Bradykinin-induced Bronchoconstriction Research Articles

Dual inhibition of cyclooxygenase and lipoxygenase by human haptoglobin: Its polymorphism and relation to hemoglobin binding

Haptoglobin (Hp) binds hemoglobin (Hb) specifically and stoichiometrically. Since Hb stimulates prostaglandin (PG biosynthesis), we investigated if Hp effects arachidonic acid (AA) metabolism. The results showed that Hp (50–250 μg protein) inhibited the biosynthesis of PGs via cyclooxygenase (COX) and 12-HETE via lipoxygenase pathway in human platelets. Additional evidence was obtained by the loss of Hp inhibitory activity upon removal of Hp by affinity chromatography on hemoglobin sepharose and by inhibition of AA or bradykinin-induced bronchoconstriction in the guinea pig. Hb reduced the inhibitory effect of Hp in a concentration-related manner such that all its inhibitory activity was lost when completely bound by Hb. Of the three Hp phenotypes, Hp 1-1 showed maximum binding capacity to Hb indicating its greater protective role. These findings implicate Hp in the regulation of COX and lipoxygenase pathways and show Hp involvement in the body’s endogenous defense system against inflammation. This indicates that mammals have dual defense system, i.e., a specific immune system and non-specific Hp defense system.

Is the upregulation of bradykinin B2 receptors by TGF-β1 one of the missing pieces in the “airway hyperresponsiveness” puzzle?

transforming growth factor (TGF)-β1 belongs to the TGF-β family of proteins corresponding to a set of pleiotropic secreted signaling molecules with unique and potent immunoregulatory properties ([10][1]). TGF-β1 is produced by every leukocyte lineage, including lymphocytes, macrophages, and

Effect of neutral endopeptidase inhibitor on bradykinin-induced bronchoconstriction

To evaluate whether neutral endopeptidase (NEP) inhibitors have adverse respiratory effects, the influence of a NEP inhibitor on bradykinin (BK)-induced bronchoconstriction was investigated. In anesthetized and artificially ventilated guinea pigs, changes in airway opening pressure (Pao) were measured as an index of bronchoconstriction. An infusion of phosphoramidon (3 mg kg −1 h −1), a NEP inhibitor, significantly enhanced the bronchoconstriction induced by high-dose BK (30 nmol kg −1, i.v.). Capsaicin (0.1 mg kg −1, i.v.) and SR48968 (0.3 mg kg −1, i.v.), an NK2 receptor antagonist, significantly inhibited the phosphoramidon-induced enhancement of BK-induced bronchoconstriction, although FK888 (3 mg kg −1, i.v.), an NK1 receptor antagonist, did not. Both neurokinin A (NKA) (0.1–3 nmol kg −1, i.v.) and substance P (SP) (0.1–3 nmol kg −1, i.v.) induced dose-dependent bronchoconstriction which was enhanced by phosphoramidon infusion, although these enhancements were more prominent in the NKA series. Phosphoramidon partially inhibited BK degradation in lung homogenate, and both NKA and SP degradation in the lung homogenate were significantly suppressed by phosphoramidon. In bronchoalveolar lavage fluid (BALF), levels of NKA and SP were significantly elevated after a bolus of BK with a phosphoramidon infusion. These results suggest that NEP inhibitors may have adverse respiratory effects resulting from inhibition of the degradation of neurokinins, but mainly of NKA, when a large amount of BK is generated.

Histamine release from human bronchoalveolar lavage mast cells by neurokinin A and bradykinin.

