thromboxane-a2 and Asthma

Airway smooth muscle (ASM) is the effector cell in the bronchoconstrictory pathway. It is believed that the bronchoconstriction present in asthma is associated with changes in the airway milieu that affect ASM excitation-contraction coupling and Ca(2+)-handling. Asthmatics also react differently to ventilatory mechanical strain. Deep inspiration (DI), which produces bronchodilation in healthy individuals, is less effective in asthmatics, and even enhances bronchoconstriction in moderate to severely affected patients. Our laboratory has previously studied the mechanotransductory pathway of airway stretch-activated contractions (Rstretch) leading to DI-induced bronchoconstriction. We demonstrated the ability of agonists acting through thromboxane A2 (TxA2) receptors to amplify airway Rstretch responses. Despite the involvement of excitatory prostanoids in bronchoconstriction, clinical trials on treatments targeting TxA2-synthase inhibition and TP-receptor antagonism have produced mixed results. Studies in Western populations produced mostly negative results, whereas studies performed in Asian populations showed mostly positive outcomes. In this review, we discuss the role of TxA2-synthase inhibition and TP-receptor antagonism in the treatment of asthmatics. We present information regarding variations in study designs and the possible role of TP-receptor gene polymorphisms in previous study outcome discrepancies. Perhaps future studies should focus on asthmatic patients with DI-induced bronchoconstriction in particular, planting the seed for the individualized treatments for asthmatics.

Topics: Animals; Asthma; Bronchoconstriction; Cyclooxygenase Inhibitors; Humans; Methacrylates; Polymorphism, Genetic; Prostaglandin-Endoperoxide Synthases; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

COPD (Chronic Obstructive Pulmonary Disease) and bronchial asthma are two severe lung diseases which represent a major problem of world public health. Leukotrienes and prostanoids play an important role in the pathogenesis of pulmonary diseases. Prostanoids: prostaglandins (PGs) and thromboxane A2 (TXA2), the cyclooxygenase metabolites of arachidonic acid are implicated in the inflammatory cascade that occurs in asthmatic airways. Recently, the roles played by isoprostanes or prostaglandin-like compounds nonenzymatically generated via peroxidation of membrane phospholipids by reactive oxygen species, in particular F2-isoprostanes, in pulmonary pathophysiology have been highlighted. This article aims to provide an overview of the role of prostanoids and isoprostanes in the pathogenesis of COPD and asthma and to discuss the pharmacological strategies developed in prevention and/or treatment of these pathologies.

Topics: Animals; Asthma; Benzoquinones; Carbazoles; Enzyme Inhibitors; F2-Isoprostanes; Heptanoic Acids; Humans; Methacrylates; Prostaglandin Antagonists; Prostaglandin D2; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Topics: Asthma; Biomarkers; Cardiovascular Diseases; Humans; Immunoenzyme Techniques; Ischemia; Kidney Failure, Chronic; Radioimmunoassay; Reference Values; Specimen Handling; Thrombosis; Thromboxane A2; Thromboxane B2

Bronchial asthma is a disease defined by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. In addition to histamine and acetylcholine, recent studies have emphasized the role of arachidonic acid metabolites (leukotrienes, prostaglandins and thromboxane A(2)) in the pathogenesis of asthma. Among these mediators, thromboxane A(2) (TXA(2)) has attracted attention as an important mediator in the pathophysiology of asthma because of its potent bronchoconstrictive activity. Thromboxane A(2) is believed to be involved not only in late asthmatic responses but also in bronchial hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA(2) include TXA(2) receptor antagonism and thromboxane synthase inhibition. Results of double-blind, placebo-controlled clinical trials have proven the efficacies of the thromboxane receptor antagonist seratrodast and the thromboxane synthase inhibitor ozagrel in the treatment of patients with asthma. Seratrodast and ozagrel are available in Japan for the treatment of asthma. Ramatroban, another thromboxane receptor antagonist, is currently under phase III clinical evaluation in Europe and Japan for the treatment of asthma. The pharmacological profiles of the thromboxane modulators may be improved by combination with leukotriene D(4) receptor antagonists. A multi-pathway inhibitory agent such as YM 158, which is a novel orally active dual antagonist for leukotriene D(4) and thromboxane A(2 )receptors, may have potent therapeutic effects in the treatment of bronchial asthma. Large scale clinical trials are necessary to further define the role of thromboxane modulators in the treatment of patients with asthma.

Topics: Anti-Asthmatic Agents; Asthma; Benzoquinones; Carbazoles; Heptanoic Acids; Humans; Methacrylates; Molecular Structure; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

This paper reviews the role of thromboxane A(2) (TXA(2)) in the pathogenesis of pulmonary allergies, particularly asthma. The potential of TXA(2) modifiers in the prevention and/or treatment of pulmonary allergies is also discussed. Bronchial asthma is characterised by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. Several studies have elucidated the role of arachidonic acid metabolites (leukotrienes, prostaglandins and TXA(2)) in the pathogenesis of asthma. Among those mediators, TXA(2) has attracted attention due to its strong physiological activity. Indeed, TXA(2) demonstrates not only potent bronchoconstrictive activity but is also believed to be involved both in late asthmatic responses and in bronchial hyperresponsiveness, a typical feature of this disease. Several thromboxane receptor antagonists (TXRAs) and thromboxane synthase inhibitors (TXSIs) have been studied with the aim of reducing or preventing asthma. As double-blind, placebo-controlled clinical trials have proven the efficiency of some TXA(2) modifiers in treating asthma, the TP receptor antagonist seratrodast (AA-2414) and the thromboxane synthase inhibitor ozagrel hydrochloride (OKY-046) are now available as anti-asthmatic agents in Japan. Moreover, seratrodast and ramatroban (BAY-U-3405), another thromboxane receptor antagonist, are currently under Phase III clinical evaluation in the US for the treatment of asthma.

