Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 May;112(1):179–187. doi: 10.1111/j.1476-5381.1994.tb13049.x

Effects of muscarinic M2 and M3 receptor stimulation and antagonism on responses to isoprenaline of guinea-pig trachea in vitro.

N Watson 1, R M Eglen 1
PMCID: PMC1910305  PMID: 8032639

Abstract

1. In guinea-pig and canine airway smooth muscle, there is reduced beta-adrenoceptor agonist sensitivity in tissues pre-contracted with muscarinic agonists when compared to tissues pre-contracted with other spasmogens, such as histamine or leukotriene D4. This reduced sensitivity may be the result of an interaction between muscarinic receptors and beta-adrenoceptors. In this study the effects of M2 receptor antagonism and stimulation have been investigated on the relaxant potency of isoprenaline in guinea-pig isolated tracheal smooth muscle. 2. (+)-cis-Dioxolane contracted isolated tracheal strips in a concentration-dependent manner (EC50 = 11.5 +/- 0.9 nM). The rank order of antagonist apparent affinities (with pA2 values in parentheses) was atropine (9.4 +/- 0.1) > zamifenacin (8.2 +/- 0.1) > para-fluoro-hexahydro-siladiphenidol (p-F-HHSiD, 7.2 +/- 0.1) > pirenzepine (6.5 +/- 0.1) > methoctramine (5.5 +/- 0.1). Schild slopes were not significantly different from unity. This was consistent with a role of muscarinic M3 receptors in mediating contraction. 3. In tissues pre-contracted to 3 g isometric tension using (+)-cis-dioxolane (0.2 microM, approximately EC80), the relaxant potency of isoprenaline was significantly (P < 0.05) increased by 0.3 microM methoctramine (control EC50 = 32.2 +/- 4.3 nM, plus methoctramine EC50 = 19.1 +/- 4.5 nM). This concentration of methoctramine had no effect on contractile responses to (+)-cis-dioxolane (control, EC50 = 17.6 +/- 3.2 nM, plus methoctramine, EC50 = 21.0 +/- 4.4 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
181

