Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1980 Aug;77(8):5003–5007. doi: 10.1073/pnas.77.8.5003

An attempt to distinguish between the actions of neuromuscular blocking drugs on the acetylcholine receptor and on its associated ionic channel

Jeremy J Lambert 1, Robert L Volle 1, Edward G Henderson 1
PMCID: PMC349978  PMID: 6254051

Abstract

The effects of lobeline and tubocurarine on the voltage-clamped endplates of frog sartorius and cutaneous pectoris muscles were examined at room temperature (20-23°C). Like tubocurarine, lobeline causes nondepolarizing neuromuscular blockade. The half-time of decay (t½) of endplate currents (e.p.c.s) recorded at a holding potential (Vm) of -90 mV was significantly shorter in endplates treated with lobeline (50 μM; mean t½ ± SEM = 0.41 ± 0.02 ms) or tubocurarine (11.4 μM; t½ = 0.64 ± 0.04 ms) than in those treated with Mg2+ (13 mM; t½ = 1.39 ± 0.11 ms) or a low concentration of tubocurarine (3 μM; t½ = 0.87 ± 0.05 ms). Similarly, lobeline (10 μM) shortened the t½ of untreated miniature e.p.c.s by 35%; tubocurarine, however, abolished miniature e.p.c.s at the concentration required to observe its actions on e.p.c. decay kinetics. The t½ of e.p.c.s recorded from preparations treated with Mg2+ (13 mM), tubocurarine at low concentrations (3 μM), or untreated miniature e.p.c.s was logarithmically related to Vm, being slower at more hyperpolarized values. By contrast, the t½s of e.p.c.s recorded in either lobeline (50 μM) or tubocurarine (11.4 μM) were independent of voltage in the range -150 to -80 mV. The ability of lobeline to shorten t½ and to remove the voltage dependence of t½ was partially antagonized by Mg2+ (13 mM). As expected, when lobeline or tubocurarine was removed from the bath or when acetylcholine release from the motor nerve terminals was increased by 4-aminopyridine (20 μM) and Ca2+ (10 mM) (in the presence of lobeline or tubocurarine), the amplitude of e.p.c.s increased as a function of time. However, the t½ of the decay phase of the e.p.c.s remained shortened (i.e., unaltered from the earlier treatment). These results suggest that both tubocurarine and lobeline have at least two distinct postjunctional actions including: (i) a block of the acetylcholine receptor and (ii) a block of the ionic channel associated with the acetylcholine receptor.

Keywords: tubocurarine, lobeline, endplate kinetics

Full text

PDF
5003

Selected References

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

  1. Adams P. R. Drug blockade of open end-plate channels. J Physiol. 1976 Sep;260(3):531–552. doi: 10.1113/jphysiol.1976.sp011530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adler M., Oliveira A. C., Albuquerque E. X., Mansour N. A., Eldefrawi A. T. Reaction of tetraethylammonium with the open and closed conformations of the acetylcholine receptor ionic channel complex. J Gen Physiol. 1979 Jul;74(1):129–152. doi: 10.1085/jgp.74.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cohen I., Van der Kloot W. Effects of [Ca2+] and [Mg2+] on the decay of miniature endplate currents. Nature. 1978 Jan 5;271(5640):77–79. doi: 10.1038/271077a0. [DOI] [PubMed] [Google Scholar]
  4. Colquhoun D., Dreyer F., Sheridan R. E. The actions of tubocurarine at the frog neuromuscular junction. J Physiol. 1979 Aug;293:247–284. doi: 10.1113/jphysiol.1979.sp012888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Deguchi T., Narahashi T. Effects of procaine on ionic conductances of end-plate membranes. J Pharmacol Exp Ther. 1971 Feb;176(2):423–433. [PubMed] [Google Scholar]
  6. Gage P. W., McBurney R. N. Effects of membrane potential, temperature and neostigmine on the conductance change caused by a quantum or acetylcholine at the toad neuromuscular junction. J Physiol. 1975 Jan;244(2):385–407. doi: 10.1113/jphysiol.1975.sp010805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Horn A. S., Lambert J. J., Marshall I. G. A comparison of the facilitatory actions of 4-aminopyridine methiodide and 4-aminopyridine on neuromuscular transmission. Br J Pharmacol. 1979 Jan;65(1):53–62. doi: 10.1111/j.1476-5381.1979.tb17333.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Katz B., Miledi R. A re-examination of curare action at the motor endplate. Proc R Soc Lond B Biol Sci. 1978 Dec 4;203(1151):119–133. doi: 10.1098/rspb.1978.0096. [DOI] [PubMed] [Google Scholar]
  9. Kordas M. The effect of membrane polarization on the time course of the end-plate current in frog sartorius muscle. J Physiol. 1969 Oct;204(2):493–502. doi: 10.1113/jphysiol.1969.sp008926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lester H. A., Krouse M. E., Nass M. M., Wassermann N. H., Erlanger B. F. Light-activated drug confirms a mechanism of ion channel blockade. Nature. 1979 Aug 9;280(5722):509–510. doi: 10.1038/280509a0. [DOI] [PubMed] [Google Scholar]
  11. Magleby K. L., Stevens C. F. The effect of voltage on the time course of end-plate currents. J Physiol. 1972 May;223(1):151–171. doi: 10.1113/jphysiol.1972.sp009839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mallart A., Molgó J. The effects of pH and curare on the time course of end-plate currents at the neuromuscular junction of the frog. J Physiol. 1978 Mar;276:343–352. doi: 10.1113/jphysiol.1978.sp012238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Manalis R. S. Voltage-dependent effect of curare at the frog neuromuscular junction. Nature. 1977 May 26;267(5609):366–368. doi: 10.1038/267366a0. [DOI] [PubMed] [Google Scholar]
  14. Molgo J., Lemeignan M., Lechat P. Effects of 4-aminopyridine at the frog neuromuscular junction. J Pharmacol Exp Ther. 1977 Dec;203(3):653–663. [PubMed] [Google Scholar]
  15. Neher E., Steinbach J. H. Local anaesthetics transiently block currents through single acetylcholine-receptor channels. J Physiol. 1978 Apr;277:153–176. doi: 10.1113/jphysiol.1978.sp012267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Steinberg M. I., Volle R. L. A comparison of lobeline and nicotine at the frog neuromuscular junction. Naunyn Schmiedebergs Arch Pharmacol. 1972;272(1):16–31. doi: 10.1007/BF00498791. [DOI] [PubMed] [Google Scholar]
  17. Volle R. L. Blockade by lobeline of potassium exchange in skeletal muscle. Relationship to receptor desensitization at the endplate. Naunyn Schmiedebergs Arch Pharmacol. 1974;282(4):335–347. doi: 10.1007/BF00500983. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES