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

Background: 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.
Methods: We 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.
Results: GLY 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.
Conclusions: At 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.