Selected References

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

  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. Bloom J. W., Yamamura H. I., Baumgartener C., Halonen M. A muscarinic receptor with high affinity for pirenzepine mediates vagally induced bronchoconstriction. Eur J Pharmacol. 1987 Jan 6;133(1):21–27. doi: 10.1016/0014-2999(87)90201-9. [DOI] [PubMed] [Google Scholar]
  3. Caulfield M. P. Muscarinic receptors--characterization, coupling and function. Pharmacol Ther. 1993 Jun;58(3):319–379. doi: 10.1016/0163-7258(93)90027-b. [DOI] [PubMed] [Google Scholar]
  4. Chilvers E. R., Nahorski S. R. Phosphoinositide metabolism in airway smooth muscle. Am Rev Respir Dis. 1990 Mar;141(3 Pt 2):S137–S140. doi: 10.1164/ajrccm/141.3_Pt_2.S137. [DOI] [PubMed] [Google Scholar]
  5. Eglen R. M., Cornett C. M., Whiting R. L. Interaction of p-F-HHSiD (p-Fluoro-hexahydrosila-difenidol) at muscarinic receptors in guinea-pig trachea. Naunyn Schmiedebergs Arch Pharmacol. 1990 Oct;342(4):394–399. doi: 10.1007/BF00169455. [DOI] [PubMed] [Google Scholar]
  6. Eglen R. M., Harris G. C., Ford A. P., Wong E. H., Pfister J. R., Whiting R. L. The action of (+/-)L-660,863 [(+/-)3-(3-amino-1,2,4-oxadiazole-5-yl)-quinuclidine] at muscarinic receptor subtypes in vitro. Naunyn Schmiedebergs Arch Pharmacol. 1992 Apr;345(4):375–381. doi: 10.1007/BF00176613. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Enz A., Shapiro G., Supavilai P., Boddeke H. W. SDZ ENS 163 is a selective M1 agonist and induces release of acetylcholine. Naunyn Schmiedebergs Arch Pharmacol. 1992 Mar;345(3):282–287. doi: 10.1007/BF00168688. [DOI] [PubMed] [Google Scholar]
  9. Fernandes L. B., Fryer A. D., Hirshman C. A. M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle. J Pharmacol Exp Ther. 1992 Jul;262(1):119–126. [PubMed] [Google Scholar]
  10. Freedman S. B., Harley E. A., Patel S., Newberry N. R., Gilbert M. J., McKnight A. T., Tang J. K., Maguire J. J., Mudunkotuwa N. T., Baker R. A novel series of non-quaternary oxadiazoles acting as full agonists at muscarinic receptors. Br J Pharmacol. 1990 Nov;101(3):575–580. doi: 10.1111/j.1476-5381.1990.tb14123.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fryer A. D., el-Fakahany E. E. Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists. Life Sci. 1990;47(7):611–618. doi: 10.1016/0024-3205(90)90572-9. [DOI] [PubMed] [Google Scholar]
  12. Griffin M. T., Ehlert F. J. Specific inhibition of isoproterenol-stimulated cyclic AMP accumulation by M2 muscarinic receptors in rat intestinal smooth muscle. J Pharmacol Exp Ther. 1992 Oct;263(1):221–225. [PubMed] [Google Scholar]
  13. Gunst S. J., Stropp J. Q., Flavahan N. A. Muscarinic receptor reserve and beta-adrenergic sensitivity in tracheal smooth muscle. J Appl Physiol (1985) 1989 Sep;67(3):1294–1298. doi: 10.1152/jappl.1989.67.3.1294. [DOI] [PubMed] [Google Scholar]
  14. Jones C. A., Madison J. M., Tom-Moy M., Brown J. K. Muscarinic cholinergic inhibition of adenylate cyclase in airway smooth muscle. Am J Physiol. 1987 Jul;253(1 Pt 1):C97–104. doi: 10.1152/ajpcell.1987.253.1.C97. [DOI] [PubMed] [Google Scholar]
  15. Koenig S. M., Mitchell R. W., Kelly E., White S. R., Leff A. R., Popovich K. J. Beta-adrenergic relaxation of dog trachealis: contractile agonist-specific interaction. J Appl Physiol (1985) 1989 Jul;67(1):181–185. doi: 10.1152/jappl.1989.67.1.181. [DOI] [PubMed] [Google Scholar]
  16. Lambrecht G., Feifel R., Forth B., Strohmann C., Tacke R., Mutschler E. p-fluoro-hexahydro-sila-difenidol: the first M2 beta-selective muscarinic antagonist. Eur J Pharmacol. 1988 Jul 26;152(1-2):193–194. doi: 10.1016/0014-2999(88)90856-4. [DOI] [PubMed] [Google Scholar]
  17. Leung E., Michelson S., Villarubia C., Perkins L. A., Eglen R. M. Analysis of concentration-response relationships by seemingly unrelated nonlinear regression (SUNR) technique. J Pharmacol Toxicol Methods. 1992 Dec;28(4):209–216. doi: 10.1016/1056-8719(92)90006-m. [DOI] [PubMed] [Google Scholar]
  18. Mahesh V. K., Nunan L. M., Halonen M., Yamamura H. I., Palmer J. D., Bloom J. W. A minority of muscarinic receptors mediate rabbit tracheal smooth muscle contraction. Am J Respir Cell Mol Biol. 1992 Mar;6(3):279–286. doi: 10.1165/ajrcmb/6.3.279. [DOI] [PubMed] [Google Scholar]
