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. 1989 Oct;98(2):499–506. doi: 10.1111/j.1476-5381.1989.tb12623.x

The interaction of hexamethonium with muscarinic receptor subtypes in vitro.

R M Eglen 1, A D Michel 1, C M Cornett 1, E A Kunysz 1, R L Whiting 1
PMCID: PMC1854706  PMID: 2819331

Abstract

1. The action of hexamethonium has been studied at a range of muscarinic receptors in vitro by use of both functional and radioligand binding studies. 2. In functional studies, hexamethonium exhibited little or no significant (P less than 0.05) antagonism of contractile responses to carbachol at muscarinic receptors in the guinea-pig ileum, oesophageal muscularis mucosae, urinary bladder and trachea. However, antagonism was observed at muscarinic receptors in the guinea-pig left atria mediating negative inotropic responses and the calculated pKB value was 3.80. Hexamethonium also antagonized contractile responses to carbachol in the canine saphenous vein. The pKB value at these receptors was 3.75. 3. In the presence of 3.2 mM hexamethonium, the pA2 value for methoctramine at atrial muscarinic receptors was reduced by approximately 10 fold (control pA2 value was 7.81 +/- 0.05; pA2 value in hexamethonium was 6.73 +/- 0.04). In contrast at tracheal muscarinic receptors, the pA2 values for methoctramine were unaffected in the presence of 3.2 mM hexamethonium (control pA2 = 5.58 +/- 0.07; pA2 value in hexamethonium was 5.63 +/- 0.12). All values quoted are mean +/- s.e. mean, n = 8. 4. In competition radioligand binding studies, hexamethonium exhibited a higher affinity for cardiac M2 receptors (pKi = 3.68) than for cerebrocortical M1 receptors (pKi = 3.28) or for submaxillary gland M3 receptors (pKi = 2.61). At M2 receptors hexamethonium at concentrations of 0.1-10 mM, increased the half life of the dissociation rate of [3H]-N-methylscopolamine 1.6-4.3 fold. This was observed at M3 receptors only at 10 mM, when the half life was increased 1.7 fold.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barlow R. B., Franks F. M., Pearson J. D. A comparison of the affinities of antagonists for acetylcholine receptors in the ileum, bronchial muscle and iris of the guinea-pig. Br J Pharmacol. 1972 Oct;46(2):300–312. doi: 10.1111/j.1476-5381.1972.tb06875.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blinks J. R. Convenient apparatus for recording contractions of isolated heart muscle. J Appl Physiol. 1965 Jul;20(4):755–757. doi: 10.1152/jappl.1965.20.4.755. [DOI] [PubMed] [Google Scholar]
  4. Brown D. A., Fatherazi S., Garthwaite J., White R. D. Muscarinic receptors in rat sympathetic ganglia. Br J Pharmacol. 1980 Dec;70(4):577–592. doi: 10.1111/j.1476-5381.1980.tb09777.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  6. Clague R. U., Eglen R. M., Strachan A. C., Whiting R. L. Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro. Br J Pharmacol. 1985 Sep;86(1):163–170. doi: 10.1111/j.1476-5381.1985.tb09446.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Delmendo R. E., Michel A. D., Whiting R. L. Affinity of muscarinic receptor antagonists for three putative muscarinic receptor binding sites. Br J Pharmacol. 1989 Feb;96(2):457–464. doi: 10.1111/j.1476-5381.1989.tb11838.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Doods H. N., Mathy M. J., Davidesko D., van Charldorp K. J., de Jonge A., van Zwieten P. A. Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2 and M3 receptors. J Pharmacol Exp Ther. 1987 Jul;242(1):257–262. [PubMed] [Google Scholar]
  9. Dunlap J., Brown J. H. Heterogeneity of binding sites on cardiac muscarinic receptors induced by the neuromuscular blocking agents gallamine and pancuronium. Mol Pharmacol. 1983 Jul;24(1):15–22. [PubMed] [Google Scholar]
