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Home , Autonomic nervous system, Nervous system

: first published as 10.1136/thx.39.8.561 on 1 August 1984. Downloaded from Thorax 1984;39:561-567

Editorial

The third nervous in the : physiology and clinical perspectives The autonomic controls many are neither adrenergic nor cholinergic were aspects of pulmonary function' and, until recently, it described by Campbell in 1971.4 Since then NANC was that this was achieved entirely by means which relax airway have been of classical cholinergic and adrenergic mechanisms. found in several species, including man.55 In these This view has recently been challenged by the studies airway strips are mounted in an bath demonstration of a third nervous system in the air- and stimulated by an electrical current that selec- ways (fig). Although the identities of the neuro- tively activates nerves. In guinea pig tracheal strips transmitters in this newly recognised nervous system electrical field stimulation produces an initial con- are not certain, there is increasing evidence that they traction that is blocked by the anticholinergic are . This third nervous system is of particu- atropine and therefore due to release lar interest as it is the predominant inhibitory nerv- from cholinergic nerves. The initial contraction is ous pathway to airway smooth muscle and followed by a relaxation, which is only partially this raises the possibility that a functional defect in inhibited by ,3 adrenergic blockers.56 Thus, although this nervous system might underlie bronchial hyper- a component of the inhibitory response is reactivity in asthma. The recognition that a third adrenergic, there is a component that is non- component of the regu- adrenergic. The toxin tetrodotoxin abolishes lates airway smooth muscle tone and other aspects these responses to field stimulation and proves that copyright. of lung physiology has stimulated great interest, they are mediated by nerves (which must be post- since it may provide new insights into diseases such ganglionic), and not due to a direct effect on smooth as asthma and chronic obstructive lung disease, and muscle. Thus guinea pig appears to have may also to novel therapeutic approaches. excitatory cholinergic nerves and inhibitory nerves

which are both adrenergic and non-adrenergic. In http://thorax.bmj.com/ A third component of the autonomic nervous system similar studies on human airway smooth muscle a cholinergic contractile component is also demon- The existence of a nervous system in the gastrointes- strable, but the inhibitory response is unaffected by tinal tract which is neither adrenergic nor adrenergic blockade.78 This indicates, rather surpris- cholinergic has been established for many years. ingly, that there is no functional sympathetic inner- Non-adrenergic, non-cholinergic (NANC) nerves vation of human airway smooth muscle and that control gut and secretions and have been inhibitory nerves are non-adrenergic. The absence demonstrated in from to man.23 of sympathetic nerves in human airway smooth Indeed, the presence of NANC nerves in primitive muscle is supported by histological studies showing on September 30, 2021 by guest. Protected vertebrates indicates that this nervous system an absence of adrenergic nerve terminals within developed early in evolution. The third nervous sys- smooth muscle,79 by studies showing a lack of effect tem has also been demonstrated in the urogenital of cocaine (a neuronal uptake inhibitor) on norad- tract, the , and the cardiovascular system.3 renaline dose-response curves,'0 and by the lack of Because the airways develop embroyologically from effect of tyramine (which directly releases norad- the foregut it is not surprising to find that NANC renaline from nerve terminals) on airway function in nerves are also present in the lung. man." There are, of course, adrenergic receptors in airway smooth muscle,'2 and these are presumably NANC nerves in the airways regulated by circulating .'3 NANC nerves appear to be the only neural inhibitory pathway in Inhibitory nerves which relax toad and which human airway smooth muscle from the trachea to the smallest bronchi,7 and for this reason there is Address for reprint requests: Dr Peter J Barnes, Department of particular interest in their physiological role and (Respiratory Division), Royal Postgraduate Medical regulation. School, Hammersmith Hospital, London W12 OHS. NANC nerves have also been demonstrated in 561 Thorax: first published as 10.1136/thx.39.8.561 on 1 August 1984. Downloaded from 562 NON-ADRENERG IC, ADRENERGIC CHOLINERGIC NON-CHOLINERGIC