Topics: Asthma; Humans; Leukotrienes; Prostaglandins; Receptors, Thromboxane; Thromboxane A2

Bronchial asthma is characterized by airway nallowing and hypersensitivity, for the occurrence of which (chemical) mediators are almost entirely responsible. Recent clinical as well as experimental reports have strongly suggested that arachidonate metabolites, especially cysteinyl leukotrienes (CysLTs), are involved in the attack of not only allergic asthma but also exercise- or aspirin-induced asthma. Because the receptor of CysLT1 but not CysLT2 largely contributes to the various pulmonary pharmacological actions of CysLTs, CysLT1 antagonists with high potency have rapidly developed recently. Other chemical mediators, tachykinins, endothelins and so on can be also candidates for the cause of the disease.

Topics: Arachidonic Acid; Asthma; Endothelins; Humans; Inflammation Mediators; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Platelet Activating Factor; Receptors, Leukotriene; Tachykinins; Thromboxane A2

Thromboxane A2 (TxA2) plays an important role in asthma. TxA2 are newly generated after cellular activation and are produced by not only platelets but also eosinophils, basophils, alveolar macrophages, and neutrophils. Pharmacological actions of TxA2 include potent bronchoconstriction, increased microvascular leakage, impairment of mucociliary clearance, and induction of airway hyperresponsiveness. Recent study demonstrated that TxA2 receptor antagonist decreased the number of eosinophils in bronchial biopsy specimens, suggesting that this type of agent possesses anti-inflammatory actions in asthma. Furthermore, addition of TxA2 synthase inhibitor significantly increased the PEF values in the persistent asthmatic patients despite the treatment with moderate-dose of inhaled corticosteroids. Therefore, these results suggest that TxA2 synthase inhibitor and receptor antagonist are useful for the treatment with symptomatic patients who had already been treated with inhaled corticosteroids.

Topics: Asthma; Benzoquinones; Bronchi; Bronchial Hyperreactivity; Eosinophils; Heptanoic Acids; Humans; Methacrylates; Practice Guidelines as Topic; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2alpha was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.

Topics: Animals; Asthma; Bicarbonates; Colonic Neoplasms; Dinoprost; Dinoprostone; Female; Fever; Hypertension; Inflammation; Labor, Obstetric; Mice; Mice, Knockout; Pregnancy; Prostaglandins; Receptors, Prostaglandin; Reproduction; Thrombosis; Thromboxane A2

Asthma is now thought to be a chronic inflammatory disease of the airways. The roles of prostanoids, thromboxane A2 (TXA2) and the prostaglandins (PGs) in the pathogenesis and pathophysiology of asthma have fostered a wealth of studies but remain controversial. TXA2 and the bronchoconstrictor PGs, PGD2 and PGF2 alpha, are generated in greater amounts in asthmatic than in normal subjects. TXA2 is a potent constrictor of airway smooth muscle, an inducer of acetylcholine release and of airway microvascular leakage. It may participate in the thickening and the remodeling of the airway wall which may contribute to the airway hyperresponsiveness, a typical feature of asthma. Strategies for inhibition of TXA2 effects include antagonism of the TXA2 receptor (TP receptor) and inhibition of the thromboxane synthase. TP receptor antagonists could block the effects of all the bronchoconstrictor prostanoids because TXA2 as well as the bronchoconstrictor PGs act through activation of lung TP receptor. The recent development of specific and potent TP receptor antagonists and inhibitors of thromboxane synthase has provided tools to assess the role of TXA2 and broncho-constrictor PGs in the pathophysiology of asthma.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Asthma; Bronchial Hyperreactivity; Clinical Trials as Topic; Humans; Lung; Muscle Contraction; Muscle, Smooth; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

Topics: Anti-Allergic Agents; Asthma; Cytokines; Histamine H1 Antagonists; Humans; Leukotriene Antagonists; Thromboxane A2

Lung tissues are capable of forming a large amount of thromboxane (TX) A2. In addition to platelet aggregation and artery smooth muscle contraction, TXA2 induces potent contraction of the airway smooth muscles and airway hypersensitivity, suggesting that this arachidonate cyclooxygenase metabolite can contribute to a pathophysiological role for bronchial asthma as well as cardiovascular diseases. In this respect, many compounds competitively antagonizing TP (PGH2/TXA2) receptor, which is stimulated by not only TXA2 but also prostaglandin (PG) D2, PGF2 alpha, PGH2 and others, have been developed so far. Among these, several compounds have been proved or are being proved to be beneficial for treating of bronchial asthma in clinical. In this review, the efficacy of TP receptor blockers for bronchial asthma through the experimental results reported was discussed.

Topics: Animals; Asthma; Humans; Receptors, Thromboxane; Thromboxane A2

Thromboxane A2(TXA2), a platelet aggregator and vasoconstricter, has been implicated as a potential mediator of bronchial asthma. TXA2 induces potent contraction of airway smooth muscles and airway hyperresponsiveness. OKY-046 (ozagrel hydrochloride) is a specific inhibitor of TXA2 synthetase and a new antiasthmatic agent. In a phase III study ozagrel has shown significantly higher effect in ameliorating the asthma symptoms and reduced the dose of concomitant steroid therapy compared to azelastine hydrochloride. Both basical and clinical studies showed that TXA2 synthetase inhibitor is effective on airway hyperresponsiveness. In this review the role of TXA2 synthetase inhibitor in current asthma therapy, which is based on the Japanese guideline of allergic disorders, was discussed.

Topics: Asthma; Bronchial Hyperreactivity; Clinical Trials as Topic; Humans; Methacrylates; Thromboxane A2; Thromboxane-A Synthase

Lung tissues produce a large amount of Thromboxane (Tx) A2. In addition to platelet aggregation and artery smooth muscle contraction, TxA2 strongly induces airway smooth muscle contraction and bronchial hyperresponsiveness. Not only TxA2, but many arachidonate cyclooxygenase metabolites such as PGD2, PGF2 alpha, PGH2, and others stimulate TP (PGH2/TxA2) receptor and can take a pathophysiological role for bronchial asthma. Several compounds competitively antagonizing TP receptor have been developed and being proved to have beneficial effects for treating of bronchial asthma in clinical. In this review the efficacy and usage of TP receptor antagonists for bronchial asthma was discussed.

Topics: Asthma; Benzoquinones; Bridged Bicyclo Compounds; Bronchi; Bronchial Hyperreactivity; Carbazoles; Fatty Acids, Monounsaturated; Heptanoic Acids; Humans; Prostaglandins; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

Selective inhibitors of mediators are among recently developed antiallegic drugs. Studies of the effects of these inhibitors on different types of asthmatic reactions can clarify the heterogeneity of asthma. Heterogeneity may be found both among patients and among types of asthmatic reactions. Although the differences among patients with regard to mediators of spontaneous asthma attacks is still unclear, the differences among asthmatic reactions induced by some well-defined stimuli are known. For example, leukotrienes are dominant in asthmatic reactions induced by analgesics, and histamine is dominant in bronchoconstriction induced by alcohol. Types of asthma may be classified according to the main contributing mediator.

Topics: Anti-Allergic Agents; Asthma; Histamine H1 Antagonists; Humans; Leukotriene Antagonists; Thromboxane A2

Topics: Adult; Asthma; Child; Histamine Antagonists; Humans; Leukotriene Antagonists; Thromboxane A2

Topics: Asthma; Eicosanoic Acids; Humans; Immunity, Cellular; Leukotriene E4; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Prostaglandins; SRS-A; Thromboxane A2

Thromboxane sensitive (TP)-receptors are widely distributed in the airways smooth muscle of various species. In man they mediate constrictor responses, not only to TxA2 but also to other prostanoids such as PGD2 and PGF2 alpha. The evidence for the involvement of these TP-receptors in human asthma is equivocal; however, the recent development of potent, selective TP-receptor blocking drugs such as GR32191 has provided the opportunity to answer this question. GR32191 (80mg p.o.) caused a marked inhibition of PGD2 but not methacholine-induced bronchospasm in asthmatic subjects, and also caused a modest reduction in allergen-induced bronchospasm. However, it had no inhibitory effect against the bronchoconstriction resulting from inhaled PAF or from exercise. Finally, GR32191 was tested in moderate to severe asthmatics for its ability to reduce symptom scores. At a dose of 40mg four times a day for three weeks, GR32191 had no effect upon morning or evening peak expiratory flow rates, on subjective symptom score, on bronchodilator usage or on occurrence of nocturnal dyspnoea. These results do not support a key role for prostanoids acting through TP-receptors in the aetiology of asthma.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchial Provocation Tests; Bronchoconstriction; Forced Expiratory Volume; Heptanoic Acids; Humans; Thromboxane A2

Topics: Animals; Asthma; beta-Thromboglobulin; Blood Platelets; Humans; Platelet Activating Factor; Platelet Factor 4; Serotonin; Thromboxane A2

Topics: Animals; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Humans; Thromboxane A2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Asthma; Blood Platelets; Humans; Prostaglandins; Thromboxane A2

Topics: Asthma; Autonomic Nervous System; Bronchi; Bronchial Spasm; Humans; Prostaglandins; Thromboxane A2

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Asthma; Bronchi; Heart Defects, Congenital; Humans; In Vitro Techniques; Lung; Mucus; Prostaglandin Antagonists; Prostaglandins; Pulmonary Embolism; Respiratory Distress Syndrome; Respiratory Tract Diseases; Smoking; Thromboxane A2

Topics: Anaphylaxis; Animals; Asthma; Bronchi; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Guinea Pigs; Humans; In Vitro Techniques; Lung; Lung Diseases; Models, Biological; Muscle, Smooth; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; SRS-A; Thromboxane A2

Topics: Arachidonic Acids; Asthma; Humans; Hypertension, Pulmonary; Lung; Prostaglandins; Thromboxane A2

Immunologic or calcium-dependent activation of proteolytically dispersed human lung cells containing 5% mast cells causes the release of large amounts of PGD2 and TxB2. In cell purification experiments, only those fractions containing mast cells had the capacity to generate PGD2 and release histamine with IgE-dependent activation. The cells of origin of T X B2 are likely to be cells of the monocyte-macrophage series, although additional eicosanoid release may occur from immunologically activated lymphocytes and eosinophils. In men who have asthma, inhalation of low concentrations of PGD2 results in bronchoconstriction, whereas higher concentrations of PGD2 are needed to produce bronchoconstriction in normal subjects. Subjects with asthma exhibited 3.5-fold greater responsiveness to inhaled PGD2 than to PGF2 alpha. These observations demonstrate that PGD2 is the most potent bronchoconstrictor prostanoid tested in man. In both normal subjects and subjects with asthma, a single inhalation of PGF2 alpha resulted in a doubling in plasma levels of 13,14-dihydro-15-keto-PGF2 alpha. Plasma levels of this metabolite did not change after PGD2 inhalation. These results indicate that the 11-keto reduction of PGD2 to PGF2 alpha with subsequent inactivation is not important in the initial metabolism of PGD2.

Topics: Airway Resistance; Animals; Antibodies, Anti-Idiotypic; Asthma; Calcimycin; Cells, Cultured; Epoprostenol; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Lung; Prostaglandins; Thromboxane A2

Topics: Arthritis, Rheumatoid; Aspirin; Asthma; Chemical Phenomena; Chemistry; Collagen; Drug Interactions; Female; Humans; Male; Platelet Aggregation; Pregnancy; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane A2; Uterine Contraction

Thromboxane A2 (TXA2), an arachidonate derivative, is a potent bronchoconstrictor; therefore, blocking TXA2 should attenuate airway narrowing. Seratrodast, a TXA2 receptor antagonist, is expected to be a potent antiasthmatic. It was reported that seratrodast reduced bronchial hyperresponsiveness. However, it is controversial whether it reduces airway inflammation. We studied some additional effects of oral seratrodast to inhaled corticosteroids on 10 adult asthmatics in an open-label, crossover design study. Eosinophil cationic protein (ECP) levels in serum and sputum, peak expiratory flow rate (PEF), clinical symptoms, and airway responsiveness were evaluated. Clinical symptom scores were improved by administration of seratrodast (p < 0.05). The addition of seratrodast to asthmatic patients significantly improved mean PEF (p < 0.05). In addition, withdrawal of seratrodast resulted in deterioration of PEF. Airway hyperresponsiveness to acetylcholine measured by Astograph was improved by administration of seratrodast (p < 0.01), and returned to the level of "run-in period" after withdrawal. Administration of seratrodast decreased the concentration of ECP in sputum significantly (p < 0.05), and sputum ECP significantly increased again after withdrawal of (p < 0.05). These results suggest that seratrodast improves clinical symptoms andairway hyperresponsiveness by reducing airway inflammation. Seratrodast may be useful as an anti-inflammatory agent and beneficial when added to inhaled corticosteroids in the treatment of bronchial asthma.