This study examined whether bradykinin and neurokinin A activate human pulmonary mast cells retrieved by bronchoalveolar lavage (BAL). BAL samples were obtained at routine bronchoscopy from 14 unpreselected patients. Histamine release experiments were performed using substance P, neurokinin A, bradykinin (peptides 25 and 50 microM), compound 48/80 (0.75-10 micrograms/ml) and A23187 (1 microM). Statistical analyses were performed using the paired Student's t-test and Pearson's linear correlation coefficient. Compound 48/80 induced release was significantly lower than that induced by the other secretagogues (p < 0.05). Neurokinin A and bradykinin induced release correlated significantly with substance P induced release (p < 0.01), suggesting similar mechanisms of action. No correlations were observed between neurokinin A or bradykinin-induced release and the non-peptide stimuli studied. The mechanism of neurokinin A- and bradykinin-induced bronchoconstriction is not yet clear but our data suggest an indirect effect mediated by mast cell degranulation.

Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B 2 receptor antagonist, FR167344

To investigate the pathophysiological role of bradykinin and to develop a drug for inflammatory diseases, we discovered an orally active, nonpeptide bradykinin B 2 receptor antagonist, FR167344, N-[ N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2,4-dichlorophenyl]- N-methylaminocarbonylmethyl]-4-(dimethylaminocarbonyl) cinnamylamide hydrochloride. This compound competitively displaced [ 3 H ]bradykinin binding to bradykinin B 2 receptors present in guinea pig ileum membrane with an IC 50 value of 6.6×10 −10 M. In isolated guinea pig ileum preparations, it also antagonized bradykinin-induced contraction with a pA 2 value of 9.3. In human lung fibroblast IMR-90 cells, FR167344 displaced [ 3 H ]bradykinin binding to human bradykinin B 2 receptors with an IC 50 value of 1.3×10 −8 M, but not [ 3 H ]des-Arg 10–kallidin binding to human bradykinin B 1 receptors. In vivo, oral administration of FR167344 inhibited bradykinin-induced bronchoconstriction in guinea pigs and the bradykinin-induced hypotensive response for 6 h in rats. These results show that FR167344 is a potent, selective, orally active and long acting bradykinin B 2 receptor antagonist.

Activity of inhaled lysine acetylsalicylate (L-ASA) on bradykinin-induced bronchoconstriction in asthmatics: evidence of contribution of prostaglandins

When administered by inhalation, bradykinin provokes dose-related bronchoconstriction in asthmatic subjects by a mechanism believed to involve activation of sensory nerve endings. However, little is known of the change in airway responsiveness to bradykinin after cyclo-oxygenase blockade. The aim of the present study was to investigate the effect of the potent cyclo-oxygenase inhibitor, lysine acetylsalicylate (L-ASA), administered by inhalation, on bradykinin-induced bronchoconstriction in a group of 12 asthmatic subjects. The subjects attended the laboratory on four separate occasions to receive nebulized L-ASA (solution of 90 mg x mL(-1)) or matched placebo (glycine, solution of 30 mg x mL(-1)) 15 min prior to bronchoprovocation tests with bradykinin and methacholine in a randomized, double-blind order with at least a 5 day interval. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1), and responsiveness to agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). Administration both of L-ASA and glycine solution caused a small but significant acute fall in FEV1 from baseline, with gradual recovery within 20 min. When compared to placebo, inhaled L-ASA reduced the airway responsiveness to bradykinin in 11 of the 12 subjects studied, the geometric mean (range) values for PC20 bradykinin increasing significantly (p<0.001) by 1.7 doubling dose from 0.55 (0.11-5.05) to 1.72 (0.26-6.05) mg x mL(-1) after placebo and L-ASA, respectively. No significant change in airway responsiveness to methacholine was recorded after L-ASA. It is concluded that administration of lysine acetylsalicylate by inhalation protects the asthmatic airways against bradykinin-induced bronchoconstriction, thus suggesting that endogenous prostaglandins may play a contributory role in the bronchoconstriction to kinins in human asthma.

