verlukast and Asthma

Peptidoleukotrienes reproduce some of the functional and histological features of clinical asthma, such as potent bronchoconstriction, airway microvascular leakage, mucus hypersecretion, eosinophilic airway infiltration, in addition to inducing bronchial hypersensitivity. An important role for peptidoleukotrienes has been demonstrated in experimental challenge studies in asthmatic patients and in acute asthma attacks. Antagonists of peptidoleukotrienes can inhibit bronchoconstriction in response to inhaled allergen, exercise or inhaled cold air, and oral or inhaled aspirin. These compounds demonstrate beneficial effects in clinical studies with improvement in symptoms and lung function. Peptidoleukotriene antagonists may provide a new therapeutic approach for the treatment of asthma.

Topics: Asthma; Chromones; Humans; Indoles; Leukotriene Antagonists; Phenylcarbamates; Propionates; Quinolines; SRS-A; Sulfonamides; Tetrazoles; Tosyl Compounds

Topics: Animals; Asthma; Glomerulonephritis; Humans; Hydroxyurea; Indoles; Inflammatory Bowel Diseases; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Propionates; Psoriasis; Quinolines; Receptors, Leukotriene

Topics: Arachidonate 5-Lipoxygenase; Asthma; Clinical Trials as Topic; Humans; Immunoglobulin E; Indoles; Phenylcarbamates; Propionates; Quinolines; Receptors, Immunologic; SRS-A; Sulfonamides; Tosyl Compounds

Topics: Acetophenones; Animals; Asthma; Bronchodilator Agents; Humans; Indoles; Phenylcarbamates; Propionates; Quinolines; SRS-A; Sulfonamides; Tetrazoles; Tosyl Compounds

Topics: Asthma; Asthma, Exercise-Induced; Humans; Lung; Propionates; Quinolines; Receptors, Immunologic; Receptors, Leukotriene; SRS-A

A potent, selective and orally active receptor antagonist of leukotriene D4, MK-571, was discovered and developed from a styrylquinoline lead structure based on a hypothetical model of the leukotriene D4 receptor. MK-571 blocks the action of LTD4 in animals and man, and is effective in a number of animal models of antigen-induced bronchoconstriction at plasma concentration at or below 2 micrograms/mL. MK-571 also blocks antigen-induced asthmatic responses in man. In addition a series of 2-indolealkanoic acids was discovered to be inhibitors of leukotriene biosynthesis. From this series, MK-886, a nanomolar inhibitor of leukotriene biosynthesis was developed. The mechanism of action of MK-886 has been found to be the inhibition of activation of the 5-lipoxygenase enzyme. This inhibition is mediated by interaction with a specific 18 kD protein termed 5-lipoxygenase activating protein (FLAP). MK-886 is an inhibitor of leukotriene biosynthesis and of antigen-induced bronchoconstriction in animal models and in asthmatic men.

Topics: Animals; Asthma; Chemistry, Pharmaceutical; Clinical Trials as Topic; Humans; Indoles; Leukotriene Antagonists; Propionates; Quinolines; SRS-A; Structure-Activity Relationship

The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) have been shown to mediate airway obstruction evoked by several factors which trigger asthmatic reactions--for example, allergen and exercise. Accordingly, drugs which block the action or formation of these leukotrienes are being evaluated as a new treatment of asthma. Elevated production of leukotrienes has been reported in asthmatic subjects who are intolerant to aspirin and related nonsteroidal anti-inflammatory drugs. In this study the influence of the specific leukotriene receptor antagonist MK-0679 was tested on basal airway function in asthmatic patients with documented aspirin intolerance.. The eight subjects in the study had a mean baseline FEV1 of 78% predicted (range 58-99%) and six required treatment with inhaled glucocorticosteroids (400-1200 micrograms budesonide/beclomethasone daily). On two separate days the subjects received either 825 mg MK-0679 or placebo, orally in a double blind, randomised, crossover design.. The leukotriene antagonist MK-0679 caused bronchodilation which lasted for at least nine hours. The average peak improvement in FEV1 was 18% above the predrug baseline, but the bronchodilator response varied between 34% and 5% and was found to correlate strongly with the severity of asthma and aspirin sensitivity.. The findings indicate that ongoing leukotriene production may be one cause of persistent airway obstruction in aspirin sensitive asthmatic subjects and that they may benefit from treatment with a leukotriene receptor antagonist.

