ovalbumin and Bronchial-Spasm

Sophora tonkinensis (Leguminosae, ST) is a traditional herbal plant in Korea and China. Its roots and rhizomes have been used to dissipate heat, to clear toxic material and to treat acute pharyngolaryngeal infections and sore throats.. In this study, we tried to investigate the anti-inflammatory and anti-asthmatic effects of a purified extract (SKI3301) from Sophora tonkinensis using in vitro enzyme assay models and ovalbumin (OVA)-induced asthma animal models.. The effect of SKI3301 on pro-inflammatory enzymes such as 5-lipoxygenase, phosphodiesterase 3 & 4, and thromboxane synthase was assayed in vitro. BALB/c mice were sensitized with OVA/Alum ip injection and nebulized with OVA to induce airway inflammation. Bronchoalveolar lavage (BAL) fluid was collected and analyzed for leukocytes infiltration and IL-5 production along with lung histopathology. Guinea pigs passively sensitized with anti-OVA antiserum were used to investigate the effect of SKI3301 on bronchospasm in vitro and in vivo.. SKI3301 potently inhibited the activities of 5-lipoxygenase, phosphodiesterase 3 & 4, and thromboxane synthase. Orally administered SKI3301 attenuated the total leukocytes and eosinophil infiltration and IL-5 level in BAL fluids. Histopathological changes associated with lung inflammation were also reduced by SKI3301. SKI3301 inhibited OVA-induced contraction of isolated trachea from sensitized guinea pigs. SKI3301 also protected OVA-induced bronchoconstriction in the sensitized guinea pigs. Maackiain, one of 3 major components of SKI3301, was effective in inhibiting 5-lipoxygenase and OVA-induced airway inflammation.. In this study, SKI3301 potently inhibited pro-inflammatory enzymes and attenuated OVA-induced bronchospasm in animal model of allergic asthma. These results suggest that SKI3301 may have therapeutic potential for allergic asthma.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Guinea Pigs; Mice; Mice, Inbred BALB C; Ovalbumin; Plant Extracts; Plant Preparations; Sophora; Trachea

The two life-threatening signs of anaphylactic shock (AS) are severe arterial hypotension and bronchospasm. Guidelines recommend epinephrine as first-line treatment. Arginine vasopressin (AVP) has been proposed as an alternative if epinephrine does not correct arterial hypotension. These two drugs may have beneficial, neutral or deleterious effects on airflow either directly or by modifying factors that regulate vasodilatation and/or edema in the bronchial wall.. To compare the effects of epinephrine and AVP on airflow and airway leakage in a rat model of AS.. Thirty-two ovalbumin-sensitized rats were randomized into four groups: control (CON), AS without treatment (OVA), AS treated with epinephrine (EPI), and AS treated with AVP (AVP). Mean arterial pressure (MAP), respiratory resistance and elastance and microvascular leakage in the airways were measured.. All OVA rats died within 20 minutes following ovalbumin injection. Ovalbumin induced severe arterial hypotension and airway obstruction (221 ± 36 hPa.s.L. Epinephrine was superior to AVP for alleviating the airway response in a rat model of AS. When bronchospasm and severe arterial hypotension are present during AS, epinephrine should be the drug of choice.

Topics: Airway Obstruction; Anaphylaxis; Animals; Arterial Pressure; Bronchial Spasm; Capillary Leak Syndrome; Epinephrine; Hypotension; Neurophysins; Ovalbumin; Protein Precursors; Rats; Respiratory System; Vasopressins

Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5α- and 5β-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5β-DHT was more potent for relaxing KCl-induced contraction, while TES and 5α-DHT were more potent for CCh- and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K(+) channels. These data indicate the absence of involvement of the epithelium-, NO- and K(+) channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca(2+)]i increment. 5β-DHT was the most potent at decreasing KCl-induced [Ca(2+)]i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca(2+) influx through L-type Ca(2+)channels but additional Ca(2+) entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action.

Topics: Androgens; Animals; Bronchial Spasm; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Calcium; Carbachol; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Male; Muscle, Smooth; Ovalbumin; Potassium Chloride; Trachea

Nucleotides released to the extracellular space stimulate purinergic receptors, and their effects are modulated by ectonucleotidases. The role of ATP in the allergic bronchospasm has been scantly studied.. We used several techniques (plethysmography, organ baths, confocal microscopy, RT-PCR, ATP measurement) to explore the role of nucleotides and ectonucleotidases in the allergic bronchospasm in guinea pigs.. While allergenic challenge with a low-dose ovalbumin (OVA) only produced a small bronchospasm (~2-fold the basal lung resistance), previous inhibition of ectonucleotidases by ARL-67156 greatly intensified this response (~11-fold the basal lung resistance, with 44% mortality). Bronchoalveolar lavage fluid obtained during this bronchospasm contained increased ATP concentration. This potentiation was abolished by antagonism of purinergic receptors (suramin+RB2) or TXA2 receptor (SQ29548), or by intratracheal apyrase. In tracheal rings and lung parenchyma strips, OVA caused a concentration-dependent contraction. Suramin+RB2 or levamisole produced a significant rightward displacement of this response, and ARL-67156 did not modify it. Platelets stimulated with OVA released ATP. Confocal images of nonsensitized tracheas showed slight fluorescence for P2Y6 receptors in epithelium and none for P2Y4 . Sensitized animals showed strong fluorescence to both receptors and to alkaline phosphatase in the airway epithelium. This correlated with a large increment in mRNA for P2Y4 and P2Y6 receptors in sensitized animals.. Nucleotides greatly potentiate the allergic bronchospasm when ectonucleotidases activity is diminished, and this effect is probably favored by the upregulation of P2Y4 and P2Y6 receptors in airway epithelium during sensitization. These results prompt for further research on these mechanisms in human asthma.

Topics: Adenosine Triphosphate; Alkaline Phosphatase; Animals; Blood Platelets; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Extracellular Space; Guinea Pigs; Hydrolysis; Hypersensitivity; Nucleotidases; Nucleotides; Ovalbumin; Receptors, Purinergic P2

To evaluate the antiasthmatic and antitussive properties of the aqueous leaf extract of Bryophyllum pinnatum (B. pinnatum) (BP) Lam.. Ovalbumin-sensitized guinea pigs which were treated with BP for 21 consecutive days were exposed to 0.2% histamine aerosol in a glass chamber. Mucus viscosity, white blood cell and lymphocyte counts and tracheal wall morphometry were measured. Bouts of cough were counted pre and post acute exposure of extract-treated (× 7 d) guinea pigs to 7.5% citric acid aerosol in a chamber. Phenol red expectoration was estimated in mice after 7 d of daily administration of BP.. Doses of 200 and 400 mg/kg/day (×21 d) BP significantly increased the time for guinea pigs to experience preconvulsive dyspnoea. BP and salbutamol (0.5 mg/kg/day ×21 d) reduced mucus viscosity in the sensitized group to values comparable with controls. White blood cell, lymphocyte counts and tracheal morphometry were not significantly altered. Both doses of BP also significantly reduced the bouts of cough but only 400 mg/kg/day significantly inhibited the amount of phenol red secreted.. BP has demonstrated antiasthmatic and antitussive properties in these rodent models. These properties may underscore its use in Nigerian ethnomedicine.

Topics: Analysis of Variance; Animals; Anti-Asthmatic Agents; Antitussive Agents; Bronchial Spasm; Citric Acid; Cough; Female; Guinea Pigs; Histamine; Kalanchoe; Lung; Male; Mice; Mucus; Ovalbumin; Plant Extracts; Plant Leaves; Trachea; Viscosity

Asthma is an allergic lung disease can be modulated by drugs that modify the activity of central nervous system (CNS) such as amphetamine (AMPH). AMPH is a highly abused drug that exerts potent effects on behavior and immunity. In this study we investigated the mechanism involved in the effects of long-term AMPH treatment on the increased magnitude of allergic lung response. We evaluated mast cells degranulation, cytokines release, airways responsiveness and, expression of adhesion molecules. Male Wistar rats were treated with AMPH or vehicle (PBS) for 21 days and sensitized with ovalbumin (OVA) one week after the first injection of vehicle or AMPH. Fourteen days after the sensitization, the rats were challenged with an OVA aerosol, and 24h later their parameters were analyzed. In allergic rats, the treatment with AMPH exacerbated the lung cell recruitment due increased expression of ICAM-1, PECAM-1 and Mac-1 in granulocytes and macrophages recovered from bronchoalveolar lavage. Elevated levels of IL-4, but decreased levels of IL-10 were also found in samples of lung explants after AMPH treatment. Conversely, the ex-vivo tracheal hyper-responsiveness to methacholine (MCh) was reduced by AMPH treatment, whereas the force contraction of tracheal segments due to in vitro antigen challenge remained unaltered. Our findings suggest that lung inflammation and airway hyper-responsiveness due to OVA challenge are under the distinct control of AMPH during long-term treatment. Our data strongly indicate that AMPH positively modulates allergic lung inflammation via the increase of ICAM-1, PECAM-1, Mac-1 and IL-4. AMPH also abrogates the release of the anti-inflammatory cytokine IL-10.

Topics: Amphetamine; Animals; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Cytokines; Drug Administration Schedule; Drug Hypersensitivity; Gene Expression Regulation; Inflammation; Male; Ovalbumin; Rats; Rats, Wistar; Sympathomimetics

In the present study, the efficacy of β-sitosterol isolated from an n-butanol extract of the seeds of the plant Moringa oleifera (Moringaceae) was examined against ovalbumin-induced airway inflammation in guinea pigs. All animals (except group I) were sensitized subcutaneously and challenged with aerosolized 0.5% ovalbumin. The test drugs, β-sitosterol (2.5mg/kg) or dexamethasone (2.5mg/kg), were administered to the animals (p.o.) prior to challenge with ovalbumin. During the experimental period (on days 18, 21, 24 and 29), a bronchoconstriction test (0.25% acetylcholine for 30s) was performed and lung function parameters (tidal volume and respiration rate) were measured for each animal. On day 30, blood and bronchoalveolar lavaged fluid were collected to assess cellular content, and serum was collected for cytokine assays. Lung tissue was utilized for a histamine assay and for histopathology. β-sitosterol significantly increased the tidal volume (V(t)) and decreased the respiration rate (f) of sensitized and challenged guinea pigs to the level of non-sensitized control guinea pigs and lowered both the total and differential cell counts, particularly eosinophils and neutrophils, in blood and bronchoalveolar lavaged fluid. Furthermore, β-sitosterol treatment suppressed the increase in cytokine levels (TNFα, IL-4 and IL-5), with the exception of IL-6, in serum and in bronchoalveolar lavaged fluid detected in model control animals. Moreover, treatment with β-sitosterol protected against airway inflammation in lung tissue histopathology. β-sitosterol possesses anti-asthmatic actions that might be mediated by inhibiting the cellular responses and subsequent release/synthesis of Th2 cytokines. This compound may have therapeutic potential in allergic asthma.

Topics: Acetylcholine; Animals; Anti-Asthmatic Agents; Asthma; Body Weight; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cell Count; Cytokines; Disease Models, Animal; Guinea Pigs; Histamine; Inflammation; Lung; Male; Ovalbumin; Respiratory System; Sitosterols; Th2 Cells

Asthma is a chronic inflammatory disorder of the airways. The available treatment options have major limitations owing to low efficacy, associated adverse events and compliance issues. Therefore, the health burden of bronchial asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics. Myrica sapida is known traditionally in Ayurveda to possess anti-asthmatic activity. Hence, the present investigation was undertaken to evaluate the bronchodilator and anti-anaphylactic activity of the stem bark of Myrica sapida.. Experimental models studied were acetylcholine induced bronchospasm in guinea pigs, egg albumin induced anaphylaxis in guinea pigs, in vitro studies on tracheal strip of egg albumin sensitized guinea pigs.. Treatment with ethanolic extract of M. sapida, 75 mg/kg, orally resulted in significant protection against acetylcholine aerosol induced bronchospasm and allergen induced anaphylaxis in guinea pigs. Ethanolic extract of M. sapida (75 mg/kg, p.o.) prevented the potentiation of responses and also produced a decrease in pD2 value of histamine and acetylcholine in guinea pig tracheal strip.. These results suggest that M. sapida possesses bronchodilator activity, has potent inhibitory effect on immediate hyper-sensitivity reactions and decreases bronchial hyper-responsiveness.

Topics: Acetylcholine; Aerosols; Anaphylaxis; Animals; Bronchial Spasm; Bronchodilator Agents; Guinea Pigs; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Myrica; Ovalbumin; Phytotherapy; Plant Extracts; Rats

The aim of this study was to investigate the anti-asthmatic effects of Perilla seed oil in vitro and in vivo in sensitized guinea pigs. Aerosolized antigen caused an immediate bronchoconstriction. Perilla seed oil per os inhibited the increase in lung resistance and the decrease in dynamic lung compliance in a dose-dependent manner with an ED50 (95 % confidence interval, CI) of 1.10 (0.98 - 1.24) g/kg and 1.07 (0.94 - 1.22) g/kg, respectively. Infiltration of leukocytes, mononuclear cells, eosinophils and neutrophils induced by inhaling antigen was also inhibited by Perilla seed oil in a dose-dependent manner with an ED50 (95 % CI) of 1.00 (0.86 - 1.15), 1.24 (1.10 - 1.38), 0.63 (0.51 - 0.77) and 0.61 (0.38 - 0.98) g/kg, respectively. Perilla seed oil (5 - 500 microg/mL) inhibited the slow reaction substance of anaphylaxis (SRS-A) release induced by antigen challenge in lung tissue of sensitized guinea pigs. It also inhibited calcium ionophore (A(23187))-induced leukotriene (LT) D4 release from the lung tissue of non-sensitized guinea pigs in a concentration-dependent manner with an IC50 (95 % CI) of 50 (36 - 69) microg/mL. These results indicate that Perilla seed oil may improve lung function in asthma by controlling eicosanoid production and suppressing LT generation.

Topics: alpha-Linolenic Acid; Animals; Antigens; Bronchial Spasm; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; In Vitro Techniques; Inhibitory Concentration 50; Lung; Male; Ovalbumin; Perilla; Phytotherapy; Plant Oils

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with roflumilast (0.3, 1.0, and 3.0mg/kg), rolipram (0.8, 2.8, and 8.3mg/kg), piclamilast (10.0, 20.0, and 30.0mg/kg), or cilomilast (10.3, 34.3, and 103.0mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-alpha) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-alpha antibody revealed that AHR was independent of neutrophil accumulation or TNF-alpha release. Roflumilast (50% inhibitory dose [ID(50)]=1.5mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg). Roflumilast, rolipram, and piclamilast-but not cilomilast-suppressed OVA-induced TNF-alpha release in a dose-dependent manner. Roflumilast (ID(50)=0.9mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-alpha release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Oral; Aminopyridines; Animals; Benzamides; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Carboxylic Acids; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Cyclopropanes; Disease Models, Animal; Immunization; Male; Neutrophils; Nitriles; Ovalbumin; Phosphodiesterase Inhibitors; Pneumonia; Pyridines; Rats; Respiratory Hypersensitivity; Rolipram; Serotonin; Treatment Outcome; Tumor Necrosis Factor-alpha

The etiology of asthma, a chronic inflammatory disorder of the airways, remains obscure, although T cells appear to be central disease mediators. Lyn tyrosine kinase has been implicated as both a facilitator and inhibitor of signaling pathways that play a role in allergic inflammation, although its role in asthma is unclear because Lyn is not expressed in T cells. We show in the present study that Lyn-/- mice develop a severe, persistent inflammatory asthma-like syndrome with lung eosinophilia, mast cell hyperdegranulation, intensified bronchospasm, hyper IgE, and Th2-polarizing dendritic cells. Dendritic cells from Lyn-/- mice have a more immature phenotype, exhibit defective inhibitory signaling pathways, produce less IL-12, and can transfer disease when adoptively transferred into wild-type recipients. Our results show that Lyn regulates the intensity and duration of multiple asthmatic traits and indicate that Lyn is an important negative regulator of Th2 immune responses.

Topics: Allergens; Animals; Asthma; B-Lymphocyte Subsets; Bronchial Spasm; Cells, Cultured; Dendritic Cells; Down-Regulation; Immunity, Mucosal; Immunoglobulin E; Inflammation Mediators; Lung; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; src-Family Kinases; Th2 Cells

Ebastine (CAS 90729-43-4), cetirizine (CAS 83881-51-0) and loratadine (CAS 79794-75-5) are second generation H1-antihistamines of proven efficacy for treating allergy. Recent clinical studies have found ebastine to be more effective than cetirizine or loratadine in alleviating the symptoms of seasonal allergic rhinitis. The objective of this study was to compare the efficacy of these compounds in three guinea-pig modeles of bronchoconstriction, elicited either by histamine, allergen or leukotriene C4 in order to shed light onto the mechanisms that might explain differences found in clinical studies. In the present experiments, ebastine and cetirizine were equipotent against aerosol histamine-induced bronchospasm in guinea pigs (ED50 115 and 100 micrograms/kg p.o., respectively), while loratadine was three-fold less potent. In the same model the effects of ebastine, loratadine and cetirizine lasted 21, 19 and 15 h, respectively. Ebastine (ED50 334 micrograms/kg p.o.) was the most potent compound in inhibiting allergen-induced bronchospasm in conscious guinea pigs. In vitro studies in tracheally perfused guinea pig lungs demonstrated that ebastine and loratadine inhibited with equal potency the bronchoconstriction induced by leukotriene C4 whilst cetirizine was significantly less potent. Finally, in another in vivo study, ebastine reverted the changes in pulmonary resistance induced by leukotriene C4 in anaesthetised guinea pigs, whereas cetirizine and loratadine were devoid of activity in this model. In accordance with the clinical data, ebastine proved to be the substance with the widest range of application in animal experiments, too.

Topics: Aerosols; Airway Resistance; Algorithms; Animals; Anti-Allergic Agents; Bronchial Spasm; Butyrophenones; Cetirizine; Guinea Pigs; Histamine; Histamine H1 Antagonists; Leukotriene C4; Loratadine; Male; Ovalbumin; Piperidines

The n-hexane extract that has shown activity in the tracheospasmolytic bioassay was fractionated by solvent extraction and from the major active fraction two compounds were isolated and identified as viteosin-A and vitexicarpin. These compounds blocked spontaneous contraction of isolated male guinea pig trachea induced by histamine; however only vitexicarpin was active in a model using sensitized guinea pig trachea stimulated by ovalbumin up to minimum dose of 1.3 x 10(-5) M. The result suggests that vitexicarpin is able to block effects of histamine released from sensitized mast cells possibly by stabilizing the mast cells membrane function.

Topics: Animals; Bronchial Spasm; Dose-Response Relationship, Drug; Flavonoids; Guinea Pigs; Histamine; Isoquinolines; Male; Ovalbumin; Phytotherapy; Plant Extracts; Plant Leaves; Trachea; Vitex

We have previously demonstrated that the administration of nerve growth factor (NGF) to guinea-pigs results in airway hyper-responsiveness within 1 h.. In the present study we document the involvement of NGF in the acute allergic airway response.. Guinea-pigs that are sensitized to ovalbumin show an acute bronchoconstriction directly after challenge with ovalbumin.. Intratracheal application of 10 microg of antibodies directed against NGF (anti-NGF) 1 h before the challenge reduces the acute severe bronchoconstriction to approximately 40% and the sustained bronchoconstriction to approximately 20% of the reaction in controls. This shows a high potency of anti-NGF in diminishing the direct bronchoconstriction. Inhibition of the tyrosine kinases of the tyrosine kinase receptor A, the high-affinity receptor for NGF, has no effect on the bronchoconstriction. Therefore, we postulate that the p75, the low-affinity receptor for neurotrophins, is responsible for the acute bronchoconstriction. Our findings suggest a role for NGF in the induction of the acute asthmatic reaction.. These findings offer a new potential therapeutic strategy for the treatment of allergic asthma.

Topics: Acute Disease; Allergens; Animals; Antibodies; Bronchial Spasm; Enzyme Inhibitors; Guinea Pigs; Male; Nerve Growth Factor; Ovalbumin; Protein-Tyrosine Kinases; Trachea; Tyrphostins

1. To determine which mediators are involved in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitised Brown Norway rats we investigated the effect of a histamine H(1) receptor antagonist, mepyramine, a 5-HT receptor antagonist, methysergide, and a cys-leukotriene-1 receptor antagonist, montelukast. 2. Ovalbumin at 1 mg kg(-1) i.v. caused a significant increase in microvascular leakage in the airways and at 3 mg kg(-1) i.v. caused a significant increase in airways resistance. 3. Histamine (1 mg kg(-1) i.v.), 5-HT (0.1 mg kg(-1) i.v.) and leukotriene D(4) (LTD(4), 50 microg kg(-1) i.v.) caused a significant increase in microvascular leakage in the airways. 4. Mepyramine (1 mg kg(-1) i.v.), methysergide (0.1 mg kg(-1) i.v.), or montelukast (30 mg kg(-1) i.v.) inhibited histamine, 5-HT or LTD(4) -induced microvascular leakage respectively. 5. Methysergide (0.1 mg kg(-1) i.v.) reduced ovalbumin-induced microvascular leakage in the trachea and at 0.3 mg kg(-1) i.v. inhibited bronchospasm (38 and 58%, respectively). Montelukast (30 mg kg(-1) p.o.) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (78%) and inhibited ovalbumin-induced bronchospasm (50%). Mepyramine (3 mg kg(-1) i.v.) had no effect on ovalbumin-induced leakage or bronchospasm. 6. A combination of all three compounds (mepyramine, methysergide and montelukast) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (70 - 78%) and almost completely inhibited bronchospasm (92%). 7. Antigen-induced bronchospasm appears to equally involve the activation of 5-HT and cys-leukotriene-1 receptors whereas ovalbumin-induced microvascular leakage appears to be predominantly mediated by cys-leukotriene-1 receptors.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Bronchi; Bronchial Spasm; Capillary Permeability; Cyclopropanes; Histamine; Histamine H1 Antagonists; Leukotriene D4; Male; Methysergide; Ovalbumin; Pyrilamine; Quinolines; Rats; Rats, Inbred BN; Respiratory Hypersensitivity; Serotonin; Serotonin Antagonists; Sulfides; Trachea

The role of allergens in asthmatic inflammation is not clearly understood. To elucidate the mechanism of cockroach allergen (CRa)-induced airway disease, we studied three groups of Hartley guinea-pigs sensitized to control, ovalbumin (OA) or CRa. Parameters measured were anaphylactic antibodies by allergy skin test (AST), PCA assay and Western blot, changes in specific airway resistance (SRaw), analysis of bronchoalveolar lavage (BAL) and contracture responses of tracheal muscle (TSM) to non-specific and specific stimuli, in vitro. Both OA and CRa animals showed a similar allergic sensitization (AST and PCA), while Western blot identified several reaginic bands in CRa group compared to a single band in OA group. SRaw illustrated that CRa induce dual-asthmatic responses (4/6) in the CRa group, whereas OA induce only an early asthmatic response (3/6) in the OA group (P<0.01). The average total leukocytes in BALF of the CRa were 27.0x10(6), mostly neutrophils and eosinophils, while those of the OA showed 3.5x10(6), mostly eosinophils, respectively (P<0.0001). TSM responses to non-specific stimuli were similar in both groups (P>0.1), while the antigen-specific TSM contractions were more brisk in the OA group than those of CRa group (P<0.001). Thus, the study indicates that both CRa and OA sensitize guinea-pigs, yet CRa induces more severe and persistent late-phase inflammation than OA. This appears to be related to an influx of neutrophils rather than anaphylactic bronchospasm.

Topics: Airway Obstruction; Allergens; Anaphylaxis; Animals; Asthma; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Cockroaches; Guinea Pigs; Immunization; In Vitro Techniques; Male; Muscle Contraction; Neutrophils; Ovalbumin; Passive Cutaneous Anaphylaxis; Respiratory Muscles; Trachea

Adenosine causes bronchoconstriction in asthmatic patients, and it is also accepted that adenosine influences histamine release from activated human mast cells and basophils in vitro.. In this study we tested the hypothesis that adenosine potentiates both the airway narrowing and the release of bronchoconstrictor mediators induced by ovalbumin challenge in sensitized guinea pigs.. After ovalbumin sensitization, 4 groups were studied: control group, adenosine group (ADO), ovalbumin group (OA), and adenosine plus ovalbumin group (ADO + OA). Changes in airway resistance were assessed from continuously recorded pulmonary insuffilation pressure (PIP). The concentration of histamine, PGD2, and thromboxane B2 were determined from bronchoalveolar lavage fluids.. Adenosine alone (6 mg/kg intravenously) did not influence baseline values of PIP and the mediator concentrations; however, ovalbumin (10 mg/kg intravenously) increased both the PIP and the levels of the measured mediators compared with the control and ADO groups. When ovalbumin challenge was preceded by adenosine administration, both PIP and mediator levels were significantly enhanced compared with values obtained after simple ovalbumin provocation (ADO + OA vs OA: P <.05).. These results suggest that adenosine potentiates the airway narrowing induced by ovalbumin challenge and that this effect may develop through facilitation of the release of bronchoconstrictor mediators during the immediate airway response.

Topics: Adenosine; Animals; Bronchial Provocation Tests; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Guinea Pigs; Histamine; Humans; Ovalbumin; Prostaglandin D2; Thromboxane B2

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Anti-Asthmatic Agents; Bronchial Spasm; Bronchoconstriction; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Enzyme Inhibitors; Guinea Pigs; Histamine; In Vitro Techniques; Leukotriene D4; Muscle Contraction; Nitriles; Ovalbumin; Trachea

The pathomechanism of the bronchospastic reaction is not fully explained. Ovalbumin induced bronchospastic reaction in guinea pigs is widely accepted as a classical experimental model and was appleid in this study. The bronchoconstriction, bronchial hypersensitivity and humoral immune response were measured after bronchial infection and chemical injury by formalin vapours. The intensity of the bronchospasm was measured by Lundberg index, the haemolytic activity of complement and the level of circulating immune complexes were measured at the beginning and at the end of the experiment. The increase of the bronchospastic reaction and bronchial hypersensitivity was observed bacterial infection and after formalin vapours too. Bronchial infection and chemical irritation of bronchial tree lead to the increase of the circulating immune complexes level and to the decrease of the haemolytic activity of the complement.

Topics: Animals; Antibody Formation; Antigen-Antibody Complex; Bronchial Spasm; Complement System Proteins; Female; Formaldehyde; Guinea Pigs; Ovalbumin; Pseudomonas Infections; Respiratory Hypersensitivity

The purpose of the research was to observe the influence of the bacterial infection and inhalation vapours on the histologic picture of bronchi and lungs in the course on the experimental asthma induced in guinea pigs. The animals were divided into 6 groups. The animals were immunized by ovalbumin. Group I was control and was subjected to inhalations of physiologic salt solutions. Group II was immunized by the soluble of ovalbumin intraperitoneally and was inhaled with the solution of ovalbumin. Group III was subjected only to inhalation of the ovalbumin. Group IV was inhaled with the solution of formalin alternately. Group V experienced only formalin inhalations. Group VI was infected with Pseudomonas aeruginosa strain and inhaled with the solution of ovalbumin. On the histologic examination of the lung tissue the authors found the atrophy of the lymphatic system, the hypertrophy of the mucous membrane and muscular coat of the bronchi, the accumulation of large amount of mucus in their lumen and the exfoliation of the bronchial epithelium.

