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Thorax 1992;47:979-983 979 Occasional review Thorax: first published as 10.1136/thx.47.11.979 on 1 November 1992. Downloaded from Bradykinin and asthma

Peter J Barnes

Many mediators have been implicated in the both high molecular weight and low molecular pathophysiology of asthma'2 but the role of weight . Other proteases that may individual mediators will become apparent be produced by inflammatory cells may also only with the use of potent and selective generate from kininogens. antagonists or synthesis of inhibitors, which tryptase is a weak kininogenase in vitro under are now becoming available for many conditions of low pH; it is unlikely that this mediators. Bradykinin has long been con- occurs to any significant extent in vivo."i sidered to be a mediator concerned in asthma, There is also some evidence that since the first demonstration of bronchocon- and may release proteases with striction after inhaled bradykinin in asthmatic activity.12 patients.3 The recent development of potent antagonists' has raised questions about the role of bradykinin in the Receptors pathophysiology of asthma and the potential Bradykinin exerts several effects on the air- of bradykinin antagonists in the treatment of ways, which are mediated via specific surface asthma. receptors. At least two subtypes of bradykinin (BK) receptor are recognised.'3 BK, receptors are selectively activated by and des- Formation Arg-bradykinin, but they have been found Kinins are vasoactive formed during only under certain experimental conditions, the inflammatory response from the a2 and these observations have usually been con- globulins high and low molecular weight fined to rabbits.'4 The effects of bradykinin on kininogens by the action of kininogenases airways are mediated via BK2 receptors, and http://thorax.bmj.com/ (figure 1). Kininogenases include plasma there is no evidence for functional BK, recep- and tissue kallikrein. High tors. A BK3 receptor has also been described molecular weight and low molecular weight in airway of sheep,'5 16 but kininogens are derived from the same gene as there are some doubts about its existence, as it a consequence of alternative splicing.7 High has been defined with weak antagonists. A BK2 molecular weight kininogen is present only in receptor from rat uterus has recently been plasma, whereas low molecular weight kinino- cloned and has the typical seven transmem-

gen also occurs in tissues. Two kinins are brane spanning segment structure common to on September 23, 2021 by guest. Protected copyright. formed in man-the nonapeptide bradykinin all G receptors.'7 Northern analysis (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), has shown strong expression in tissue. which is generated from high molecular Pharmacological studies suggest that there weight kininogen, and the decapeptide lysyl- may be subtypes of the BK2 receptor.'8 The bradykinin (kallidin), which is generated from [Thi5 8,D-Phe7]bradykinin appears to low molecular weight kininogen. Kallidin is distinguish a "neuronal" form, which is fully rapidly converted to bradykinin by the activated, and a "smooth muscle" form, -N.8 There is evidence which is only partially activated by this agon- for activity in bronchoalveolar lavage ist. The availability of a specific cDNA probe fluid from asthmatic patients9 and bradykinin for the BK2 receptor should make it possible is likely to be formed from plasma that has to discover whether there are true differences exuded from the inflamed airways, by the in BK receptors between tissues. action of plasma and tissue . The The distribution of BK2 receptors has been Department of concentration of kallikrein and kinins in mapped out in human and guinea pig lung by Thoracic Medicine, bronchoalveolar lavage fluid