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Muscarinic Receptor Subtypes: Implications for Lung Disease

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Muscarinic Receptor Subtypes: Implications for Lung Disease Thorax: first published as 10.1136/thx.44.3.161 on 1 March 1989. Downloaded from Thorax 1989;44:161-167 Editorial Muscarinic receptor subtypes: implications for lung disease Introduction subtypes is more than a pharmacological curiosity as it is now clear that the subtypes may have different Dale in 1914 first showed that acetylcholine produced physiological roles, may be coupled to different two types of response, which were mimicked by transduction mechanisms, and may be differentially nicotine and by muscarine, and that the muscarinic regulated. action was blocked by atropine.' Only very recently, Recent research has shown that different subtypes however, have muscarinic receptors been subdivided. of muscarinic receptor are present in the airways of This has been made possible by the development of several species, including man'"'5 (fig 1). These selective drugs, and muscarinic receptor subtypes have observations may have clinical importance, as the now been identified in several tissues.23 The evidence receptor subtypes will have different functions and the for muscarinic receptor subtypes was initially development of selective drugs may therefore be of challenged, but advances in molecular biology have clinical benefit in the treatment of airway disease. confirmed their existence and as many as five different receptor subtypes have now been cloned and Muscarinic receptors in airways expressed." The precise relation between these cloned receptor subtypes and receptors identified Cholinergic nerves are the predominant neural pharmacologically, however, is still not clear and the pathway in human airways" " and cholinergic drugs that differentiate receptor subtypes lack a high bronchoconstriction may be important in airway degree of selectivity. obstruction. Cholinergic nerves pass down the vagus http://thorax.bmj.com/ nerve to form synapses in parasympathetic ganglia Muscarnnic receptor classification within the airway wall, from which short post- ganglionic fibres pass to target cells, which include There is still some confusion over the classification and airway smooth muscle and submucosal glands. nomenclature of muscarinic receptors. At least three Acetylcholine is released from postganglionic nerve distinct receptor subtypes have been differentiated varicosities, leading to contraction of airway smooth pharmacologically, both by radioligand binding muscle and mucus secretion, effects that are blocked assays and by functional studies.8 by muscarinic antagonists such as atropine or Pirenzepine was the first selective muscarinic ipratropium bromide. Autoradiographic mapping on October 2, 2021 by guest. Protected copyright. antagonist to be recognised,9 and pirenzepine sensitive studies have shown that muscarinic receptors are muscarinic receptors are termed Ml receptors. Other localised to airway smooth muscle cells and to sub- muscarinic receptors were termed M2 receptors, until it mucosal glands in the airways of animals'8 and man.'9 became clear that they were heterogeneous as new Muscarinic receptors are also localised to nerves and antagonists, such as AF-DX 116'° and methoc- parasympathetic ganglia but they are not found on tramine,"t 12 were developed. M2 receptors in atria were epithelium or bronchial vessels. clearly different from those in smooth muscle and glands, which have now been termed M3 receptors. M3 Ml RECEPTORS receptors are selectively blocked by 4-diphenyl- M, receptors with a high affinity for pirenzepine are acetoxy-N-methyl piperidine methiodide (4-DAMP) generally found in the cerebral cortex and on auto- and hexahydrosiladifenidine. Further subdivision nomic ganglia.?' Pirenzepine is used clinically to may be possible with the development of more reduce gastric acid secretion and, although it was selective drugs. The recognition of muscarinic previously believed to act directly on acid secreting cells, it is now apparent that it acts predominantly on Address for reprint requests: Professor P J Barnes, Department of ganglia in the stomach to inhibit neurally mediated Thoracic Medicine, National Heart and Lung Institute, London gastric secretion.2' As the innervation ofthe airways is SW3 6LY derived embryologically from that of the gut, 161 Thorax: first published as 10.1136/thx.44.3.161 on 1 March 1989. Downloaded from 162 MUSCARINIC RECEPTOR SUBTYPES ACh Ganglion Airway Cholinergic nerve smooth muscle Ml AGONIST McN-A-343 Pilocarpine ANTAGONIST Pirenzepine Gallamine 4-DAMP AF-DX 11 6 Hexahydrosila-difenidol Methoctramine Fig 1 Muscarinic receptor subtypes in airways. M, receptors are localised to parasympathetic ganglia,facilitating neurotransmission; M2 receptors to cholinergic nerves, inhibiting