I c2 v vagus sympathetic nerve cholinergic efferent

ik non -adrenergic, mnt

afferent

ACh NVIP

smooth muscle copyright. epithelium Im *M ef Xa * X 0* * 0 a 0-Gre). a% lm )JI/Millil IIIIIIIIII)nfliff/ I)IIJImill a airway lumen http://thorax.bmj.com/ Innervation ofhuman airway smooth muscle: the three components ofthe autonomic nervous system. In addition to classical adrenergic and cholinergic pathways, there is a third component to the autonomic nervous system, shown by the dashed lines. The non-cholinergic, non-adrenergic pathway is inhibitory to airway smooth muscle, the of which is likely to be vasoactive intestinal (VIP). There may also be an excitatory non-cholinergic pathway, which may consist ofcollateral branches ofafferent nerves which release substance P. Specific receptors for these present on airway smooth muscle cells: 3,-8 adrenergic, M-muscarnic cholinergic, V-VIP, and P-substance on September 30, 2021 by guest. Protected P receptors. ACh-acety1choline.

cats and guinea pigs in vivo by electrical stimulation promotes mucus secretion in cat trachea, which is of the after cholinergic and adrenergic reduced but not abolished by cholinergic and blockade.'4-'6 Stimulation of this pathway produces adrenergic blockers"; and electrical field stimula- pronounced and long lasting bronchodilatation. This tion of ferret tracheal segments in vitro also indi- response can be inhibited by blockers, sug- cates that NANC nerves stimulate mucus secre- gesting that these NANC nerves are preganglionic tion.'8 NANC nerves may also mediate relaxation of as well as postganglionic.'4 It has not yet been poss- pulmonary blood vessels.'9 ible to establish whether NANC nerves mediate bronchodilation in human airways in vivo, although The search for the neurotransmitter such studies should be possible with pharmacologi- cal blockade and stimulation. Although it has been possible to demonstrate the NANC nerves also regulate secretion of airway existence of NANC nerves in the lung both in vitro mucus in . Stimulation of the vagus nerves and in vivo, it is difficult to investigate the physio- Thorax: first published as 10.1136/thx.39.8.561 on 1 August 1984. Downloaded from 563 logical role of this nervous system until the neuro- ised to neurones and nerve terminals in airway transmitter has been identified and a specific blocker smooth muscle (particularly in the upper airways), developed. Burnstock originally proposed that the around submucosal glands, beneath airway epi- neurotransmitter might be a purine nucleotide such thelial cells, and in bronchial and pulmonary as (ATP) or adenosine, vessels. 273132 In addition, VIP is localised in airway since in the gut these purines are released on nerve ganglia in both neurones and preganglionic nerve stimulation and both exogenous ATP and adenosine terminals (CB Basbaum, PJ Barnes, unpublished mimic some of the effects of NANC nerve stimula- observations). VIP produces prolonged relaxation tion.2 These nerves were therefore termed of airway smooth muscle in vitro, which is unaf- purinergic. The evidence is, however, against a fected by adrenergic or cholinergic blockers.2'2230 purine as the neurotransmitter of NANC nerves in Moreover, VIP mimics the electrophysiological the airways. Although ATP relaxes isolated guinea changes in airway smooth muscle produced by pig airway smooth muscle,202' its antagonist