increases after autoradiography with [3H]bradykinin.'9 There National Heart and is a high density of binding sites in bronchial Lung Institute, allergen challenge.'0 High molecular weight London SW3 6LY kininogen is the preferred substrate for and pulmonary vessels, particularly on P J Barnes , which is generated from the endothelial cells. Epithelial cells, airway Reprint requests to: inactive by contact with certain smooth muscle (particularly in peripheral air- Professor P J Barnes negatively charged surfaces, including ways), submucosal glands, and nerves are also Received 6 April 1992 that may have Returned to authors basement membrane components and proteo- labelled, indicating bradykinin 8 May 1992 glycans, such as heparin, released from mast diverse effects on airway function. A par- Revised version received cells. Tissue kallikreins are produced in ticularly high density of labelling is observed II June 1992 Accepted 2 July 1992 glandular secretions and release kinins from in the lamina propria immediately beneath the 980 Barnes

Effects of bradykinin on airwayfunction of converting enzyme by cap- topril.28 29 Airway cells Effect Intravenous bradykinin causes intense bron-

Airway smooth Contraction (small airways > large choconstriction in the guinea pig, which is Thorax: first published as 10.1136/thx.47.11.979 on 1 November 1992. Downloaded from muscle airways?) strongly inhibited by indomethacin, suggesting Nerves Activation of C fibre endings a bronchoconstrictor cyclooxygenase Enhanced release from that sensory nerves product (probably thromboxane) largely medi- Increased cholinergic reflex ates this effect.0 The bronchoconstrictor res- mechanisms ponse to bradykinin instilled directly into the Cough airways is not reduced by indomethacin, Bronchial vessels Vasodilatation ( dependent) however, suggesting a different mechanism of Plasma exudation (direct and bronchoconstriction after airway delivery of indirect) the mediator.30 In airway it is Epithelium Increased ion transport (via PGE,) likely that bradykinin would be formed at the Release of bronchodilators (PGE2) Mucus Increased mucus secretion airway surface from plasma kininogens exuded into the airway lumen from leaky superficial blood vessles. In human subjects inhibition of cyclooxygenase by aspirin or flurbiprofen epithelium; it is not clear what cellular struc- similary has no effect on the bronchoconstrictor tures are labelled but a very similar pattern of effect of inhaled bradykinin.223 The bron- labelling has been observed in other epi- choconstrictor response to both intravenous thelialised structures.20 The subepithelial and inhaled bradykinin in the guinea pig is binding sites may be on nerves and superficial mediated via a BK2 receptor because the BK2 blood vessels. receptor antagonists NPC 349 and HOE 140 inhibit the bronchoconstrictor response, whereas a BK, selective antagonist is ineffec- Effects of airways tive. In human airways the bronchocon- Bradykinin has several potent effects on airway strictor effect of bradykinin is also likely to be function, all of which are mediated via a BK2 mediated via a BK2 receptor because the BK, receptor (table). selective agonist [desArg9]-bradykinin has no effect on airway function in asthmatic patients.23 AIRWAY SMOOTH MUSCLE The distribution of BK receptors in both Inhaled bradykinin is a potent bronchocon- guinea pig and human airways suggests that strictor in asthmatic patients, but has no effect bradykinin may have a greater direct effect on even in high concentration in normal the smooth muscle of peripheral airways than individuals,21-23 suggesting an increased res- of central airways, and indicates that in more ponsiveness of airway smooth muscle to proximal airways the effects of bradykinin are bradykinin, as is observed with other spas- more