Modulation of Myocardial Oxygen Consumption Through ACE Inhibitors

In this issue of Circulation ,1 Zhang and coworkers provide convincing evidence that ACE inhibitors reduce myocardial oxygen consumption by preventing the degradation of bradykinin, which subsequently stimulates the release of nitric oxide (NO). They propose that NO inhibits mitochondrial respiration, thus reducing myocyte oxygen use. This is an exciting observation because it provides a new mechanism whereby ACE inhibitors might benefit ischemia beyond simply inhibiting the formation of angiotensin II, thus reducing the vasoconstrictor effect of this octapeptide. These results are further evidence for a role of bradykinin in the response of tissues to ACE inhibitors. The mechanism enabling these interactions to occur is coming to light on the basis of studies such as the current one from Zhang et al. Interest in bradykinin and related kinins as cardiovascular mediators has grown tremendously in the past several years, largely because it has been recognized that they potently stimulate release of NO and prostacyclin from endothelial cells. Bradykinin and Lys-bradykinin, respectively, are formed when one of a family of enzymes, known as kallikreins, act on either heavy- or low-molecular-weight kininogens.2 This action involves cleavage of amino acids from both the C- and N-terminal ends of the kininogen peptides and takes place both in plasma (for heavy-molecular-weight kininogen) and tissues (for low-molecular-weight kininogen). The kininogens were previously thought to be expressed primarily by hepatocytes; however, it is now clear that many tissues, including vascular cells3 4 and the heart,5 also express kininogens. The kallikreins as well are made by many cell types and are produced by vascular cells in a continuous fashion.6 Thus, many tissues, including the heart and vascular cells, have an intact kallikrein/kininogen system capable of producing bradykinin. The mechanisms whereby bradykinin production is regulated remain unclear; however, there is some evidence that flow …

A new type of bradykinin B2 receptor antagonists: bradykinin analogs with N-alkyl amino acids at position 2

It is commonly assumed that bradykinin B2 receptor antagonists bind to a receptor site partially different from that for agonists. Thus, it is likely that there exists more than one key modification to convert bradykinin receptor agonists into antagonists. In this respect, [L-NMePhe2]-BK represents the basic structure of a new type of bradykinin B2 receptor antagonists without any replacement at position 7. This compound inhibits both in vitro bradykinin-induced contraction of the guinea pig lung strip and in vivo bradykinin-induced bronchoconstriction. Furthermore, this analog shows analgesic activity, blocks in a dose-dependent manner the bradykinin-induced Ca2+ release from macrophages and inhibits at a concentration of 10−13 M the bradykinin-induced cytokine release from mononuclear cells. Combinations with structural modifications previously performed for other B2 receptor antagonists rather reduce than enhance the potency.

Role of tachykinins in enhancement of bradykinin-induced bronchoconstriction by captopril.

In anesthetized, mechanically ventilated guinea pigs, infusion of captopril (1 mg/kg/h), an angiotensin converting enzyme inhibitor, significantly enhanced bronchoconstriction induced by intravenous injection of bradykinin (BK; 0.1-30 nmol/kg). Pretreatment of guinea pigs with capsaicin (100 mu g/kg) slightly suppressed the bronchoconstriction by BK alone and almost all of the enhancement of BK-induced bronchoconstriction by captopril was suppressed. Intravenous injection of substance P (SP; 0.1-100 nmol/kg), neurokinin A (NKA; 0.1-30 nmol/kg) and neurokinin B (NKB; 0.1-30 nmol/kg) also induced dose-dependent bronchoconstriction but captopril treatment enhanced only the bronchoconstriction induced by SP. BK degradation in bronchoalveolar lavage fluid (BALF) in vitro was significantly suppressed by captopril (p < 0.05). Captopril infusion to guinea pigs significantly increased the levels of BK, SP, and NKA in BALF after BK injection (p < 0.05). FK224, an NK1 and NK2 receptor antagonist and SR 48968, an NK2 receptor antagonist, significantly suppressed the bronchoconstriction induced by BK alone (p < 0.01 and p < 0.05, respectively) as well as the enhancement by captopril (p < 0.01). It can be concluded that the enhancement of BK-induced bronchoconstriction by captopril was attributable to inhibition of the degradation of BK itself and thereby enhanced release of NKA and partly of SP from sensory nerves by BK.

Perception of bronchial obstruction in asthmatic patients. Relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment.

We studied the perception of bronchoconstriction in asthmatic subjects who were randomly treated with inhaled beta 2 agonist given either alone (n = 9) or associated with inhaled corticosteroids (n = 9). Methacholine and bradykinin challenges, bronchoalveolar lavage, and bronchial biopsies were performed in all subjects. After each dose of agonist, breathlessness was assessed using a visual analog scale (VAS) and the forced expiratory volume in 1 s (FEV1) was measured. The relationship between VAS scores and FEV1 and the slope of the regression line of VAS scores on the corresponding FEV1 (VAS/FEV1 slope) were analyzed for each agonist. Subjects without corticosteroids had good perception of methacholine but poor perception of bradykinin-induced bronchoconstriction. In subjects with corticosteroids, bronchoconstriction was well perceived whatever the agonist. VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa. VAS/FEV1 slopes for each agonist correlated positively with the percentage of basement membrane covered by airway epithelium. We conclude that in asthmatic patients perception of bronchoconstriction is related to eosinophilic inflammation and to epithelial damage in airways and that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin, a mediator endogenously produced in asthma.

Effect of inhaled frusemide on responses of airways to bradykinin and adenosine 5'-monophosphate in asthma.

Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma. This effect could be caused by interference with neural pathways. The effect of inhaled frusemide on bronchoconstriction induced by inhaled bradykinin, which is thought to cause bronchoconstriction via neural mechanisms, was studied and compared with the effects of adenosine 5'-monophosphate (AMP) which probably produces its airway effects by augmenting mast cell mediator release and interfering with neural pathways. Patients first underwent AMP and bradykinin challenges. They were then studied in a randomised, placebo controlled, double blind fashion. Ten atopic asthmatic subjects, studied on four days, were pretreated with inhaled frusemide (40 mg) or placebo for 10 minutes, five minutes before challenge with increasing concentrations of nebulised AMP or bradykinin. On the open visit days the provocative concentrations required to reduce forced expiratory volume in one second (FEV1) by 20% from baseline (PC20) for AMP and bradykinin were 16.23 (1.42-67.16) and 2.75 (0.81-6.6) mg/ml. There was a significant correlation between baseline AMP and bradykinin PC20 values. For AMP the geometric mean PC20 values following pretreatment with inhaled frusemide and matched placebo were 80.97 (9.97- > 400.0) and 14.86 (2.6-104.6) mg/ml respectively (95% CI 0.49 to 0.98). For bradykinin the geometric mean PC20 values following pretreatment with inhaled frusemide and matched placebo were 13.22 (2.53- > 16.0) and 2.52 (0.45-5.61) mg/ml respectively (95% CI 0.43 to 1.01). Frusemide afforded 5.45 and 5.24 fold protection against AMP and bradykinin-induced bronchoconstriction respectively. Furthermore, there was a significant correlation between protection afforded to the airways against AMP and bradykinin. These data suggest that inhaled frusemide affords protection against bradykinin-induced bronchoconstriction which is comparable to that against AMP, supporting a common mechanism of action for frusemide.

Effects of peptidase inhibitors on bradykinin-induced bronchoconstriction in the rat

Objectives of this study were to determine if aerosolized bradykinin causes bronchoconstriction in anesthetized, mechanically ventilated rats, and if pretreatment with enalaprilat, an inhibitor of angiotensin-converting enzyme (ACE), or phosphoramidon, an inhibitor of endopeptidase 24.11 (EP 24.11), alters the response. We found that aerosolized bradykinin elicited a reproducible bronchoconstrictor response that was significantly amplified by pretreatment with aerosolized enalaprilat or phosphoramidon. Neither inhibitor alone affected airway tone or caused nonspecific airway hyperreactivity. These findings indicate that both ACE and EP 24.11 contribute to bradykinin degradation in rat airways.