Topics: Adult; Airway Obstruction; Aspirin; Asthma; Bronchi; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Propionates; Quinolines; SRS-A

Descriptive studies suggest an association between the release of the cysteinyl leukotrienes and clinical asthma. To help clarify this association, we tested the hypothesis that an intravenous infusion of a potent and specific investigational LTD4 receptor antagonist, MK-679, would cause rapid bronchodilation. In a three-period, randomized, double-blind, crossover study, single doses of MK-679, 125 and 500 mg, and placebo were given intravenously by bolus infusion to nine patients with moderate, stable asthma (FEV1 40 to 80% predicted) on individual study days separated by a week. Spirometry was preformed predose and at intervals for as long as 8 h postdosing; blood samples for MK-679 concentrations were drawn over this time. Fifteen minutes after the end of infusion, the FEV1 percent change from baseline increased a mean of 15.8 +/- 15.7 and 7.8 +/- 11.6% with the 500- and 125-mg doses, respectively, compared with a mean decrease of 2.6 +/- 6.2% with placebo (p = 0.01, overall; p = 0.003, 500 mg versus placebo). The mean end-of-infusion MK-679 plasma concentrations were 86.2 +/- 13.9 and 19.9 +/- 2.7 micrograms/ml for the 500- and 125-mg doses, respectively. MK-679 was well-tolerated, with no significant adverse experiences observed. We conclude that a single, intravenously administered, bolus infusion of MK-679 causes bronchodilation in patients with moderate, stable asthma.

Topics: Adult; Analysis of Variance; Asthma; Bronchi; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Infusions, Intravenous; Male; Middle Aged; Propionates; Quinolines; Receptors, Immunologic; Receptors, Leukotriene

Drugs which block the action or formation of the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) inhibit asthmatic responses evoked by allergen, exercise and cold dry air. The purpose of this study was to determine whether the specific leukotriene-receptor antagonist MK-0679 could block the airway obstruction induced by aspirin (acetylsalicylic acid (ASA)) in aspirin-intolerant asthmatics. Eight asthmatics (mean age 45 yrs), with an average history of asthma and ASA-sensitivity of about 10 yrs duration, were subjected to bronchial provocation with lysine-ASA. Baseline ASA-sensitivity was first determined in an open prestudy session by inhalation of cumulative doses of lysine-ASA to establish the dose of ASA decreasing forced expiratory volume in one second (FEV1) by 20% (PD20). Rechallenge with lysine-ASA was performed on two different occasions, 1 h after oral administration of placebo, or 750 mg of MK-0679, under double-blind conditions, in a randomized, cross-over design. Leukotriene formation was estimated by the measurement of urinary LTE4. The lysine-ASA challenge was highly reproducible (geometric mean for group PD20 being identical for the open prestudy and the placebo session), and was associated with a post-challenge increase in urinary LTE4. In contrast, after MK-0679, there was a rightward shift in the dose response relationship for all eight subjects (median shift being 4.4 fold), with three of the subjects failing to produce a 20% decrease in FEV1 despite inhalation of the highest dose of lysine-ASA feasible to deliver.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aspirin; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Female; Humans; Leukotriene Antagonists; Leukotrienes; Lysine; Male; Middle Aged; Propionates; Quinolines; Receptors, Immunologic; Receptors, Leukotriene