Topics: Adult; Anti-Asthmatic Agents; Asthma; Benzoquinones; Blood Proteins; Bronchial Hyperreactivity; Cross-Over Studies; Eosinophil Granule Proteins; Eosinophils; Female; Heptanoic Acids; Humans; Inflammation Mediators; Male; Peak Expiratory Flow Rate; Ribonucleases; Sputum; Thromboxane A2

beta-adrenoreceptor blockers such as propranolol provoke bronchoconstriction only in asthmatic patients. Although cysteinyl leukotrienes (cLTs) and thromboxane A2 (TXA2) have been proposed to be involved in the pathophysiology of asthma, the role of these lipid mediators in propranolol-induced bronchoconstriction (PIB) has not been evaluated in asthmatics. This study was conducted to elucidate it. Nine patients with stable asthma, in whom a 20% or more decrease in FEV(1) occurred by inhalation of 20 mg/ml or less propranolol, participated in this study. A cLT antagonist, pranlukast (225 mg twice a day), a TXA2 antagonist, seratrodast (80 mg once a day), and placebo were orally given for 2 wk in a randomized and double-blinded manner. The provocative concentration of propranolol causing a 20% fall in FEV(1) (PC(20)) was determined on the last day of each 2-wk treatment. Pranlukast, but not seratrodast, tented to increase FEV(1) compared with placebo (2.14 +/- 0.29 versus 1.99 +/- 0.34 L, p = 0.0543). Pranlukast or seratrodast did not affect the PC(20) in comparison with placebo. We conclude that cLTs or TXA2 are not involved in PIB of asthmatics.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Asthma; Benzoquinones; Bronchoconstriction; Chromones; Double-Blind Method; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Leukotriene Antagonists; Male; Middle Aged; Propranolol; Thromboxane A2; Vital Capacity

Thromboxane A2 (TxA2) has been implicated in the pathogenesis of airway hyperresponsiveness. U46619 is a chemical that mimics the effects of TxA2. Both TxA2 and U46619 have been demonstrated to act presynaptically to enhance the release of acetylcholine from cholinergic nerves in canine airway smooth muscle. The purpose of this study was to determine whether the bronchoconstriction caused by inhaled U46619 in asthmatic subjects is caused by acetylcholine release. Airway responsiveness to inhaled methacholine and U46619 was measured in eight subjects with mild stable asthma and expressed as the provocation concentration causing a 20% fall in FEV1 (PC20). Subjects were studied on 4 d, each separated by 3 days. On each study day, subjects inhaled a cholinergic antagonist ipratropium bromide (80 micrograms), or placebo, and 1 h later, increasing doubling doses of methacholine or U46619 were inhaled, and a PC20 value was obtained. The mean methacholine PC20 on the placebo day was 1.42 mg/ml (%SEM, 1.47) and after treatment with ipratropium bromide this increased to 127.33 mg/ml (%SEM, 1.29) (p = 0.0001), a mean 89.4-fold (%SEM, 1.19) increase. The mean U46619 PC20 on the placebo day was 2.09 micrograms/ml (%SEM, 1.56) and after treatment with ipratropium bromide this increased to 47.54 micrograms/ml (%SEM, 1.43) (p = 0.0001), a mean 22.8-fold (%SEM, 1.36) increase. The ability of ipratropium bromide to attenuate responsiveness to the noncholinergic mediator histamine was also investigated in six subjects. The mean increase in histamine PC20 was a 3.09-fold (%SEM, 1.17) increase, significantly less than the increase seen for both methacholine and U46619 (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adolescent; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Cross-Over Studies; Double-Blind Method; Female; Humans; Ipratropium; Male; Methacholine Chloride; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstrictor Agents

It has been considered that thromboxane A2 (TXA2) is involved in the development of bronchial hyperresponsiveness (BHR), a characteristic feature of asthma. To ensure the involvement of TXA2 in BHR of asthma, effects of a 1-week treatment with two orally active TXA2 antagonists, BAY u 3405 and S-1452, on BHR were examined in 10 and 13 patients with stable asthma, respectively, in two consecutive double-blinded, randomized, placebo-controlled, two-phase crossover studies. Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20-FEV1) with BAY u 3405 (0.78 (GSEM, 1.50) mg/ml) was significantly greater than the value with placebo (0.65 (GSEM, 1.46) mg/ml) (ratio 1.23 times, 95% CI 1.01 to 1.46: P = 0.0401). PC20-FEV1 was also significantly increased with S-1452 (0.43 (GSEM, 1.39) mg/ml) compared with placebo (0.29 (GSEM, 1.27) mg/ml) (ratio 1.75 times, 95% CI 1.05 to 2.45: P = 0.0189). Baseline pulmonary function was not altered by these treatments. These results may ensure that TXA2 is significantly involved in the BHR of asthma while the degree of contribution may be small.