NANC nerve stimulation.2' 22 In vivo inhaled VIP quinidine does not block NANC relaxation either in protects against histamine induced bronchoconstric- vitro or in vivo,202223 nor does the purine uptake tion in dogs'9 and guinea pigs,33 and infused VIP inhibitor dipyridamole enhance non-adrenergic reverses induced bronchoconstriction in bronchodilation.2'22 cats.34 In isolated human airways VIP has a small More recent studies suggest that the neurotrans- relaxant effect8 and inhaled VIP has only a weak mitter may be a regulatory peptide, so that NANC protective effect against histamine induced bron- nerves are probably "peptidergic." There is now choconstriction compared with a /8 agonist.35 VIP rather convincing evidence that several regulatory given by infusion has a small effect peptides may be neurotransmitters or and protects against histamine induced wheeze in neuromodulators in the gut.24 Electron microscopy asthmatics,36 although the cardiovascular actions of has revealed different types of neurosecretory the infused peptide may have accounted for these granules in terminals in the gut25: effects. The relative lack of effect of VIP in human small clear vesicles which contain acetylcholine and airways by no means excludes it as a possible small dense granules containing catecholamines re- neurotransmitter as the exogenous peptide may copyright. present cholinergic and adrenergic nerves. In addi- have relatively poor access to airway smooth muscle tion, there are large dense vesicles resembling compared with peptide released from nerves within neurosecretory granules in the central nervous sys- the muscle. tem that are known to contain peptides, and which Electrical field stimulation of tracheobronchial were therefore called "p" type granules.25 Ultra- preparations releases VIP into the bathing medium http://thorax.bmj.com/ structural immunocytochemical techniques have and the release is blocked by tetrodotoxin, indicat- now confirmed that peptides such as substance P and ing that VIP is derived from nerve stimulation.223' vasoactive intestinal peptide (VIP-see below) are Furthermore, the amount of VIP released is related localised to these granules.24 Similar "p" type to the magnitude of NANC relaxation.3' Unfortu- granules have also been described in nerves of the nately no specific blocker of VIP is yet available, but airways, 26 suggesting that peptides may function as prolonged incubation of airway smooth muscle with neurotransmitters of NANC nerves in the lung. Sev- VIP reduces subsequent responses to VIP eral regulatory peptides have been recently (tachyphylaxis) and also reduces the magnitude of on September 30, 2021 by guest. Protected identified by radioimmunoassay in lung tissue of NANC nerve relaxation in cats.2' Preincubation of several species (including man); they include VIP, guinea pig trachea with a specific antibody to VIP substance P, bombesin, cholecystokinin, and also reduces the NANC relaxation response.37 somatostatin.2728 Immunocytochemical studies have Taken together, all this evidence points strongly to demonstrated that some of these peptides are local- VIP as a likely candidate for the role of neurotrans- ised to nerves within the airway. mitter of non-adrenergic inhibitory nerves. Conclu- sive proof, particularly in human airways, awaits VIP and NANC neurotransmintter development of a specific blocker.