We have tested the hypothesis that leukotriene D4 (LTD4) receptor activation is involved in the development of antigen-induced bronchoconstriction. In two studies, patients with asthma received infusions of placebo or MK-571, a potent and specific LTD4 receptor antagonist (450 mg or 37.5 mg total dose, respectively). Antigen was inhaled during test-drug administration, and FEV1 was measured for 10 hours after challenge. Urine samples were collected for measurement of LTE4; plasma samples were drawn repeatedly for assay of MK-571. MK-571 infusions inhibited both immediate (0 to 3 hours) and late (3 to 10 hours) asthmatic responses. For the high MK-571 dose, the extent of inhibition, as assessed by the area under the curve of FEV1 versus time was 88% (p = 0.01) and 63% (p = 0.01), for immediate and late responses, respectively. The low MK-571 dose also inhibited both responses but to a minor extent. Mean urinary LTE4 excretion was elevated after antigen challenge and was unaffected by administration of the LTD4 receptor antagonist. The present study demonstrates that MK-571 inhibits antigen-induced asthma in a dose-related fashion; it had not effect on antigen-induced increases in urinary LTE4 excretions. The results suggest that LTD4 receptor activation plays an important role in antigen-induced asthma.

Topics: Administration, Inhalation; Adult; Antigens; Asthma; Bronchoconstriction; Creatinine; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Propionates; Quinolines; Receptors, Immunologic; Receptors, Leukotriene; SRS-A

The sulfidopeptide leukotrienes LTC4, LTD4, and LTE4 can cause airway smooth muscle contraction and have been implicated in the pathophysiology of asthma. MK-571 is a selective, potent LTD4 receptor antagonist that could attenuate airway obstruction in asthma by inhibiting the actions of sulfidopeptides at the LTD4 receptor site. The objectives of this study were to investigate the potential for MK-571 to cause bronchodilation in asthma patients with existing airway obstruction and to evaluate its effect on the bronchodilation response to an inhaled beta 2-agonist (albuterol). Twelve male patients (ages 19 to 42 yr) with asthma (baseline FEV1 50 to 80% predicted) participated in this placebo-controlled, randomized, two-period, cross-over study. On separate treatment days, each patient received either MK-571 or placebo intravenously for 6 h; inhaled albuterol was administered at the fifth and sixth hour of MK-571/placebo treatment to achieve maximal bronchodilation on that study day. Spirometry (forced expiratory volume in 1 s, FEV1) was monitored at intervals throughout each study period. MK-571 caused clinically significant bronchodilation; the increase in FEV1 above baseline, 20 min after the start of the MK-571 infusion, was 22 +/- 3.9% compared with 1.3 +/- 2.3% for placebo (mean +/- SE, p < 0.01). This degree of bronchodilation was maintained throughout the MK-571 infusion. In addition, bronchodilation from inhaled albuterol appeared additive with MK-571. Finally, baseline airway obstruction correlated with the degree of bronchodilation achieved with MK-571 (r = -0.73; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Airway Obstruction; Albuterol; Analysis of Variance; Asthma; Double-Blind Method; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Propionates; Quinolines; SRS-A

The safety, tolerability and bronchodilator properties of inhaled verlukast (MK-0679), a new potent and selective LTD4-receptor antagonist, were studied in 12 asthmatic subjects with more than 15% increase in FEV1 after salbutamol inhalation. On three separate study days the patients inhaled placebo, verlukast 2 mg and verlukast 8 mg from a metered dose inhaler according to a randomized, double-blind, cross-over allocation schedule. Pulmonary function and tolerability were assessed regularly and after 8 h a second dose of test drug was inhaled. Thirty minutes later a beta 2-agonist dose-response curve was performed by inhaling salbutamol in cumulative doses of 200, 400 and 800 micrograms. Verlukast (8 mg) caused significant improvement in mean FEV1 from 1.5 through 8 h after inhalation as compared to placebo (P less than 0.05). The maximum change in FEV1 occurred at 2 h after inhalation with mean percent increases above baseline of 3.5, 7.7, and 9.2% after placebo, verlukast 2 mg and 8 mg, respectively. The bronchodilator response to inhaled salbutamol was significantly larger after verlukast 8 mg than after placebo pretreatment (P less than 0.05), whereas verlukast 2 mg afforded no additive bronchodilator effect. We conclude that inhalation of the LTD4-antagonist verlukast induces modest but significant bronchodilatation and may be beneficial in the treatment of asthma.

