Skip to main content
PMC home page
The Journal of General Physiology logoLink to The Journal of General Physiology
. 1987 Apr 1;89(4):645–667. doi: 10.1085/jgp.89.4.645

Inhibition of sodium currents by local anesthetics in chloramine-T- treated squid axons. The role of channel activation

PMCID: PMC2215916  PMID: 2438374

Abstract

In order to test the requirement of Na channel inactivation for the action of local anesthetics, we investigated the inhibitory effects of quaternary and tertiary amine anesthetics on normally inactivating and noninactivating Na currents in squid axons under voltage clamp. Either the enzymatic mixture pronase, or chloramine-T (CT), a noncleaving, oxidizing reagent, was used to abolish Na channel inactivation. We found that both the local anesthetics QX-314 and etidocaine, when perfused internally at 1 mM, elicited a "tonic" (resting) block of Na currents, a "time-dependent" block that increased during single depolarizations, and a "use-dependent" (phasic) block that accumulated as a result of repetitive depolarizations. All three effects occurred in both control and CT-treated axons. As in previous reports, little time-dependent or phasic block by QX-314 appeared in pronase-treated axons, although tonic block remained. Time-dependent block was greatest and fastest at large depolarizations (Em greater than +60 mV) for both the control and CT-treated axons. The recovery kinetics from phasic block were the same in control and CT-modified axons. The voltage dependence of the steady state phasic block in CT-treated axons differed from that in the controls; an 8-10% reduction of the maximum phasic block and a steepening and shift of the voltage dependence in the hyperpolarizing direction resulted from CT treatment. The results show that these anesthetics can bind rapidly to open Na channels in a voltage-dependent manner, with no requirement for fast inactivation. We propose that the rapid phasic blocking reactions in nerve are consequences primarily of channel activation, mediated by binding of anesthetics to open channels, and that the voltage dependence of phasic block arises directly from that of channel activation.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adelman W. J., Jr, Palti Y. The influence of external potassium on the inactivation of sodium currents in the giant axon of the squid, Loligo pealei. J Gen Physiol. 1969 Jun;53(6):685–703. doi: 10.1085/jgp.53.6.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armstrong C. M., Bezanilla F., Rojas E. Destruction of sodium conductance inactivation in squid axons perfused with pronase. J Gen Physiol. 1973 Oct;62(4):375–391. doi: 10.1085/jgp.62.4.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armstrong C. M. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J Gen Physiol. 1969 Nov;54(5):553–575. doi: 10.1085/jgp.54.5.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bean B. P., Cohen C. J., Tsien R. W. Lidocaine block of cardiac sodium channels. J Gen Physiol. 1983 May;81(5):613–642. doi: 10.1085/jgp.81.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cahalan M. D. Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons. Biophys J. 1978 Aug;23(2):285–311. doi: 10.1016/S0006-3495(78)85449-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chandler W. K., Meves H. Evidence for two types of sodium conductance in axons perfused with sodium fluoride solution. J Physiol. 1970 Dec;211(3):653–678. doi: 10.1113/jphysiol.1970.sp009298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hille B. The pH-dependent rate of action of local anesthetics on the node of Ranvier. J Gen Physiol. 1977 Apr;69(4):475–496. doi: 10.1085/jgp.69.4.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hondeghem L. M., Katzung B. G. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta. 1977 Nov 14;472(3-4):373–398. doi: 10.1016/0304-4157(77)90003-x. [DOI] [PubMed] [Google Scholar]
  10. Matteson D. R., Armstrong C. M. Evidence for a population of sleepy sodium channels in squid axon at low temperature. J Gen Physiol. 1982 May;79(5):739–758. doi: 10.1085/jgp.79.5.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Schwarz W., Palade P. T., Hille B. Local anesthetics. Effect of pH on use-dependent block of sodium channels in frog muscle. Biophys J. 1977 Dec;20(3):343–368. doi: 10.1016/S0006-3495(77)85554-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Starmer C. F., Grant A. O., Strauss H. C. Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J. 1984 Jul;46(1):15–27. doi: 10.1016/S0006-3495(84)83994-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Strichartz G. R. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol. 1973 Jul;62(1):37–57. doi: 10.1085/jgp.62.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ulbricht W., Stoye-Herzog M. Distinctly different rates of benzocaine action on sodium channels of Ranvier nodes kept open by chloramine-T and veratridine. Pflugers Arch. 1984 Dec;402(4):439–445. doi: 10.1007/BF00583945. [DOI] [PubMed] [Google Scholar]
  15. Wang G. K., Brodwick M. S., Eaton D. C. Removal of sodium channel inactivation in squid axon by the oxidant chloramine-T. J Gen Physiol. 1985 Aug;86(2):289–302. doi: 10.1085/jgp.86.2.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Wang H. H., Yeh J. Z., Narahashi T. Interaction of spin-labeled local anesthetics with the sodium channel of squid axon membranes. J Membr Biol. 1982;66(3):227–233. doi: 10.1007/BF01868497. [DOI] [PubMed] [Google Scholar]
  17. Wu C. H., Narahashi T. Mechanism of action of propranolol on squid axon membranes. J Pharmacol Exp Ther. 1973 Jan;184(1):155–162. [PubMed] [Google Scholar]
  18. Yeh J. Z., Oxford G. S. Interactions of monovalent cations with sodium channels in squid axon. II. Modification of pharmacological inactivation gating. J Gen Physiol. 1985 Apr;85(4):603–620. doi: 10.1085/jgp.85.4.603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Yeh J. Z. Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons. Biophys J. 1978 Nov;24(2):569–574. doi: 10.1016/S0006-3495(78)85403-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Yeh J. Z., Tanguy J. Na channel activation gate modulates slow recovery from use-dependent block by local anesthetics in squid giant axons. Biophys J. 1985 May;47(5):685–694. doi: 10.1016/S0006-3495(85)83965-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Zaborovskaya L. D., Khodorov B. I. The role of inactivation in the cumulative blockage of voltage-dependent sodium channels by local anesthetics and antiarrythmics. Gen Physiol Biophys. 1984 Dec;3(6):517–520. [PubMed] [Google Scholar]

Articles from The Journal of General Physiology are provided here courtesy of The Rockefeller University Press

RESOURCES