Topics: Adolescent; Adult; Airway Resistance; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Carbazoles; Cross-Over Studies; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Prostaglandin Antagonists; Sulfonamides; Thromboxane A2

We recently reported that inhaled acetaldehyde causes bronchoconstriction indirectly via histamine release in patients with asthma. The purpose of this study was to investigate a role of thromboxane A2 in acetaldehyde-induced bronchoconstriction in asthmatic airways. We investigated the bronchial response to inhalation of ascending doses (5, 10, 20, and 40 mg/ml) of acetaldehyde in nine asthmatic subjects who were treated with placebo or OKY-046, a selective thromboxane A2 synthetase inhibitor, of 200 mg twice a day for 3 days, and 200 mg on the fourth day (test day) in a double-blind, randomized, placebo-controlled, crossover fashion. Percentage decreases in FEV1 caused by 20 and 40 mg/ml of acetaldehyde inhalation were significantly (p < 0.05 and p < 0.01, respectively) prevented by the pretreatment with OKY-046. Geometric mean value (geometric standard error of the mean) of acetaldehyde concentration producing a 20 percent fall in FEV1 (PC20-Ac-CHO) was significantly (p < 0.01) greater with the OKY-046 pretreatment (72.2 [1.1] mg/ml) than with the placebo pretreatment (19.8 [1.2] mg/ml). We conclude that thromboxane A2 is one of contributors to acetaldehyde-induced bronchoconstriction in asthmatic subjects. It suggests that thromboxane A2 may play an important role in endogenous histamine-induced bronchoconstriction caused by acetaldehyde in asthmatic airways. We believe that this is a first report on the interaction between endogenous histamine and thromboxane A2 in asthmatic subjects.

Topics: Acetaldehyde; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Cross-Over Studies; Depression, Chemical; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Middle Aged; Statistics, Nonparametric; Thromboxane A2; Thromboxane-A Synthase; Vital Capacity

Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.

Topics: Adult; Asthma; Bronchial Provocation Tests; Double-Blind Method; Female; Humans; Imidazoles; Male; Methacholine Chloride; Middle Aged; Thromboxane A2; Thromboxane-A Synthase; Time Factors

Airway responsiveness to methacholine was measured in nine subjects (22-53 years, seven male) with chronic stable asthma. All subjects were taking inhaled beclomethasone (less than 1000 micrograms daily). The mean baseline FEV1 was 2.841 (77% of predicted) and the geometric mean PD20FEV1 was 31 micrograms. After a run-in period, the subjects were randomly allocated to two treatment periods with the specific thromboxane receptor antagonist GR32191, 40 mg four times daily for 3 weeks, and identical placebo capsules. A double-blind, placebo-controlled, cross-over design was employed with 4 weeks between the two treatment periods. Treatment with GR32191 did not result in any significant improvement in mean FEV1 (2.941 after placebo and 2.861 after GR3219; F7.71 = 1.02, P greater than 0.1) or PD20FEV1 (24.3 micrograms after placebo and 38.5 micrograms after GR32191; F7.71 = 0.59, P greater than 0.1). We conclude that thromboxane is not important in the maintenance of airway hyperresponsiveness in chronic asthma and that thromboxane receptor antagonists are unlikely to provide effective treatment for this group of patients.

Topics: Adult; Asthma; Biphenyl Compounds; Bronchial Hyperreactivity; Double-Blind Method; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Male; Methacholine Chloride; Middle Aged; Receptors, Thromboxane; Thromboxane A2

Thromboxane sensitive (TP)-receptors are widely distributed in the airways smooth muscle of various species. In man they mediate constrictor responses, not only to TxA2 but also to other prostanoids such as PGD2 and PGF2 alpha. The evidence for the involvement of these TP-receptors in human asthma is equivocal; however, the recent development of potent, selective TP-receptor blocking drugs such as GR32191 has provided the opportunity to answer this question. GR32191 (80mg p.o.) caused a marked inhibition of PGD2 but not methacholine-induced bronchospasm in asthmatic subjects, and also caused a modest reduction in allergen-induced bronchospasm. However, it had no inhibitory effect against the bronchoconstriction resulting from inhaled PAF or from exercise. Finally, GR32191 was tested in moderate to severe asthmatics for its ability to reduce symptom scores. At a dose of 40mg four times a day for three weeks, GR32191 had no effect upon morning or evening peak expiratory flow rates, on subjective symptom score, on bronchodilator usage or on occurrence of nocturnal dyspnoea. These results do not support a key role for prostanoids acting through TP-receptors in the aetiology of asthma.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchial Provocation Tests; Bronchoconstriction; Forced Expiratory Volume; Heptanoic Acids; Humans; Thromboxane A2

Bronchial hyperresponsiveness (BHR) to various stimuli is one of the major clinical features of bronchial asthma. In this study, the effect of a thromboxane A2 (TXA2) receptor antagonist, AA-2414, on BHR to methacholine was evaluated in 15 patients with asthma. The methacholine inhalation test was performed before and after oral administration of AA-2414 for 4 days (20 or 40 mg/day). The provocative concentration of methacholine producing a 20% fall in FEV1 (PC20) was measured as an index of BHR. There was a significant increase in PC20 (p less than 0.01) from 0.43 (geometric SEM, 1.42) mg/ml to 0.93 (geometric SEM, 1.43) mg/ml after 40 mg/day of AA-2414, whereas baseline values of FVC and FEV1 were not changed by the treatment. Twenty milligrams per day of AA-2414 did not alter the PC20 value nor the parameter of baseline pulmonary functions. These findings might support our hypothesis that the subthreshold concentration of TXA2 in the bronchial tissues, which has no effect on bronchomotor tone per se, may be involved in BHR in asthma. Further studies with more potent and specific TXA2 receptor antagonists are needed to confirm the conclusion.

Topics: Adult; Aged; Asthma; Benzoquinones; Bronchi; Dose-Response Relationship, Drug; Drug Synergism; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Male; Methacholine Chloride; Middle Aged; Quinones; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Vital Capacity

Allergen-stimulated release of a cyclooxygenase product (thromboxane [TX] A2) and a 5-lipoxygenase product (leukotriene [LT] E4) into the urine was measured in 10 atopic asthmatics undergoing allergen inhalation. Because indomethacin has been reported to increase allergic-stimulated 5-lipoxygenase product formation and to inhibit the late asthmatic response, we determined the effect of indomethacin (50 mg 3 times a day) or placebo on airway and biochemical responses to inhaled allergen in a randomized, blinded study. Urinary levels of the enzymatic metabolite of TXB2, 11-dehydro-TXB2, increased from 585 +/- 330 to 1,500 +/- 250 pg/mg creatinine (mean +/- SEM, p less than 0.05) 2 h after allergen. Urinary LTE4 increased from 190 +/- 37 to 1,100 +/- 400 (p less than 0.05) 2 h after challenge. The urinary levels of these eicosanoids were not elevated during the late response. Indomethacin significantly reduced urinary 11-dehydro-TXB2 levels without affecting the excretion of LTE4 or pulmonary function. Thus, we failed to obtain evidence for enhanced leukotriene formation during allergic stimulation in vivo in the presence of cyclooxygenase inhibition. Furthermore, we conclude that cyclooxygenase products are likely to play only a marginal role in allergic bronchoconstriction.