Topics: Animals; Asthma; Atrophy; Bronchi; Bronchial Spasm; Epithelium; Formaldehyde; Guinea Pigs; Hypertrophy; Lung; Male; Mucous Membrane; Ovalbumin; Pseudomonas Infections

1. The aim of this study was to determine whether an inhalation of ovalbumin (OA, 10 or 20 mg ml-1) by conscious OA-sensitized guinea-pigs leads to airway hyperreactivity to spasmogens 24 h later. In contrast to most previous studies, the spasmogens (5-HT, methacholine (MCh), U-46619 and adenosine) were administered by inhalation and airway function was measured in conscious guinea-pigs. 2. Guinea-pigs were sensitized by i.p. injection of 10 micrograms OA and 100 mg aluminium hydroxide in 1 ml normal saline; 14-21 days later they were exposed to an inhalation of 5-HT, MCh, U-46619 or adenosine. Specific airway conductance (sGaw) was measured in conscious animals by whole body plethysmography. The spasmogens caused bronchoconstriction, measured as a reduction in sGaw from the pre-inhalation basal values. Dose-related bronchoconstrictions were observed with 5-HT, MCh and U-46619. 3. The effect of an ovalbumin macroshock challenge upon the responses to each spasmogen were examined by giving an inhalation of aerosolized OA at 24 h (or 7 days in the cause of adenosine) after an initial spasmogen challenge. Eighteen to twenty-four hours after the OA macroshock, the same guinea-pigs were exposed to a repeated inhalation of 5-HT, MCh, U-46619 or adenosine. 4. U-46619 was the only spasmogen to demonstrate hyperresponsiveness, the peak change in sGaw being increased from -12.3 +/- 9.9 to -38.8 +/- 5.0% by 10 mg ml-1 OA challenge. In contrast, the ovalbumin challenge (20 mg ml-1) inhibited the bronchoconstrictions to 5-HT (50 micrograms ml-1) and MCh (100 micrograms ml-1). Adenosine demonstrated bronchoconstriction in sensitized guinea-pigs but no significant change in the response was observed after an OA challenge. 5. All results were compared with a control group of sensitized guinea-pigs receiving a NaCl challenge. The bronchoconstrictor responses to 5-HT, MCh, U-46619 or adenosine did not differ significantly before and after the saline challenge, indicating reproducibility of the responses. 6. In further experiments, guinea-pigs were exposed to inhalation of 5-HT (50 micrograms ml-1) or MCh (300 micrograms ml-1) 24 h before atropine (10 micrograms, 100 micrograms or 1 mg ml-1) and again at 0.5 to 1.5 h afterwards. Atropine, antagonized the 5-HT- and MCh-induced bronchoconstrictions over the same antagonist dose-range. This suggests that the bronchoconstriction induced in the conscious guinea-pig by 5-HT is mediated primarily via muscarinic receptors, possibly

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Administration, Inhalation; Airway Resistance; Animals; Asthma; Atropine; Bronchial Spasm; Bronchoconstrictor Agents; Bronchodilator Agents; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Male; Methacholine Chloride; Ovalbumin; Plethysmography, Whole Body; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

The effect of theophylline (a non-selective phosphodiesterase (PDE) inhibitor), dosed intratracheally (it) as a dry powder, on histamine- and platelet activating factor (Paf)-induced bronchospasm and antigen (ovalbumin, OA)-, histamine- and Paf-induced microvascular leakage (MVL) in the airways, was studied in the anaesthetized guinea-pig. Bronchospasm was measured as the increase in pulmonary inflation pressure (PIP). MVL was assessed by fluorometric assay of fluorescein isothiocyanate dextran (FITC-dextran) content in airway tissues and tracheobronchial lavage fluid. OA (200 micrograms), histamine (60 nmol) and Paf (4 nmol), all given it, significantly increased MVL by up to 350% over levels in undosed unchallenged animals. Theophylline (50-500 micrograms it, n = 5-6) inhibited histamine-induced bronchospasm (30% inhibitory dose, ID30: 258 +/- 30 micrograms), and Paf-induced bronchospasm (ID30: 190 +/- 80 micrograms). An inhibition of 40-50% of maximal bronchospasm was the largest attained. Theophylline, at approximately the bronchospasm ID30 dose (200 micrograms it, n = 4-8), inhibited MVL induced by all agents by 30-80% in airway tissues and in lavage fluid samples. Theophylline (50-500 micrograms it, n = 3) produced plasma drug levels of 0.13 +/- 0.07 to 0.83 +/- 0.39 microgram/ml 10 min after dosing. Plasma levels were the same 60 min after dosing, suggesting retention of theophylline in the airways. The local concentration of theophylline retained in the airways should be sufficient to inhibit PDE activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Anesthesia; Animals; Bronchi; Bronchial Spasm; Capillary Permeability; Dextrans; Dose-Response Relationship, Drug; Fluorescein-5-isothiocyanate; Guinea Pigs; Histamine; Intubation, Intratracheal; Male; Ovalbumin; Powders; Theophylline; Trachea

Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 microgram/kg per min) for < 1 h. More prolonged infusion of rac-salbutamol induced a progressive susceptibility to inhaled antigen so that, by 48 h, animals collapsed and died following inhalation of antigen. In anaesthetized animals, acute infusion of rac-salbutamol (1.67 micrograms/kg per min) suppressed airway obstruction, an effect that can be attributed to beta 2-adrenoceptor activation by the eutomer (R-salbutamol). Acute intravenous infusion of the distomer (S-salbutamol) (1.67 micrograms/kg per min) induced hyperresponsiveness to histamine without having any effect upon airway calibre. It is suggested therefore that subcutaneous infusion of rac-salbutamol initially abrogates the bronchoconstrictor response to antigen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protection to susceptibility was not determined by reduced beta 2-adrenoceptor activation since animals could be protected from a lethal response to antigen by inhalation of rac-isoprenaline or by subcutaneous injection of rac-salbutamol. The seeming progressive loss of efficacy of R-salbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. The capacity of S-salbutamol to evoke hyperresponsiveness is shared by S-isoprenaline and S-terbutaline and, as has been shown previously for rac-isoprenaline, the capacity of S-salbutamol to elicit hyperresponsiveness was not evidenced following section of the vagus nerves. No mechanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.

Topics: Administration, Topical; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Airway Resistance; Albuterol; Anesthesia; Animals; Bronchial Hyperreactivity; Bronchial Spasm; Bronchodilator Agents; Guinea Pigs; Isoproterenol; Male; Ovalbumin; Respiratory Function Tests; Stereoisomerism; Terbutaline

In passively sensitized guinea pigs, show infusion of an amount of ovalbumin insufficient to evoke airway obstruction induces hyperreactivity of the airways. A wide range of changed responsivity was observed for different test spasmogens, with leukotriene C4 > histamine > prostaglandin F2 alpha > bradykinin > leukotriene E4 > serotonin > acetylcholine. Injection of ovalbumin as a bolus produced pronounced airway obstruction without hyperreactivity. Airway obstruction due to vascular engorgement (dextran infusion) or edema (histamine infusion) did not result in hyperreactivity. Infusion of PAF induced pronounced airway obstruction together with hyperreactivity, but with a rank order of histamine > leukotriene C4 > serotonin > bradykinin > leukotriene E4 > acetylcholine. It can be concluded that allergic airway hyperreactivity in the guinea pig is spasmogen-selective and largely independent of airway obstruction. These observations question the presumption of non-selective hyperreactivity in allergic asthma and cast doubt upon the proposal that airway hyperreactivity is secondary to airway obstruction.

Topics: Airway Obstruction; Animals; Bronchial Hyperreactivity; Bronchial Spasm; Guinea Pigs; Histamine; Immunoglobulin E; Male; Ovalbumin

Recent evidence supports a role for T lymphocytes in allergic airway responses. We hypothesized that reducing blood T suppressor cells (Ts) might increase the late airway response (LR). Sprague-Dawley (SD) rats were sensitized with ovalbumin (OA). On days 8, 10, and 12, post-sensitization test SD (n = 14) received monoclonal antibody intravenously (OX-8; 1 mg) specific to rat Ts. Controls received saline (n = 7) or mouse ascites IgG (n = 7). On day 14, animals were challenged with OA aerosol (5% wt/vol) for 5 min, lung resistance was recorded for 8 h (n = 18) and bronchoalveolar lavage was performed. The LR was determined from the area under the lung resistance vs time curve from 75 to 480 min after challenge. In the remaining 10 rats, airway lymphocyte subsets were measured 8 h after OA aerosol challenge in minced and digested lungs. A decrease in percentage of blood and airway Ts, respectively, in test animals was observed vs controls (blood: 6.27 +/- 0.84 vs 32.95 +/- 1.94, P < 0.001); (airway: 5.05 +/- 0.66 vs 24.5 +/- 3.05, P < 0.02). Blood and airway helper T lymphocytes did not differ between test and control animals. The LR was significantly increased in test (22.89 +/- 3.92) vs controls (4.22 +/- 2.18, P < 0.001). Bronchoalveolar lavage macrophages, neutrophils and lymphocytes, and serum OA-specific IgE were also significantly elevated (P < 0.05) in test animals. We conclude that Ts play an important role in attenuating the LR in SD rats.

Topics: Aerosols; Animals; Bronchial Provocation Tests; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Hypersensitivity; Immunoglobulin E; Lymphocyte Depletion; Male; Ovalbumin; Rats; Rats, Sprague-Dawley; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Time Factors

The PAF antagonists RP 59227 and WEB 2086 (100 micrograms.kg-1 i.v., 10 min prior to platelet-activating factor (PAF) infusion) abolished or reduced (P less than 0.05) hyperreactivity to bombesin measured at 1 h. Similarly, RP 59227 and WEB 2086 (10 mg.kg-1 p.o., 1 h prior to PAF aerosol) abolished or reduced (P less than 0.01) hyperreactivity to bombesin measured at 24 h. Lower concentrations of RP 59227 and WEB 2086 (3 mg.kg-1 p.o.) were without effect. RP 59227 or WEB 2086 (3 or 10 mg.kg-1 p.o., 1 h prior to antigen aerosol) did not protect against antigen-induced hyperreactivity to histamine measured at 24 h. Antigen-(but not PAF)-induced hyperreactivity was accompanied by an increase in total cell number and, specifically, eosinophil number in bronchoalveolar lavage fluid. The PAF antagonists did not affect BALF cell populations. It is concluded that RP 59227 and WEB 2086 are potent PAF antagonists which inhibit PAF-but not antigen-induced airway hyperreactivity. These data suggest that endogenous PAF may not be involved in antigen-induced hyperreactivity in the guinea pig.

