The effect of tussive and non-tussive agents on airway sensory nerves in the anaesthetised rabbit

John Adcock, Ruth Keir, Brian Moore, Mike Yeadon and Mike Trevethick. Allergy & Respiratory Biology, Pfizer Global R&D, Sandwich, UK.

Three types of sensory nerve ending with fibres in the vagus nerve found in the tracheobronchial tree are involved directly/indirectly in cough: the rapidly adapting stretch receptors (RARs), the slowly adapting stretch receptors (SARs) and C-fibre receptors (Widdicombe, 1998). We have compared the effects of 2 agents (citric acid, capsaicin) that evoke cough, with 2 agents (salmeterol, beclomethasone) that do not cause cough in humans, on the activity of Aδ -fibres originating from RARs and C-fibres with endings of pulmonary (PC) and bronchial (BC) origin in the airways of anaesthetised rabbits.

Male NZW rabbits (2.6–3.4 kg), anaesthetised with a -chloralose (60-80 mg kg-1 i.v.) after induction with sodium pentobarbital (20–40mg kg-1 i.v.), were paralysed with vecuronium bromide (0.10 mg kg-1 i.v. followed every 15 min with 0.05 mg kg-1 i.v. to maintain blockade) and artificially ventilated (48 breaths min-1; tidal volume, 10mL kg-1). Nerve fibres of the left vagus, cut centrally, were dissected and impulse discharges in Aδ - and C-fibres recorded and counted using extracellular electrophysiological techniques. Fibres were identified by their spontaneous activity, responses to inflation, deflation, drugs and by conduction velocities. To activate and identify RARs, histamine was administered i.v. (20 μg kg-1 in 0.89% w/v NaCl) and by aerosol (DeVilbiss ultraneb; 6 breaths 1.0mg ml-1). Capsaicin (30μg kg-1 in an ethanol, Tween 80, saline mixture, 1:1:23, v/v) was injected i.v. (jugular vein) or i.a. (carotid artery) to differentiate between pulmonary (response £ 2 s after i.v.) and bronchial C-fibres (response £ 2 s after i.a.), respectively, and also by aerosol (6 breaths 100μg ml-1). For comparative purposes, citric acid (1, 3, 10μmol), capsaicin (1, 3, 10nmol), salmeterol (83, 249, 830nmol), beclomethasone (0.5, 1.5, 5.0μmol), solubilised in a micelle vehicle, at doses of 1, 3 and 10x active human dose were administered (n=4 for each compound and each fibre type) via the tracheal cannula (i.t.) using a Penn-Century Microsprayer. Statistical comparisons were performed using ANOVA and a Multiple Comparison test. Values of P<0.05 were considered significant.

Administration of micelle vehicle i.t. (50-400 m L) had no significant (P>0.05) effects on the firing rate in Aδ- and C-fibres. Capsaicin (at all doses tested) and citric acid (at 3, 10 μmol) evoked significant (P<0.05) activation of RARs. In addition, they also caused significant (P<0.05) activation of PC-fibre endings at all doses examined. Furthermore, capsaicin at 10 nmol and citric acid at 1, 3, and 10 μmol evoked significant (P<0.05) increases in the discharge rates recorded in BC-fibres. In contrast, neither salmeterol nor beclomethasone, at any dose, had any significant (P>0.05) effects on the discharge rates of RARs, PC and BC-fibre endings. After compound administration, RARs were still activated with aerosolised histamine (6 breaths of 1.0 mg ml-1) and C-fibres were activated with aerosolised capsaicin (6 breaths of 100 μg ml-1), confirming cell viability.

Our data suggest that agents known to cause cough in humans activate, in rabbit airways, RARs, PCs and BCs, whereas agents that fail to induce cough in humans do not activate any of the airway sensory nerves examined.

Widdicombe, JG. (1998) Respir. Physiol., 114: 5-15.