.Trans. N.Y. Acad. Sci. 34: 255
Shanes, A.M., Freygang, W.H., Grundfest, H., Amatniek, E. 1959. Anesthetic and calcium action in the voltage clamped squid giant axon.J. Gen. Physiol. 43: 793
Shapiro, B.I., Wang, C.M., Narahashi, T. 1974. Effects of strychnine on ionic conductances of squid axon membrane.J. Pharmacol. Exp. Ther. 188: 66
Strichartz, G.R. 1973. The inhibition of sodium current in myelinated nerve by quaternary derivatives of lidocaine.J. Gen. Physiol. 62: 37
Taylor, R.E. 1959. Effects of procaine on electrical properties of squid axon membrane.Am. J. Physiol. 196: 1071
Wang, C.M., Narahashi, T., Scuba, M. 1972. Mechanism of negative temperature coefficient of nerve blocking action of allethrin.J. Pharmacol. Exp. Ther. 182: 442
Wu, C.H. 1973. Mode of action of trihexyphenidyl on squid axon membranes.Fed. Proc. 32(3): 222
Wu, C.H., Narahashi, T. 1973. Mechanism of action of propranolol on squid axon membranes.J. Pharmacol. Exp. Ther. 184: 155
Yeh, J.Z., Narahashi, T. 1974a. Non-cholinergic mechanism of action of cholinergic drugs on squid axon membranes.J. Pharmacol. Exp. Ther. 189: 697
Yeh, J.Z., Narahashi, T. 1974b. Effects of lobeline on ionic conductances of squid axon membranes.Fed. Proc. 33(3): 272
Yeh, J.Z., Narahashi, T. 1974c. Mechanism of action of quinidine on ionic conductances of squid axon membranes.Pharmacologist 16(2): 202
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yeh, J.Z., Takeno, K., Rosen, G.M. et al. Ionic mechanism of action of a spin-labeled local anesthetic on squid axon membranes. J. Membrain Biol. 25, 237–247 (1975). https://doi.org/10.1007/BF01868577
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01868577