Interactions between glycopyrronium and indacaterol on cholinergic neurotransmission and contractile response in bovine trachealis

Michele Baroffio,Giovanni Barisione,Vito Brusasco

doi:10.1186/s12931-017-0627-5

Michele Baroffio, Giovanni Barisione + Show 1 more

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https://doi.org/10.1186/s12931-017-0627-5

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Abstract

BackgroundMuscarinic-receptor antagonists and β-adrenoceptor agonists are used, alone or in combination, as first-line treatment for chronic obstructive pulmonary disease. Both drugs decrease airway smooth muscle tone by post-junctional mechanisms but they may have opposing effects on pre-junctional acetylcholine (ACh)-release.MethodsWe studied the effects of the muscarinic-receptor antagonist glycopyrronium (GLY), the β-adrenoceptor agonist indacaterol (IND) and their combination on electrically-induced ACh-release and contractile response in isolated bovine trachealis. Data were analyzed by paired t-test and analysis of variance for repeated or independent measures with Newmann-Keuls post-hoc test when appropriate.ResultsGLY 10−8 M decreased contractile response by 19 ± 6% (p = 0.010) without altering ACh-release. GLY 10−7 M and 10−6 M almost abolished contractile responses even if the ACh-release was increased by 27 ± 19% (p < 0.001) and 20 ± 8% (p = 0.004), respectively. IND 10−7 M had no significant effects on contractile response and ACh-release, whereas IND 10−6 M reduced contractile response by 24 ± 12% (p = 0.002) without altering ACh-release. IND 10−5 M decreased contractile response by 51 ± 17% (p < 0.001) and ACh-release by 22 ± 11% (p = 0.004). Co-incubation with GLY 10−8 M and IND 10−7 M did not alter ACh-release but inhibited contractile response by 41 ± 8% (p < 0.001). The latter effect was greater than with GLY 10−8 M, or IND 10−7 M, or IND 10−6 M given separately (p < 0.001 for all). The increment of ACh-release caused by GLY was attenuated by IND 10−5 M, though this did not affect contractile response.ConclusionsAt equimolar concentration, GLY alone attenuates airway smooth muscle contraction more than IND, despite an increased ACh-release. Combination of GLY with IND at submaximal concentrations has more than additive effect suggesting a synergistic post-junctional effect. Adding GLY to IND provides a greater inhibitory effect on airway smooth muscle contraction than increasing IND concentration.

Highlights

Muscarinic-receptor antagonists and β-adrenoceptor agonists are used, alone or in combination, as first-line treatment for chronic obstructive pulmonary disease
The airway smooth muscle contractile response is enhanced by ACh acting on post-junctional M3 receptors and inhibited by catecholamine acting on postjunctional β2-adrenoceptors
Muscles where first washed, one muscle from each animal was used as control, while other 7 strips were incubated with a single dose of GLY (10−9-10−6 M, halfLog increments) for 45 min

Summary

Introduction

Muscarinic-receptor antagonists and β-adrenoceptor agonists are used, alone or in combination, as first-line treatment for chronic obstructive pulmonary disease Both drugs decrease airway smooth muscle tone by post-junctional mechanisms but they may have opposing effects on pre-junctional acetylcholine (ACh)-release. The airway smooth muscle contractile response is enhanced by ACh acting on post-junctional M3 receptors and inhibited by catecholamine acting on postjunctional β2-adrenoceptors. M-receptor antagonists and β2-adrenoceptor agonists are used alone or in combination for treatment of chronic obstructive pulmonary disease (COPD) Their effects at pre-junctional level are opposing, with muscarinicreceptor antagonists increasing [1,2,3,4,5,6,7] and β2-adrenoceptor agonists decreasing ACh-release [8, 9] from post-ganglionic nerves. One can speculate that the inhibitory pre-junctional effect of β2-adrenoceptor agonists on ACh-release may counteract the stimulatory pre-junctional effect of Mreceptor antagonists by functional antagonism

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