Topics: Adult; Allergens; Arachidonate 5-Lipoxygenase; Asthma; Bronchial Provocation Tests; Humans; Indomethacin; Leukotriene E4; Prostaglandin-Endoperoxide Synthases; Random Allocation; SRS-A; Thromboxane A2

Cysteinyl leukotrienes (cysLTs) are bronchoconstricting lipid mediators that amplify eosinophilic airway inflammation by incompletely understood mechanisms. We recently found that LTC4, the parent cysLT, potently activates platelets in vitro and induces airway eosinophilia in allergen-sensitized and -challenged mice by a platelet- and type 2 cysLT receptor-dependent pathway. We now demonstrate that this pathway requires production of thromboxane A2 and signaling through both hematopoietic and lung tissue-associated T prostanoid (TP) receptors. Intranasal administration of LTC4 to OVA-sensitized C57BL/6 mice markedly increased the numbers of eosinophils in the bronchoalveolar lavage fluid, while simultaneously decreasing the percentages of eosinophils in the blood by a TP receptor-dependent mechanism. LTC4 upregulated the expressions of ICAM-1 and VCAM-1 in an aspirin-sensitive and TP receptor-dependent manner. Both hematopoietic and nonhematopoietic TP receptors were essential for LTC4 to induce eosinophil recruitment. Thus, the autocrine and paracrine functions of thromboxane A2 act downstream of LTC4/type 2 cysLT receptor signaling on platelets to markedly amplify eosinophil recruitment through pulmonary vascular adhesion pathways. The findings suggest applications for TP receptor antagonists in cases of asthma with high levels of cysLT production.

Topics: Allergens; Animals; Aspirin; Asthma; Blood Platelets; Bone Marrow Transplantation; Bronchoalveolar Lavage Fluid; Cysteine; Eosinophilia; Inflammation; Intercellular Adhesion Molecule-1; Leukotriene Antagonists; Leukotriene C4; Leukotrienes; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Platelet Activation; Receptors, Prostaglandin; Thromboxane A2; Vascular Cell Adhesion Molecule-1

Airway obstruction after antigen challenge is not always observed in patients with allergic asthma, even if they develop hyperresponsiveness. A similar event is observed in our guinea pig model of allergic asthma. Our aim was to study this phenomenon.. Sensitized guinea pigs were challenged with ovalbumin (OVA) 3 times every 10 days. Animals were divided into 2 groups: (1) Guinea pigs exhibiting airway obstruction after antigen challenge (R = responders), and (2) guinea pigs lacking airway obstruction response (NR = nonresponders). After the third antigen challenge, antigen-induced airway hyperresponsiveness (AI-AHR), serum OVA-specific immunoglobulins, bronchoalveolar lavage fluid (BALF) inflammatory cells, histamine, cysteinyl leukotrienes and thromboxane A2 (TxA2) BALF levels, and in vitro tracheal contraction induced by contractile mediators and OVA were evaluated.. R group consistently displayed a transient antigen-induced airway obstruction (AI-AO) as well as AI-AHR, high T×A2, histamine, OVA-IgG1, OVA-IgE and OVA-IgA levels, and intense granulocyte infiltration. NR group displayed no AI-AO and no changes in BALF measurements; nevertheless, AI-AHR and elevated OVA-IgG1 and OVA-IgA levels were observed. In all groups, histamine, TxA2 and leukotriene D4 induced a similar contraction. Tracheal OVA-induced contraction was observed only in R group. AI-AHR magnitude showed a direct association with OVA-IgG1 and OVA-IgA levels. The extent of AI-AO correlated directly with OVA-IgE and inversely with OVA-IgA levels.. Our data suggest that TxA2 and histamine participate in AI-AO likely through an IgE mechanism. AI-AHR might occur independently of AI-AO, contractile mediators release, and airway inflammatory cell infiltration, but IgA and IgG1 seem to be involved.

Topics: Airway Obstruction; Animals; Antigens; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; Histamine; Humans; Immunization; Immunoglobulins; Leukotriene D4; Male; Ovalbumin; Respiratory Hypersensitivity; Thromboxane A2

Actions of thromboxane (TXA(2)) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated. We show that the response of the airways to TXA(2) is complex: it depends on expression of other G protein-coupled receptors but also on the physiological context of the signal. In the healthy airway, TXA(2)-mediated airway constriction depends on expression of TP receptors by smooth muscle cells. In contrast, in the inflamed lung, the direct actions of TXA(2) on smooth muscle cell TP receptors no longer contribute to bronchoconstriction. Instead, in allergic lung disease, TXA(2)-mediated airway constriction depends on neuronal TP receptors. Furthermore, this mechanistic switch persists long after resolution of pulmonary inflammation. Our findings demonstrate the powerful ability of lung inflammation to modify pathways leading to airway constriction, resulting in persistent changes in mechanisms of airway reactivity to key bronchoconstrictors. Such alterations are likely to shape the pathogenesis of asthmatic lung disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Asthma; Bronchi; Bronchoconstriction; Cells, Cultured; Hypersensitivity; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Neurons, Afferent; Pneumonia; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Respiratory System; Thromboxane A2; Vasoconstrictor Agents

Prostaglandin E(2) (PGE(2)) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE(2) generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE(2)-deficient ptges(-/-) mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smooth-muscle hyperplasia compared with PGE(2)-sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE(2) deficiency depend on thromboxane A(2) and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges(-/-) mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP)(1) and EP(2) receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE(2) deficiency. Thus, PGE(2) controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.