Topics: Animals; Antigens; Azepines; Bronchial Hyperreactivity; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Guinea Pigs; Male; Ovalbumin; Platelet Activating Factor; Pyridines; Thiazoles; Triazoles

The effect of 5-amino-4-imidazolecarboxamide riboside (AICA riboside), a modulator of purine metabolism, was studied on antigen-induced bronchospasm in ovalbumin (OA)-sensitized guinea pigs. In separate experiments, sodium cromoglycate (SCG) and terbutaline were used to compare their effectiveness with that of AICA riboside (wt/vol). AICA riboside and SCG were administered as an aerosol daily for a minimum of 2 weeks before OA aerosol challenge. Terbutaline, as an aerosol, was administered once 5 minutes before OA challenge. Airway reactivity was determined through the use of a whole-body plethysmography by monitoring specific airway resistance (SRaw). OA aerosol challenge of 0.05%, 0.1%, and 0.25% (wt/vol), administered for a period of 1 minute, increased SRaw. Each of the three agents attenuated the effect of OA on SRaw, although terbutaline demonstrated more consistency and potency as compared to either AICA riboside or SCG. However, at moderate degrees of OA challenge, AICA riboside appeared to be as effective as either agent. Although the mechanism of action of AICA riboside remains uncertain, it may have therapeutic benefit in the treatment of asthma or allergic diseases.

Topics: Aminoimidazole Carboxamide; Analysis of Variance; Animals; Bronchial Hyperreactivity; Bronchial Spasm; Bronchoconstriction; Cromolyn Sodium; Guinea Pigs; Ovalbumin; Plethysmography, Whole Body; Ribonucleosides; Terbutaline

Topics: Acrylates; Allergens; Animals; Azepines; Benzoates; Bronchial Spasm; Disease Models, Animal; Guinea Pigs; Immunization, Passive; Male; Ovalbumin; Phospholipases A; Platelet Activating Factor; Tetrazoles; Thienopyridines; Triazoles

A synthetic program of rational drug design was undertaken to develop a series of quinazoline-3-oxides as pulmonary-selective inhibitors of ovalbumin-induced, leukotriene-mediated bronchoconstriction. The most active and selective compounds contained a methyl group at the 4-position, a medium sized branched alkyl group at the 2-position, and a small electron donating group on the phenyl ring. Significant enhancement in selectivity was observed in comparing the pulmonary versus cardiovascular effects of these new bronchodilators with the effects of theophylline.

Topics: Animals; Bronchial Spasm; Bronchodilator Agents; Dogs; Drug Design; Female; Guinea Pigs; Hemodynamics; Leukotrienes; Magnetic Resonance Spectroscopy; Male; Ovalbumin; Pilocarpine; Quinazolines; Theophylline

Four series of N-[(arylmethoxy)phenyl] compounds were prepared as leukotriene D4 (LTD4) antagonists. In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg. Compound 20 also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg. In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08. In the sulfonyl carboxamide series, N-[(4-methylphenyl)sulfonyl]-3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist. Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively. In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78. In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99% at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79). In the tetrazole series, the most potent inhibitor was 2-[[3-(1H-tetrazol-5-ylmethyl)phenoxy]methyl]quinoline (Wy-49,451, 41). The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin. In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.

Topics: Animals; Azoles; Benzamides; Biological Assay; Bronchial Spasm; Carrageenan; Chemical Phenomena; Chemistry; Cyclooxygenase Inhibitors; Edema; Guinea Pigs; Hydroxamic Acids; Lipoxygenase Inhibitors; Molecular Structure; Muscle Contraction; Neutrophils; Ovalbumin; Quinolines; Rats; SRS-A; Structure-Activity Relationship; Tetrazoles; Trachea

The role of platelet-activating factor (PAF) in Ag-induced airway hyperresponsiveness was evaluated in a guinea pig model using the PAF antagonist SDZ 64-412. Repeated OVA challenge by aerosol (twice weekly x 4 wk) of previously sensitized guinea pigs produced striking airway hyperresponsiveness as determined by pulmonary resistance changes to increasing doses of inhaled acetylcholine given 3 days after the last OVA challenge. Each OVA challenge produced significant hypoxia that was unaffected by oral pretreatment with 20 mg/kg SDZ 64-412, 2 h before each challenge (pO2 = 35 +/- 2 mm Hg for OVA alone vs 40 +/- 6 mm Hg for SDZ and OVA groups, respectively). SDZ 64-412 pretreatment abolished the airway hyperresponsiveness resulting from repeated Ag challenge. Morphometric analysis revealed that SDZ 64-412 treatment had no effect on the increased numbers of eosinophils that infiltrated the airways of OVA-challenged guinea pigs. These results suggest that PAF may be a primary mediator of airway hyperresponsiveness, but not acute bronchoconstriction, induced by repeated Ag challenge. This activity of PAF appears independent of eosinophil recruitment to airways.

Topics: Acetylcholine; Airway Resistance; Animals; Bronchial Provocation Tests; Bronchial Spasm; Connective Tissue Cells; Eosinophils; Epithelial Cells; Guinea Pigs; Hypersensitivity; Isoquinolines; Ovalbumin; Platelet Activating Factor; Platelet Aggregation; Respiratory System

Topics: Animals; Bronchial Spasm; Guinea Pigs; Ovalbumin; Spiro Compounds

In order to investigate whether bronchopulmonary hyperresponsiveness represents a unique property of sensitized lungs, we examined the responses of lungs from either actively sensitized, passively sensitized, or nonsensitized (control) guinea pigs to in vitro bronchoconstriction (BC) and release of thromboxane (TX) B2, 6-keto-PGF1 alpha, and histamine induced by platelet-activating factor (PAF-acether) or leukotriene (LT) D4. Guinea pigs were actively sensitized with 10 micrograms of either ovalbumin or Dermatophagoides farinae extract in AI(OH)3 injected intraperitoneally twice at a 2-wk interval. Seven days after the second injection (booster injection), the lungs were removed, ventilated, and perfused via the pulmonary artery with Krebs solution containing 2.5 g/L bovine serum albumin. In lungs from actively sensitized animals, BC was induced by significantly lower doses of PAF-acether and LTD4 than those required to elicit the same response in control preparations. In addition, sensitized lungs released more TxB2, 6-keto-PGF1 alpha, and histamine in response to PAF-acether and LTD4 than did control lungs. Increased mediator release was also observed upon challenge of lungs from actively sensitized animals with arachidonic acid and histamine. Lungs from guinea pigs passively sensitized with serum from actively sensitized animals did not exhibit increased responsiveness to PAF-acether as compared to control lungs. The hyperresponsiveness induced after booster injection of the antigen occurred concomitantly with an increase in the homocytotropic antibody titer (as measured by passive cutaneous anaphylaxis) and persisted for 3 months after sensitization, when the levels of circulating antibodies and lung response to antigen challenge returned to control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchial Spasm; Capillary Permeability; Female; Guinea Pigs; Histamine; Immunization; Immunization, Secondary; Kinetics; Lung; Male; Ovalbumin; Perfusion; Platelet Activating Factor; Pulmonary Circulation; Respiratory Hypersensitivity; SRS-A; Thromboxane B2

Bronchoconstriction following the aerosolization of PAF-acether or antigen to guinea pigs induces autodesensitization, but the responses to direct spasmogenic substances are not modified. Bronchoconstriction by PAF-acether is not reduced when it is aerosolized to passively sensitized animals previously desensitized by repeated inhalations of the allergen (ovalbumin). In contrast, when passively sensitized animals are initially desensitized to PAF-acether by repeated inhalations of this agonist, ovalbumin aerosolization induces a bronchoconstriction which is significantly reduced when compared with the response obtained in nondesensitized animals though, in this case, the response to aerosolized histamine is not modified. Thus, PAF-acether is released during intrapulmonary anaphylactic shock induced by aerosolized ovalbumin and can be a prime candidate for its development.

Topics: Aerosols; Anaphylaxis; Animals; Antigens; Bronchial Spasm; Chromones; Desensitization, Immunologic; Female; Guinea Pigs; Histamine; Male; Ovalbumin; Platelet Activating Factor; Pyrilamine; Time Factors

Topics: Anaphylaxis; Animals; Bronchial Spasm; Capsaicin; Desensitization, Immunologic; Guinea Pigs; Male; Ovalbumin; Respiration; Substance P; Trachea

1 A threshold dose of Prostaglandin D2 (PGD2) (0.5 microgram/kg i.v.), which did not modify the basal values of airway resistance, potentiated the acetylcholine induced bronchospasm in anaesthetized guinea-pigs. 2 beta-adrenoreceptors blockade induced by propranolol enhanced the positive interaction between PGD2 and acetylcholine in the pulmonary dynamics. 3 Active sensitization of guinea-pigs by ovalbumin increased the pulmonary PGD2-acetylcholine interaction and the phenomenon was sustained during the time. 4 The inability of PGD2 to potentiate histamine-induced bronchoconstriction suggests a specificity for the interaction.