There is now considerable evidence in favour of VIP Other VIPergic nerves in lung as a neurotransmitter of NANC nerves in the air- way. VIP is a 28 amino acid peptide which was orig- VIPergic nerves may regulate other aspects of pul- inally discovered by Said as a vasoactive substance monary function, since they are widely distributed in lung extracts,29 and was later shown to relax air- within the lung. VIPergic nerves are closely associ- way smooth muscle in vitro.30 More recently VIP has ated with airway submuscosal glands27 32 and in vitro been found in both and human lungs local- VIP stimulates secretion of mucus from tracheal Thorax: first published as 10.1136/thx.39.8.561 on 1 August 1984. Downloaded from 564 glands in ferrets." VIP is therefore a possible effect on VIP receptors of target cells, also has a neurotransmitter of non-adrenergic, non- prejunctional effect on acetylcholine release or, as cholinergic nervous secretion of mucus. VIP has an demonstrated in submaxillary glands,47 an effect on unexpected inhibitory effect on secretion of mac- postjunctional cholinergic receptors. The relation- romolecules from isolated human airways, how- ship between cholinergic and VIPergic neurotrans- ever.39 VIPergic nerves are also present in close mission in the lung is worthy of further exploration. association with the airway epithelium and VIP is a potent of active ion transport and there- Substance P and non-cholinergic excitatory nerves fore water secretion across airway epithelium in dogs.40 Thus VIPergic nerves may regulate secretion Substance P, an 11 amino acid peptide, is localised of both mucus and water, and so influence mucocili- to afferent nerves in the airways of several species, ary transport in the airways. including man.2748 Substance P immunoreactive VIP is a potent vasodilator in the pulmonary cir- nerves in the airway are found beneath and within culation, and the finding of a rich supply of VIPergic the airway epithelium, around blood vessels, and to nerves in pulmonary vessels indicates that it is quite a lesser extent within airway smooth muscle. Treat- likely to be the mediator for NANC nervous vasodi- ment of animals with capsaicin, a pungent extract of lation in the lung.'9 VIPergic nerves may also mod- red peppers, releases substance P from sensory ulate cholinergic in airway gang- nerves and depletes the lung of substance P.49 Sub- lia. VIP inhibits antigen induced release of his- stance P contracts airway smooth muscle of several tamine from sensitised guinea pig lung fragments in species, including man.4850 Moreover, capsaicin is vitro4' and this raises the possibility that VIPergic capable of inducing a similar contraction, indicating nerves also regulate mast cell mediator secretion. release of substance P from intrinsic nerves within airway smooth muscle.50 In rats substance P and Mode of action of VIP capsaicin induce oedema of the airway mucosa by increasing vascular permeability, and depletion of VIP is released from nerve terminals and stimulates substance P nerves by neonatal capsaicin pretreat- specific receptors, which have been demonstrated in ment prevents irritants such as cigarette smoke fromcopyright. lung membranes by radioligand binding techniques causing mucosal oedema, suggesting that substance with labelled VIP.42 Preliminary results with auto- P nerves mediate this effect.5' Substance P also radiography of radiolabelled VIP indicate that the stimulates airway mucus secretion.5' Electrical receptors are widely distributed within the lung (A stimulation of guinea pig bronchi in vitro produces a Nimmo et al, unpublished observations). Stimula- component of bronchoconstriction which is not http://thorax.bmj.com/ tion of VIP receptors activates adenylate cyclase, inhibited by atropine,5253 but which is blocked by a thereby increasing the cellular concentration of substance P antagonist.52 In human airways, how- cyclic AMP. Thus VIP increases the cyclic AMP ever, this non-cholinergic non-adrenergic excitatory content of lung and trachea,43 and this increase in nervous pathway was found in only one out of eight cyclic AMP has been localised immunocytochemi- airways tested.50 In man inhalation of capsaicin cally to epithelial cells, submucosal glands, and air- induces and transient bronchoconstriction way smooth muscle cells.44 Beta adrenoceptor agon- which is seen in both normal and asthmatic sub- ists also activate adenylate cyclase and the jects,54 and substance P is a bronchoconstrictor physiological effects of VIP on the airways are simi- when given by inhalation (R Fuller et al, unpub- on September 30, 2021 by guest. Protected lar to those of m agonists. It is possible that there lished observations). may be a deficiency in VIP receptors in the airways of asthmatic patients, in the