Neurokinin-receptor antagonist inhibits bradykinin-induced bronchoconstriction and cough in asthmatic patients

Neurokinin-receptor antagonist inhibits bradykinin-induced bronchoconstriction and cough in asthmatic patients

Protection against bradykinin-induced bronchoconstriction in asthmatic patients by neurokinin receptor antagonist

Axon reflex mechanisms may be involved in the pathogenesis of asthma, but there has been no direct evidence that endogenous tachykinins cause bronchoconstriction in asthmatic subjects. We have studied the effect of a tachykinin receptor antagonist (FK-224) on bronchoconstriction induced by inhalation of bradykinin in asthmatic patients. In a double-blind, placebo-controlled, crossover trial, ten subjects with stable asthma were given FK-224 (4 mg) or placebo by inhalation 20 min before challenge with bradykinin (0-1250 μg/ml, five breaths of each concentration) given with 5 min intervals. Bradykinin caused dose-dependent bronchoconstriction in all subjects. FK-224 significantly opposed the bronchoconstrictor effect; the geometric mean of the cumulative concentration required to elicit a 35% fall in specific airway conductance was 5·3 μg/ml after placebo and 40 μg/ml after FK-224 (p<0·001). Inhalation of bradykinin caused coughing in three subjects, which was inhibited by FK-224 in all three. Antagonism of the tachykinin receptor by FK-224 greatly inhibited both bronchoconstriction and coughing induced by bradykinin in asthmatic patients, suggesting that tachykinin release from the airway sensory nerves is involved in responses to bradykinin. Tachykinin receptor antagonists may be useful in the treatment of asthma.

Effect of Hoe 140, a new bradykinin receptor antagonist, on bradykinin- and platelet-activating factor-induced bronchoconstriction and airway microvascular leakage in guinea pig

We have investigated the effect of a new bradykinin receptor antagonist, Hoe 140 (D-Arg-[Hyp 3,Thi 5,D-Tic 7,Oic 8]-bradykinin), on bradykinin- and platelet-activating factor (PAF)-induced bronchoconstriction and airway microvascular leakage in anesthetized guinea pigs. Extravasation of Evans blue dye and lung resistance were measured simultaneously. Both i.v. (15 nmol/kg) and inhaled bradykinin (1 mM, 45 breaths) caused a significant increase in lung resistance and leakage of dye at all airway levels. Hoe 140 (100 nmol/kg i.v.) almost completely inhibited these airway responses induced by bradykinin except for dye extravasation in trachea induced by inhaled bradykinin. Inhaled PAF (3 mM, 30 breaths) significantly increased lung resistance and leakage of due at all airway levels, but Hoe 140 had no effect on these responses. Bradykinin-induced bronchoconstriction and airway microvascular leakage are predominantly mediated by activation of B 2 receptor, since Hoe 140 is a B 2 receptor antagonist. Bradykinin receptor-mediated mechanisms do not play an important role on inhaled PAF-induced bronchoconstriction and microvascular leakage.

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.

Synergistic potentiation by captopril and propranolol of bradykinin-induced bronchoconstriction in the guinea-pig.

1. Captopril (30 or 100 micrograms/kg intravenous (i.v.] in anaesthetized artificially ventilated guinea-pigs potentiated bronchoconstrictor responses to bradykinin, but not those to histamine or the thromboxane A2-mimetic U46619. 2. Propranolol (5 mg/kg, i.v.) potentiated bradykinin-induced broncho-constriction. The potentiated responses were further augmented by captopril. 3. The captopril-potentiated responses to bradykinin were inhibited during cyclo-oxygenase inhibition with indomethacin. Bronchoconstrictor responses to bradykinin, but not those to histamine or U46619, were reduced after thromboxane synthase inhibition with dazoxiben. The thromboxane A2 antagonist AH23848 inhibited bronchoconstrictor responses to bradykinin, arachidonic acid or U46619 whereas it did not affect those to histamine. 4. A kininase I inhibitor DL-2-mercaptomethyl-3-guanidinoethyl thiopropanoic acid caused no change in bronchoconstriction caused by bradykinin and did not alter the potentiated responses occurring after captopril. 5. Thus, confirmation has been obtained that bradykinin causes broncho-constriction in the guinea-pig indirectly, by release of eicosanoids. Thromboxane A2 is likely to be the major eicosanoid released, since the bronchoconstrictor effect of bradykinin was blocked by indomethacin, dazoxiben and AH23848. The intensity of the bronchoconstriction appears dependent on sympathetic influences mediated by beta-adrenoceptors. Kininase I, in contrast to kininase II apparently has little role in terminating the effects of bradykinin in the lung.