acetylcholine (ACh) release (autoreceptors); and M3 receptors to airway smooth muscle. From Barnes et al 13; reproduced by courtesy of "Trends in Pharmacological Science. " excitatory M, receptors seem likely to exist also in Recent evidence suggests that M, receptors may also airway ganglia. There appear to be considerable be present on human airway cholinergic nerves. Thehttp://thorax.bmj.com/ species differences in the location of muscarinic effects of inhaled pirenzepine and ipratropium receptors in pulmonary nerves, however. Pirenzepine bromide on cholinergic reflex bronchoconstriction, was shown to be very effective in blocking broncho- triggered by inhalation of sulphur dioxide, were constriction due to stimulation of the vagus nerve in compared in atopic subjects. A dose of inhaled both rabbits' and dogs,23 although the studies did not pirenzepine was found that failed to inhibit clearly show that pirenzepine was effective at doses significantly the bronchoconstriction due to inhaled that had little action on the direct bronchoconstrictor methacholine (which acts directly on airway smooth action ofacetylcholine. In vitro, pirenzepine has a low muscle), whereas ipratropium bromide was able to on October 2, 2021 by guest. Protected copyright. potency against acetylcholine induced contraction of block this response as expected. The same dose of rabbit airways' and for binding of the non-selective pirenzepine, however, was as effective as ipratropium antagonist [3H]quinucidinyl benzilate to bovine bromide in blocking bronchoconstriction induced by airways,2425 suggesting that Ml receptors are sulphur dioxide, and as it could not be acting directly not present in airway smooth muscle. Similarly, on airway smooth muscle receptors it must be acting pirenzepine is only weakly effective in inhibiting the on some part of the cholinergic reflex pathway.29 This phosphoinositide turnover stimulated by cholinergic is most likely to be the parasympathetic ganglia in the agonist in bovine airway smooth muscle.24 airways, which may be accessible to inhaled Pirenzepine is a bronchodilator when given pirenzepine. In support ofthis possibility, pirenzepine intravenously to human subjects,2627 although at the has been shown to depress parasympathetic neuro- dose used it might be acting non-selectively and transmission in rabbit bronchi in vitro.30 Furthermore, blocking smooth muscle muscarinic receptors. A human airway parasympathetic ganglia show a high recent study has shown that lower doses of intra- density of muscarinic receptors in autoradiographic venous pirenzepine, although having no effect on studies.'9 FEV,, increase expiratory flow at low lung volumes, The physiological role ofM, receptors in autonomic indicating perhaps a selective action on peripheral ganglia is still not certain. Classically, ganglionic airways.28 transmission is via nicotinic cholinergic receptors, Thorax: first published as 10.1136/thx.44.3.161 on 1 March 1989. Downloaded from 163 which are activated by nicotine and blocked by find similar receptors in airway cholinergic nerves. hexamethonium. Possibly excitatory Ml receptors are These autoreceptors are inhibited by gallamine and facilitatory to nicotinic receptors and may play a part are therefore classified as M2 receptors, thus differing in "setting" the efficacy of ganglion transmission. from the muscarinic receptor subtypes on airway Activation of these receptors probably closes potas- smooth muscle, which are classified as M3 recep- sium channels, resulting in a slow depolarisation ofthe tors.394 M2 receptors appear to be located before the ganglion cell.3' They might perhaps have a role in the junctions on postganglionic parasympathetic nerves,4' long term regulation of cholinergic tone, whereas where they have a powerful inhibitory effect on nicotinic receptors are more important in rapid acetylcholine release. Muscarinic autoreceptors have signalling, such as occurs during reflex activation of now been identified in guinea pig,3942 cat,'" and dog the cholinergic pathway. If so, M, antagonists such as airways,43 but they are lacking in the rat and rabbit.39 pirenzepine or telenzepine might have a useful Recently, similar feedback inhibitory receptors have therapeutic role in asthma as they may reduce vagal been localised to postganglionic cholinergic nerves in tone. As increased vagal tone may have an important human airways in vitro.42 role in nocturnal exacerbations of asthma,32 33 Pilocarpine, a selective agonist of M2 receptors, pirenzepine might prove to be efficacious in preventing inhibits cholinergic nerve induced contraction of nocturnal wheeze. human bronchi elicited by electrical field stimulation, M, receptors have also been detected in the lungs by while not affecting contraction induced directly by radioligand binding studies, but the results are unex-
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