likely to be indirectly mediated.'9 http://thorax.bmj.com/ mogens. In vitro bradykinin is only a weak constrictor of human airways, suggesting that NEURAL EFFECTS its potent bronchoconstrictor effect in asthmatic Perhaps the most important property of patients is mediated indirectly. Bradykinin bradykinin is its ability to activate C fibre contracts airway smooth muscle in vitro,24 but nociceptive sensory nerve endings. Bradykinin in guinea pig airways in vitro bradykinin has is the mediator of inflammatory ,35 and in weak and variable effects, which are influenced the airways this may be manifest as cough and

by the presence ofairway epithelium and by the tightness of the chest, which are commonly on September 23, 2021 by guest. Protected copyright. activity of local degrading . Brady- observed after inhalation of bradykinin in kinin causes relaxation of intact guinea pig patients with asthma.22 Bradykinin stimulates trachea in vitro, but constricts airways if epith- bronchial C fibres in dogs.36 In guinea pigs the elium is removed mechanically.25 26 Bradykinin bronchoconstrictor response to instilled releases the bronchodilator prostaglandin E2 bradykinin is reduced by atropine and by from epithelial cells26 and removing the epi- pretreatment, which depletes thelium therefore reduces the functional from sensory nerves, indicating antagonism, resulting in a bronchoconstrictor that both a cholinergic reflex and release of effect of bradykinin. Furthermore, the enzyme neuropeptides from sensory nerves play a neutral endopeptidase 24 11 is strongly expres- part.0 Indeed, a combination of atropine and sed on airway epithelial cells27 and thus removal capsaicin pretreatment largely abolishes the of the epithelium may reduce bradykinin bronchoconstrictor response to instilled metabolism. A combination of indomethacin bradykinin, but has little effect on the (to inhibit PGE2 formation) and phos- bronchoconstrictor response to intravenous phoramidon (which inhibits neutral endopep- bradykinin (which is largely inhibited by tidase) mimics the effect of removal of the indomethacin).'0 Bradykinin also releases epithelium.25 Shedding of the epithelium is tachykinins from perfused guinea pig lung37 commonly observed in asthmatic airways and and rat trachea,38 and enhances the bron- this could be a factor contributing to the choconstrictor response to electrical field increased bronchoconstrictor effect of brady- stimulation (mediated by release of endogen- kinin in asthma. The bronchoconstrictor effect ous tachykinins) in guinea pig bronchi in of bradykinin in ferrets in vitro and in guinea vitro."9 The effect of bradykinin on airway pig in vivo is enhanced by the inhibition both of sensory nerves is blocked by the BK2 antagonist neutral endopeptidase by and HOE 140. Single fibre recordings from sensory Bradykinin and asthma 981

Figure I Bradykinin LMW kininogen enzyme (BK) and its precursors: HMW kininogen Angiotensin converting inhibitors do effects on the airways. not worsen asthma, presumably because other LMW-low molecular enzymes, such as neutral endopeptidase, are weight; HMW-high more important in degrading bradykinin in Thorax: first published as 10.1136/thx.47.11.979 on 1 November 1992. Downloaded from molecular weight; PLA2- Tissue Plasma phospholipase A2 kallikrein kallikrein airways. Indeed, a potent angiotensin convert- ing enzyme inhibitor has been shown to have no effect on the bronchoconstrictor response to Kallidin BRADYKININ inhaled bradykinin in asthmatic patients, indicating that angiotensin converting enzyme is not of critical importance in degrading B K2 receptors B1K,-receptors? bradykinin in the lumen of human airways.47 VASCULAR ACTIONS PLA2 Bradykinin is a potent inducer of airway microvascular leak and causes a prolonged leakage at all levels of the