neurokinin-a and Asthma

Tachykinins substance P, neurokinin A and neurokinin B seem to account for asthma pathophysiology by mediating neurogenic inflammation and several aspects of lung mechanics. These neuropeptides act mainly by their receptors NK1, NK2 and NK3, respectively which may be targets for new asthma therapy.. This review systematically examines randomized controlled trials evaluating the effect of tachykinins receptors antagonism on asthma. Symptoms, airway inflammation, lung function and airway inflammation were considered as outcomes. We searched the Cochrane Airways Group Specialized Register of Asthma Trials, Cochrane Database of Systematic Reviews, MEDLINE/PubMed and EMBASE. The search is as current as June 2010. Quality rating of included studies followed the Cochrane Collaboration and GRADE Profiler approaches. However, data were not pooled together due to different measures among the studies.. Our systematic review showed the potential of NK receptor antagonist to decrease airway responsiveness and to improve lung function. However, effects on airway inflammation and asthma symptoms were poorly or not described.. The limited available evidence suggests that tachykinin receptors antagonists may decrease airway responsiveness and improve lung function in patients with asthma. Further large randomized trials are still required.

Topics: Anti-Asthmatic Agents; Asthma; Humans; Neurokinin A; Neurokinin B; Receptors, Tachykinin; Substance P; Treatment Outcome

The tachykinins substance P and neurokinin A are present in human airways, in sensory nerves and immune cells. Tachykinins can be recovered from the airways after inhalation of ozone, cigarette smoke or allergen. They interact in the airways with tachykinin NK1, NK2 and NK3 receptors to cause bronchoconstriction, plasma protein extravasation, and mucus secretion and to attract and activate immune cells. In preclinical studies they have been implicated in the pathophysiology of asthma and chronic obstructive pulmonary disease, including allergen- and cigarette smoke induced airway inflammation and bronchial hyperresponsiveness and mucus secretion. Dual NK1/NK2 or triple NK1/NK2/NK3 tachykinin receptor antagonists offer therapeutic potential in airway diseases such as asthma and chronic obstructive pulmonary disease.

Topics: Animals; Asthma; Bronchoconstriction; Clinical Trials as Topic; Disease Models, Animal; Humans; Neurokinin A; Neurons, Afferent; Neurotransmitter Agents; Pulmonary Disease, Chronic Obstructive; Receptors, Tachykinin; Respiratory System; Respiratory System Agents; Substance P

Asthma represents a chronic inflammatory process of the airways. The neurothrophin (NGF) and neuropeptides such as substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) play important role in stimulation of airways inflammation in asthmatics. NGF stimulates the differentiation and the migration of mast cells to bronchi epithelium. Furthermore, NGF stimulates mast cell degranulation and mediator upregulation and release. It also influences activity of basophils, eosinophils, neurophils, macrophages and T-cells. In addition, its important role in releasing of hyperresponsiveness has been proved. Neuropeptides such as CGRP and SP stimulate migration and degranulation of eosinophils and influence on airway responsiveness in asthmatics. This review article discusses the neuropeptides and NGF actions and mechanisms in the pathogenesis of asthma.

Topics: Asthma; Calcitonin Gene-Related Peptide; Humans; Nerve Growth Factor; Neurokinin A; Neuropeptides; Substance P

Menarini Richerche is developing nepadutant, an NK2 antagonist, for the potential treatment of asthma and irritable bowel syndrome. The compound is in phase IIa trials in Belgium and Sweden for both these indications [359518].

Topics: Animals; Asthma; Bronchodilator Agents; Colonic Diseases, Functional; Humans; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Structure-Activity Relationship

The sensory neuropeptides substance P (SP) and neurokinin A (NKA) are localized to sensory airway nerves, from which they can be released by a variety of stimuli, including allergen, ozone, or inflammatory mediators. Sensory nerves containing these peptides are relatively scarce in human airways, but it is becoming increasingly evident that inflammatory cells such as eosinophils, macrophages, lymphocytes, and dendritic cells can produce the tachykinins SP and NKA. Moreover, immune stimuli can boost the production and secretion of SP and NKA. SP and NKA have potent effects on bronchomotor tone, airway secretions, and bronchial circulation (vasodilation and microvascular leakage) and on inflammatory and immune cells. Following their release, tachykinins are degraded by neutral endopeptidase (NEP) and angiotensin-converting enzyme. The airway effects of the tachykinins are largely mediated by tachykinin NK1 and NK2 receptors. Tachykinins contract smooth muscle mainly by interaction with NK2 receptors, while the vascular and proinflammatory effects are mediated by the NK1 receptor. In view of their potent effects on the airways, tachykinins have been put forward as possible mediators of asthma, and tachykinin receptor antagonists are a potential new class of antiasthmatic medication.

Topics: Asthma; Humans; Lung; Neurogenic Inflammation; Neurokinin A; Neurons, Afferent; Receptors, Tachykinin; Substance P

There has been increased recognition of the importance of inflammatory cells and their products in the pathogenesis of asthma. From this recognition has evolved a number of new approaches to treat the various components of the asthmatic inflammatory response. Nonselective anti-inflammatory agents such as cyclosporine and gold appear to decrease symptoms and allow a steroid-sparing effect in many cases, though side effects from cyclosporine often necessitate dose reduction. Novel oral compounds as the 5-lipoxygenase inhibitors have been effective in controlling asthma symptoms triggered by various stimuli, and the cysteinyl leukotriene receptor antagonists have shown promise in this regard as well. Neurokinin antagonists, inhaled loop diuretics, and lidocaine may play significant roles in asthma therapy through inhibition of neurogenic inflammation and possibly mast cell function. Inhibition of mast cell products by existing drugs such as heparin or the development of specific inhibitors of mast cell tryptase may also be effective agents, as are selective phosphodiesterase inhibitors, which appear to have anti-inflammatory properties. Finally, specific cytokine antagonists, agonists, inhibitors of T-cell function, selective inducible nitric oxide synthase inhibitors, and even gene-directed strategies may provide not only insights into the pathogenesis of asthma but also novel therapeutic approaches to treat the inflammation in this disease.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Antirheumatic Agents; Asthma; Auranofin; Bradykinin; Cholinergic Antagonists; Chymases; Cyclosporine; Diuretics; Drugs, Investigational; Genetic Therapy; Heparin Antagonists; Humans; Immunosuppressive Agents; Kinins; Leukotriene Antagonists; Lidocaine; Muscarinic Antagonists; Neurokinin A; Phosphodiesterase Inhibitors; Prostaglandin-Endoperoxide Synthases; Receptors, Tachykinin; Serine Endopeptidases; T-Lymphocytes; Tryptases

Topics: Adrenergic beta-Antagonists; Animals; Asthma; Bronchial Hyperreactivity; Guinea Pigs; Humans; Neurokinin A; Neurons, Afferent; Substance P

Topics: Adenosine; Animals; Asthma; Bronchi; Humans; Inflammation; Neurokinin A; Neuropeptides; Rats

Leukotrienes, especially LTC4, are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways. Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase.. To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps, and determine its dependency on aspirin sensitization.. Twenty-four patients (7 women, 17 men; median age, 55.5 years) with nasal polyps and controlled asthma (n=12 with aspirin intolerance) were treated with 10 mg montelukast once daily for 6 weeks in a blinded, placebo-controlled fashion. The placebo phase was randomly assigned 4 weeks before (n=12) or after treatment (n=12). Symptom score, rhinoendoscopy, rhinomanometry, smears for eosinophils, and nasal lavages for the determination of different mediators were performed.. Compared to placebo, there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment. Furthermore, reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment.. Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma, with or without aspirin intolerance.

Topics: Acetates; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Asthma, Aspirin-Induced; Cell Count; Cyclopropanes; Cysteine; Eosinophils; Female; Humans; Leukotriene Antagonists; Leukotrienes; Male; Middle Aged; Nasal Lavage Fluid; Nasal Polyps; Neurokinin A; Quinolines; Substance P; Sulfides; Treatment Outcome

We previously reported that the nonpeptide tachykinin NK(2) receptor antagonist SR48968 (saredutant) significantly inhibits neurokinin A-induced bronchoconstriction in patients with asthma. MEN11420 (nepadutant) is a bicyclic peptide tachykinin NK(2) receptor antagonist. The aim of the trial was to examine the effect of nepadutant on neurokinin A-induced bronchoconstriction in man.. 12 patients with stable, mild to moderate asthma participated in a double-blind, placebo-controlled crossover trial and received, with intervals of 1 week, MEN11420 2 mg, MEN11420 8 mg and placebo (i.v.). Increasing concentrations of NKA (10(-9) to 10(-6) moles/ml) were inhaled immediately after (d1) and 24 hours after (d2) administration of treatment.. On d1 both MEN11420 2 and 8 mg shifted the dose response curve for neurokinin A to the right (log PC(20) FEV(1) neurokinin A [moles/ml]; mean + or = or - SEM -6.38 + or - 0.26 after 2 mg, -6.11 + or - 0.23 after 8 mg, versus -6.95 + or - 0.27 after placebo]. On d2 MEN11420 had no effect on neurokinin A-induced bronchoconstriction.. In conclusion, the tachykinin NK(2) receptor antagonist nepadutant significantly inhibits bronchoconstriction induced by neurokinin A in patients with asthma.

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Respiratory Function Tests; Young Adult

The bronchoconstriction caused by inhaled neurokinin A (NKA) in patients with asthma is indirect. The mediators involved in NKA-induced bronchoconstriction are unknown. Studies with various H1 receptor antagonists were negative, making an important contribution of histamine unlikely. To study the role of cysteinyl leukotrienes in neurokinin A-induced bronchoconstriction, we performed a randomised, double-blind, cross-over, placebo controlled trial in 12 patients with mild to moderate asthma. Zafirlukast and matching placebo were given orally, 40 mg the evening before and 40 mg the morning of assessment. In one period NKA was administered, in the other period leukotriene D4 (LTD4). Increasing concentrations of NKA and LTD4 were inhaled from a 30 L bag, after nebulization via a Mallinckrodt nebuliser. The difference between log10PC20LTD4 after treatment with placebo or zafirlukast was highly significant (p<0.0001). A trend was observed towards a difference between log10PC20 neurokinin A after treatment with placebo or zafirlukast (p=0.0741). The dose ratio for the neurokinin A provocation was 4.4 and for the LTD4 provocation 67.7. In conclusion, zafirlukast had a large inhibitory effect on LTD4-induced bronchoconstriction, but offered only limited protective effect against neurokinin A-induced bronchoconstriction. We suggest that leukotrienes play a limited role in the bronchoconstrictor effect of neurokinin A in patients with asthma.

Topics: Adult; Arachidonate 5-Lipoxygenase; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Glutathione Transferase; Humans; Indoles; Leukotriene Antagonists; Leukotriene D4; Neurokinin A; Phenylcarbamates; Polymorphism, Genetic; Sulfonamides; Tosyl Compounds

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory agents available for the treatment of asthma but they produce only modest effects on airway inflammation and non-specific bronchial hyperresponsiveness (BHR). However, little is known about the possibility that treatment with ICS might cause additional protection on BHR to inhaled tachykinins such as neurokinin A (NKA).. Therefore, we compared the effects of beclomethasone dipropionate (BDP) on the degree of BHR to inhaled histamine and NKA in a double-blind, controlled, cross-over study of asthmatic patients.. Patients attended the laboratory before and after each 6 weeks treatment period to undertake concentration-response studies with histamine and NKA. Bronchial responsiveness to both funs was expressed as the provocative concentration producing a 20% decrease in FEV(1) from baseline (PC(20)).. BDP therapy attenuated the constrictor response to both agonists to a similar degree, their geometric mean (range) PC(20) values increasing from 0.47 (0.21-1.41) mg/ml to 2.43 (0.51-4.50) mg/ml (P<0.01, post-salb vs. post-BDP treatment) and from 101.7 (27.3-356.1) microg/ml to 666.7 (151.5-1,000) microg/ml (P<0.01, post-salb vs. post-BDP treatment) for histamine and NKA, respectively.. Airway responsiveness to histamine and NKA is reduced by BDP to the same extent. As a result of these findings, provocation with NKA is unlikely to provide additional useful information in the assessment of airway inflammation in asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Albuterol; Analysis of Variance; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine; Humans; Male; Neurokinin A; Statistics, Nonparametric

Neurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK1 and NK2 receptors can mediate airway contraction. Moreover in guinea pigs, NK3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK1/NK2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKA-induced bronchoconstriction in asthmatics. A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKA-provocation tests were performed pre-dose and 1, 8 and 24 h after dosing. There was a significant shift to the right of the dose-response curve at 1 and 8 h after intake of CS-003. PC20 was not reached in 12/16 patients at 1h post-dose and in 5/16 patients at 8 h post-dose. This did not occur under placebo treatment. A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8h post-dose in mild asthmatics.

Topics: Adolescent; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Neurokinin A; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Reproducibility of Results; Respiratory Function Tests

Non-adrenergic non-cholinergic (NANC) nerves release bronchoactive tachykinins such as substance P (SP) and neurokinin A (NKA) that can induce features of asthma. The airway response to NKA in humans closely resembles that of methacholine (M). Hence, we investigated the relationship between airway responsiveness to NKA and M in subjects with asthma. To this end, we analyzed baseline data of 27 subjects with mild persistent asthma (20F/7M) 19-46 y; FEV1 81-136% pred.; PC20FEV1 (M)<80 micromol/mL) participating in a proof-of-concept study. All subjects were non-smokers and asthma was controlled by on demand short-acting beta2-agonists only. Dose-response curves to M (0.15-80 micromol/mL) and NKA (3.4 (10(-3))-0.88 micromol/mL) were performed on two separate days, and airway response was measured by FEV1 until a > or = 20% fall from baseline (PC20FEV1). Twenty-two subjects reached a PC20FEV1 on both occasions. The PC20FEV1 values of both agonists correlated significantly (Spearman's r=-0.721; p=0.0002), and the relationship was given by 10log(PC20FEV1(NKA))= -1.36 + (0.60 x 10log(PC20FEV1(M)). We have demonstrated a significant relationship between airway responsiveness to NKA and methacholine in asthma. This suggests that both agonists may share common final pathways in causing bronchoconstriction in patients with mild persistent asthma. Based on our data and previous studies in asthma, it can be hypothesized that this direct NKA-induced bronchoconstrictor response may be mediated by predominant stimulation of the tachykinin NK-2 receptors on airway smooth muscle cells.

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchoconstrictor Agents; Female; Humans; Male; Methacholine Chloride; Middle Aged; Neurokinin A; Respiratory Function Tests

Inhalation of neurokinin A (NKA) causes bronchoconstriction in patients with asthma. In vitro both tachykinin NK1 and NK2 receptors can mediate airway contraction. In this study the authors examined the effects of a single dose of the dual tachykinin NK1/NK2 receptor antagonist, DNK333, on NKA-induced bronchoconstriction in asthma. A total of 19 male adults with mild asthma completed a randomised, double-blind, placebo-controlled crossover trial. Increasing concentrations of NKA (3.3x10(-9) to 1.0x10(-6) mol x mLP(-1)) were inhaled at 1 and 10 h intervals after a single oral dosing with either DNK333 (100 mg) or a placebo. It was observed that DNK333 did not affect baseline lung function but did protect against NKA-induced bronchoconstriction in those patients. The mean log10 provocative concentration causing a 20% fall in forced expiratory volume in one second for NKA was -5.6 log10 mol x mL(-1) at 1 h after DNK333 treatment and -6.8 log10 mol x mL(-1) after placebo. This was equivalent to a difference of 4.08 doubling doses, which decreased to a difference of 0.90 doubling doses 10 h after treatment. The results shown in this report indicate that DNK333 blocks neurokinin A-induced bronchoconstriction in patients with asthma.

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Aza Compounds; Benzamides; Bronchoconstriction; Cross-Over Studies; Double-Blind Method; Humans; Middle Aged; Neurokinin A; Receptors, Tachykinin

Neurokinin (NK) A causes airway narrowing in patients with asthma through direct and indirect mechanisms. The effects of the inhaled glucocorticosteroid fluticasone propionate (FP) on the bronchial responsiveness to NKA and methacholine were studied. Patients (n=11) with mild asthma participated in a randomized, double-blind, placebo-controlled crossover trial. FP (500 microg b.i.d.) or matched placebo was administered via Diskhaler for 14 days. Bronchial challenges were performed on days 1 and 13 (methacholine) and 0 and 14 (NKA) for each treatment period. At the active treatment period, the mean log2 provocative concentration causing a 20% fall in the forced expiratory volume in one second (PC20)+/-SEM for NKA was -12.72+/-0.63 at the beginning and -9.77+/-0.49 at the end of the period (p<0.0001), while under placebo, it was -12.16+/-0.82 and -12.19+/-0.51 respectively (NS). At the active treatment period, the mean log2 PC20 for methacholine was -5.25+/-0.40 at the beginning and -4.22+/-0.31 at the end of the period (p=0.012), while under placebo, it was -5.47+/-0.47 and -5.24+/-0.42 respectively (NS). The reduction in response to NKA was significantly larger than that for methacholine. A 2-week course of an inhaled steroid reduces bronchial responsiveness to neurokinin A, an effect more pronounced than the reduction in bronchial responsiveness to methacholine.

Topics: Administration, Inhalation; Adolescent; Adult; Androstadienes; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Neurokinin A

Microvascular leakage is an important feature of inflammation. However, the assessment of vascular leakage has seldom been used to monitor airway inflammation in asthma. The aim of this study was to determine the effect of inhaled substance P, a potent neurokinin 1 (NK1) agonist and mediator of plasma extravasation, on markers of microvascular leakage in induced sputum from patients with asthma. In a crossover study, sputum was induced before and 30 minutes after inhalation of substance P or neurokinin A (as control) by 12 subjects with atopic and mild, steroid-naive asthma. The levels of alpha2-macroglobulin, ceruloplasmin, albumin, and fibrinogen were determined in induced sputum as markers of leakage. Substance P induced a significant increase in the levels of alpha2-macroglobulin, ceruloplasmin, and albumin in induced sputum (median fold change, 3.1, 2.2, and 2.9, respectively) (p < 0.013), whereas inhaled neurokinin A was not able to induce significant changes (p > 0.31). The increase in sputum leakage markers was not associated with the cumulative dose of substance P (p > 0.12). These results indicate that NK1 receptor stimulation causes a rapid increase in microvascular leakage as shown in induced sputum in patients with asthma. This investigational model of "dual induction" (first leakage, then sputum) may therefore be useful to test the antiexudative effect of newly develop drugs, such as NK1 antagonists.

Topics: Adult; Albumins; alpha-Macroglobulins; Asthma; Biomarkers; Capillary Permeability; Ceruloplasmin; Cross-Over Studies; Female; Fibrinogen; Humans; Male; Neurokinin A; Single-Blind Method; Sputum; Statistics, Nonparametric; Substance P

Inhalation of neurokinin (NK) A causes bronchoconstriction in patients with asthma. The NKA-induced bronchoconstriction in isolated human airways is mediated via the NK2 receptor and inhibited by SR 48968, a potent and specific nonpeptide tachykinin NK2 receptor antagonist. In the present study, the effect of orally administered SR 48968 on NKA-induced bronchoconstriction was examined in 12 mild asthmatics. On the screening day and during the study periods, increasing concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol x mL(-1)) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing. At 1.5 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0.05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0.05). At 24 h, the mean log10 PC20 FEV1 was -6.21 (0.17) after SR 48968 and -6.65 (0.11) after placebo (p=0.05); the mean log10 PC35 sGaw was -6.85 (0.23) after SR 48968 and -7.17 (0.15) after placebo (nonsignificant). As PC20 FEV1 and/or PC35 sGaw were not reached in up to 4 patients per SR 48968 group, the differences between SR 48968 and placebo were underestimated. In conclusion, oral treatment with 100 mg SR 48968 caused a significant inhibition of neurokinin A-induced bronchoconstriction in asthmatics. This finding constitutes the first evidence of inhibition of sensory neuropeptide-induced bronchoconstriction by a selective tachykinin receptor antagonist in humans.

Topics: Adult; Asthma; Benzamides; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Forced Expiratory Volume; Humans; Male; Neurokinin A; Piperidines; Receptors, Neurokinin-2; Treatment Outcome

Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects.. Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20).. Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively.. The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.

Topics: Administration, Inhalation; Adult; Analysis of Variance; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Furosemide; Histamine; Humans; Male; Neurokinin A

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.

Topics: Administration, Inhalation; Asthma; Bronchoconstriction; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptides, Cyclic; Receptors, Neurokinin-2; Respiratory Function Tests

Endogenously released cyclooxygenase products modulate the bronchoconstrictor response to various stimuli in asthma. Little is known of the change in airway responsiveness to neurokinin A (NKA) after cyclooxygenase blockade. In this randomized, double-blind, placebo-controlled study, we have investigated the effect of the potent cyclooxygenase inhibitor, lysine acetylsalicylate (L-ASA) administered by inhalation, on the bronchoconstrictor response both to neurokinin A (NKA) and methacholine in nine asthmatic subjects. Subjects attended the laboratory on four separate occasions to receive nebulized L-ASA (solution of 90 mg.mL-1) or matched placebo (glycine, solution of 30 mg.mL-1) 15 min prior to bronchial challenge with NKA or methacholine, in a randomized, double-blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and agonist responsiveness, expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). L-ASA elicited a significant fall in FEV1 from baseline. When compared with placebo, inhaled L-ASA reduced the airway responsiveness to NKA in 8 of the 9 subjects studied, the geometric mean (range) values for PC20 NKA increasing significantly from 153.2 (52.0-258.9) to 303.1 (83.4-668.5) micrograms.mL-1 after placebo and L-ASA, respectively. However, no significant change in airway responsiveness to methacholine was recorded after L-ASA, their geometric mean (range) PC20 values being 1.60 (0.17-9.59) and 1.53 (0.09-14.01) mg.mL-1 after placebo and L-ASA, respectively. The small decrease in airway responsiveness to neurokinin A after administration of lysine acetylsalicylate by inhalation suggests that endogenous prostaglandins may play a contributory protective role in the airway response to neurokinin A in human asthma.

Topics: Administration, Inhalation; Adult; Aspirin; Asthma; Bronchial Provocation Tests; Constriction, Pathologic; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Female; Humans; Lysine; Male; Methacholine Chloride; Middle Aged; Neurokinin A; Respiratory Function Tests

The endogenous tachykinins exhibit a range of properties which may be relevant in the pathophysiology of asthma. Their effects on the airways seem to be modulated by a variety of lung peptidases, including neutral endopeptidase (NEP). In order to evaluate the potential role of endogenous NEP activity in modulating tachykinins-induced bronchoconstriction in man in vivo, six atopic asthmatic patients, with a mean FEV1 value of 3.38 +/- 0.76 l, and a histamine PD20 mean value of 0.024 mg, were studied. The influence of inhaled phosphoramidon (a potent NEP inhibitor) was examined against the NKA-induced bronchospasm in a double-blind, placebo-controlled randomized study. Changes in airway calibre were followed as FEV1 and agonists responsiveness expressed as PD20 and PD15 for histamine and NKA respectively. Patients received nebulized phosphoramidon sodium salt (10(-5) M) or a control solution 10 min prior to the bronchoprovocation test with NKA. No significant difference was noticed between any of the study days and after inhaled phosphoramidon on baseline FEV1 values (3.29 +/- 0.90 l) in comparison with the control solution (3.31 +/- 0.79 l). Inhaled NKA produced a dose-dependent fall in FEV1 values in all the subjects studied with a mean PD15 value of 20.91 x 10(-9) mol. Phosphoramidon administered by inhalation elicited a significant (P < 0.01 vs baseline and control solution) potentiation in the airway responsiveness to inhaled NKA, the NKA PD15 value decreasing to 9.45 x 10(-9) mol. The present study confirms that inhaled NKA induces a dose-related bronchoconstriction in asthmatic patients and demonstrates that inhaled phosphoramidon potentiates NKA-induced bronchoconstriction.