Bradykinin‐induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.

1. The effects of inhaled nedocromil sodium and sodium cromoglycate on bradykinin-induced bronchoconstriction have been studied in a double-blind, placebo controlled study, in eight mild asthmatic subjects. 2. The subjects attended on four occasions. Fifteen minutes after drug pre-treatment a bradykinin challenge was performed. Increasing concentrations were inhaled until a greater than 40% fall in expiratory flow at 30% of vital capacity from a partial flow volume manoeuvre (V p30) was demonstrated. 3. Inhaled bradykinin (0.06-8.0 mg ml-1) caused dose-related bronchoconstriction with the geometric mean cumulative dose causing a 40% fall in V p30 (PD40) of 0.035 (95% CI: 0.02-0.07) mumol, after placebo inhalation, which was similar to that measured before the trial (0.04: 0.02-0.09 mumol). 4. Both nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) gave significant protection (P less than 0.05) against bradykinin-induced bronchoconstriction (PD40 0.37: 0.19-0.72 mumol after nedocromil sodium and 0.22: 0.11-0.49 after sodium cromoglycate). 5. Since bradykinin-induced bronchoconstriction is probably neurally mediated we conclude that both nedocromil sodium and sodium cromoglycate have an action on neural pathways which may be useful in the control of asthma symptoms.

Inhibition of bradykinin‐induced bronchoconstriction in the guinea‐pig by a synthetic B2 receptor antagonist

1. Intravenous bradykinin (Bk) elicited bronchoconstriction in the anaesthetized ventilated guinea-pig which was not mimicked by the B1 receptor agonist, des-Arg9-Bk. 2. Bradykinin-induced bronchoconstriction was inhibited by the B2 receptor antagonist B4881, but not by the B1 receptor antagonist des-Arg9-Leu8-Bk. The effect of B4881 was short-lived. 3. The B2 receptor antagonist as B4881 was selective for bradykinin as B4881 did not significantly inhibit bronchoconstriction induced by i.v. bombesin, platelet activating factor, acetylcholine, histamine or vagal stimulation. 4. These results suggest that bradykinin-induced bronchoconstriction in the guinea-pig is via activation of a B2 receptor population and that B4881 is a selective B2 antagonist that may be useful for investigating the involvement of bradykinin in the lung.

Effects of Nedocromil Sodium on Airway Microvascular Leakage and Neural Reflexes

Microvascular leakage and neurogenic mechanisms may be important components of the inflammatory response in asthmatic airways. We have examined the effects of nedocromil sodium on these responses. In guinea-pig airway, microvascular leakage induced by allergen was significantly inhibited by prior treatment with nedocromil sodium (100 micrograms/kg IV), but this had no effect on histamine-induced leakage and reduced PAF-induced leakage only at a dosage of 5 mg/kg. This suggests that nedocromil sodium acts mainly by preventing the release of inflammatory mediators. Both sulphur dioxide (SO2) and bradykinin cause bronchoconstriction in asthmatic patients, which is likely to be due to a neural mechanism since SO2 activates C-fibre sensory nerve endings in airways. Inhaled nedocromil sodium is effective in inhibiting both SO2- and bradykinin-induced bronchoconstriction, and furthermore reduces the sensation of dyspnoea, indicating a possible action on sensory nerve endings in airways.