airway. This is partly Lipid mediators mediated via the release of activating factor, because a PAF antagonist stongly inhibits the prolonged leak.48 The immediate AIRWAY EFFECTS leakage response to bradykinin is partly mediated via the release of neuropeptides (probably ) from airway sensory nerves of guinea pig airways indicate that nerves. The effect of bradykinin on leakage is bradykinin is a potent activator of C fibres, and mediated via BK2 receptors, which are located that this is a direct action as it is not blocked by on endothelial cells on postcapillary venules cyclooxygenase inhibition.' Bradykinin has no because BK2 antagonists inhibit the leakage direct effect on the release ofneurotransmitters response.3334 The microvascular leakage from airway cholinergic nerves.39 induced by bradykinin is increased by inhibi- In asthmatic patients the bronchoconstrictor tion of both neutral endopeptidase and angio- response to bradykinin is also reduced by tensin converting enzyme.49 anticholinergic pretreatment, indicating that a Bradykinin is a potent vasodilator of bron- cholinergic reflex is concerned.22 Pretreatment chial vessels and causes an increase in airway with sodium cromoglycate and nedocromil blood flow.5152 This is consistent with the high sodium is very effective in inhibiting the airways density of bradykinin receptors on bronchial response to bradykinin. This may indicate a vessels,'9 and suggests that a major effect of role of C fibre activation in asthmatic airways,41 bradykinin in asthma may be hyperaemia ofthe as both drugs have been found to inhibit C airways. fibres in animals.4243 Thus bradykinin may be http://thorax.bmj.com/ an important mediator of cough and chest EFFECTS ON SECRETIONS discomfort in asthma. Bradykinin stimulates airway mucus secretion Bradykinin induces cough in normal and from canine and feline airways in vitro,53 54 asthmatic subjects" and has been implicated in presumably indicating a direct effect of brady- cough induced by angiotensin converting kinin on submucosal glands-and indeed enzyme inhibitors, which is seen in about 10% autoradiographic mapping has shown BK2 of patients having long term treatment.45 receptors on these glands.'9 Bradykinin also stimulates the release of mucus Cough induced by angiotensin converting glycoproteins on September 23, 2021 by guest. Protected copyright. enzyme inhibitors is reduced by cyclooxygen- from human nasal mucosa in vitro.54 Brady- ase inhibitors, suggesting that prostaglandins kinin stimulates ion transport in airway epi- thelial which is (such as PGE2 or PGF2,) may play a part.' cells, mediated via the release of Endogenous bradykinin may stimulate the prostaglandins.55 release of these prostaglandins in the larynx and trachea, leading to cough, though it is not clear why only some patients are affected. Metabolism Bradykinin is metabolised by several pep- tidases that may be present in the asthmatic airways (fig 2). Angiotensin converting enzyme Aminopeptidase-M (kininase 2) may be important for degrading bradykinin in the circulation as it is present in endothelial cells, but it may also be present in Lys -Arg -Pro- Pro - Gly - Phe -Ser - Pro - Phe - Arg the airway tissue.' Angiotensin converting enzyme inhibitors potentiate both the bron- Kallidin Angiotensin converting Kallidin | enzyme (kininase 11) choconstrictor effect and the microvascular leakage produced by bradykinin,29 56 suggesting that this may be the mechanism of cough Arg - Pro - Pro - Gly - Phe - Ser Pro Phe - Arg induced by angiotensin converting enzyme inhibitors. Neutral endopeptidase appears to be the Bradykinin Neutral -N endopeptidase 24.11 (kininase 1) most important enzyme in degradation of bradykinin in the airways. Phosphoramidon, Figure 2 Degradation of lys-bradykinin (kallidin) and bradykinin by enzymes. which inhibits neutral endopeptidase, enhan- 982 Barnes