same way that (8 Other regulatory peptides in lung adrenoceptor dysfunction has been postulated as an underlying mechanism of asthma.45 The protective Several other peptides have recently been found in effect of VIP against histamine induced bron- lung. Peptide histidine isoleucine (PHI) is structur- choconstriction is not, however, correlated with the ally similar to VIP and is localised to VIPergic degree of bronchial hyperreactivity, which argues nerves.55 PHI, like VIP, relaxes airway smooth mus- against a defect in VIP receptors that contributes to cle but stimulates specific PHI receptors. It is there- this phenomenon." fore another candidate for the role of neurotrans- VIPergic nerves are usually distributed with mitter of NANC nerves and probably functions in cholinergic nerves. Ultrastructural evidence suggests conjunction with VIP. A newly discovered peptide, that VIP may coexist in the same nerve terminals as neuropeptide Y (NPY), has also been localised to acetylcholine and may therefore function as a co- nerves in the lung and is associated with sympathetic transmitter.46 Possibly VIP, in addition to a direct nerves, so that it is found in blood vessels rather Thorax: first published as 10.1136/thx.39.8.561 on 1 August 1984. Downloaded from 565 than airway smooth muscle in human airways.2856 response when injected intradermally48 and causes Cholecystokinin and somatostatin, which function as the direct release of histamine from human neurotransmitters in the gut, have also been mast cells in vivo (D Heavey et al, unpublished identified in airways, although in concentrations too observations). If this were to occur in the airway low to permit localisation at present.27 Another pep- then stimulation of substance P nerves could lead to tide, bombesin, causes bronchoconstriction in high a local reflex, with release of substance P, concentrations,5' but is localised to neuroendocrine resulting in bronchial smooth cells rather than nerves.27 As assay techniques and and mucosal oedema. It is tempting to speculate that isolation procedures improve it is almost certain that in asthma these substance P nerves may be sensi- other peptides will be identified in the respiratory tised by inflammation, or that airway mast cells may tract. be more sensitive to substance P, so that constrictor responses become exaggerated. Clinical significance of NANC nerves in lung The clinical implications of NANC innervation in the lungs are only now being appreciated, but The recent discovery of NANC innervation in the abnormal function of non-adrenergic inhibitory lung has important clinical implications and may nerves (which are probably VIPergic and PHIergic) lead to further understanding and new treatment of or of non-cholinergic excitatory nerves (probably several pulmonary diseases. Asthmatic subjects substance P containing) could underly bronchial show exaggerated bronchoconstrictor responses to a hyperreactivity in asthma. NANC nerves also wide variety of stimuli, and, because changes in air- influence airway mucus secretion and pulmonary way tone are rapid, it is suggested that abnormal vascular tone, so that there are important implica- nervous control of the airway is the underlying tions for chronic bronchitis and for pulmonary vas- mechanism of bronchial hyperreactivity, with a pre- cular disease. Future development of novel ponderance of excitatory (cholinergic and a which interact with NANC neurotransmission adrenergic) or a deficiency of inhibitory (,8 should lead to new forms of treatment for these dis- adrenergic) control. Although minor abnormalities eases. It is certain that much more will be heard of in classical autonomic mechanisms have been found NANC nerves and their neurotransmitters in the copyright. in asthma, they are insufficient to account for bron- lungs as their physiology and pathophysiology are chial hyperreactivity.' The recent discovery of non- unravelled. adrenergic inhibitory nerves in the airways has PETER J BARNES therefore raised the possibility that this nervous sys- Department of Medicine tem is defective in asthma, particularly since it is the (Respiratory Division) http://thorax.bmj.com/ only neural inhibitory system in human airways. Royal Postgraduate Medical School Non-adrenergic inhibitory nerves may exert a brak- Hammersmith Hospital ing effect on bronchoconstriction, and a functional London defect would presumably lead to exaggerated responses to constrictor stimuli. Unfortunately the References absence of specific blocking drugs for these nerves makes it difficult to evaluate this possibility at pres- 'Nadel JA, Barnes PJ. Autonomic regulation of the air- ent, although it seems likely that specific inhibitors ways. Ann Rev Med 1984;35:451-67. 