Topics: Acetylcholine; Airway Resistance; Animals; Bronchial Spasm; Drug Synergism; Guinea Pigs; Histamine; Male; Ovalbumin; Propranolol; Prostaglandin D2; Prostaglandins D; Respiratory Hypersensitivity

Newborn mongrel dogs were sensitized with conjugates of ovalbumin (OA) and 2,4-dinitrophenol (OA-DNP3) in the presence of Al(OH)3 to produce high levels of anti-OA and anti-DNP IgE antibody. At 4-6 months of age, when anti-DNP and anti-OA antibody levels reached titers of 64 by passive cutaneous anaphylaxis, the dogs underwent separate inhalation and intravenous challenges with conjugates of DNP and bovine gamma globulin (DNP15-BGG) and OA. Inhalation challenge with DNP15-BGG and OA resulted in 5- and 10-fold increases in airflow resistance, respectively. Intravenous challenge with either DNP15-BGG or OA produced profound anaphylaxis with 60-80% decreases in blood pressure, cardiac output and regional blood flows in the carotid, superior mesenteric and renal arteries, and the distal aorta. Treatment of sensitized dogs with 5 doses of 20 mg of conjugates of DNP and polyvinyl alcohol (DNP2-PVA) on alternate days resulted in suppression of anti-DNP IgE antibody production; abrogation of established airway and vascular anaphylactic sensitivities; no change in regional blood flows, and no effect on sensitivities to challenge with OA.

Topics: 2,4-Dinitrophenol; Anaphylaxis; Animals; Bronchial Provocation Tests; Bronchial Spasm; Dinitrophenols; Disease Models, Animal; Dogs; Haptens; Immunoglobulin E; Immunosuppression Therapy; Ovalbumin; Regional Blood Flow

Daily sensitization with ovalbumin (OA) and dog serum albumin (DSA) without adjuvant was performed in rats for 2-week periods. When the antigen was administered subcutaneously (s.c.), antibody responses were induced, as assessed in serum and bronchial lavage, and strong increases in transpulmonary pressure (TPP) after intravenous (i.v.) challenge with antigen. Sensitization without adjuvant with antigen as aerosol for similar periods also evoked pronounced antibody formation, although only weak increases of TPP were seen after challenge. Animals sensitized s.c. with OA and simultaneously exposed to OA as aerosol exhibited suppression of the TPP increase after challenge, whereas the antibody responses were not affected to any great extent. In contrast, the increase of TPP after challenge in animals similarly sensitized s.c. with DSA were not suppressed by OA given simultaneously as aerosol or vice versa.

Topics: Adjuvants, Immunologic; Administration, Inhalation; Animals; Antigens; Bronchi; Bronchial Spasm; Desensitization, Immunologic; Dogs; Dose-Response Relationship, Immunologic; Epitopes; Female; Immunization; Injections, Intravenous; Injections, Subcutaneous; Male; Ovalbumin; Rats; Rats, Inbred Strains; Serum Albumin; Time Factors

The effects of clonidine on the bronchospastic responses induced by vagal stimulation or antigen challenge were studied in anaesthetized guinea-pigs. Electrical stimulation of the vagus nerves by 2-4 Hz induced a vigorous, mainly atropine-sensitive bronchoconstriction, which was strongly inhibited by clonidine (0.05 mg/kg i.v.). The inhibitory effect of clonidine was significantly reduced by the alpha 2-adrenoceptor antagonist yohimbine (1 mg/kg i.v.). Another series of experiments was done with ovalbumin-sensitized guinea-pigs. Respiratory anaphylaxis was induced by antigen inhalation resulting in an increase of pulmonary resistance from 100% (baseline) to about 190% in the control group. Animals pretreated with a clonidine aerosol (0.03%) showed a marked inhibition of the bronchospastic response. It is suggested that the inhibition of the bronchospastic responses induced by clonidine may be mediated by a stimulation of alpha 2-adrenoceptors, which exerts an inhibitory control of the excitatory vagal activity in the guinea-pig airways.

Topics: Anaphylaxis; Animals; Antigens; Bronchial Spasm; Clonidine; Electric Stimulation; Guinea Pigs; Immunization; Male; Ovalbumin; Receptors, Adrenergic, alpha; Vagus Nerve

A test hierarchy for potential antibronchoconstrictive drugs acting as lipoxygenase inhibitors was developed which includes a purified mammalian lipoxygenase/leukotriene A4 synthase, purified cyclooxygenase, arachidonic acid metabolism of polymorphonuclear leukocytes, arachidonic acid-induced contraction of lung strips, isolated human bronchi, and ovalbumin-induced bronchoconstriction with sensitized guinea pigs. The lipoxygenase from rabbit reticulocytes turned out to be superior to a variety of other animal and plant lipoxygenases. Among the various test systems with respiratory tract preparations, the arachidonic acid-induced contraction of guinea pig lung strips gave the most reliable results in the search for new antiasthmatic drugs. The validity of the test hierarchy was ascertained in screening investigations. Novel classes of antibronchoconstrictory lipoxygenase inhibitors were found.

Topics: Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Bronchial Provocation Tests; Bronchial Spasm; Clinical Enzyme Tests; Cyclooxygenase Inhibitors; Drug Evaluation, Preclinical; Guinea Pigs; Humans; In Vitro Techniques; Lipoxygenase; Lipoxygenase Inhibitors; Muscle Contraction; Neutrophils; Ovalbumin; Rabbits

The present studies were undertaken to obtain histamine (HIST) dose-response curves for tracheal smooth muscle (TSM) from an actively ragweed-sensitized canine model of asthma and to compare these results with 1) HIST dose-response data from littermate control dogs, 2) initially nonsensitized TSM passively sensitized (in vitro) to ragweed and 3) the dose-response curve to an agonist that opens primarily voltage-sensitive calcium channels, i.e., K+. Actively ragweed-sensitized TSM was significantly hyperreactive (upward shift of the dose-response curve) to HIST (1.882 kg of force produced normalized to cross-sectional area-kg/cm2 +/- 0.087 S.E. vs. littermate controls 1.151 +/- 0.253) and hypersensitive as indicated by the leftward shift in the median effective dose or ED50 (1.86 X 10(-6) +/- 0.24 vs. 5.54 X 10(-6) +/- 1.35 M). Passively sensitized TSM (using serum from ragweed-sensitized dogs) also showed a hyperreactivity to HIST when compared to control TSM incubated with control serum (1.204 +/- 0.127 vs. 0.825 +/- 0.081 kg/cm2). No significant difference was found in the ED50 values, indicating similar sensitivities. Atropine (10(-7) M) reduced the hypersensitivity of actively sensitized TSM significantly toward control values; however, the hyperreactivity persisted. Atropine did not affect responses to HIST in control TSM. Ragweed actively sensitized TSMs were also hyperreactive and hypersensitive to K+ when compared to littermate control TSM. Atropine abolished both the hyperreactivity and hypersensitivity to K+ but had no effect on the dose-response curve of control TSM to K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Asthma; Atropine; Bronchial Spasm; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Histamine; In Vitro Techniques; Muscle, Smooth; Ovalbumin; Pollen; Potassium; Receptors, Histamine; Trachea

The stimulation of intrabronchial mast cells and macrophages by inhaled allergens play a major role in allergic bronchial asthma. Bronchial surfactant is proposed to change cell surface receptor response in the bronchial tree. In this investigation natural surfactant was found to reduce bronchial obstruction after intratracheal ovalbumin challenge in artificially ventilated guinea pigs sensitized to ovalbumin. After ovalbumin challenge tidal volume decreased to 59.2 +/- 14 % of the control value in surfactant treated animals. In solvent treated and untreated control animals, tidal volume decreased to 18.8 +/- 11% and 18.1 +/- 11% of the control value, respectively.

Topics: Aerosols; Animals; Bronchial Spasm; Guinea Pigs; Immunization; Ovalbumin; Pulmonary Surfactants; Time Factors

The extracellular calcium antagonists, nifedipine and verapamil, the mixed extra/intracellular calcium antagonist diazoxide and the intracellular calcium antagonist TMB-8 were studied for their effects on histamine-induced bronchospasm in guinea pigs and on antigen-induced bronchospasms in guinea pigs and rats when administered directly to the tracheobronchial tree. Nifedipine and verapamil inhibited histamine and antigen-induced bronchoconstriction in guinea pigs, and verapamil was effective in preventing antigen-induced bronchospasms in rats. However, using doses of the extracellular blockers which produce these pulmonary effects, significant reduction of blood pressure occurred in both guinea pigs and rats. Diazoxide was inactive against histamine and antigen-induced bronchoconstrictions in guinea pigs. TMB-8 was inactive against histamine and antigen-induced bronchospasm in guinea pigs and rats. These studies demonstrate the antibronchoconstrictor activity of extracellular Ca2+ antagonists in guinea pigs and rats, but indicate that intracellular Ca2+ antagonists are not antibronchospastic agents in these species in vivo.

Topics: Albuterol; Animals; Bronchial Spasm; Calcium Channel Blockers; Diazoxide; Gallic Acid; Guinea Pigs; Hemodynamics; Histamine; Immunization; Male; Nifedipine; Ovalbumin; Rats; Species Specificity; Verapamil

The intrathoracic accumulation of radiolabelled platelets and concomitant changes in airway resistance have been recorded continuously in anaesthetised guinea pigs. Platelet-activating factor (PAF-acether) and antigen (in sensitised animals) elicited dose-related intrathoracic accumulation of platelets that could be associated with an increase in airway resistance. Maximal increases in airway resistance preceded maximal increases in platelet accumulation. Low doses of antigen could elicit substantial platelet accumulation, without detectable changes in lung function. It is concluded that physical obstruction of the pulmonary vasculature is not the sole determinant of platelet-dependent bronchoconstriction.

Topics: Airway Resistance; Animals; Bronchial Spasm; Guinea Pigs; Male; Ovalbumin; Platelet Activating Factor; Platelet Aggregation; Time Factors

Antihistamine-resistant anaphylactic bronchospasm in guinea pigs is increased with increasing doses of antigen (ovalbumin, OA) challenge. This was observed in passively and actively sensitized animals, and by both i.v. and aerosol routes of antigen challenge. At a challenge concentration of 100 mg/kg OA, antihistamines were virtually inactive. Indeed, the resulting bronchospasm was inhibited by isoproterenol, theophylline and ketotifen but not any anticholinergics, anti-5HT, SRS-A antagonists, arachidonic acid lipoxygenase inhibitors or antiallergic drugs. However, in the presence of chlorpheniramine, the response was antagonized by SRS-A antagonists (FPL 55712 and isamoxole), but not the lipoxygenase inhibitors (BW 755C, ETYA, NDGA and phenidone). This suggests that the antihistamine-resistant bronchospasm produced in guinea pigs challenged with high antigen concentrations might be the result of SRS-A release. This is by no means certain since the currently available SRS-A antagonists possess other mechanisms of action; furthermore, the failure of lipoxygenase inhibitors to influence this response is not consistent with a role for SRS-A. Elucidation of the mechanism of the antihistamine-resistant bronchospasm awaits development of more specific SRS-A antagonists.

Topics: Aerosols; Anaphylaxis; Animals; Bronchial Spasm; Chlorpheniramine; Chromones; Guinea Pigs; Immunization, Passive; Lipoxygenase Inhibitors; Male; Ovalbumin; SRS-A

1 Pharmacological modulation of antigen-induced anaphylaxis in actively sensitized guinea-pigs with intravenously administered indomethacin (10 mg/kg), pyrilamine (2.0 mg/kg) and propranolol (0.1 mg/kg) resulted in a delayed onset, slowly developing bronchoconstriction indicative of a slow-reacting substance of anaphylaxis (SRS-A) response. 2 Measurements of pulmonary mechanics on the drug-pretreated animals challenged with ovalbumin demonstrated a more prominent effect on dynamic compliance than resistance. This is consistent with the more potent effects of SRS-A on peripheral rather than central airways. 3 The slowly developing bronchoconstriction obtained after treatment with indomethacin, pyrilamine and propranolol was inhibited by the standard SRS-A antagonist, FPL 55712 and the SRS-A synthesis inhibitors, phenidone, BW 755C and nordihydroguaiaretic acid. 4 Plasma SRS-A levels were determined in guinea-pigs following antigen challenge. The appearance of SRS-A in the plasma preceded the onset of bronchoconstriction and SRS-A levels remained elevated throughout its development. Coincident with the inhibition of bronchoconstriction by the SRS-A synthesis inhibitor, phenidone, was a dose-dependent reduction in plasma SRS-A. The intravenous ED50 in each case was 4 mg/kg. 5 This model of antigen-induced SRS-A-mediated bronchoconstriction should prove useful for the in vivo evaluation and development of therapeutics which regulate the synthesis of SRS-A.

Topics: Animals; Antigens; Bronchial Spasm; Guinea Pigs; Male; Ovalbumin; Pyrilamine; Respiration; SRS-A; Time Factors

Sprague Dawley rats were immunized with graded doses of ovalbumin (OA) together with alum. The capacity of the animals to produce a bronchial anaphylactic response to intravenous antigen challenge was related to serum OA-IgE and OA-IgG2a antibody levels estimated by radioimmunoassay. A significant correlation between bronchial anaphylactic response capacity and OA-IgE antibody levels was found under a few, but not all, of several carefully chosen experimental conditions. No correlation was demonstrable between the in vivo reactivity of the animals and their serum levels of OA-specific IgG2a antibodies.

Topics: Anaphylaxis; Animals; Antigens; Bronchial Spasm; Dose-Response Relationship, Immunologic; Immunoglobulin E; Immunoglobulin G; Male; Ovalbumin; Rats; Rats, Inbred Strains; Time Factors

Bronchial anaphylactic reactions, estimated as increase in intratracheal pressure, were precipitated by intravenous injections of antigen into actively sensitized SD rats. The degree of bronchial reactivity was found to depend on both the challenge dose and the immunization dose of antigen; therefore the course of the capacity to respond was recorded as a function of these variables. The degree of the bronchial anaphylactic response could be reduced by pretreatment with disodium cromoglycate, terbutaline or a new anti-allergic xanthine derivative, D 4026, in some groups of animals. The efficacy of each agent was found to depend on the dose of antigen used for sensitization and for provocation of the bronchial reaction rather than on the strength of the response. Taken together, the data suggest that more than one type of homocytotropic antibody mediates bronchial anaphylactic reactivity in the SD rat.

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Anaphylaxis; Animals; Antigens; Bronchial Spasm; Cromolyn Sodium; Dose-Response Relationship, Immunologic; Immunization, Passive; Immunization, Secondary; Male; Methacholine Compounds; Ovalbumin; Pertussis Vaccine; Rats; Serotonin; Silicon Dioxide; Terbutaline; Theophylline; Time Factors

Topics: Anaphylaxis; Animals; Autacoids; Bronchial Spasm; Drug Interactions; Guinea Pigs; Lipoxygenase Inhibitors; Male; Ovalbumin; Pyrilamine; SRS-A

The influence of Haemophilus influenzae on anaphylactic mediator release from ovalbumin-sensitized isolated guinea pig lungs was investigated. Lungs from H. influenzae-vaccinated animals released prostaglandins and thromboxanes following a smaller dose of ovalbumin than was effective in non-vaccinated animals. Histamine release was significantly increased in 4 day-vaccinated animals but not 1 or 10 days after vaccination, while broncho-constriction was potentiated in 1 and in 4 day-vaccinated animals. This increased histamine release was achieved following 2 micrograms ovalbumin. In contrast, doses of 10 micrograms and 1 mg ovalbumin respectively did not affect and decreased histamine release in the vaccinated group. The inhibition of anaphylactic mediator release by an infusion of 6 x 10(-9) M isoprenaline was significantly attenuated by H. influenzae vaccination. These results indicate an increased sensitivity to antigenic challenge and suggest that the functioning of beta-adrenoceptors was decreased as a result of H. influenzae vaccination.

Topics: Anaphylaxis; Animals; Arachidonic Acids; Asthma; Autacoids; Bradykinin; Bronchial Spasm; Disease Models, Animal; Guinea Pigs; Haemophilus influenzae; Histamine; Histamine Release; In Vitro Techniques; Isoproterenol; Lung; Male; Ovalbumin; Prostaglandins; Rabbits; Rats; Thromboxanes; Vaccination

1 The inhibitory effects of sodium cromoglycate (SCG) and aminophylline on antigen-induced bronchial anaphylaxis in guinea-pigs, actively sensitized according to different regimens, were examined. 2 SCG (1 mg/kg administered intravenously) reduced the anaphylactic response in animals sensitized with 1 microgram ovalbumin (OA) together with A1(OH)3 100 mg, and challenged at 14 and 40 days after sensitization. If higher doses of antigen (10 micrograms OA together with A1(OH)3 or 5 mg OA on day 0 plus 10 mg OA on day 2) were used for sensitization, the protective effect of SCG was found only in animals tested 14 days after sensitization. 3 A low dose of aminophylline (0.3 mg/kg) that was without a direct bronchodilator effect when tested against a histamine (4 micrograms/kg)-induced bronchospasm, produced an anti-anaphylactic effect. The anti-anaphylactic effect of aminophylline varied slightly with the way the animals were immunized and the time at which they were tested. 4 It is concluded that bronchial anaphylaxis in guinea-pigs sensitized with low doses of ovalbumin is a suitable model for the evaluation of anti-anaphylactic properties of drugs.

Topics: Aminophylline; Anaphylaxis; Animals; Bronchial Spasm; Cromolyn Sodium; Female; Guinea Pigs; Male; Ovalbumin; Respiration; Theophylline; Time Factors

This work studies the temporal development of the acute anaphylactic bronchoconstriction in guinea-pigs sensitized to ovalbumin by different regimens, including IgE-antibody promoting ones. The results show that guinea-pigs sensitized with low amounts (1-10 micrograms) of ovalbumin together with alum produce the most pronounced bronchospasm when challenged with an intravenous injection of a low dose of antigen. Examination of the antibody classes by PCA technique shows that guinea-pigs sensitized with small amounts of antigen together with alum produced IgE and IgG1 antibodies. However, in sera from animals immunized with large amounts of antigen, only IgG1 antibodies could be detected.