ces the bronchoconstrictor effect of bradykinin that are relevant to asthma. Perhaps the most both in vitro25 and in vivo.2956 As neutral important property of bradykinin is its ability endopeptidase is expressed on airway epi- to activate nociceptive nerve fibres in the airway thelium, the shedding of airway epithelium in because these may mediate the cough and chest Thorax: first published as 10.1136/thx.47.11.979 on 1 November 1992. Downloaded from asthma may result in the enhanced airway tightness that are such characteristic symptoms responses to bradykinin seen in asthmatic of asthma. This effect of bradykinin may be patients. enhanced by hyperaesthesia of sensory nerves A third enzyme, carboxypeptidase-N (kinin- in the airways that have been sensitised by ase 1), may be important in degrading brady- inflammatory mediators. Inhalation of brady- kinin in the circulation, but an inhibitor of this kinin in asthmatic patients has effects rather enzyme, DL-2-mercaptomethyl-3-guanidino- closely mimicking an asthma attack; in addition ethylthiopropionic acid, does not have any to wheezing, patients observe chest tightness, effect on the bronchoconstrictor response to coughing, and sometimes itching under the bradykinin in vivo." Carboxypeptidase N con- chin, which are common sensory manifesta- verts bradykinin to [desArg9]-bradykinin, tions during an exacerbation of asthma. which is selective for BK, receptors.'3 Amin- The contribution of bradykinin to asthma opeptidase M, which converts lysyl-bradykinin will be determined only with the use of potent to bradykinin, is widely distributed, so that and specific bradykinin antagonists, which are kallidin is rapidly converted to bradykinin. now in clinical development. As many mediators may contribute to the patho- physiology of asthma it is difficult to predict Bradykinin antagonists how useful bradykinin antagonists will be; they Several antagonists to bradykinin (BK2 may be of particular value in controlling antagonists) have now been developed. The asthma symptoms, but they are unlikely to be as early antagonists were relatively weak and were effective,Bas or corticosteroids. rapidly degraded in tissues."58 One such antagonist, D-Arg-[Hyp',Thi5',D-Phe']brady- broncho- kinin (NPC 349), reduces the I Barnes PJ, Chung KF, Page CP. Inflammatory mediators constrictor and microvascular leakage response and asthma. Pharmacol Rev1988;40:49-84. 2 Chung KF, BarnesPJ. Role of inflammatory mediators in to bradykinin, but its effect is transient.3233 asthma. Br Med Bull 992;48:135-48. Suprisingly, in view of its short duration of 3 Herxheimer H, Streseman E. The effect of bradykinin aerosol in guinea-pigs and in man [abstract].J Physiol action, the same antagonist appears to block 1961;158:38P. allergen induced airway hyperresponsiveness 4 HockFJ, Wirth K, Albus U, Linz W, Gerhards HJ, Wiemer G, et al. HOE 140 a new potent and long acting bradyk- in sheep, many hours after allergen exposure.59 inin-antagonist: in vitro studies. BrJ Pharmacol 1991; A related antagonist, [D-Arg0-Hyp3,D-Phe'] 102:769-73. 5 Wirth K, Hock FJ, Albus U, Linz W, Alperman H, bradykinin (NPC 567), is unable to inhibit the Anostopoulos H, et al. HOE 140, a new potent and long effect of bradykinin on nasal secretions, even acting bradykinin antagonist, in vivo studies. BrJ Phar-