Topics: Administration, Inhalation; Adult; Albuterol; Asthma; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Lung; Male; Middle Aged; Propionates; Quinolines; Respiratory Function Tests; SRS-A

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Arachidonate 5-Lipoxygenase; Asthma; Bronchoconstriction; Carrier Proteins; Depression, Chemical; Double-Blind Method; Enzyme Activation; Guinea Pigs; Humans; Indoles; Leukotrienes; Lipoxygenase Inhibitors; Membrane Proteins; Propionates; Protein Processing, Post-Translational; Quinolines; Receptors, Immunologic; Receptors, Leukotriene; SRS-A

MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind, placebo-controlled, randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1,500, 86, or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers, up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects, 28 mg MK-571 caused a significant, at least 44-fold, rightward shift of the dose-response curve to LTD4, whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients, suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.

Topics: Adolescent; Adult; Airway Resistance; Asthma; Bronchoconstriction; Dose-Response Relationship, Drug; Double-Blind Method; Forced Expiratory Volume; Humans; Male; Middle Aged; Propionates; Quinolines; SRS-A

The multidrug resistance protein 4 (Mrp4) is an ATP-binding cassette transporter that is capable of exporting the second messenger cAMP from cells, a process that might regulate cAMP-mediated anti-inflammatory processes. However, using LPS- or cigarette smoke (CS)-inflammation models, we found that neutrophil numbers in the bronchoalveolar lavage fluid (BALF) were similar in Mrp4(-/-) and Mrp4(+/+) mice treated with LPS or CS. Similarly, neutrophil numbers were not reduced in the BALF of LPS-challenged wt mice after treatment with 10 or 30 mg/kg of the Mrp1/4 inhibitor MK571. The absence of Mrp4 also had no impact on the influx of eosinophils or IL-4 and IL-5 levels in the BALF after OVA airway challenge in mice sensitized with OVA/alum. LPS-induced cytokine release in whole blood ex vivo was also not affected by the absence of Mrp4. These data clearly suggest that Mrp4 deficiency alone is not sufficient to reduce inflammatory processes in vivo. We hypothesized that in combination with PDE4 inhibitors, used at suboptimal concentrations, the anti-inflammatory effect would be more pronounced. However, LPS-induced neutrophil recruitment into the lung was no different between Mrp4(-/-) and Mrp4(+/+) mice treated with 3 mg/kg Roflumilast. Finally, the single and combined administration of 10 and 30 mg/kg MK571 and the specific breast cancer resistance protein (BCRP) inhibitor KO143 showed no reduction of LPS-induced TNFα release into the BALF compared to vehicle treated control animals. Similarly, LPS-induced TNFα release in murine whole blood of Mrp4(+/+) or Mrp4(-/-) mice was not reduced by KO143 (1, 10 µM). Thus, BCRP seems not to be able to compensate for the absence or inhibition of Mrp4 in the used models. Taken together, our data suggest that Mrp4 is not essential for the recruitment of neutrophils into the lung after LPS or CS exposure or of eosinophils after allergen exposure.

Topics: Adenosine; Allergens; Animals; Asthma; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bronchoalveolar Lavage Fluid; Cyclic AMP; Cytokines; Diketopiperazines; Eosinophils; Heterocyclic Compounds, 4 or More Rings; Lipopolysaccharides; Lung; Mice; Multidrug Resistance-Associated Proteins; Neutrophils; Ovalbumin; Phosphodiesterase 4 Inhibitors; Propionates; Pulmonary Disease, Chronic Obstructive; Quinolines; Rolipram; Smoking; Th2 Cells; Time Factors