Topics: Adolescent; Adult; Analysis of Variance; Asthma; Bronchoconstriction; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycopeptides; Humans; Male; Middle Aged; Neprilysin; Neurokinin A; Respiratory Function Tests

Neurokinin A (NKA) elicits a potent contractile effect in asthmatic airways. Its mechanism of action in bronchial asthma is still unknown. Recent work supports the view that NKA may stimulate mediator release from mast cells. To investigate the relative contribution of mast cell degranulation to the action of NKA, a randomized, double-blind study has been undertaken, to evaluate the effect of a potent and selective histamine H1-receptor antagonist, terfenadine (180 mg q.d., for three days), on bronchoconstriction provoked by inhaled NKA in six asthmatic subjects. Bronchial provocation tests with histamine were included in this study as control challenge. In the subjects studied, oral terfenadine, when compared to placebo, significantly increased the geometric mean (range) provocation dose of inhaled histamine required to reduce forced expiratory volume in one second (FEV1) by 20% of baseline (PD20) from 0.05 (0.03-0.08) mg (0.16 (0.10-0.26) mumol) to 1.19 (0.63-2.04) mg (3.88 (2.05-6.64) mumol). However, terfenadine failed to increase the airway responsiveness to NKA in all of the subjects studied, the geometric mean (range) PD15 NKA value being 0.94 (0.47-2.49) micrograms (8.36 (4.14-21.9 nmol) and 0.75 (0.48-1.59) micrograms (6.62 (4.23-14.0) nmol) after placebo and terfenadine, respectively. We conclude that NKA is a potent bronchoconstrictor agonist in asthma, being approximately 19 times more potent than histamine in molar terms. In this study on a small number of subjects, pharmacological intervention with oral terfenadine failed to achieve significant protection of the airways against the constrictor effect of NKA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adolescent; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Double-Blind Method; Female; Histamine; Humans; Male; Neurokinin A; Terfenadine

Neurokinin A (NKA) has been shown to exert a potent contractile action on bronchial smooth muscles both in vitro and in vivo. Although this effect seems to be due either to a direct action of this peptide on specific muscular receptors or to an indirect effect on mast cells and/or nerves, its mechanism of action in bronchial asthma is still unknown. In the present study we have investigated the airway response to inhaled NKA in 10 asthmatic subjects and the activity of the novel pyranoquinoline dicarboxylic acid drug, nedocromil sodium, on this response. Ten asthmatic patients with stable asthma took part in the study consisting of four separate visits. On the first two occasions we derived histamine and NKA PD15 values in absence of any drug treatment. On the following two visits the inhalation challenge with NKA was performed after administration of either nedocromil sodium or matched placebo administered as pressurized aerosols via metered dose inhalers in a randomized double-blind order. Inhaled NKA produced a dose-related fall in FEV1 in all the subjects studied. Inhaled nedocromil sodium had a significant effect on the FEV1 response to NKA inhalation, the geometric mean PD15 value increasing from 16.6 to 32.2 x 10(-9) mol. We conclude that nedocromil sodium attenuates subsequent responsiveness to inhaled NKA in asthmatic subjects.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bronchoconstriction; Female; Forced Expiratory Volume; Humans; Male; Nedocromil; Neurokinin A; Quinolones

Neuropeptides such as neurokinin A (NKA) have been proposed as important mediators of bronchoconstriction and airway hyperresponsiveness in asthma. Inhaled NKA causes bronchoconstriction in patients with asthma, but not in normal subjects. This is possibly due to the activity of an endogenous neuropeptide-degrading enzyme: neutral endopeptidase (NEP). We investigated whether a NEP-inhibitor, thiorphan, reveals bronchoconstriction to NKA or NKA-induced changes in airway responsiveness to methacholine in normal humans in vivo. Eight normal male subjects participated in a double-blind crossover study, using thiorphan as pretreatment to NKA challenge. Dose-response curves to inhaled NKA (8 to 1,000 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, and methacholine tests were performed 48 h before and 24 h after the NKA challenge. Ten minutes prior to NKA challenge the subjects inhaled either thiorphan (2.5 mg/ml, 0.5 ml) or placebo. To detect a possible nonspecific effect of thiorphan, we investigated the effect of the same pretreatment with thiorphan or placebo on the dose-response curve to methacholine in a separate set of experiments. The response was measured by the flow from standardized partial expiratory flow-volume curves (V40p), expressed in percent fall from baseline. NKA log dose-response curves were analyzed using the area under the curve (AUC) and the response to the highest dose of 1,000 micrograms/ml (V40p,1000). The methacholine dose-response curves were characterized by their position (PC40V40p) and the maximal-response plateau (MV40p). Baseline V40p was not affected by either pretreatment (p greater than 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aerosols; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Double-Blind Method; Humans; Male; Methacholine Chloride; Neprilysin; Neurokinin A; Premedication; Thiorphan; Time Factors

We have previously demonstrated that the neuropeptide, neurokinin A (NKA) (substance K), causes bronchoconstriction in subjects with asthma. In a double-blind, crossover study we investigated the effect of nedocromil sodium on NKA-induced bronchoconstriction in subjects with asthma. Twelve patients with mild asthma (mean FEV1 percent predicted +/- SE, 87.3 +/- 3.4) inhaled on 2 separate days either nedocromil sodium, 4 mg, or placebo, as two puffs from a metered-dose aerosol, 30 minutes before challenge with NKA. NKA was inhaled at three concentrations (10(-7), 3.10(-7), and 10(-6) mol/ml). The specific airway conductance (SGaw) and FEV1 were measured before and 5 and 15 minutes after each concentration step. On the placebo-treatment day, NKA caused a concentration-dependent decrease in SGaw and FEV1 (mean log for the provocative concentration of NKA causing a 35% fall in SGaw [10(-7) mol/ml], 0.49; mean log for the provocative concentration of NKA causing a 15% fall in SGaw [10(-7) mol/ml], 0.90). The inhalation of 4 mg of nedocromil sodium reduced the decrease in both SGaw and FEV1. The maximal percentage decrease in SGaw on the nedocromil sodium-treatment day was 27 +/- 5.2 (versus placebo, 53.3 +/- 5.4; p less than 0.05), and the maximal percentage decrease in FEV1 was 5.5 +/- 1.4 (versus placebo, 12.4 +/- 2.3; p less than 0.05). The dose-response curves for NKA after nedocromil sodium treatment were significantly shifted to the right compared to the curve after placebo-treatment. We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in subjects with asthma.

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Bronchi; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nedocromil; Neurokinin A; Quinolones

In a double-blind, crossover study we have investigated the effect of nedocromil sodium on neurokinin A (NKA)-induced bronchoconstriction in asthmatics. 12 patients with mild asthma inhaled either nedocromil sodium 4mg or placebo, on 2 separate days, as 2 puffs from a metered-dose aerosol 30 minutes before challenge with NKA. On the placebo treatment day, NKA produced a concentration-dependent decrease in basal specific airway conductance (sGaw) and forced expiratory volume in 1 second (FEV1). The inhalation of nedocromil sodium 4mg inhibited the decrease in both sGaw and FEV1. The maximal percentage decrease in sGaw on the nedocromil sodium day was 27.0 +/- 5.2 (vs placebo, 53.3 +/- 5.4; p less than 0.05) and the maximal percentage decrease in FEV1 5.5 +/- 1.4 (vs placebo, 12.4 +/- 2.3; p less than 0.05). We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in asthmatics.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung Compliance; Male; Middle Aged; Nedocromil; Neurokinin A; Quinolones

In some animal species substance P and neurokinin A (NKA) cause bronchoconstriction by the release of acetylcholine from postganglionic cholinergic nerve endings. The aim of the present study was to investigate the effect of an anticholinergic drug, oxitropium bromide, on bronchoprovocation with NKA in asthmatics. Eleven mild asthmatics (mean % predicted FEV1 85.5) received on 2 separate days, double blind, in a randomised order, 400 mcg oxitropium bromide or placebo, 90 min before challenge with NKA. NKA was inhaled at 3 concentrations (10(-4), 3.10(-4) and 10(-3) M). Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1) were used as parameters of airway calibre. Compared to the placebo-aerosol, oxitropium bromide caused a significant increase in sGaw and FEV1. On the placebo-treatment day, NKA caused a concentration-dependent decrease in sGaw and FEV1. The percentage changes in sGaw and FEV1 on the oxitropium day were not statistically different from those occurring on the placebo day. We conclude that oxitropium bromide caused a significant bronchodilation but offered no significant protection against NKA-induced bronchoconstriction in mild asthmatic subjects.

Topics: Adult; Asthma; Bronchoconstriction; Female; Humans; Male; Neurokinin A; Parasympatholytics; Scopolamine Derivatives

Airway inflammation and airway hyperresponsiveness (AHR) are pivotal characteristics of equine asthma. Lipopolysaccharide (LPS) may have a central role in modulating airway inflammation and dysfunction. Therefore, the aim of this study was to match the inflammatory and contractile profile in LPS-challenged equine isolated bronchi to identify molecular targets potentially suitable to counteract AHR in asthmatic horses.. Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml). The contractile response to electrical field stimulation (EFS) and the levels of cytokines, chemokines, and neurokinin A (NKA) were quantified. The role of capsaicin sensitive-sensory nerves, neurokinin-2 (NK. LPS 1 ng/ml elicited AHR to EFS (+238.17 ± 25.20% P < 0.001 vs. control). LPS significantly (P < 0.05 vs. control) increased the levels of IL-4 (+36.08 ± 1.62%), IL-5 (+38.60 ± 3.58%), IL-6 (+33.79 ± 2.59%), IL-13 (+40.91 ± 1.93%), IL-1β (+1650.16 ± 71.16%), IL-33 (+88.14 ± 8.93%), TGF-β (22.29 ± 1.03%), TNF-α (+56.13 ± 4.61%), CXCL-8 (+98.49 ± 17.70%), EOTAXIN (+32.26 ± 2.27%), MCP-1 (+49.63 ± 4.59%), RANTES (+36.38 ± 2.24%), and NKA (+112.81 ± 6.42%). Capsaicin sensitive-sensory nerves, NK. Targeting IL-6 with specific antibody may represent an effective strategy to treat equine asthma, especially in those animals suffering from severe forms of this disease.

Topics: Animals; Asthma; Bronchi; Capsaicin; Horses; Inflammation; Interleukin-33; Interleukin-6; Lipopolysaccharides; Neurokinin A; Transforming Growth Factor beta

Topics: Alveolitis, Extrinsic Allergic; Antigen Presentation; Antigens, Surface; Asthma; Cell Differentiation; Cytokines; Dendritic Cells; Humans; Neurokinin A; Neurokinin-1 Receptor Antagonists; Poly I-C; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P

To observe the effect of suspending-moxibustion stimulation of "Dazhui" (GV 14) with different quantities on the levels of nerve growth factor(NGF) , substance P(SP) , calcitonin gene-related peptide (CGRP), neurokinin A (NKA) , neurokinin B (NKB) and phosphorylated extracellular signal-regulated kinases (pERK) in the bronchoalveolar lavage fluid (BALF) of asthma rats, so as to analyze its mechanisms underlying improving asthma.. Sixty male SD rats were randomly divided into six groups: blank control, model, 15 min-moxibustion (15 min-moxi), 30 min-moxi, 60 min-moxi and 90 min-moxi (n = 10 rats in each group). The asthma model was established by intraperitoneal injection of suspension of egg protein, magaldrate, and inactivated Bacillus pertussis (on day 1 and 8), and inhaling the atomized ovalbumin saline (from day 15 on for 14 days). Mild moxibustion was conducted at "Dazhui" (GV 14) for 15 min, 30 min, 60 min and 90 min, respectively, once daily for 7 days. The levels of NGF, SP, CGRP, NKA, NKB, and pERK in the BALF were detected by ELISA (enzyme-linked immuno sorbent assay).. The contents of NGF, SP, CGRP, NKA, NKB and pERK in the BALF in the model group were obviously higher than those in the blank control group (P < 0.01), suggesting an apparent inflammatory reaction in rats after modeling. Following moxibustion, the levels of NGF, SP, CGRP, NKA, NKB and pERK of the four treatment groups were significantly down-regulated compared with the model group (P < 0.01). The effect of 30 min-moxi group was obviously superior to that of 15 min-moxi group (P < 0.01), and those of 60 min-moxi and 90 min-moxi groups were markedly superior to those of 15 min-moxi and 30 min-moxi groups (P < 0.01) in down-regulating NGF, SP, CGRP, NKA, NKB, and pERK levels in the BALF. No significant differences were found between the 60 min-moxi and 90 min-moxi groups in down-regulating NGF, SP, CGRP, NKA, NKB, and pERK levels (P > 0.05).. Suspending-moxibustion stimulation of GV 14 can down-regulate the contents of NGF, SP, CGRP, NKA, NKB, and pERK levels in the BALF in asthma rats, suggesting a relief of neurogenic inflammation reaction after moxibustion. The effect of moxibustion presents a time-dependant manner and peaks at 60 min.

Topics: Acupuncture Points; Animals; Asthma; Bronchoalveolar Lavage Fluid; Humans; Male; Moxibustion; Nerve Growth Factor; Neurogenic Inflammation; Neurokinin A; Rats; Rats, Sprague-Dawley; Substance P

The adoptive transfer of OVA-specific Th1 cells into WT mice followed by OVA inhalation induces a significant elevation of airway hyper-responsiveness (AHR) with neutrophilia but not mucus hypersecretion. Here, we demonstrate that the airway inflammation model, pathogenically characterized as severe asthma, was partly mimicked by i.n. administration of IFN-γ. The administration of IFN-γ instead of Th1 cells caused AHR elevation but not neutrophilia, and remarkably induced neurokinin-2 receptor (NK2R) expression along with neurokinin A (NKA) production in the lung. To evaluate whether NKA/NK2R was involved in airway inflammation, we first investigated the role of NKA/NK2R-signaling in airway smooth muscle cells (ASMCs) in vitro. NK2R mRNA expression was significantly augmented in tracheal tube-derived ASMCs of WT mice but not STAT-1(-/-) mice after stimulation with IFN-γ. In addition, methacholine-mediated Ca(2+) influx into the ASMCs was significantly reduced in the presence of NK2R antagonist. Moreover, the NK2R antagonist strongly inhibited IFN-γ-dependent AHR elevation in vivo. Thus, these results demonstrated that IFN-γ directly acts on ASMCs to elevate AHR via the NKA/NK2R-signaling cascade. Our present findings suggested that NK2R-mediated neuro-immuno crosstalk would be a promising target for developing novel drugs in Th1-cell-mediated airway inflammation, including severe asthma.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Calcium Signaling; Cells, Cultured; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Humans; Interferon-gamma; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Myocytes, Smooth Muscle; Neuroimmunomodulation; Neurokinin A; Receptors, Neurokinin-2; Respiratory System; STAT1 Transcription Factor

Neurogenic inflammation may participate in the development and progression of bronchial asthma. The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as neurokinin A (NKA) and substance P. Tachykinins are secreted from sensory airway nerves and inflammatory cells after allergens exposure. In clinical practice, assessment of airway inflammation is difficult. Therefore, detection of biological markers of airway inflammation in sputum might offer help for proper monitoring of asthma severity.. We aimed to measure sputum NKA in relation to acute asthma exacerbations of varying severity.. Sputum NKA was measured by enzyme-linked immunosorbent assay in 24 children and adolescents during and after acute asthma exacerbation and 24 healthy matched controls.. Sputum NKA was significantly higher in asthmatic patients during acute exacerbation than controls [217.5 (284) vs 10 (7) ng/ml, P < 0.001]. When patients with acute asthma exacerbation were followed-up till remission, sputum NKA levels decreased significantly, but they remained significantly higher than controls. Sputum NKA levels were significantly higher in severe than moderate and in moderate than mild exacerbations, and was negatively correlated to peak expiratory flow rate (r = -0.9, P < 0.001). Sputum NKA had significant positive correlations to eosinophil counts in blood and sputum (r = 0.6, P < 0.001 and r = 0.7, P < 0.001 respectively).. Sputum NKA is up-regulated during acute asthma exacerbation and it positively correlates to its severity. Thus, NKA may aid in objective classification of the exacerbation severity. In addition, NKA may be a target for new asthma therapy.

Topics: Adolescent; Asthma; Biomarkers; Case-Control Studies; Child; Egypt; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Neurokinin A; Severity of Illness Index; Sputum; Up-Regulation

80 children aged from 2 to 14 years,72 boys and 8 girls, 44 with moderate and 36 with severe form of atopic bronchial asthma were investigated. Substance P, neurokinin A and vasoactive intestinal peptide (VIP) were defined in blood plasma. In comparison with the control group, children suffering from bronchial asthma showed statistically significant (p<0,001) increase of substance P and neurokinin A and decrease of VIP. Analogous changes were observed by comparison of data received from children with moderate and severe asthma. Received data indicate the participation of neuropeptides in pathogenesis of bronchial asthma in children.

Topics: Adolescent; Asthma; Child; Child, Preschool; Female; Humans; Male; Neurokinin A; Substance P

Bronchial asthma is a chronic inflammatory disorder of the airways caused by many complicated elements. Recently, a close attention has been paid to the neurogenic inflammation in airways, which is mediated by sensory neuropeptides secreted by sensory nerve. Neurokinin A (NKA) is an important transmitter of non-cholinergic excitatory nerves in the lung which is an important sensory neuropeptide causing airway neurogenic inflammation. The purpose of this study was to investigate the effect of glucocorticoid (dexamethasone) on neurokinin A in plasma and lungs of guinea pigs with asthma and to explore its molecular mechanism.. Thirty guinea pigs (1.5 months old and weighed 200 - 225 g) were sensitized by exposure to aerosolized ovalbumin and challenged with the same antigen to establish asthma model. These animals were divided randomly into dexamethasone-treatment group and non-dexamethasone-treatment group (15 guinea pigs in each group). Normal control group animals (n = 15) were treated with normal saline (NS) instead of aerosolized ovalbumin. The guinea pigs in the dexamethasone-treatment group were treated with dexamethasone (5.0 mg/kg, intraperitoneal injection) one day before asthma-inducement, on the day of inducement and 24 h after inducement. The non-dexamethasone-treatment group animals were treated with NS (5.0 mg/kg, intraperitoneal injection) on the same days as the dexamethasone-treatment group was treated. The normal control group animals were treated with NS (5.0 mg/kg, intraperitoneal injection). The contents of NKA in the plasma and lung tissues were detected by ELISA; the expression of NKA mRNA in lung tissues was examined by RT-PCR.. (1) The contents of NKA in the plasma (2.20 +/- 0.46 ng/ml), lung tissues (5.02 +/- 2.11 ng/g x protein) and the NKA mRNA expression in the lung tissues (1.10 +/- 0.06) of guinea pigs with induced asthma were significantly higher than those of the normal control group (plasma 0.84 +/- 0.33 ng/ml, lung tissues 2.56 +/- 0.80 ng/g x protein, mRNA 0.30 +/- 0.04; P < 0.001, respectively). (2) The contents of NKA in the plasma, lung tissues and the NKA mRNA expression in the lung tissues of guinea pigs with induced asthma were significantly lower in dexamethasone-treatment group (plasma 0.98 +/- 0.23 ng/ml, lung tissues 2.71 +/- 0.50 ng/g x protein, mRNA 0.35 +/- 0.07) than those in the non-dexamethasone-treatment group (plasma 2.20 +/- 0.46 ng/ml, lung tissues 5.02 +/- 2.11 ng/g x protein, mRNA 1.10 +/- 0.06; P < 0.001, respectively). No significant difference was found between the dexamethasone-treatment group and the normal control group (P > 0.05, respectively).. (1) NKA mRNA expression in the lungs of guinea pigs with asthma was up-regulated and NKA contents were higher in plasma and lungs; (2) Glucocorticoid could significantly decrease the contents of NKA in plasma, lung tissues of guinea pigs with induced asthma; the mechanism of the effect may be related to down-regulation of NKA mRNA expression in lung tissues caused by glucocorticoid.

Topics: Animals; Asthma; Dexamethasone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glucocorticoids; Guinea Pigs; Lung; Neurokinin A; Ovalbumin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Involvement of neurokinins in asthma has been previously pointed out by several reports. However, the relationship between neurokinins and the severity of asthma has remained unclear. We developed a model of mild asthma (model I) and severe asthma (model II) in guinea pigs, and investigated the function of neurokinins in both models.. In models I and II, systemically sensitized guinea pigs were made to inhale ovalbumin once and three times, respectively. Substance P (SP) and neurokinin A (NKA) concentrations in the bronchoalveolar lavage fluid (BALF) were measured in models I and II. Then, the effects of a capsaicin pretreatment, which depletes neurokinins, in both animal models on airway narrowing induced by the last ovalbumin inhalation, airway hyperresponsiveness to inhaled methacholine, and eosinophil accumulation in BALF, were investigated.. SP concentration tended to increase and the NKA concentration increased significantly in model II, but not in model I. Capsaicin pretreatment significantly inhibited the late bronchial response that was observed 2-6 h after the last ovalbumin inhalation, airway hyperresponsiveness and eosinophil accumulation in model II. On the other hand, it had no effects on the responses in model I.. It is suggested that the more severe the disease, the greater the involvement of neurokinins.

Topics: Administration, Inhalation; Airway Resistance; Allergens; Animals; Asthma; Biomarkers; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Capsaicin; Disease Models, Animal; Eosinophils; Guinea Pigs; Lung; Male; Methacholine Chloride; Neprilysin; Neurokinin A; Respiratory Hypersensitivity; Severity of Illness Index; Substance P

Chronic inflammation of airway in bronchial asthma is caused by many complicated elements. Recently, a close attention has been paid to the neurogenic inflammation in airway which is mediated by sensory neuropeptides secreted by sensory nerve in the lung. Neurokinin A (NKA) is an important sensory neuropeptide leading to neurogenic inflammation in airway. Experimental studies showed that NKA has a close relation to asthma. The purpose of the present study was to investigate the changes of NKA in plasma of asthmatic children and possible relationship between sensory neuropeptides and asthma in children.. Thirty-five children with bronchial asthma were studied; 16 of the cases were < 3 yrs and 19 were >or= 3 yrs. Eighteen of the cases had severe asthma and 16 had mild asthma. None of the subjects was treated with glucocorticoid within 3 days before the study started; 15 healthy children without history of asthma or family history of asthma were enrolled as control subjects. Plasma was collected from each case during acute attack of asthma and their clinical remission of the asthmatic children. After purifying with SEP-pak C(18), NKA content was detect by enzyme-linked immunosorbent assay (ELISA) as instructed by the manufacturer of the NKA Kit (NKA unit: ng/L).. (1) The content of plasma NKA of asthmatic children was significantly higher at the asthma attack (256 +/- 153) than that at their clinical remission stage (70 +/- 66; q = 9.497, P < 0.01) and than that of the normal control group (38 +/- 6; q = 8.599, P < 0.01); no significant difference in plasma NKA was found between the clinical remission stage and the normal control group (q = 1.245, P > 0.05). (2) There was a significant positive correlation between the asthmatic clinical state and the levels of plasma NKA; the contents of plasma NKA at the stage of acute attack in severe asthma (296 +/- 170) were significantly higher than those of the mild asthmatic children (190 +/- 99; q = 3.77, P < 0.05).. The contents of plasma NKA were significantly higher during the asthma attack stage of children, and the higher was the level of NKA, the more severe the attack.; with asthma remission, the contents of plasma NKA decreased to normal; the contents of plasma NKA has a close relation to the asthmatic children.