macl 991;102:774-7. http://thorax.bmj.com/ when given at the same time as bradykinin,60 6 Farmer SG, Burch RM, Kyle DJ, Martin JA, Meeker SN, presumably because of rapid local metabolism. Togo J. D-Arg [Hyp'-Thi'-D-Tic'-Tic']-bradykinin, a brady- potent antagonist of smooth muscle BK2 receptors and More recently a potent antagonist of BK, receptors. BrJ Pharmacol1991;102:785-7. kinin, D-Arg[Hyp3,Thi5,D-Tic', Oic'] brady- 7 Nakanishi S. Substance P precursor and kininogen: their structures, gene organizations, and regulation. Physiol kinin (HOE 140), has been described,45 which Rev1987;67:1117-42. not only is potent but also has a long duration of 8 Proud D, Kaplan AP. Kinin formation: mechanisms and role in inflammatory disorders. Ann Rev Immunol 1988;6: action in animals in vivo as it is resistant to 49-83. enzymatic degradation. This antagonist is 9 Christiansen SC, Proud D, Cochrane CG. Detection of tissue kallikrein in the bronchoalveolar lavage fluid of and on September 23, 2021 by guest. Protected copyright. potent at inhibiting the bronchoconstrictor asthmatic patients.J Clin Invest 1987;79:188-97. the microvascular leakage response to brady- 10 Christiansen SC, Proud D, Sarnoff RB, Juergens U, on airway Cochrane CG, Zuran BL. Elevation of tissue kallikrein kinin34 and the effect of bradykinin and kinin in the airways of asthmatic subjects after sensory nerves.39 Other potent bradykinin endobronchial allergen challenge. Am Rev Respir Dis as 1992;145:900-5. antagonists have been developed, such 11 Proud D, Siekierski ES, Bailey GS. Identification of human D-Arg[Hyp3, Thi5, D-Tic7, Tic']bradykinin lung mast cell kininogenase as tryptase and relevance of tryptase kininogenase activity. Biochem Pharmacol 1988; (NPC 16731),6 and there is now a search for 37:1473-80. non-peptide antagonists. 12 Proud D. Production and metabolism of kinins. In: Crystal RG, West JB, Barnes PJ, Cherniak NS, Wiebel ER, eds. The lung: scientific foundations. New York: Raven Press, 1991:61-8. 13 Regoli D, Barabe J. Pharmacology of bradykinin and related A role for bradykinin in asthma? kinins. Pharmacol Rev 1980;32:1-46. Although the role of bradykinin in asthma is 14 Regoli D, Drapeau G, Rovgro P, Dion S, Khaled N-E, Barabe J, et al. Conversions of kinins and their antagonists still not clear, the development of potent and with B,-receptor activators and blockers in isolated ves- stable BK2 receptor antagonists offers the pos- sels.EurJ Pharmacol 1986;127:219-24. in 15 Farmer SG, Burch RM, Meeker SA, Wilkins DE. Evidence sibility of clarifying its role in airway disease for a pulmonary B,-bradykinin receptor. Mol Pharmacol the near future.45 Bradykinin is generated in 1989;36: 1-8. 16 Farmer SG, Ensor JE, Burch RM. Evidence that cultured asthmatic airways by the action of various airway smooth muscle cells contain bradykinin B, and B, kininogenases generated in the inflammatory receptors. AmJ Resp Cell Mol Biol 1991;4:273-7. 17 McEachern AE, Shelton ER, Bhakta S, Obernolte R, Bach response on high molecular weight kinogen C, Zuppan P, et al. Expression cloning of a rat B2 present in the exuded plasma and on low bradykinin receptor. Proc Natl Acad Sci USA 1991; the 88:7724-8. molecular weight kinogens secreted in 18 Braas KM, Manning DC, Perry DC, Snyder SH. Bradyk- airways. The degradation of bradykinin may be inin analogues: differental agonist and antagonist activities suggesting multiple receptors. Br J Pharmacol 1988;94: impaired in the airways if neutral endopep- 3-5. tidase is down regulated in asthmatic airways or 19 Mak JCW, Barnes PJ. Autoradiographic visualization of bradykinin receptors in human and guinea pig lung. Fur J epithelial shedding occurs.27 Pharmacol 1991;194:37-44. Bradykinin has many effects on the airway 20 Manning DC, Snyder SH. Bradykinin rcceptors localized by Bradykinin and asthma 983

quantitative autoradiography in kidney, ureter and blad- guinea-pig trachea in vitro. J Physiol (in press). der. AmJ Physiol 1989;256(F):9-18. 41 Dixon CMS, Barnes PJ. Bradykinin induced bronchocon- 21 Simonsson BG, Skoogh BE, Bergh NP, Anderson R, striction: inhibition by nedocromil sodium and sodium Svedmyr N. In vivo and in vitro effect of bradykinin on cromoglycate. Br J Clin Pharmacol 1989;270:8310-60.

bronchial motor tone in normal subjects and in patients 42 Dixon N, Jackson DM, Richards IM. The effect of sodium Thorax: first published as 10.1136/thx.47.11.979 on 1 November 1992. Downloaded from with airway obstruction. Respiration 1973;30:378-88. cromoglycate on lung irritant receptors and lef ventricular 22 Fuller RW, Dixon CMS, Cuss FMC, Barnes PJ. Bradyk- receptors in anasthetized dogs. Br J Pharmacol 1979; inin-induced bronchoconstriction in man: mode of action. 67:569-74. Am Rev Respir Dis 1987;135:176-80. 43 Jackson DM, Norris AA, Eady RP. Nedocromil sodium and 23 Polosa R, Holgate ST. Comparative airway responses to sensory nerves in the dog lung. Pulm Pharmacol 1989; inhaled bradykinin, kallidin and [desArg9]-bradykinin in 2:179-84. normal and asthmatic airways. Am Rev Respir Dis 1990; 44 Choudry NB, Fuller RW, Pride NB. Sensitivity of the 142:1367-71. human cough reflex: effect of inflammatory mediators 24 Bhoola KD, Bewley J, Crothers DM, Cingi MI, Figeroa prostaglandin E2, bradykinin and . Am Rev CD. Kinin receptors on epithelial cells and smooth muscle Respir Dis 1989;140:137-41. of trachea. Adv Exp Med Biol 1990;247A:1-6. 45 Fuller RW. Cough associated with angiotensin converting 25 Frossard N, Stretton CD, Barnes PJ. Modulation of bradyk- enzyme inhibitors. J Hum 1989;3:159-61. inin responses in airway smooth muscle by epithelial 46 McEwanJR, Choudry NB, Fuller RW. The effectofsulindac enzymes. Agents Actions 1990;31:204-9. on the abnormal cough reflex associated with dry cough. J 26 Bramley AM, Samhoun MN, Piper PJ. The role of epith- PharmacolExp Ther 1990;255:161-4. elium in modulating the responses of guinea-pig trachae 47 Dixon CMS, Fuller RW, Barnes PJ. The effect of an induced by bradykinin in vitro. Br J Pharmacol 1990; angiotensin converting enzyme inhibitor, ramipil, on 99:762-6. bronchial responses to inhaled histamine and bradykinin 27 Nadel JA. Neutral endopeptidase modulates neurogenic in asthmatic subjects. Br J Clin Pharmacol 1987;23:91-3. inflammation. Eur Respir J 1991;4:745-54. 48 Rogers DF, Dijk S, Barnes PJ. Bradykinin-induced plasma 28 Dusser DJ, Nadel JA, Sekizawa K, Graf PD, Borson DB. exudation in guinea pig airways: involvement of platelet Neutral endopeptidase and angiotensin converting activating factor. Br J Pharmacol 1990;101:739-45. enzyme inhibitors potentiate kinin-induced contraction of 49 Lotvall JO, Tokuyama K, Lofdahl C-G, Ullman A, Barnes ferret trachea. J Pharmacol Exp Ther 1988;244:531-6. PJ, Chung KF. Peptidase modulation of noncholinergic 29 Ichinose M, Barnes PJ. The effect of peptidase inhibitors on vagal bronchoconstriction and airway microvascular leak- bradykinin-induced bronchoconstriction in guinea-pigs age. J Appl Physiol 1991;70:2730-5. in vivo. Br J Pharmacol 1990;101:77-80. 50 Laitinen LA, Laitinen A, Widdicombe JG. Effects of inm- 30 Ichinose M, Belvisi MG, Barnes PJ. Bradykinin-induced flamatory and other meditors on airway vascular beds. Am bronchoconstriction in guinea-pig in vivo: role of neural Rev Respir Dis 1987;135:567-70. mechanisms. J Pharmacol Exp Ther 1990;253:1207-2. 51 Parsons GH, Nichol GM, Barnes PJ, Chung KF. Peptide mediator effects on bronchial blood velocity and lung 31 Polosa R,Phillips GD, Lai CKW, Holgate ST. Contribution J of histamine and prostanoids to bronchoconstriction pro- resistance in conscious sheep. Appl Physiol 1992; voked by inhaled bradykinin in atopic asthma. Allergy 72:1118-22. 1990;45: 174-82. 52 Corfield DR, Webber SE, Hanafi Z, Widdicombe JG. The 32 Jin LS. Seeds E, Page CP, Schachter M. Inhibition of actions of bradykinin and lys-bradykinin on tracheal blood bradykinin-induced bronchoconstriction in the guinea pig flow and smooth muscle in anaesthetized sheep. Pulm Pharmacol 1991;4:85-90. by synthetic B, . Br J Pharmacol 1988;97:598-602. 53 Baker AP, Hillegass LM, Holden DA, Smith WJ. Effect of 33 Ichinose M, Barnes PJ. Bradykinin-induced airway micro- kallidin, substance P and other basic polypeptides on the vascular leakage and bronchoconstriction are mediated via production of respiratory macromolecules. Am Rev Respir Dis 1977;115:811-7. a bradykinin B,-receptor. Am Rev Respir Dis 1990; 142:1104-7. 54 Baraniuk JN, Lundgren JD, Goff J, Gawin AZ, Mizuguchi 34 Sakamoto T, Elwood W, Barnes PJ, Chung KF. Effect of H, Peden D, et al. Bradykinin receptor distribution in HOE 104, a new bradykinin antagonist, on bradykinin and human nasal mucosa, and analysis of in vitro secretory platelet-activating factor-induced bronchoconstriction responses in vitro and in vivo. Am Rev Respir Dis and airway microvascular leakage in guinea pig. Eur J 1990;141:706-14. Pharmacol 1992;213:367-73. 55 Leikhauf GD, Ueki IF, Nadel JA, Widdicombe JH. Bradyk- Manning DL, de C, Ferkany JW, inin stimulates chloride secretion and prostaglandin E2 35 Steranka LR, Haas release by canine tracheal epithelium. J Borosky SA, Connor JR, et al. Bradykinin as a pain Am Physiol mediator: receptors are localized to sensory neurons and 1985;248:F48-55.

antagonists haveanalgesic effects. Proc NatlAcad Sci USA 56 Lotvall JO, Tokuyama K, Barnes PJ, Chung KF. Bradyk- http://thorax.bmj.com/ inin-induced airway microvascular leakage is potentiated 1988;85:3245-9. by and phosphoramidon. Eur J Pharmacol 36 Kaufman MP, Coleridge HM, Coleridge JCG, Baker DG. 1991;200:21 1-8. Bradykinin stimulates afferent vagal C-fibres in intrapul- 57 Vavrek Stewart JM. Competitive antagonists of monary airways of dogs. J Appl Physiol 1980;48:511-7. RJ, bradyk- inin. Peptides 1985;6:161-4. 37 Saria A, Martling CR, Yan Z, Theodorsson-Norheim E, 58 Burch RM, Farmer SG, Steranka LR. Bradykinin receptor Gamse R, Lundberg JM. Release of multiple tachykinins antagonists. Med Res Rev from capsaicin-sensitive nerves in the lung by bradykinin, 1990;10:237-69. histamine, dimethylphenlpiperainium, and vagal nerve 59 Soler M, Sielczak MW, Abraham WM. A bradykinin stimulation. Am Rev Respir Dis 1988;137:1330-5. antagonist blocks antigen-induced airway hyperrespon- 38 Ray NJ, Jones AJ, Keen P. Morphine, but not sodium siveness and inflammation in sheep. Pulm Pharmacol cromoglycate, modulates the release of substance P from 1990;3:9-15. neurones 60 Pongracic JA, Naclerio RM, Reynolds CJ, Proud D. capsaicin-sensitive in the rat trachea in vitro. Br A competitive kinin receptor antagonist, [DArg',Hyp3, on September 23, 2021 by guest. Protected copyright. J Pharmacol 1991;102:797-800. DPhe']bradykinin, does not affect the response to nasal 39 Miura M, Belvisi MG, Barnes PJ. Effect of bradykinin on provocation with bradykin. Br J Clin Pharmacol 1991; airway neural responses in vitro. J Appl Physiol (in press). 40 Fox AJ, Barnes PJ, Urban L, Dray A. Selective activation of 31:287-94. single vagal C fibres by capsaicin and bradykinin in the