  19. Mak J. C., Barnes P. J. Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis. 1990 Jun;141(6):1559–1568. doi: 10.1164/ajrccm/141.6.1559. [DOI] [PubMed] [Google Scholar]
  20. Melchiorre C., Cassinelli A., Quaglia W. Differential blockade of muscarinic receptor subtypes by polymethylene tetraamines. Novel class of selective antagonists of cardiac M-2 muscarinic receptors. J Med Chem. 1987 Jan;30(1):201–204. doi: 10.1021/jm00384a034. [DOI] [PubMed] [Google Scholar]
  21. Mitchell R. W., Koenig S. M., Popovich K. J., Kelly E., Tallet J., Leff A. R. Pertussis toxin augments beta-adrenergic relaxation of muscarinic contraction in canine trachealis. Am Rev Respir Dis. 1993 Feb;147(2):327–331. doi: 10.1164/ajrccm/147.2.327. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Pyne N. J., Grady M. W., Shehnaz D., Stevens P. A., Pyne S., Rodger I. W. Muscarinic blockade of beta-adrenoceptor-stimulated adenylyl cyclase: the role of stimulatory and inhibitory guanine-nucleotide binding regulatory proteins (Gs and Gi). Br J Pharmacol. 1992 Nov;107(3):881–887. doi: 10.1111/j.1476-5381.1992.tb14541.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Roffel A. F., Meurs H., Elzinga C. R., Zaagsma J. Characterization of the muscarinic receptor subtype involved in phosphoinositide metabolism in bovine tracheal smooth muscle. Br J Pharmacol. 1990 Feb;99(2):293–296. doi: 10.1111/j.1476-5381.1990.tb14697.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Russell J. A. Differential inhibitory effect of isoproterenol on contractions of canine airways. J Appl Physiol Respir Environ Exerc Physiol. 1984 Sep;57(3):801–807. doi: 10.1152/jappl.1984.57.3.801. [DOI] [PubMed] [Google Scholar]
  26. Sahin I., Ilhan M. The antimuscarinic activity of a dopamine receptor agonist (RDS-127) differentiates M2-muscarinic receptors of heart, ileum and trachea in guinea-pig. Arch Int Pharmacodyn Ther. 1988 Nov-Dec;296:163–172. [PubMed] [Google Scholar]
  27. Sankary R. M., Jones C. A., Madison J. M., Brown J. K. Muscarinic cholinergic inhibition of cyclic AMP accumulation in airway smooth muscle. Role of a pertussis toxin-sensitive protein. Am Rev Respir Dis. 1988 Jul;138(1):145–150. doi: 10.1164/ajrccm/138.1.145. [DOI] [PubMed] [Google Scholar]
  28. Ten Berge R. E., Roffel A. F., Zaagsma J. The interaction of selective and non-selective antagonists with pre- and postjunctional muscarinic receptor subtypes in the guinea pig trachea. Eur J Pharmacol. 1993 Mar 23;233(2-3):279–284. doi: 10.1016/0014-2999(93)90062-m. [DOI] [PubMed] [Google Scholar]
  29. Thomas E. A., Baker S. A., Ehlert F. J. Functional role for the M2 muscarinic receptor in smooth muscle of guinea pig ileum. Mol Pharmacol. 1993 Jul;44(1):102–110. [PubMed] [Google Scholar]
  30. Torphy T. J. Differential relaxant effects of isoproterenol on methacholine- versus leukotriene D4-induced contraction in the guinea-pig trachea. Eur J Pharmacol. 1984 Jul 20;102(3-4):549–553. doi: 10.1016/0014-2999(84)90580-6. [DOI] [PubMed] [Google Scholar]
  31. Torphy T. J., Zheng C., Peterson S. M., Fiscus R. R., Rinard G. A., Mayer S. E. Inhibitory effect of methacholine on drug-induced relaxation, cyclic AMP accumulation, and cyclic AMP-dependent protein kinase activation in canine tracheal smooth muscle. J Pharmacol Exp Ther. 1985 May;233(2):409–417. [PubMed] [Google Scholar]
  32. Van Amsterdam R. G., Meurs H., Brouwer F., Postema J. B., Timmermans A., Zaagsma J. Role of phosphoinositide metabolism in functional antagonism of airway smooth muscle contraction by beta-adrenoceptor agonists. Eur J Pharmacol. 1989 May 11;172(2):175–183. doi: 10.1016/0922-4106(89)90008-4. [DOI] [PubMed] [Google Scholar]
  33. Van Amsterdam R. G., Meurs H., Ten Berge R. E., Veninga N. C., Brouwer F., Zaagsma J. Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by beta-adrenoceptor agonists. Am Rev Respir Dis. 1990 Nov;142(5):1124–1128. doi: 10.1164/ajrccm/142.5.1124. [DOI] [PubMed] [Google Scholar]
  34. Yang C. M., Chou S. P., Sung T. C. Muscarinic receptor subtypes coupled to generation of different second messengers in isolated tracheal smooth muscle cells. Br J Pharmacol. 1991 Nov;104(3):613–618. doi: 10.1111/j.1476-5381.1991.tb12478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES