airway receptors - postgraduate medical journal · airway epithelium in bovine airways in vitro...

Postgraduate Medical Journal (1989) 65, 532- 542

Mechanisms of Disease

Airway receptors

Peter J. Barnes

Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6L Y, UK.

Introduction

Airway smooth muscle tone is influenced by many

hormones, neurotransmitters, drugs and mediators,which produce their effects by binding to specificsurface receptors on airway smooth muscle cells.Bronchoconstriction and bronchodilatation may

therefore be viewed in terms of receptor activation or

blockade and the contractile state of airway smoothmuscle is probably the resultant effect of interactingexcitatory and inhibitory receptors.

It is important to recognize that airway calibre is notonly the result of airway smooth muscle tone, but inasthma it is likely that airway narrowing may also beexplained by oedema of the bronchial wall (resultingfrom microvascular leakage) and to luminal pluggingby viscous mucus secretions and extravasated plasmaproteins, which may be produced by a 'soup' ofmediators released from inflammatory cells, includingmast cells, macrophages and eosinophils. Activationof receptors on other target cells, such as submucosalglands, airway epithelium, post capillary venules, mastcells and other inflammatory cells may, therefore, alsoinfluence airway calibre.

In this article I will concentrate on some of thereceptors present on airway smooth muscle which maybe relevant to airway disease.

Indirect regulation of airway smooth muscle

There is a complex interaction between different cellsin the airway and, while many stimuli may act directlyon airway smooth muscle cells, others may affectsmooth muscle tone indirectly, either via neural con-trol mechanisms, via release of mediators frominflammatory cells, or possibly via release of epithelialfactors. Thus, bradykinin is a potent bronchoconstric-tor when given by inhalation in man, but has littleeffect on human airway muscle in vitro,' suggesting an

indirect action which, in part, is due to activation of acholinergic reflex, since the bronchoconstriction maybe reduced by a cholinergic antagonist. Othermediators may have a bronchoconstrictor effectwhich, in the case of adenosine, is due to mast cellmediator release,2 or in the case of platelet-activatingfactor due to platelet products.3

Epithelial-derived relaxantfactor

Recently there has been considerable interest in thepossibility of a relaxant factor released from airwayepithelial cells, which may be analogous toendothelial-derived relaxant factor.4 The presence ofairway epithelium in bovine airways in vitro reducesthe sensitivity to and maximum contractile effect ofspasmogens, such as histamine, acetylcholine or

serotonin, although not potassium which depolarisesairway smooth muscle directly.5 Similar results havebeen obtained in dog,6 guinea pig7 and human air-ways.4 One possibility is that these spasmogens releasefactor from epithelium, rather like endothelium-derived relaxant factor, which directly relaxes airwaysmooth muscle. The nature of this putative factor isuncertain, but it does not appear to be influenced byeither cyclo-oxygenase or lipoxygenase blockade.5'6Another possibility is that enzymes present inepithelial cells normally degrade mediators so thatepithelial removal enhances their effect.

Airway receptors and disease

Since surface receptors may determine tissue respon-siveness it is possible that alterations in receptors onairway smooth muscle might account for increasedairway responsiveness seen in asthma, and, to a lesserextent, in chronic obstructive airways disease. Manydifferent factors are known to alter receptor expres-sion and could change either receptor density, affinity,or coupling. Thus, inflammatory mediators which are

formed in the airway wall may have effects on variousreceptors which could lead to an increased responsive-ness. Since in asthma the increased responsiveness is

t) The Fellowship of Postgraduate Medicine, 1989

Correspondence: Professor P.J. Barnes, M.A., D.Sc., D.M.,F.R.C.P.Received: 27 December 1988Supported by Medical Research Council and AsthmaResearch Council

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AIRWAY RECEPTORS 533

found with many different bronchoconstrictor stimuli,it is unlikely that there is an effect on a single type ofreceptor (e.g. muscarinic or histamine receptors). It ismore probable that there is enhanced coupling of allreceptors, perhaps via phosphoinositide hydrolysis, orthat there is a defect in inhibitory receptors (e.g.beta-adrenoceptors).

Receptor coupling and second messengers

There have recently been considerable advances inmolecular pharmacology of receptors. Several recep-tors have now been cloned and expressed and this hasgiven important insights into the mechanisms ofreceptor activation. Many receptors are linked toadenylate cyclase by a coupling protein (G protein),which either stimulates (Gs) or inhibits the enzyme(Gi).8 Thus, beta-adrenoceptors and vasoactive-intestinal peptide (VIP) stimulate adenylate cyclase inairway smooth muscle, resulting in increased intracel-lular cyclic-AMP and bronchodilatation. Conversely,acetylcholine inhibits adenylate cyclase, resulting inreduced cyclic-AMP and bronchoconstriction. It isnow apparent that several receptors which interactwith G proteins have C-terminal homology and thus acommon sequence of amino acids may be involved inthe interaction with these coupling proteins.9 Indeed,there are remarkable similarities in structure betweenthese receptor proteins with severe hydrophobic mem-brane spanning sections, hydrophilic loops on theexternal surface which contain the ligand recognitionsites, and the hydrophilic intracellular loops whichlink with the G protein.

It is now apparent that several receptors are coupledin a different fashion and activation leads to thehydrolysis of membrane phosphoinositides (PI) withthe formation of inositol trisphosphate which releasescalcium from intracellular stores.'0 This stimulation ofPI turnover is initiated by activation of phospholipaseC via a distinct G protein. In airway smooth musclemany spasmogens stimulate PI hydrolysis." Foracetylcholine there is a close relationship betweenmuscarinic receptor occupancy and the stimulation ofPI turnover'2 and, in general, there is a close relation-ship between receptor density and the magnitude ofPIhydrolysis. The discovery of this transductionmechanism clarifies the mechanisms of bronchocon-striction and may, in the future, lead to novel broncho-dilator drugs.

Activation of PI hydrolysis also leads to the forma-tion of diacyl glycerol which stimulates protein kinaseC, a key enzyme involved in phosphorylation ofseveral regulatory proteins, including receptors and Gproteins.'3 Thus, activation of one receptor mayinfluence quite different receptors, and this may bepertinent in diseases such as asthma.

Autonomic receptors in airways

Autonomic innervation of the airways is complex.'4 Inaddition to classical cholinergic pathways which causebronchoconstriction and adrenergic mechanismswhich are usually bronchodilator, there is a morerecently recognized component of autonomic controlwhich is neither cholinergic nor adrenergic.Autonomic nerves influence airway tone by activatingspecific receptors on airway smooth muscle. In thecase of cholinergic pathways acetylcholine releasedfrom postganglionic nerve endings stimulates mus-carinic cholinergic receptors. Adrenergic mechanismsinclude sympathetic nerves which release noradrena-line, and circulating adrenaline secreted from theadrenal medulla; these catecholamines activate alpha-or beta-receptors. The neurotransmitters of the non-adrenergic non-cholinergic (NANC) nervous systemare not certain, but the most likely candidate fornon-adrenergic inhibitory nerves is VIP, whereas thatof non-cholinergic excitatory nerves is probably subs-tance P (SP) or a related peptide. These neuropeptidesinteract with specific receptors on target cells.The different components ofthe autonomic nervous

system interact with each other in a complex way, bothby affecting release of neurotransmitter (via prejunc-tional receptors), at ganglia in the airways, and byinteraction at postjunctional receptors. Thus, airwaytone may be determined by a complex interplaybetween different components of the autonomic ner-vous system.

Beta-adrenoceptors

Both histochemical and functional studies indicatethat there are few, if any, adrenergic nerve fibresdirectly supplying airway smooth muscle in humanairways,14 although in other species, such as cat anddog, adrenergic bronchodilator nerves have beendescribed. This suggests that beta-receptors in airwaysmooth muscle are under the control of circulatingadrenaline.

Direct receptor binding studies indicate that beta-receptors are present in high density in lung of manyspecies, including humans. 5 Autoradiographic studieshave revealed that beta-receptors are found on manydifferent cell types within lung, including airwaysmooth muscle from trachea down to terminal bron-chioles.'6 This is consistent with functional studiesindicating that beta-agonists are potent relaxants ofbronchi, bronchioles and peripheral lung strips.'7While a direct relaxant effect of beta-agonists onairway smooth muscle is undoubtedly their majormode of action as bronchodilators, they may also leadto bronchodilatation indirectly, either by inhibitingrelease of bronchoconstrictor mediators from airway

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mast cells,'8 by inhibiting acetylcholine release fromcholinergic nerves,1920 or by stimulating release of anepithelial relaxant factor.4 Indeed, a very high densityof beta-receptors is seen in airway epithelium, whichfar exceeds the density of receptors in smooth muscleitself.'6

Beta-receptor subtypes

Although originally beta-receptors of airway smoothmuscle were classified as beta2-receptors, later studiesshowed that, in several species, relaxation of trachealsmooth muscle was intermediate between a beta, andbeta2 mediated response, suggesting the presence ofbeta, in addition to beta2-receptors. Using directreceptor binding techniques and selective beta-antagonists the coexistence of beta, and beta2-receptors was confirmed in animal and human lung.2'In dog tracheal smooth muscle, while beta2-receptorspredominate, 20% of receptors are of the beta2subtype.22 Functional studies ofthe same tissue in vitroshow that relaxation to exogenous beta-agonists ismediated by beta2-receptors, but relaxation to sym-pathetic nerve stimulation is mediated by beta,-receptors. These findings are consistent with thehypothesis that beta,-receptors are regulated by sym-pathetic nerves ('neuronal' beta-receptors), whereasbeta2-receptors are regulated by circulating adrenaline('hormonal' beta-receptors).Further support for this idea is provided by studies

of airway beta-receptor function in other species.Thus, in cat trachea, which has a dense sympatheticnerve supply, relaxation to beta-agonists is mediatedpredominantly by beta,-receptors, whereas in lungstrips, which contain bronchioles devoid of sympa-thetic nerves, responses are mediated by beta2-receptors.23 In human airway smooth muscle, with itsabsence of significant innervation, no beta,-receptormediated effects would be expected. This has beenconfirmed in functional studies in vitro, in whichrelaxation of central and peripheral airways ismediated by beta2-receptors.'7 Similarly, in vivoprenalterol, a beta,-selective agonist, has no bron-chodilator effect in asthmatic subjects, despitesignificant cardiac effects.24 Autoradiographic studiesofhuman lung have confirmed that the beta-receptorsof human airway smooth muscle from bronchi toterminal bronchioles are entirely of the beta2 sub-type.25

Beta-receptor dysfunction in asthma

The suggestion that there may be a defect in beta-receptor function in asthma26 provided a great impetusto research and the question is still unresolved. Whilethe defects in peripheral beta-receptor function des-cribed in asthmatic subjects can largely be ascribed to

the effects of prior adrenergic therapy,'4 it is still notcertain whether airway smooth muscle beta-receptorfunction is impaired, largely because of the difficultiesin obtaining asthmatic airways to study in vitro.Asthmatic subjects are apparently less responsive toinhaled beta-agonists than normal subjects,27 but thiscould be explained by reduced aerosol penetration orby functional antagonism (a larger dose of beta-agonist is required to reverse a greater initial degree ofbronchoconstriction), rather than a defect in airwaybeta-receptors. Recent observations in asthmatic air-ways in vitro, however, suggest that there is a reducedrelaxant response to isoprenaline with no evidence ofan increase in responsiveness to spasmogens.28,29A reduction in lung beta-receptor density is found in

a guinea pig model of asthma,30 and this reduction isfound in several cell types, including airway smoothmuscle.' In bovine tracheal smooth muscle choliner-gic stimulation reduces beta-receptor density anduncouples beta-receptors.32 This is probably mediatedvia activation ofprotein kinase C, since phorbol esters,which also activate this enzyme, have a similar effect.Several inflammatory mediators stimulate PI turnoverin airway muscle, which may result in a reduction inbeta-receptor function. In guinea pigs, exposure to theinflammatory mediator, platelet-activating factor, in-creases bronchial responsiveness and reduces thebronchial responsiveness to isoprenaline in vivo,although tracheal smooth muscle responds normallyto isoprenaline in vitro and the density or affinity ofbeta-receptors is not altered.33 Beta-adrenoceptorfunction in asthmatic airways has recently beenreviewed.33a

Alpha-adrenoceptors

Alpha-receptors which mediate contraction of airwaysmooth muscle have been demonstrated in manyspecies, including human,34 although it may only bepossible to demonstrate their presence under certainconditions. Human peripheral lung strips contractwith alpha-agonists, although it is likely that contrac-tile elements other than airway smooth muscle areresponsible.35 Autoradiographic studies confirm avery low density of alpha,-receptors in smooth muscleof large airways, but have revealed a surprisingly highdensity in small airways.36

Alpha-receptor subtypes

The classical alpha-receptor which mediates contrac-tile effects is the alpha,-receptor, which is selectivelyblocked by prazosin, whereas prejunctional alpha-receptors, mediating negative feedback of noradrena-line release, are alpha2-receptors and selectivelyblocked by yohimbine. More recently, alpha2-

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receptors have also been found postjunctionally. Indog tracheal smooth muscle the contractile responseto both sympathetic nerve stimulation and toexogenous alpha-agonists are mediated almostentirely by alpha2-receptors, and the majority ofalpha-receptors measured by radioligand binding inthe same tissue are of this subtype." The role ofalpha2-receptors in human airways is not yet certain.

Alpha-receptors in asthma

There is some evidence that alpha-adrenergic res-ponses may be increased in asthma and may,therefore, contribute to bronchial hyperrespon-siveness. The alpha-agonist methoxamine causesbronchoconstriction in asthmatic but not in normalsubjects, even in the absence of beta-blockade.38 Thissuggests that alpha-adrenergic responses may be in-creased in the airways of asthmatics.No alpha-adrenergic response can be demonstrated

in normal canine or human smooth muscle in vitro,even after beta-blockade, but in diseased humanairways or after pretreatment of normal canine air-ways with histamine or serotonin a marked alpha-adrenergic contractile response is seen,34'39 suggestingan activation of alpha-adrenergic responses bymediators or disease. Similar activation of alpha-adrenergic responses can also be demonstrated invivo.' This suggests that inflammatory mediators may'turn on' alpha-adrenergic responses in asthma. Themechanism for this activation does not involve anychange in density or affinity of alpha-receptors inairway smooth muscle and is likely to be a post-receptor mechanism, possibly involving voltage-dependent calcium channels.39 In a guinea pig modelof asthma there is an increase in lung alpha,-receptors,30 although no increased alpha-adrenergicresponsiveness has been found in airway smoothmuscle.41

If exaggerated alpha-adrenergic responsiveness ofairway smooth muscle were an important factor inbronchial hyperresponsiveness, then alpha-blockersshould be beneficial in asthma. Alpha-antagonists,such as phentolamine and thymoxamine, have beenshown to inhibit bronchoconstriction induced byhistamine, allergen and exercise, but such drugs lackspecificity and their protective effects may beexplained by their pharmacological actions such asantihistamine activity.'4 The specific alpha,-blockerprazosin given by inhalation has no bronchodilatoreffect in asthmatics, who readily bronchodilate with abeta-agonist, suggesting that an alpha-hyperrespon-siveness does not contribute to resting bronchomotortone in asthma.42 Similarly, prazosin has no effect onhistamine-induced bronchoconstriction, but has aweak protective effect against exercise-induced bron-chospasm,43 which may be explained by an effect on

bronchial blood flow rather than on airway smoothmuscle. It is possible that stimulation of alpha-receptors may, if anything, be beneficial in asthmasince adrenaline prevents microvascular leakage inguinea pig airways via alpha,-receptor stimulation,44and alpha2-agonists inhibit both cholinergic andNANC constrictor nerve effects prejunctionally.45

Cholinergic receptors

Acetylcholine released from cholinergic nerves causescontraction of airway smooth muscle by activation ofmuscarinic receptors which are blocked by atropine.There is a close association between receptor occupa-tion and stimulation of PI hydrolysis but the contrac-tion curve is well to the left and maximum contractionis obtained when only about 20% of receptors areoccupied, indicating the existence of 'spare' recep-tors.'2 This is confirmed by the use of phenoxyben-zamine which irreversibly alkylates muscarinic recep-tors and with progressive loss of receptors, althoughthere is a rightward shift in the concentration responsecurve, the maximum response is only reduced whenreceptor density falls below 20%."

Direct receptor binding studies have demonstrateda high density of muscarinic receptors in smoothmuscle of large airways,46 and this has been confirmedautoradiographically.36 The density of muscarinicreceptors decreases as airways become smaller, so thatterminal bronchioles are almost devoid of muscarinicreceptors.36 This is consistent with physiologicalstudies in dogs using tantalum bronchography, show-ing that vagal stimulation has a marked effect on largeairways but little effect on bronchioles.47 In humans,anticholinergic drugs have more effect on large thanon small airways, as measured by helium-oxygenflow-volume curves, whereas beta-agonists relax all

48airways.

Muscarinic receptor subtypes

Recent evidence from binding and functional studieswith selective antagonists suggests that muscarinicreceptors may be subclassified into at least three types,and four distinct receptor proteins have now beencloned,9 although there is still considerable confusionabout terminology.49 In gut, pirenzepine selectivityblocks muscarinic receptors on ganglia, which aretermed M,-receptors, but not those on smooth musclewhich are designated M2-receptors. In airway smoothmuscle, as expected, there is no evidence for Ml-receptors, since pirenzepine has low affinity in bothinhibition of receptor binding and in blocking PIhydrolysis.'2'50 Recently it has been possible to demon-strate M,-receptors in human cholinergic reflex path-way, probably localized to ganglia.5'

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It has also been possible to demonstrate a differenttype of muscarinic receptor in postganglionic airwaynerves, since in cat and guinea pig the non-competitiveantagonist gallamine selectively inhibits a muscarinicreceptor on cholinergic nerve terminals whichenhances acetylcholine release and has little inhibitoryeffect on acetylcholine in airway smooth muscle.52'"This suggests that acetylcholine inhibits its releasefrom cholinergic nerves via an autoreceptor whichdiffers from the receptor on airway smooth muscle.Similar observations have recently been made inhuman airway smooth muscle in vitro54 and in vivo.5"Since the gallamine-sensitive receptor in heart isclassified as an M2-receptor, it follows that the recep-tor on airway smooth muscle must be of a differentsubtype, and may be designated an M3-receptor. Thisreceptor is selectively inhibited by the drugs 4-DAMPand hexahydorsila-difenidol, whereas the prejunc-tional M2-receptor is inhibited by gallamine, AF-DX1 16 and the recently developed selective drug methoc-tramine. There is some evidence that the prejunctionalM2-receptor may be dysfunctional in asthma, whichwould lead to exaggerated cholinergic reflex effects,and this may also account for the profound bron-choconstriction which may occur after beta-blockadein asthma.

Neuropeptide receptors

Many different neuropeptides have now been localizedto airway nerves in several species, includinghumans:*`" There is increasing evidence that thesepeptides play a neurotransmitter or cotransmitter role,and may be the neurotransmitters of NANC nerves.These neuropeptides have effects on airway smoothmuscle which are mediated by specific surface recep-tors. The functional significance of airway neuropep-tides is still uncertain and will remain so until specificreceptor antagonists become available. Both inhib-itory and excitatory NANC nerves have been des-cribed; evidence is in favour of VIP as a neurotrans-mitter ofthe inhibitory nerves, and ofsubstance P (SP)and related tachykinins as the neurotransmitters ofexcitatory nerves.

VIP-receptors

VIP is a potent relaxant ofanimal and human airwaysin vitro and is 50-100 times more potent thanisoprenaline as a bronchodilator.58 VIP is a potentbronchodilator in cats when given intravenously, butin human subjects the cardiovascular effects of thepeptide prevent the infusion of a dose high enough tobronchodilate.59 Inhaled VIP also has no bron-chodilator effect in man, probably because it is notable to reach receptors on smooth muscle.' VIP is the

most favoured candidate as neurotransmitter of non-adrenergic inhibitory nerves in airways since in manyrespects it mimics NANC inhibitory nerve effects. VIPproduces its effects by activation of specific receptorson airway smooth muscle and it is unaffected bybeta-blockers, indomethacin or tetrodotoxin. VIP,like beta-agonists, stimulates adenylate cyclase intarget cells and therefore increases cyclic AMP in lungtissue. Using an immunocytochemical method, it hasbeen possible to demonstrate increases in cyclic AMPcontent of airway smooth muscle cells in severalspecies.6' VIP-receptors have been identified by 1251-VIP binding in lung homogenates,62 and the distribu-tion of these receptors in lung has been studied byautoradiography.63 VIP-receptors are found in severalcell types, including smooth muscle of large airways,but not of small airways, which is consistent with thelack of effect of VIP in relaxing small airways,although isoprenaline relaxes both large and smallairways to an equal extent.58 The lack ofVIP-receptorsin small airway smooth muscle is also in keeping withthe paucity of VIP-immunoreactive nerves, and withthe lack ofNANC inhibitorv nerves in small airways.

Peptide histidine isoleucine (PHI) which exists inhumans, with a terminal methionine (PHM), is closelyrelated in structure to VIP and is coded by the samegene. It has similar effects to VIP and is equipotent inrelaxing airways smooth muscle. It may activate thesame receptors, although evidence now suggests that itmay have different receptors since it has a differentpotency from VIP on vascular smooth muscle.

Tachykinin receptors

Substance P is localized to sensory nerves in theairways and may be released as part ofan axon reflex.SP constricts airway smooth muscle of animals andhumans in vitro by activating specific receptors. In vivoSP infusion causes bronchoconstriction in animalswhich may be partially blocked with atropine, sugges-ting that SP release of acetylcholine may contribute toits bronchoconstrictor effect.64 Autoradiographicstudies using labelled SP have demonstrated highdensities of SP receptors on smooth muscle of guineapig and human airways from large airways down toterminal bronchioles.65

Recently, related peptides (tachykinins) have beenisolated from the mammalian nervous systemfi.Neurokinins A and B appear to activate distinctreceptors which have been termed NK-2 and NK-3receptors, repetively, whereas SP activates NK- 1receptors.66 In airway smooth muscle of severalspecies, including humans, the order of potency isNKA > NKB > SP (NKA being about 100-foldmore potent than SP), indicating an NK-2 recep-tor.67,' This suggests that NKA is the endogenousbronchoconstrictor tachykinin. This has recently been

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confirmed in human subjects in vivo, since infused andinhaled NKA causes bronchoconstriction with littlecardiovascular effect,69'70 whereas SP has profoundcardiovascular actions but no bronchoconstrictoreffect." Tachykinins appear to cause airway smoothmuscle contraction by stimulating PI hydrolysis and,as expected, NKA is more potent than NKB or sp."Mechanical removal of airway epithelium markedlyenhances the contractile reponse toNKA in guinea pigtrachea, and asimilar effect is produced in the presenceofphosphoramidon, an inhibitor ofthe major degrad-ing enzyme (enkephalinase)." Thus, loss ofepitheliumin asthma may enhance the effects of tachykininsreleased from sensory nerves, since degradation wouldbe prevented by loss of the enzyme contained inepithelial cells.

Other neuropeptides

Calcitonin gene-related peptide (CGRP) is alsolocalized to sensory nerves in airways and contracts onhuman bronchi in vitro.74 Autoradiographic mappingofCGRP receptors in human and guinea pig lung haveshown a high density of receptors in airway bloodvessels, suggesting that CGRP may regulate airwayblood flow.75

Neuropeptide Y (NPY) is a cotransmitter ofnoradrenaline but has no direct effect on airwaysmooth muscle, but modulates cholinergic nerveeffects via a prejunctional receptor.76 This suggeststhat NPY receptors are localized to cholinergic nerveterminals rather than to airway smooth muscle.

Mediator receptors

Many inflammatory mediators have effects on airwaysmooth muscle and produce their effects by activationof specific receptors on airway smooth muscle cells.77Several mediators produce their effects indirectly onairway smooth muscle, either by activating broncho-constrictor nerves or by releasing bronchoconstrictormediators from other inflammatory cells.78 Indeed,there is increasing emphasis on the concept thatasthma is, to a considerable degree, an inflammatorydisease. 78a

Histamine receptors

Histamine produces its effects by activation of H1- andH2-receptors. Inhaled histamine causes bronchocon-striction in vivo and contraction of large and smallhuman airways in vitro by activating H 1-receptors,which are antagonized by the classical antihistaminessuch as chlorpheniramine.79 HI-receptors have beenidentified in guinea pig and human lunghomogenates.808' HI-receptors have been character-

ized in bovine tracheal smooth muscle by [3H]-pyrilamine binding; there is a close relationshipbetween HI-receptor occupancy and stimulation of PIturnover by histamine, indicating that HI-receptorsmay lead to contraction by stimulating PI hydrolysisand release of intracellular calcium, as in othertissues." There is also a close association between thecontractile response and H,-receptor occupancy inthis tissue, indicating that there are no 'spare' recep-tors.The role of H2-receptors in airways is less certain. In

some species H2-receptors mediate bronchodilata-tion.82 Human peripheral lung strips may also relaxwith histamine,83 although this is likely to reflect thepresence of vascular smooth muscle in these prepara-tions. In vivo H2-receptor antagonists have no effect onthe bronchoconstrictor effect of histamine, suggestingthat H2-receptors do not play a role in regulatinghuman airway smooth muscle tone.' H2-receptorshave been identified in guinea pig lung homogenatesby receptor binding using [3H]-tiotidine, but theirlocalization is uncertain.85

Prostanoid receptors

Prostaglandin receptors have not been well character-ized since few specific antagonists are available.86Prostacyclin receptors have been identified in guineapig lung by measuring activation ofadenylate cyclase87and by direct receptor binding.88 These receptors areprobably localized to pulmonary vessels, rather thanairways, since prostacyclin has little effect on airwaysmooth muscle.89 PGD2 and PGF2, are potent con-strictors of human airways in vitro and in vivo,presumably by activation of specific receptors inairway smooth muscle.' PGD2 enhances histamineand methacholine responsiveness, possibly via partici-pation ofa thromboxane receptor.9' Thromboxane A2is also a potent bronchoconstrictor which activatesspecific receptors and specific thromboxane receptorantagonists have recently been developed.

Leukotriene receptors

There has been considerable interest in the role ofleukotriene B4 and the sulphidopeptide leukotrienesC4, D4 and E4 (which comprise slow-reacting sub-stance of anaphylaxis) in the pathogenesis of asthma.Leukotrienes produce their effects by activatingspecific, and probably distinct, receptors which haverecently been identified using [3HI-labelled leuko-trienes. LTB4 has potent chemotactic activity, partic-ularly for neutrophils, and has little direct effect onairway smooth muscle.

Functional studies with sulphidopeptide leuko-trienes have indicated that there may be discretereceptors for LTC4 and LTD4 in guinea pig lung,92 and

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binding studies have confirmed that there are twodistinct binding sites in lung homogenates whichcorrespond with the functional LTC4 and LTD4receptors.93 LTE4 appears to bind to the D4 receptorbut, although it is less potent than LTD4, it is moreslowly metabolized and so may have a more significantfunctional effect and contribute to the prolongedduration of bronchoconstriction of leukotrienes. Inhuman airways there may be only a single leukotrienereceptor, however.94 The signal transduction system ofthe LTD4 receptor has very recently been reviewed.94aThe biochemical mechanisms by which LT recep-

tors lead to contraction of airway smooth muscle haverecently been investigated. Both LTC4 and LTD4stimulate PI hydrolysis in guinea pig treachea, butLTC4 is significantly more potent and has a greaterstimulatory effect.95 Functionally, the two LTs have asimilar potency, however, and the greater effect ofLTC4 may be related to the much higher number ofbinding sites. Both LTs also inhibit adenylate cyclasebut, again, LTC4 is more potent than LTD4.Autoradiographic studies have mapped the distri-bution of LTC4 and D4 receptors in guinea pig lung.96There appears to be a differential distribution, withLTC4 receptors being more widely distributed andpresent in higher density, particularly in airwaysmooth muscle, than LTD4 receptors.

Platelet activatingfactor receptors

Platelet activating factor (PAF) is a phospholipidwhich is a potent bronchoconstrictor in several animalspecies, including humans.97 Bronchoconstriction isindirect, since PAF has no direct effect on airwaysmooth muscle in vitro and is presumed to interactwith other cells, such as platelets, neutrophils, macro-phages or eosinophils.97 PAF produces its effects byactivation of specific receptors which have beenidentified by direct binding assays on humanplatelets,93 neutrophils9 and lung membranes.'" PAFreceptors are presumably not present on humanairway smooth muscle, since PAF has no directconstrictor effect, but may cause constriction in thepresence of platelets.'°'PAF also causes microvascular leakage in airways,

which appears to be due to a direct action of PAF onairway vascular endothelial cells.'02

Adenosine receptors

At least two cell surface receptors for adenosine havebeen recognized with the development of a series ofadenosine analogues.'03 Al-receptors are usuallyexcitatory and associated with a fall in intracellularcyclic-AMP, whereas A2-receptors are usuallyinhibitory and associated with a rise in cyclic-AMP.Inhaled adenosine causes bronchoconstriction in

asthmatic subjects.'04 Adenosine relaxes guinea pigairways by an A2-receptor and has little effect onisolated human airways in vitro,105 suggesting that thebronchoconstrictor effect may be indirect, possibly bypotentiating inflammatory mediator release. Theo-phylline is a specific antagonist of both Al- andA2-receptors, but there is evidence against this as itsmajor mechanism of bronchodilatation, since ananalogue of theophylline, enprofylline, is a morepotent bronchodilator, without significant adenosineantagonism.'05

Bradykinin receptors

Bradykinin is a potent bronchoconstrictor when givenby inhalation to asthmatic subjects, being significantlymore potent than methacholine, but has little effect onhuman airways in vitro, suggesting that its broncho-constrictor action is indirect, and that human airwaysmooth muscle does not have a significant populationof bradykinin receptors.' Bradykinin releases prosta-glandins in several species, suggesting that its effectsmight be mediated via bronchoconstrictor prostaglan-dins, but aspirin has no inhibitory effect.' To someextent the bronchoconstrictor effect is diminished byanticholinergic drugs, implicating a vagal cholinergicreflex. There is evidence that bradykinin may activateC-fibre afferent nerve endings in bronchi, so that theeffect of bradykinin may be due to a cholinergic reflexand also due to release of bronchoconstrictor sensoryneuropeptides via a local (axon) reflex. Two receptorsubtypes (designated B, and B2) have been recognizedusing peptide analogues of bradykinin and there issome evidence that experimental inflammation mayenhance the responsiveness of B, receptors.'07

Conclusions

Many different receptors have now been characterizedin airway smooth muscle by functional studies and bydirect receptor binding methods. Recently the mech-anisms by which receptors are coupled to contractionof airway smooth muscle have been elucidated. Thedevelopment of techniques to measure electro-physiological changes after receptor activation, andthe study of isolated airway smooth muscle cells,should further increase our understanding of airwaysmooth muscle receptors. The demonstration thatseveral agonists may have different effects on differentsized airways is important, since the receptor popula-tion of smooth muscle in peripheral airways may bequite different from that in proximal airways. Sincestudies have usually been performed in larger airways,this may give misleading information about respon-siveness of peripheral airways which may be involvedin airway disease. The question of whether receptor

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populations may be changed in airway disease is stillnot answered. Stimulation ofone receptor may changethe expression of another. Thus, stimulation of mus-carinic receptors may reduce the number and couplingof beta-adrenoceptors, possibly via the enzyme pro-tein kinase C which is stimulated by PI breakdown.This implies that other inflammatory mediators,which also lead to receptor-mediated PI hydrolysis,may produce marked changes in surface receptorpopulations, resulting in altered responsiveness in

asthma. Advances in molecular biology have nowmade it possible to study gene expression of receptorproteins and this should give great insight into theregulation of receptor expression in disease.

Acknowledgement

I am very grateful to Madeleine Wray for the carefulpreparation of the manuscript.

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