Topics: Allergens; Animals; Antigens, Dermatophagoides; Asthma; Dinoprostone; Intercellular Adhesion Molecule-1; Intramolecular Oxidoreductases; Male; Mice; Mice, Knockout; Pneumonia; Prostaglandin-E Synthases; Pulmonary Eosinophilia; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Thromboxane; Signal Transduction; Thromboxane A2; Up-Regulation

Differences between detection techniques may be partly responsible for variable mediator concentrations reported in exhaled breath condensate (EBC). We compared two types of immunoassays to estimate thromboxane A(2) (TxA(2)) concentration.. Thromboxane B(2) (TxB(2)) levels were measured by enzyme immunoassay (EIA) and TxB(2)/2,3-dinor TxB(2) by radioimmunoassay (RIA) in 10 healthy subjects and 13 asthmatic patients. 2,3-Dinor TxB(2) was also determined by a separate EIA.. Thromboxane was detected in all samples by RIA, but only in about 75% of samples by EIA. 2,3-Dinor TxB(2) was detected in most samples. There was no agreement between the results of the different immunoassays. As compared to healthy subjects, exhaled breath condensates of asthmatic patients contained significantly more immunoreactivity by RIA and TxB(2) EIA (but not by 2,3-dinor TxB(2) EIA).. RIA and EIA resulted in vastly different absolute values. The difference found between healthy volunteers and asthmatic patients however, suggests an increased level of TxA(2) in the airways of asthmatics.

Topics: Adult; Aged; Asthma; Breath Tests; Bronchi; Female; Humans; Immunoassay; Immunoenzyme Techniques; Male; Middle Aged; Radioimmunoassay; Respiratory Function Tests; Thromboxane A2

Disodium cromoglycate is an anti-asthmatic drug that has mast cell-stabilizing effects and other anti-inflammatory effects. However, the mechanisms of its anti-inflammatory effects are unclear. In this study, we evaluated effects of disodium cromoglycate on eosinophilia, early and late asthmatic responses, and production of arachidonic acid metabolites in guinea pig lungs. Guinea pigs were alternately sensitized and challenged by exposure to mists of ovalbumin+Al(OH)(3) and ovalbumin, respectively. Disodium cromoglycate (0.5-2 mg/0.1 ml/animal) administered intratracheally before the fifth challenge dose-dependently inhibited asthmatic response, but early asthmatic response was not affected. Disodium cromoglycate at 2 mg/animal potently suppressed increases in cysteinyl leukotrienes (CysLTs) and thromboxane A(2) in the lung during late asthmatic response. Eosinophilia was slightly reduced by disodium cromoglycate. The inhibitory effect of disodium cromoglycate on late asthmatic response is apparently due to inhibition of the release of arachidonic acid metabolites, some of which may be derived from eosinophils that infiltrate the lung.

Topics: Animals; Anti-Asthmatic Agents; Arachidonic Acids; Asthma; Bronchoalveolar Lavage Fluid; Cromolyn Sodium; Cysteine; Dose-Response Relationship, Drug; Eicosanoids; Eosinophilia; Guinea Pigs; Leukotrienes; Lung; Male; Ovalbumin; Thromboxane A2; Time Factors

Leukotrienes, generated from arachidonic acid via the lipoxygenase pathway, play an important role in the pathophysiology of asthma. Therefore, leukotriene inhibitors, such as Zileuton, are used in the treatment of asthma. However, thromboxanes, generated from arachidonic acid via the cyclooxygenase pathway, play an important role in platelet aggregation and thrombosis. Therefore, we studied whether Zileuton, by shifting arachidonic acid to the cyclooxygenase pathway, enhances thromboxane production and, hence, platelet aggregation. Blood samples were collected from 10 asthmatic patients before and 2 weeks after standard Zileuton treatment. Spontaneous platelet aggregation was measured in platelet-rich plasma. Platelet-rich plasma was also used to determine thromboxane B(2), a stable metabolite of thromboxane A(2), as the indirect measure of thromboxane A(2) because thromboxane A(2) is too unstable for assay. Baseline thromboxane B(2) and platelet aggregation values in the 10 asthmatic patients were normal. Treatment with Zileuton for 2 weeks significantly increased thromboxane B(2) levels from baseline levels of 267 +/- 54 microg/l to 389 +/- 62 microg/l after 2 weeks of treatment (P < 0.0002). Spontaneous platelet aggregation also increased significantly from baseline values of 4.2 +/- 2.4% to 6.8 +/- 2.8% after 2 weeks of treatment (P < 0.0001). These results establish that Zileuton, an effective drug for asthma, adversely affects in vitro platelet function. The findings suggest that this drug, and perhaps related agents also, may pose a thrombotic risk; clinical attention will be needed to address this possibility.

Topics: Adult; Aged; Asthma; Female; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2

We have reported that thromboxane A2 induces suppression of leukotriene (LT) C4 synthase activity in human platelets.. In the present study, we describe a mechanism whereby aspirin treatment can lead to increased formation of LTC4, which is a potent bronchoconstrictor and inflammatory mediator. This mechanism is also demonstrated to be present in platelets from aspirin-intolerant asthmatics (AIA).. The effect of arachidonic acid or platelet agonists on LTC4 synthase activity was investigated in platelets obtained from healthy volunteers, aspirin-intolerant asthmatics or aspirin-tolerant asthmatics after in vivo treatment or in vitro pre-incubation with aspirin.. Incubation of normal platelets with arachidonic acid or collagen provoked approximately 50% reduction of platelet LTC4 synthase activity, as determined by the conversion of LTA4 to LTC4. However, the inhibitory effect of arachidonic acid or collagen was not observed after oral administration of aspirin prior to collection of the platelets. Arachidonic acid-induced inhibition of LTC4 synthase activity was totally abolished in platelets collected from peripheral blood already 30 min after aspirin ingestion but was fully restored in platelets collected 3 to 7 days after the administration of aspirin. Treatment of platelet suspensions with aspirin in vitro dose-dependently counteracted the suppressive effect of arachidonic acid on LTC4 formation, with total reversal at approximately 40 microm. In contrast, the major aspirin metabolite, salicylic acid did not alter arachidonic acid-induced reduction of LTC4 synthase activity. Similarly, LTC4 synthase activity in platelets from AIA and aspirin-tolerant asthmatics (ATA) was reduced by approximately 50% after pre-treatment with arachidonic acid in vitro. Again the inhibitory effect was abolished when platelets were pre-incubated in the presence of aspirin.. The results indicate that oral aspirin administration can lead to uncoupling of thromboxane A2-dependent negative feedback mechanisms, which may normally restrict the production of cysteinyl leukotrienes. This mechanism can be of potential interest in aspirin-induced asthma.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Aspirin; Asthma; Blood Platelets; Case-Control Studies; Collagen; Depression, Chemical; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Glutathione Transferase; Humans; Male; Middle Aged; Thromboxane A2