Topics: Asthma; Child; Child, Preschool; Humans; Infant; Neurokinin A

Multiple sensory neuropeptides are present in human airways and may contribute to diseases such as asthma. This study quantified and characterised substance P (SP), neurokinin A (NKA), and calcitonin gene related peptide (CGRP) immunoreactivity in bronchoalveolar lavage fluid in asthmatic and normal subjects.. Using specific radioimmunoassay (RIA), SP, NKA and CGRP were measured in bronchoalveolar lavage fluid from asthmatic subjects (n = 5), normal subjects (n = 5), atopic non-asthmatic subjects (n = 6), and asthmatic subjects four hours after allergen challenge (n = 12). Peptide immunoreactivity was characterised using high performance liquid chromatography (HPLC) and RIA.. No SP or CGRP immunoreactivity was detected in any of the fractions from samples after extraction, HPLC, and RIA. Non-specific binding resulted in spurious SP immunoreactivity being detected in bronchoalveolar lavage fluid when no extraction process was employed. NKA was detected in significant amounts in asthmatic (median 550, range 425-625 pg/ml) and normal subjects (median 725, range 350-1425 pg/ml). The level of NKA was significantly higher in the asthmatic subjects after allergen challenge (median 750, range 350-1250 pg/ml) than in unchallenged asthmatic subjects (median 600, range 425-600 pg/ml, p < 0.01).. Extraction and characterisation of peptides from bronchoalveolar lavage fluid must be performed to ensure that the measured immunoreactivity represents target peptide. NKA is present in bronchoalveolar lavage fluid in high concentrations and is the predominant tachykinin. The concentrations of NKA are similar in normal subjects and subjects with mild asthma.

Topics: Adolescent; Adult; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Calcitonin Gene-Related Peptide; Chromatography, High Pressure Liquid; Female; Humans; Male; Methacholine Chloride; Neurokinin A; Radioimmunoassay; Statistics, Nonparametric; Substance P

An increasing number of studies have been performed to address a possible role for endothelin-1 (ET-1) as a significant mediator in asthma. However, the effects of subthreshold concentrations of ET-1, which cannot elicit bronchial smooth muscle contraction itself, in asthma has yet to be determined. This study determined these effects of ET-1 on capsaicin-induced bronchoconstriction in anaesthetized guinea-pigs. Aerosolized ET-1 administered at doses of 10(-9) M and higher induced a dose-dependent increase in pulmonary resistance, but ET-1 at 10(-10) M did not have any bronchoconstrictive effect. However, this subthreshold concentration of ET-1 potentiated capsaicin-induced bronchoconstriction. In addition, the potentiation of capsaicin-induced bronchoconstriction by this subthreshold concentration of ET-1 was completely abolished by BQ788 (ET(B) receptor antagonist), but not BQ123 (ET(A) receptor antagonists). Immunoreactive substance P (SP) levels in bronchoalveolar lavage fluid after capsaicin administration were significantly higher than those after solvent administration. However, ET-1 alone did not significantly stimulate immunoreactive SP release and ET-1 (10(-10) M) did not potentiate capsaicin-induced immunoreactive SP release. In contrast, ET-1 (10(-10) M) potentiated exogenous neurokinin A- and SP-induced bronchoconstriction. These findings suggest that a subthreshold concentration of endothelin-1 does not potentiate the tachykinin release induced by capsaicin but the airway smooth muscle contraction through endothelin-B receptors.

Topics: Aerosols; Airway Resistance; Anesthesia; Animals; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Capsaicin; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Guinea Pigs; Male; Neurokinin A; Oligopeptides; Peptides, Cyclic; Piperidines; Substance P

Phosphodiesterase (PDE) 4 inhibitors are well known for their inhibitory effect on bronchoconstriction and inflammation and may be promising anti-asthma drugs. Platelet-activating factor (PAF) has been proposed as an inflammatory mediator to be relevant to asthma. It causes bronchoconstriction, airway microvascular leakage, inflammatory cell accumulation in the lung and hyperresponsiveness. In this study, we therefore have investigated the anti-asthmatic effects of the inhaled KF19514 [5-phenyl-3'-(3-pyridyl)methyl-3H-imidazo(4,5-c)(1,8) naphthyridin-4(5H)-one], a PDE 4 and 1 inhibitor, on PAF-induced lung inflammatory responses in guinea pigs. The inhaled KF19514 (0.0001-0.01%) significantly inhibited PAF-induced eosinophil and neutrophil accumulation into the airway and hyperresponsiveness in guinea pigs. The IC50 value of KF19514 against eosinophil accumulation was 14.8 microM (0.00063%). Moreover, the effect of KF19514 on the electrical field stimulation-induced bronchial contraction was examined using the main bronchi of guinea pigs in vitro. KF19514 inhibited both cholinergic and tachykininergic contraction and, in particular, produced a potent inhibitory effect on tachykininergic contraction (IC50 = 0.49 microM). The mechanism by which KF19514 inhibited the PAF-induced hyperresponsiveness may in part be the suppression of the tachykinin release. Based on these results, it was demonstrated that the inhaled KF19514 might have a significant potential effect on the inflammatory cell accumulation and hyperresponsiveness induced by PAF.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 4; Dose-Response Relationship, Drug; Electric Stimulation; Eosinophils; Guinea Pigs; Muscle Contraction; Muscle, Smooth; Naphthyridines; Neurokinin A; Neutrophils; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Platelet Activating Factor; Pyrrolidinones; Respiratory Therapy; Rolipram; Substance P

We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.

Topics: Amino Acid Sequence; Animals; Asthma; Bronchoconstriction; Capillary Permeability; Guinea Pigs; Humans; Inositol Phosphates; Male; Methacholine Chloride; Mice; Molecular Sequence Data; Neurokinin A; Neurokinin-1 Receptor Antagonists; Piperidines; Pyrrolidines; Rats; Receptors, Neurokinin-2; Respiration; Species Specificity; Substance P

Administration of propranolol can provoke bronchoconstriction in asthmatic patients. We hypothesized that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. We recently developed a guinea pig model for propranolol-induced bronchoconstriction (PIB). Neuropeptides which are released from C-fibre nerve endings have been postulated to induce bronchial hyperresponsiveness through neurogenic inflammation.. The purpose of this study was to examine whether sensory neuropeptides are involved in the development of PIB after allergic reaction.. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after antigen challenge in passively sensitized, anaesthetized and artificially ventilated guinea pigs. The animals were treated intravenously with a NK1 and NK2 dual antagonist, FK224, in a dose of 1 or 10 mg/kg or vehicle or a selective NK1 antagonist, FK888, in a dose of 1 or 10 mg/kg or vehicle 10 min before or 15 min after antigen challenge.. Propranolol inhaled 20 min after antigen challenge caused bronchoconstriction. FK224 or FK888 administered 15 min after antigen challenge as well as 10 min before antigen challenge did not reduce the PIB.. We conclude that neuropeptides such as neurokinin A and substance P do not directly contribute to the development of PIB after allergic reaction.

Topics: Adrenergic beta-Antagonists; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Dipeptides; Guinea Pigs; Indoles; Male; Neurokinin A; Peptides, Cyclic; Propranolol; Substance P

In a previous study we have shown that inhibition of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP), potentiates airway narrowing to neurokinin A (NKA) in normal humans in vivo. In the present study, we tested the hypothesis that hyperresponsiveness to NKA in asthma is caused by a reduction in endogenous NEP activity. To that end, we used the NEP inhibitor, thiorphan, or placebo as inhaled pretreatment to NKA challenge in eight atopic asthmatic men, who were controlled by on-demand usage of beta 2-agonists alone. The dose of thiorphan pretreatment was obtained from pilot experiments in which 0.5 ml of a 2.5-mg/ml concentration appeared to be the maximally effective nebulized dose. Dose-response curves to inhaled NKA (1 to 125 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, in a cross-over study. To detect any effects of thiorphan on bronchoconstriction per se, we also investigated the effect of thiorphan or placebo on the dose-response curve to inhaled methacholine in a separate set of experiments. The response was measured by FEV1 and by partial expiratory flow-volume curves (V40p). The position of the dose-response curves was expressed as the concentration causing a 20% fall in FEV1 (PC20FEV1) or a 40% fall in V40p (PC40V40p). Baseline FEV1 and V40p were not affected by either pretreatment (p > 0.06). PC20FEV1 and PC40V40p to NKA were significantly lower after thiorphan pretreatment as compared with placebo (mean difference +/- SEM: 2.3 +/- 0.6 and 1.6 +/- 0.5 doubling dose, respectively; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Dose-Response Relationship, Drug; Double-Blind Method; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Neprilysin; Neurokinin A; Thiorphan

Enkephalinase exists in airway epithelial cells, smooth muscle, and submucosa near glands, and cleaves tachykinins to inactive metabolites, thereby reducing there effects. To study the role of enkephalinase in asthmatic response, we measured its activity in guinea pig model of asthma. When compared with the control values, the enkephalinase activity was reduced during in immediate asthmatic response (IAR) and late asthmatic response (LAR). Compared with the control values (100%), each value was 79.7%, 73.4% in the trachea and 74.3%, 55.7% in the lung respectively. Tracheal muscle preparation taken from the control, IAR, and LAR groups were made and mounted in oxygenated modified Krebs-Ringer solution. The response was monitored by isometric transducer. Concentration response curves to NKA with or without phosphoramidon were obtained. The contractile responses of the LAR groups were enhanced in potency and efficiency. Phosphoramidon potentiated the NKA induced contraction of control and the IAR groups but was less potent in enhancing the contractile response in the LAR group, showing less enkephalinase activity in the LAR. These results suggest that the enkephalinase plays an important role in LAR. In LAR, the enkephalinase activity may be inhibited and the responsiveness of the smooth muscle to some bronchoconstrictor, such as tachykinins, may be increased.

Topics: Allergens; Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Guinea Pigs; In Vitro Techniques; Lung; Muscle Contraction; Muscle, Smooth; Neprilysin; Neurokinin A; Trachea

The interaction between the nervous system, immune system and bronchial reactivity was studied in rats by using the neurotoxin capsaicin. Rats were treated with capsaicin at 1-2 days of age or at adult age, before or after sensitization by subcutaneous injections with ovalbumin (OA). The levels of the neuropeptides neurokinin A and calcitonin gene-related peptide were decreased in the lung after capsaicin treatment, as determined with radioimmunoassay, whereas the levels of neuropeptide Y were unaffected. The levels of IgA, IgE and IgG in bronchial lavage were also affected by capsaicin treatment; however, the results were heterogeneous. Capsaicin treatment after sensitization reduced the bronchial reactivity to challenge with OA aerosol and serotonin iv. The results demonstrated that reduction of neuropeptide levels with capsaicin affected both bronchial reactivity and the levels of antibodies in bronchial lavage fluid. However, no correlation between these two parameters was seen, demonstrating the complexity of the system.

Topics: Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Calcitonin Gene-Related Peptide; Capsaicin; Female; Injections, Subcutaneous; Lung; Male; Neurokinin A; Neuropeptide Y; Radioimmunoassay; Rats; Rats, Inbred BN

Substance P (SP) is believed to be a major mediator of neurogenic inflammation. To determine whether the skin reactivity of SP is increased in asthmatics, we examined the reactivity to intradermal injections of SP, the C-terminal and N-terminal peptides SP6-11 and SP1-9, respectively, and neurokinin A (10(-7)-10(-5) M) in 12 asthmatics and 9 normal subjects. SP and the N-terminal peptide SP1-9 induced both erythemas and wheals in asthmatics and in normal subjects, whereas the C-terminal peptide SP6-11 and neurokinin A primarily induced only wheals in both groups. SP induced greater erythemas and wheals in asthmatics than in normal subjects. SP1-9 also induced greater erythemas and wheals in asthmatics than in normal subjects. However, the wheals induced by SP6-11 or neurokinin A were not significantly different in either group. Therefore, the increased skin reactivity to SP was the N-terminal peptide dependent, which has been shown to be able to activate skin mast cells. We conclude that the skin reactivity to SP is increased in asthmatics, possibly through the increased reactivity of skin mast cells.

Topics: Adult; Asthma; Female; Humans; Male; Middle Aged; Neurokinin A; Peptide Fragments; Skin; Skin Tests; Substance P

The tachykinins substance P (SP) and neurokinin A are believed to be major mediators of neurogenic inflammation. To determine whether the skin reactivity to tachykinins is increased in asthmatics, we examined the erythemas and wheals induced by intradermal injections of SP, the C-terminal peptide SP6-11, the N-terminal peptide SP1-9 and neurokinin A (10(-7)-10(-5) M) in 10 allergic asthmatics and 9 normal subjects. SP and SP1-9 induced both erythemas and wheals in a concentration-dependent manner in allergic asthmatics and in normal subjects, whereas SP6-11 and neurokinin A induced only wheals in both groups. SP induced greater erythemas and wheals in allergic asthmatics than in normal subjects. However, the wheals induced by neurokinin A were not significantly different between the two groups. SP1-9 also induced greater erythemas and wheals in allergic asthmatics than in normal subjects, whereas the wheals induced by SP6-11 were not significantly different between the two groups. Therefore, the increased skin reactivity to SP was dependent on the N-terminal peptide but not on the C-terminal peptide. We conclude that the skin reactivity to SP but not to neurokinin A is increased in allergic asthmatics.

Topics: Adult; Asthma; Erythema; Female; Humans; Male; Middle Aged; Neurokinin A; Peptide Fragments; Skin; Substance P

The neuropeptides substance P and neurokinin A are present in sensory airway nerves. Their effect on airway calibre was compared in six healthy non-smoking subjects and six asthmatic subjects. On separate days increasing concentrations (from 10(-9) to 10(-6) mol/ml) of each neuropeptide were administered by nebuliser and the airway response measured as change in specific airway conductance (sGaw). Substance P and neurokinin A caused no change in sGaw in the healthy subjects. Inhalation of substance P up to the highest concentration of 10(-6) mol/ml caused no change in sGaw in the asthmatic subjects. Neurokinin A, however, caused bronchoconstriction with a mean fall in sGaw of 48% (SEM 12%) after 5 x 10(-7) mol/ml. The onset of bronchoconstriction was rapid, but sGaw had returned to baseline values within one hour in all but one patient.

Topics: Administration, Inhalation; Adolescent; Adult; Airway Resistance; Asthma; Bronchial Provocation Tests; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Lung; Male; Neurokinin A; Neuropeptides; Random Allocation; Substance P