2-Agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway

Abstract

b 2 -Adrenoceptor agonists are the most effective bronchodilators currently available, and are used for symptom management in asthmatics. However, whether b 2 -agonists are also antitussive is controversial. Identifying an antitussive role for b 2 -agonists and dissecting the possible mechanism of action may help to explain the inconsistencies in the clinical literature and lead to the development of novel therapeutic agents. The aim of the present study was to determine whether or not b 2 -agonists attenuate the tussive response in guinea pig and human models, and, if so, to identify the mechanism(s) involved.Depolarisation of vagal sensory nerves (human and guinea pig) was assessed as an indicator of sensory nerve activity. Cough was measured in a conscious guinea pig model.A b 2 -agonist, terbutaline, dose-dependently inhibited the cough response to tussive agents in conscious guinea pigs. Terbutaline and another b 2 -agonist, fenoterol, blocked sensory nerve activation in vitro. Using these mechanistic models, it was established that b 2 -agonists suppress the tussive response via a nonclassical cyclic adenosine monosphosphate-dependent pathway that involves the activation of protein kinase G and, subsequently, the opening of largeconductance calcium-activated potassium channels.In conclusion, b 2 -adrenoceptor agonists are antitussive, and this property occurs due to a direct inhibition of sensory nerve activation. These findings may help to explain the confusion that exists in the clinical literature, and could be exploited to identify novel therapies for the treatment of cough, which is a significant unmet medical need.

Do 2-agonists inhibit capsaicin-induced cough?

“…We read with great interest the paper by FREUND-MICHEL et al [1] in a recent issue of the European Respiratory Journal, because the results are inconsistent with the medical common sense that b 2 -agonists do not have common antitussive property.…”

“…The recoil of the chest wall and lungs is equal at the functional residual capacity (FRC). The difference of values obtained from RV and FRC is not important in healthy subjects [1]. In patients with neuromuscular disorders, the advantage of measuring the voluntary inspiratory strength from FRC is that only the force of the inspiratory muscles is assessed and not the negative recoil pressure of the respiratory system.…”

“…N.G Koulouris demonstrates that better values of inspiratory strength were obtained with a tube mouthpiece rather than a flanged mouthpiece in healthy subjects [3]. Patients find the flanged mouthpiece easier than the tube explaining its widespead use [1]. In our experience with neuromuscular disorders, especially in amyotrophic lateral sclerosis with bulbar involvement, air leaks were less important with a flanged mouthpiece [4].…”

“…FREUND-MICHEL et al [1] exposed capsaicin (10 -4 M) for 5 min and measured the number of coughs for 10 min. However, we exposed capsaicin (10 -4 M) for 2 min and measured the number of coughs for 3 min.…”

“…In order to elucidate the different results, we actually measured the number of coughs using the method described by FREUND-MICHEL et al [1]. Guinea pigs were assigned to one of two groups: a control group and a procaterol group (n56 for each group).…”