  10. Eglen R. M., Montgomery W. W., Dainty I. A., Dubuque L. K., Whiting R. L. The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro. Br J Pharmacol. 1988 Dec;95(4):1031–1038. doi: 10.1111/j.1476-5381.1988.tb11736.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Eglen R. M., Whiting R. L. Comparison of the muscarinic receptors of the guinea-pig oesophageal muscularis mucosae and trachea in vitro. J Auton Pharmacol. 1988 Sep;8(3):181–189. doi: 10.1111/j.1474-8673.1988.tb00181.x. [DOI] [PubMed] [Google Scholar]
  12. Eglen R. M., Whiting R. L. Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes. Br J Pharmacol. 1987 Apr;90(4):701–707. doi: 10.1111/j.1476-5381.1987.tb11223.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Eglen R. M., Whiting R. L. Muscarinic receptor subtypes: a critique of the current classification and a proposal for a working nomenclature. J Auton Pharmacol. 1986 Dec;6(4):323–346. doi: 10.1111/j.1474-8673.1986.tb00661.x. [DOI] [PubMed] [Google Scholar]
  14. Geddes B. A., Bogart L. F., Hamilton J. T. Conditions affecting the interaction of cholinergic agents on the longitudinal muscle of the guinea-pig ileum--unexpected effects with hexamethonium. J Pharm Pharmacol. 1974 Sep;26(9):699–706. doi: 10.1111/j.2042-7158.1974.tb09353.x. [DOI] [PubMed] [Google Scholar]
  15. Gillespie J. S. The rat anococcygeus muscle and its response to nerve stimulation and to some drugs. Br J Pharmacol. 1972 Jul;45(3):404–416. doi: 10.1111/j.1476-5381.1972.tb08097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Giraldo E., Viganò M. A., Hammer R., Ladinsky H. Characterization of muscarinic receptors in guinea pig ileum longitudinal smooth muscle. Mol Pharmacol. 1988 Jun;33(6):617–625. [PubMed] [Google Scholar]
  17. Kamikawa Y., Uchida K., Shimo Y. Heterogeneity of muscarinic receptors in the guinea pig esophageal muscularis mucosae and ileal longitudinal muscle. Gastroenterology. 1985 Mar;88(3):706–716. doi: 10.1016/0016-5085(85)90141-6. [DOI] [PubMed] [Google Scholar]
  18. Leung E., Mitchelson F. Modification by hexamethonium of the muscarinic receptors blocking activity of pancuronium and homatropine in isolated tissues of the guinea-pig. Eur J Pharmacol. 1982 May 7;80(1):11–17. doi: 10.1016/0014-2999(82)90172-8. [DOI] [PubMed] [Google Scholar]
  19. Lüllmann H., Ohnesorge F. K., Schauwecker G. C., Wassermann O. Inhibition of the actions of carbachol and DFP on guinea pig isolated atria by alkane-bis-ammonium compounds. Eur J Pharmacol. 1969;6(3):241–247. doi: 10.1016/0014-2999(69)90181-2. [DOI] [PubMed] [Google Scholar]
  20. Michel A. D., Whiting R. L. Direct binding studies on ileal and cardiac muscarinic receptors. Br J Pharmacol. 1987 Dec;92(4):755–767. doi: 10.1111/j.1476-5381.1987.tb11379.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Michel A. D., Whiting R. L. Methoctramine reveals heterogeneity of M2 muscarinic receptors in longitudinal ileal smooth muscle membranes. Eur J Pharmacol. 1988 Jan 19;145(3):305–311. doi: 10.1016/0014-2999(88)90434-7. [DOI] [PubMed] [Google Scholar]
  22. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  23. O'Rourke S. T., Vanhoutte P. M. Subtypes of muscarinic receptors on adrenergic nerves and vascular smooth muscle of the canine saphenous vein. J Pharmacol Exp Ther. 1987 Apr;241(1):64–67. [PubMed] [Google Scholar]
  24. Parker R. B., Waud D. R. Pharmacological estimation of drug-receptor dissociation constants. Statistical evaluation. I. Agonists. J Pharmacol Exp Ther. 1971 Apr;177(1):1–12. [PubMed] [Google Scholar]

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