Topics: Anaphylaxis; Animals; Antigen-Antibody Reactions; Antigens; Bronchi; Bronchial Provocation Tests; Bronchial Spasm; Female; Guinea Pigs; Immunization; Immunoglobulin E; Immunoglobulin G; Injections, Intravenous; Male; Ovalbumin; Passive Cutaneous Anaphylaxis

The proposal that some naturally occurring prostaglandins (PGs) or their by-products may be implicated in the pathogenesis of the asthmatic bronchospasm has been suggested. Other PGs may be potentially useful in the treatment of this lung disease. The present investigation compared the bronchodilator effects of PGE1 and PGE2 in pharmacologically constricted experimental animals. In pentobarbital-anesthetized, spontaneously breathing dogs, aerosols of PGE1 and PGE2, 0.0002 to 0.2%, effectively inhibited the increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN) produced by PGF2 alpha (3.0 micrograms/kg i.v.). PGE2 was found to be more effective than PGE1 in preventing RL responses to PGF2 alpha; however, both bronchodilators were equally effective vs. CDYN changes. These agents inhibited central airway constriction more than peripheral. Transient decreases in systemic arterial pressure and increases in heart rate occurred especially at the higher concentrations. In a group of trained conscious dogs, effective concentrations did not evoke adverse subjective discomfort or irritation. Higher concentrations, i.e., 1.0%, did produce coughing, breathholding, restlessness and altered patterns of breathing. In normal or sensitized guinea pigs, PGE aerosols were effective in reducing the bronchopulmonary provocation produced by histamine or specific antigen. These in vivo results suggest that aerosols of the classical PGEs are effective bronchospasmolytics in laboratory animals and that irritation may be related to concentration.

Topics: Aerosols; Anaphylaxis; Animals; Blood Pressure; Bronchial Spasm; Bronchodilator Agents; Dogs; Dose-Response Relationship, Drug; Female; Guinea Pigs; Heart Rate; Histamine Antagonists; Lung; Male; Ovalbumin; Prostaglandins E; Prostaglandins F

Subdivisions of lung volume and pressure-volume (PV) curves of the lung and chest wall were measured in guinea pigs immunized to ovalbumin before and after acute (group 1) and chronic (group 2) antigen exposure. The histopathology produced in chronically exposed animals was also assessed. Animals were anesthetized with pentobarbital sodium and studied in a pressure-sensitive body plethysmograph, using a fluid-filled esophageal catheter to measure transpulmonary pressure (PL). Functional residual capacity (FRC) was determined by the Boyle's law technique; total lung capacity (TLC) was defined as the lung volume at a PL of 30 cmH20, and residual volume (RV) was defined as the lung volume at a transrespiratory pressure of -50 cmH2O. Acute antigen challenge of group 1 animals resulted in a decrease in TLC (22%), and increases in FRC (20%) and RV (110%), suggesting combined bronchoconstriction and alveolar duct constriction. Chronic antigen exposure of group 2 animals resulted in minimal changes in subdivisions of lung volume and PV curves, and produced a histological lesion resembling allergic alveolitis rather than asthma.

Topics: Aerosols; Animals; Antigens; Asthma; Bronchial Spasm; Guinea Pigs; Lung; Lung Volume Measurements; Ovalbumin; Respiratory Hypersensitivity; Time Factors

Immunization of neonatal dogs with a conjugate of 2,4-dinitrobenzene and ovalbumin (DNP2-OA), using aluminum hydroxide as the adjuvant, elicited long-lasting (over 30 wk) anti-DNP and anti-OA IgE antibody responses of high titers as determined by homologous passive cutaneous anaphylaxis. Low antigen doses of 10 or 50 mug were more effective than the higher doses of 250 or 1,250 mug in inducing high IgE antibody levels. However, this method of immunization failed to elicity any detectable IgE antibody response in adult dogs. Bronchoprovocation with antigen of sensitized animals having IgE antibody titers in excess of 64 resulted in a marked increase in airflow resistance, which could be corrected by the administration of nebulized isoproterenol. On the other hand, sensitized animals with IgE antibody titers in the order of 64 did not manifest significant bronchoconstriction on inhalation challenge but developed anaphylaxis following intravenous injection of the antigen.

Topics: Aging; Animals; Animals, Newborn; Antibodies; Bronchial Spasm; Dinitrobenzenes; Disease Models, Animal; Dogs; Dose-Response Relationship, Immunologic; Hypersensitivity, Delayed; Immunoglobulin E; Ovalbumin; Passive Cutaneous Anaphylaxis; Reagins; Respiratory Function Tests

The protective effects of pretreatment with zinc sulphate aerosols against bronchoconstriction induced by egg albumen or histamine aerosols were assessed in sensitized or non-sensitized guinea-pigs respectively. Pretreatment with an adequate concentration of zinc sulphate aerosol significantly prolonged the time of onset of bronchoconstriction in sensitized guinea-pigs challenged with egg albumen, but did not appreciably alter the onset time of histamine-induced bronchoconstriction in non-sensitized animals. These findings suggest that zinc aerosols may be of prophylactic value against bronchoconstriction of allergic origin.

Topics: Aerosols; Anaphylaxis; Animals; Bronchial Spasm; Female; Guinea Pigs; Histamine; Male; Ovalbumin; Zinc

Topics: Anaphylaxis; Animals; Bronchial Spasm; Constriction; Epinephrine; Female; Guinea Pigs; Histamine Release; Indomethacin; Injections, Intraperitoneal; Isoproterenol; Lung; Male; Ovalbumin; Perfusion; Propranolol; Prostaglandin Antagonists; Prostaglandins; Pulmonary Alveoli; SRS-A; Tritium

Topics: Aerosols; Anaphylaxis; Animals; Bile; Bronchial Spasm; Guinea Pigs; Histamine; Histamine H1 Antagonists; Methods; Ovalbumin; Time Factors

Topics: Aluminum Hydroxide; Analysis of Variance; Anaphylaxis; Animals; Antibody Specificity; Asthma; Bordetella pertussis; Bronchial Spasm; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Immunization; Immunoglobulin E; Immunoglobulin G; Lung; Ovalbumin; Passive Cutaneous Anaphylaxis; Pressure; Rats; Rodent Diseases; Time Factors

Topics: Aluminum Hydroxide; Anaphylaxis; Animals; Atropine; Bordetella pertussis; Bronchial Spasm; Cromolyn Sodium; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Indomethacin; Isoproterenol; Mecamylamine; Methysergide; Ovalbumin; Pressure; Propranolol; Rats; Time Factors; Trachea; Vagotomy; Vagus Nerve

Topics: Animals; Antigens; Bronchi; Bronchial Spasm; Eosinophils; Female; Guinea Pigs; Leukocytes; Lung; Lymphocytes; Macrophages; Ovalbumin; Respiratory Hypersensitivity

Topics: Anaphylaxis; Animals; Antigens; Bronchial Spasm; Chickens; Histamine H1 Antagonists; Histamine Release; In Vitro Techniques; Lung; Muscle Contraction; Muscle, Smooth; Ovalbumin; Perfusion

Topics: Anaphylaxis; Animals; Aorta; Aspirin; Bronchial Spasm; Guinea Pigs; Histamine Release; Immunity, Cellular; Lung; Ovalbumin; Prostaglandins; Pulmonary Embolism; Rabbits; SRS-A

Topics: Aerosols; Anaphylaxis; Animals; Blood Pressure; Bronchi; Bronchial Spasm; Bronchodilator Agents; Cats; Constriction; Guinea Pigs; Heart Rate; Histamine H1 Antagonists; In Vitro Techniques; Isoproterenol; Metaproterenol; Muscle, Smooth; Nictitating Membrane; Ovalbumin; Serotonin Antagonists; Trachea

Topics: Acetylcholine; Animals; Blood Pressure; Blood Vessels; Bronchi; Bronchial Spasm; Drug Hypersensitivity; Extrachromosomal Inheritance; Female; Guinea Pigs; Histamine; Ileum; Male; Ovalbumin; Pilocarpine; Respiratory Hypersensitivity; Salivary Glands; Salivation; Serotonin; Skin

Topics: Anaphylaxis; Animals; Bronchial Spasm; Coronary Vessels; Dexamethasone; Esophageal Achalasia; Female; Guinea Pigs; Heart; Heart Rate; Histamine; In Vitro Techniques; Male; Muscle Contraction; Ovalbumin; Perfusion; Pulmonary Circulation; Vascular Resistance

Topics: Adrenalectomy; Anaphylaxis; Animals; Bronchial Spasm; Catecholamines; Guinea Pigs; Histamine; Histamine H1 Antagonists; Immunization; Lung; Ovalbumin; Pyridines; Pyrroles; Reserpine; Sympatholytics; Urethane

Topics: Anaphylaxis; Animals; Blood Pressure; Bronchial Spasm; Cardiac Output; Drug Synergism; Epinephrine; Female; Guinea Pigs; Heart Atria; Histamine; Histamine H1 Antagonists; Male; Ovalbumin; Papaverine; Pulmonary Artery; Pulmonary Circulation; Vascular Resistance

Topics: Animals; Antigens; Bronchial Spasm; Guinea Pigs; Lung; Ovalbumin; Respiratory Hypersensitivity

Topics: Anaphylaxis; Animals; Bronchial Spasm; Guinea Pigs; Heart; Histamine; Histamine H1 Antagonists; Hypersensitivity, Immediate; Hypoxia; In Vitro Techniques; Lung; Myocardium; Ovalbumin; Pyridines

Topics: Anaphylaxis; Animals; Bronchial Spasm; Guinea Pigs; Histamine H1 Antagonists; Ischemia; Lung; Myocardium; Ovalbumin

Topics: Acetylcholine; Aerosols; Anaphylaxis; Animals; Bradykinin; Bronchi; Bronchial Spasm; Chlordiazepoxide; Drug Antagonism; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Isoproterenol; Ovalbumin; Pulmonary Circulation; Respiration; Serotonin Antagonists

Topics: Animals; Bronchial Spasm; Bronchodilator Agents; Dexamethasone; Hydrocortisone; Injections, Intravenous; Isoproterenol; Ovalbumin; Oxygen; Rabbits