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Glycopyrronium bromide blocks differentially responses mediated by muscarinic receptor subtypes

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Summary

To analyse the potency of glycopyrronium bromide in blocking responses mediated via subtypes of muscarinic receptors in vitro, we tried to determine its equilibrium dissociation constants at prejunctional muscarinic receptors inhibiting the twitch response of rabbit vas deferens (presumed M1 type), at M2 (paced rat left atria), M3 (guinea pig ileum) muscarinic receptor subtypes and at the muscarinic receptor of the rabbit iris sphincter (not M1–M4, not m5). Glycopyrronium bromide shifted to the right the curve for inhibition of the twitch response induced by the agonist McN-A-343, and the methacholine-induced curves for inhibition of rat atrial contraction, and for tonic contraction of guinea pig ileum and rabbit iris sphincter.

Glycopyrronium bromide blocked with very high potency (> 11, apparent -log KB) the response in rabbit vas deferens. Its affinity was low (9.09) for the M2 subtype, and intermediate (10.31 or 10.13) for the ileal M3 and the atypical iris muscarinic receptor subtype, respectively. Except at the receptors in rabbit vas deferens, the blockade of agonist effect appeared to be of simple competitive type.

In conclusion, glycopyrronium bromide is about 10 or 100fold more potent in preventing a response to activation of the prejunctional receptor in rabbit vas deferens than in blocking an M3 or M2 muscarinic receptor subtype, respectively, in vitro. The low affinity for M2 receptors may, in part, explain the low incidence of unwanted tachycardia in therapy. The drug failed to discriminate between an M3 receptor and the atypical rabbit iris sphincter receptor.

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References

  • Ali-Melkkila T, Kaila T, Kanto J (1989) Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings. Acta Anaesthesiol Scand 33:513–517

    Google Scholar 

  • Ali-Melkkila T, Kaila T, Antila K, Halkola L, lisalo E (1991) Effects of glycopyrrolate and atropine on heart rate variability. Acta Anaesthesiol Scand 35:436–441

    Google Scholar 

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58

    Google Scholar 

  • Barlow RB, Berry KJ, Glenton PAM, Nikolaou NM, Soh KS (1976) A comparison of affinity constants for muscarine sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29'C and in ileum at 29°C and 37°C. Br J Pharmacol 58:613–620

    Google Scholar 

  • Berger J, Gravenstein J, van der Aa J, Paulus L, Sabah-Maren E, McLaughlin G (1988) Comparative potency of atropine sulphate and glycopyrrolate on heart rate in man. Eur J Anaesthesiol 5:23–30 Bognar IT, Altes U, Beinhauer C, Kessler I, Fuder H (1992) A muscarinic receptor different from M1, M2, M3 and M4 subtypes mediates the contraction of the rabbit iris sphincter. Naunyn-Schmiedeberg's Arch Pharmacol 345:611–618

    Google Scholar 

  • Doods HN (1991) Muscarinic receptors. In: Doods HN, van Meel JCA (eds) Receptor data for biological experiments: a guide to drug selectivity. Ellis Howood, New York, pp 31–34

    Google Scholar 

  • Dörje F, Wess J, Lambrecht G, Tacke R, Mutschler E, Brann MR (1991) Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther 256:727–733

    Google Scholar 

  • Durant PAC, Shankley NP, Welsh NJ, Black JW (1991) Pharmacological analysis of antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay. Br J Pharmacol 104:145–150

    Google Scholar 

  • Dworacek B, Rupreht J, Bode A, Walhout MJ (1987) Atropine methylbromide and glycopyrrolate: a comparative study during reversal of neuromuscular block. Acta Anaesthesiol Belg 38:147–152

    Google Scholar 

  • Eglen RM, Whiting RL (1986) Muscarinic receptor subtypes: a critique of the current classification and a proposal for a working nomenclature. J Anton Pharmacol 6:323–346

    Google Scholar 

  • Eglen RM, Whiting RL (1988) Comparison of the muscarinic receptors of the guinea-pig oesophageal muscularis mucosae and trachea in vitro. J Anton Pharmacol 8:181–189

    Google Scholar 

  • Eltze M (1988) Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens. Eur J Pharmacol 151:205–221

    Google Scholar 

  • Eltze M, Figala V (1988) Affinity and selectivity of biperiden enantiomers for muscarinic receptor subtypes. Eur J Pharmacol 158:11–19

    Google Scholar 

  • Fuder H, Kilbinger H, Müller H (1985) Organ selectivity of hexahydrosiladifenidol in blocking pre- and postjunctional muscarinic receptors studied in guinea-pig ileum and rat heart. Eur J Pharmacol 113:125–127

    Google Scholar 

  • Fuder H, SchÖpf J, Unckell J, Wesner MTh, Melchiorre C, Tacke R, Mutschler E, Lambrecht G (1989) Different muscarine receptors mediate the prejunctional inhibition of [3H]-noradrenaline release in rat or guinea-pig iris and the contraction of the rabbit iris sphincter muscle. Naunyn-Schmiedeberg's Arch Pharmacol 340:597–604

    Google Scholar 

  • Gilman MJ, Meyer L, Carter J, Slovis C (1990) Comparison of aerosolized glycopyrrolate and metaproterenol in acute asthma. Chest 98:1095–1098

    Google Scholar 

  • Hulme EC, Birdsall NJM, Buckley NJ (1990) Muscarinic receptor subtypes. Ann Rev Pharmacol Toxicol 30:633–673

    Google Scholar 

  • Kanto J, Klotz U (1988) Pharmacokinetic implications for the clinical use of atropine, scopolamine and glycopyrrolate. Acta Anaesthesiol Scand 32:69–78

    Google Scholar 

  • Kentala E, Salonen M, Kanto J (1990) Anticholinergic premedication in Finland 1988. Acta Anaesthesiol Scand 34:17–20

    Google Scholar 

  • Martindale (1989) Antimuscarinic agents. In: Reynolds JEF (ed) Martindale The Extra Pharmacopoea, 29 edn. Pharmaceutical Press London, pp 532–533

  • Mirakhur RK (1979) Intravenous administration of glycopyrronium: effects on cardiac rate and rhythm. Anaesthesia 34:458–462

    Google Scholar 

  • Schroeckenstein DC, Bush RK, Chervinsky P, Busse WW (1988) Twelve-hour bronchodilatation in asthma with a single aerosol dose of the anticholinergic compound glycopyrrolate. J Allgergy Clin Immunol 82:115–119

    Google Scholar 

  • Slovis CM, Daniels GM, Wharton DR (1987) Intravenous use of glycopyrrolate in acute respiratory distress due to bronchospastic pulmonary disease. Ann Emerg Med 16:898–900

    Google Scholar 

  • Walker FB, Kaiser DL, Kowal MB, Suratt PM (1987) Prolonged effect of inhaled glycopryrrolate in asthma. Chest 91:49–51

    Google Scholar 

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Authors and Affiliations

  1. Pharmakologisches Institut der Universität, Obere Zahlbacher Strasse 67, W-6500, Mainz, Federal Republic of Germany

    H. Fuder & M. Meincke

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  1. H. Fuder
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  2. M. Meincke
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Correspondence to H. Fuder at the above address

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Fuder, H., Meincke, M. Glycopyrronium bromide blocks differentially responses mediated by muscarinic receptor subtypes. Naunyn-Schmiedeberg's Arch Pharmacol 347, 591–595 (1993). https://doi.org/10.1007/BF00166941

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  • DOI: https://doi.org/10.1007/BF00166941

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