Topics: Asthma; Cell Line; Chemokine CCL2; Cysteine; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Leukotriene Antagonists; Leukotriene D4; Leukotrienes; Propionates; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Cysteinyl leukotriene receptor type 1 (leukotriene CysLT(1) receptor) antagonist is one of the most effective anti-inflammatory agents for asthma. The spectrum of protein targets that can be regulated by leukotriene CysLT(1) receptor antagonist in asthma is not fully understood. The present study tried to identify novel protein targets of a selective leukotriene CysLT(1) receptor antagonist MK-571 in allergic airway inflammation by analyzing the proteome of mouse bronchoalveolar lavage fluid. BALB/c mice sensitized and challenged with ovalbumin showed increased pulmonary inflammatory cell infiltration, airway mucus production and serum ovalbumin-specific IgE level. MK-571 inhibited all these allergic airway inflammation endpoints. Lavage fluid proteins were resolved by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The level of fourteen bronchoalveolar lavage fluid protein spots was markedly altered by MK-571. A family of chitinases (Ym1, Ym2 and acidic mammalian chitinase), lungkine, surfactant protein-D and gamma-actin have been found for the first time to be down-regulated by leukotriene CysLT(1) receptor antagonist in mouse allergic airways. Some of the down-regulatory effects were confirmed with reverse transcription-polymerase chain reaction analyses. Taken together, we have identified novel protein targets that can be regulated by leukotriene CysLT(1) receptor antagonist in mouse allergic airway inflammation, and our findings reveal additional pharmacological actions of leukotriene CysLT(1) receptor antagonist in the treatment of asthma.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Base Sequence; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Leukotriene Antagonists; Membrane Proteins; Mice; Mice, Inbred BALB C; Microscopy; Propionates; Proteome; Quinolines; Receptors, Leukotriene; Respiratory Hypersensitivity; Reverse Transcriptase Polymerase Chain Reaction

Cysteinyl leukotrienes (CysLTs) contribute to the development of airway obstruction and inflammation in asthma; however little information is available on the role of these molecules in the pathophysiology of respiratory syncytial virus (RSV) bronchiolitis. This study was designed to evaluate the effects of RSV infection on CysLTs production in a well-established mouse infection model. Furthermore, we assessed the effect of anti-inflammatory agents (a leukotriene receptor antagonist, MK-571, and dexamethasone) on the functional and immune changes induced by RSV infection. Six to 8-wk-old BALB/c mice were infected with human RSV (strain A2). Measurements of airway function were performed using whole body plethysmography. Lung inflammation was assessed by cell counts, measurement of cytokines and CysLTs in bronchoalveolar lavage fluid (BALF) in the absence and presence of treatment with MK-571 or dexamethasone. RSV infection produced a marked increase in CysLTs in the BALF and lung tissue, recruitment of neutrophils and lymphocytes into the airways, increased IFN-gamma levels and airway hyperresponsiveness (AHR). Treatment with MK-571 decreased RSV-induced AHR without affecting the cellular and inflammatory responses to RSV. Dexamethasone decreased AHR and markedly reduced the recruitment of inflammatory cells and production of IFN-gamma. Our findings suggest CysLTs play an important role in the pathogenesis of RSV-induced airway dysfunction. Treatment with MK-571 decreases RSV-induced AHR but does not appear to alter the lung inflammatory responses to RSV. In contrast, dexamethasone decreases RSV-induced AHR but interferes with recruitment of inflammatory cells, resulting in decreased Th1 cytokines (a potentially Th2-prone environment) in this model. These studies support recent reports on the beneficial effects of CysLT receptor antagonist in human trials and provide a model for investigating the role of CysLTs in RSV bronchiolitis.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cysteine; Dexamethasone; Disease Models, Animal; Female; Inflammation; Interferon-gamma; Leukotrienes; Lymphocyte Count; Lymphocytes; Macrophages; Membrane Proteins; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Propionates; Quinolines; Receptors, Leukotriene; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human

Cysteinyl leukotrienes are potent inflammatory molecules playing a major role in asthma. The involvement of these mediators in hypersensitivity in mice is not well known. This study aimed at elucidating their implication by using MK-571, a cysLT(1)receptor antagonist. Mice were sensitized with a suspension of ovalbumin (8 microg) adsorbed to alum (2 mg) and were challenged with an aerosolized ovalbumin solution (0.5%). Inflammatory cell infiltration in the bronchoalveolar lavage (mostly eosinophils) following antigen challenge was inhibited by dexamethasone (0.1, 1 and 5 mg kg(-1)s.c.) and MK-571 (1, 10, 100 mg kg(-1)i.v.) in a dose-dependent manner. Maximal inhibition was 95% with 5 mg kg(-1)dexamethasone and 90% with 100 mg kg(-1)MK-571. When injected together they showed an additive inhibitory effect on eosinophil infiltration. Bronchial hyperreactivity, measured by the increased pulmonary insufflation pressure to carbachol injections, was also inhibited dose-dependently by MK-571. The EC(50)values for carbachol were of 22.39+/-1.12 microg kg(-1)in sensitized and challenged animals that did not receive MK-571 and increased to 43.65+/-1.10, 50.12+/-1.15 and 83.18+/-1.16 microg kg(-1)in animals treated with 1, 10 and 100 mg kg(-1)MK-571 respectively. Lung microvascular leakage (as measured by Evans blue extravasation) induced by antigen bronchoprovocation was reduced by 22% after treatment with 10 mg kg(-1)MK-571. All these inhibitory effects of MK-571 suggest a role for leukotriene D(4)in this animal model of allergic asthma.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Capillary Permeability; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Leukotriene Antagonists; Leukotriene D4; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Ovalbumin; Propionates; Pulmonary Eosinophilia; Quinolines; Receptors, Leukotriene

Human airways in vitro contract when stimulated by anti-IgE, whereas human pulmonary vessels relax. Leukotriene D4 (LTD4) induced a contractile response in the airways, while in pulmonary vessels both contractions and relaxations were observed. The LTD4 contractions in airways were blocked by cysLT1 receptor antagonists (MK 571, ICI 198615, and BAY x7195). In contrast none of the compounds affected the LTD4 contractions of pulmonary veins. These results suggest that the leukotrienes which are released during antigen challenge of airways and pulmonary vessels may be acting at distinct receptors in the human lung.

Topics: Antigens; Asthma; Bronchi; Bronchodilator Agents; Cell Separation; Humans; Hydroxy Acids; Indazoles; Leukotriene D4; Muscle, Smooth; Norepinephrine; Propionates; Pulmonary Veins; Quinolines

The ovalbumin (OA)-sensitized Brown Norway rat (BN) demonstrates early-response (ER) and late-response (LR) allergic bronchoconstriction. To determine whether these responses could be replicated in vitro, we studied lung explants from 8-wk-old male BN rats (wt: 239 +/- 28 g), of which 19 were sensitized to OA (test) and 16 served as controls. Two weeks after sensitization, the animals' lungs were removed, filled with a 1% (wt/vol) agarose-containing solution at 37 degrees C, and cooled to 4 degrees C. Transverse slices (0.5 to 1.0 mm thick) were cut and cultured overnight. Airways were visualized with an inverted microscope and baseline images were obtained with a video camera. To study the ER, 40 airways from 15 test rats and 29 airways from 10 control rats were challenged with 2 micrograms OA and imaged each minute for 10 min. To study the LR, 40 airways from 12 test rats and 44 airways from 12 control rats were challenged with 2 micrograms OA and imaged each hour for 8 h. The maximal response (MR) for each airway was defined as the percent of airway closure. The ER and LR were both defined as an MR > or = mean + 2 SD of the controls. An ER occurred in 38 of 40 test and 2 of 29 control airways (mean MR: 42 +/- 24% versus 4 +/- 3%, p < 0.001), and was completely blocked by methysergide pretreatment in 13 airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Airway Resistance; Animals; Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Constriction, Pathologic; Disease Models, Animal; Drug Hypersensitivity; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Immunoglobulin E; In Vitro Techniques; Leukotriene D4; Male; Methysergide; Ovalbumin; Premedication; Propionates; Quinolines; Rats; Serotonin; Time Factors

Topics: Asthma; Humans; Hydroxyeicosatetraenoic Acids; Hydroxyurea; Leukotrienes; Lipoxygenase Inhibitors; Propionates; Quinolines

Topics: Antigens; Asthma; Double-Blind Method; Forced Expiratory Volume; Humans; Propionates; Quinolines; Random Allocation; SRS-A