NON‐ADRENERGIC, NON‐CHOLINERGIC NEURAL CONTROL OF THE AIRWAYS

SUMMARY 1. In addition to the classical cholinergic bronchoconstrictor and adrenergic bronchodilator neural mechanisms, there is a large volume of evidence to suggest the existence of neural pathways within the airways of a variety of species which are neither adrenergic nor cholinergic, the non‐adrenergic, non‐cholinergic (NANC) mechanisms. With respect to airway smooth muscle tone, NANC neural responses may induce either contraction (excitatory, e‐NANC) or relaxation (inhibitory, i‐NANC). Early investigations of NANC mechanisms in both human and other animal airways suggested a role for neuropeptides as the putative neurotransmitters. 2. Excitatory NANC (e‐NANC) bronchoconstrictor responses are believed to be mediated by the release of sensory neuropeptides from a subpopulation of non‐myelinated C‐fibre primary afferent neurones in the airways. e‐NANC nerves, which release tachykinins such as substance P (SP), neurokinin A (NKA) and the peptide calcitonin gene‐related peptide (CGRP, produced as a result of alternative splicing of the calcitonin gene) are selectively degenerated by the nerve toxin capsaicin (an extract from hot peppers), with the subsequent abolition of the e‐NANC responses. Tachykinin receptors have been detected by radio‐ligand receptor binding studies and visualized by autoradiographic mapping, and exogenous addition of these peptides elicits a bronchoconstrictor response in both human and other animal airways. In addition to these effects on airway smooth muscle tone, tachykinins produce an increase in microvascular permeability (and associated oedema formation), mucus hypersecretion and cause an exaggerated cholinergic bronchoconstrictor response. Thus, tachykinins may play a role in the inflammatory process and contribute to the neurogenic inflammation as seen in asthma. 3. Inhibitory NANC (i‐NANC) bronchodilator responses were believed to be due to the release of peptides such as vasoactive intestinal peptide (VIP) and peptide histidine isoleucine/methionine (PHI/M). VIP is believed to be co‐localized to cholinergic nerves in the airways and is co‐released upon cholinergic nerve stimulation. Recent evidence, however, would suggest that, together with VIP and related peptides, another substance may mediate i‐NANC responses in the airways. Nitric oxide (NO), which is formed from arginine in a reaction catalysed by the enzyme NO synthase, has been shown to mediate bronchodilator responses evoked in both human and other animal airway smooth muscles following nerve stimulation in vitro. 4. NANC neural mechanisms play an important role in the maintenance and regulation of bronchomotor tone, either via the direct effects of the transmitters released or by neuromodulation of autonomic control mechanisms. The study of NANC nerves in the airways has led to a greater understanding of the interaction between different nerve types in the respiratory tract and provided new insights into, and understanding of, the pathogenesis of airway disease.