2 on September 30, 2021 by guest. Protected of putative neurotransmitters such as VIP will be Burnstock G. Purinergic nerves. Pharm Rev 1972; 24:509-81. developed soon. There are analogies between 3Burnstock G. Comparative studies of purinergic nerves. asthma and other conditions in which there is J Exp Zool 1975;194:103-34. abnormal smooth muscle control and in which Campbell G. Autonomic innervation of the lung muscu- abnormalities of peptidergic nerves have been lature of a toad (Bufo marinus). Comp Gen Phar- found. In Hirschprung' s disease there is contraction macol 1971;2:281-6. of colonic smooth muscle and an absence of ganglia 'Coburn RF, Tomita T. Evidence for nonadrenergic inhibitory nerves in guinea pig trachealis muscle. Am J and peptidergic nerves in the colon wall.58 A similar Physiol 1973;224:1072-80. reduction in VIPergic nerves has also been found in 6 Richardson JB. Nonadrenergic inhibitory innervation of the wall of unstable bladders.58 the lung. Lung 1981;159:315-22. The demonstration of substance P containing Richardson J, Beland J. Nonadrenergic inhibitory nerv- nerves in human airways is also clinically relevant ous system in human airways. J Appl Physiol 1976;41:764-71. since this peptide can produce bronchoconstriction, 8 Davis C, Kannan MS, Jones TR, Daniel EE. Control of bronchial mucosal oedema, and mucus hypersecre- human airway smooth muscle: in vitro studies. J Appl tion, all of which are features of asthma. In human Physiol 1982;53:1080-7. skin substance P produces a weal and flare 9 Sheppard MN, Kurian SS, Henzen-Logmans SC et al. Thorax: first published as 10.1136/thx.39.8.561 on 1 August 1984. Downloaded from 566 Neurone-specific enolase and S-100: new markers for of man and other animals. Exp Lung delineating the innervation of the respiratory tract in Res 1982;3:313-28. man and other mammals. Thorax 1983;38:333-40. 28 Hakanson R, Sundler F, Moghimzadeh E, Leander S. '0 Zaagsma J, Van der Heijden PJCM, Van der Schaar Peptide-containing nerve fibres in the airways: dis- MWG, Bank CMC. Comparison of functional beta- tribution and functional implications. Eur J Respir Dis adrenoceptor heterogeneity in central and peripheral 1983;64, suppl 131:115-46. airway smooth muscle of guinea pig and man. J Recept 29 Said SI, Mutt V. 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Science 1980; 33 Cox CP, Lerner MR, Wells JH, Said SI. Inhaled vasoac- 208:185-8. tive intestinal peptide (VIP) prevents bronchocon- ,s Irvin CG, Boileau R, Tremblay J, Martin RR, Macklem striction induced by inhaled histamine. Am Rev Respir PT. Bronchodilatation: noncholinergic, nonadrenergic Dis 1983; 127:249. mediation demonstrated in vivo in the cat. Science 34 Diamond L, Szarek JL, Gillespie MN, Altiere RJ. In 1980;207:791-2. vivo bronchodilator activity of vasoactive intestinal 16 Chesrown SE, Venugopalan CS, Gold WM, Drazen JM. peptide in the cat. Am Rev Respir Dis 1983; In vivo demonstration of nonadrenergic inhibitory 128:827-32. innervation of the guinea pig trachea. J Clin Invest 3S Barnes PJ, Dixon CMS. The effect of inhaled vasoactive 1980;65:314-20. intestinal peptide on bronchial reactivity to 7 Peatfield AC, Richardson PS. Evidence for non- histamine in man. 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secretion into the cat trachea. J Physiol 1983; peptide causes bronchodilatation and protects against copyright. 342:335-45. histamine-induced bronchoconstriction in asthmatic 8 Borson DB, Charlin M, Gold BD, Nadel JA. Nonad- subjects. Lancet 1983;ii: 1225-6. renergic noncholinergic nerves mediate secretion of 37 Matsuzaki Y, Hamasaki Y, Said SI. Vasoactive intestinal macromolecules by tracheal glands of ferrets. Fed peptide: a possible transmitter of nonadrenergic Proc 1982;42:1715. relaxation of guinea pig airways. Science 1980; 9 Said SI. Vasoactive peptides in the lung, with special 210:1252-3. http://thorax.bmj.com/ reference to vasoactive intestinal peptide. Exp Lung 38 Peatfield AC, Barnes PJ, Bratcher C, Nadel JA, Davis B. Res 1982;3:343-8. Vasoactive intestinal peptide stimulates tracheal sub- 20 Kamikawa Y, Shimo Y. Pharmacological differences in mucosal gland secretion in ferret. Am Rev Respir Dis non-adrenergic inhibitory response and of ATP- 1983; 128:89-93. induced relaxations in guinea pig tracheal strip chains. 39 Coles SJ, Said SI, Reid LM. Inhibition by vasoactive J Pharm Pharmacol 1976;28:854-5. intestinal peptide of glycoconjugate and lysozyme sec- 21 Ito Y, Takeda K. Non-adrenergic inhibitory nerves and retion by human airways in vitro. Am Rev Respir Dis putative transmitters in the smooth muscle of cat 1981; 124:531-6. trachea. J Physiol 1982;330:497-51 1. 40 Nathanson I, Widdicombe JH, Barnes PJ. Effect of 22 Cameron AC, Johnson CF, Kirkpatrick CT, Kirkpatrick vasoactive intestinal across tracheal

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