The aim of this study was to elucidate the role of thromboxane A(2) (TxA(2)) on asthma-related cough in guinea pigs. Animals were immunosensitized and repeatedly challenged with ovalbumin as an antigen. Coughs were induced by the inhalation of 10(-5) M capsaicin solution for 10 min. Thromboxane synthetase (TxS) inhibitor OKY-046 and thromboxane-receptor antagonist AA-2414 significantly inhibited cough responses in repeatedly challenged animals. Inhalation of TxA(2) mimic STA-2- potentiated cough responses in normal and immunosensitized animals but not in repeatedly challenged ones. Moreover, STA-2-potentiated coughs were inhibited by administration of neurokinin-receptor antagonist FK-224. In repeatedly challenged animals, concentration of TxB(2) in airway lavage fluid, expression of TxS mRNA in tracheal epithelia, and the immunostaining intensity against TxS in mucous cells of the epithelium significantly increased compared with normal and sensitized animals. These results suggest that TxA(2) derived from mucous cells potentiated cough responses to capsaicin in allergic airway inflammation.

Topics: Animals; Asthma; Base Sequence; Bronchoalveolar Lavage Fluid; Cough; DNA, Complementary; Female; Guinea Pigs; Immunohistochemistry; Lung; Respiratory Mucosa; RNA, Messenger; Thromboxane A2; Thromboxane-A Synthase; Trachea

Airway hyperresponsiveness (AHR) is one of the characteristic features of human asthma. The presence of AHR and the precise mechanisms immediately after establishment of sensitization in guinea pigs are unclear, although there are many reports showing allergen exposure that causes an increase in bronchial responsiveness associated with eosinophil influx into the airway in sensitized guinea pigs.. We investigated the inhibitory effects on AHR to histamine of ONO-1078, a leukotriene antagonist; indomethacin, a cyclooxygenase inhibitor; S-145, a thromboxane A(2) (TXA(2)) antagonist, and Y-24180, a platelet-activating factor (PAF) antagonist, to assess the involvement of chemical mediators in AHR employing ovalbumin (OA) sensitized guinea pig models.. Male Hartley guinea pigs were used. Each group comprised 4-7 animals. The animals were sensitized to OA, injecting intraperitoneally 30 mg of cyclophosphamide and 2,000 microg of OA together with 100 mg of aluminum hydroxide as the adjuvant. The guinea pigs were artificially ventilated via a cannula using a small-animal respirator after intraperitoneal anesthesia with pentobarbital sodium for tracheotomy. The pressure at the airway opening (PAO) was measured using a differential pressure transducer, and a differential pressure of peak PAO (peak DeltaPAO) at inspiratory phase as an overall index of bronchial response to bronchoactive agents was used. While being artificially ventilated, the animals were exposed to physiological saline solution containing various concentrations of histamine (4.9, 9.8, 20, 39, 78, and 156 microg/ml) by inhalation for 30 s at 3-min intervals. Determinations were made at 1 min after each inhalation. The chemical mediators were each (30 mg/kg of ONO-1078, 3 mg/kg of S-1452, and 1 mg/kg of Y-24180) administered orally to sensitized guinea pigs, and the airway response to histamine was assessed. Each group comprised 4-7 animals.. The airway response to histamine was significantly greater in the sensitized group than in the nonsensitized group at histamine concentrations of 36 (p < 0.05), 78, and 156 mg/ml (p < 0.01). Leukotrienes C(4) and D(4): 30 mg/kg of ONO-178 did not show any inhibitory effect on airway response to inhaled histamine. Cyclooxygenase: 5 mg/kg of indomethacin did not show any inhibitory effect on the airway response to inhaled histamine. TXA(2): the AHR to inhaled histamine at doses of 9.8, 39, 78, and 156 microg/ml was significantly inhibited by prior administration of 3 mg/kg of S-1452. PAF: the AHR to inhaled histamine at doses of 9.8, 39, and 78 microg/ml was significantly inhibited by prior administration of 1 mg/kg of Y-24180.. S-1452 (3 mg/kg) and Y-24180 (1 mg/kg) significantly inhibited AHR to histamine, while ONO-108 (30 mg/kg) and indomethacin (5 mg/kg) did not. The results suggest that TXA(2) and PAF are involved in AHR in OA-sensitized guinea pigs.

Topics: Airway Resistance; Animals; Asthma; Bronchial Hyperreactivity; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Indomethacin; Leukotriene C4; Leukotriene D4; Male; Ovalbumin; Platelet Activating Factor; Probability; Reference Values; Sensitivity and Specificity; Thromboxane A2

Seratrodast, an antagonist to thromboxane A2 (TXA2) receptors, is not always effective in patients with bronchial asthma. In fact, some respond definitely to this drug while others not. In the present study, to clarify the predictability of the clinical effects of Seratrodast, we investigated whether there is a correlation between the levels of TXB2 and 11-DHTXB2, both of which are metabolites of TXA2, in urine and sputum taken before the administration and the clinical effects seen after initiation of the treatment. Baseline concentrations of TXA2 metabolites in urine/sputum were not significantly different between responders and non-responders. However, 4 cases who had remarkably responded to Seratrodast had significantly higher baseline 11-DHTXB2 levels than the rest of the patients. These results suggested that bronchial asthma patients with high urinary 11-DHTXB2 levels could markedly respond to Seratrodast treatment.

Topics: Adult; Aged; Anti-Asthmatic Agents; Asthma; Benzoquinones; Female; Heptanoic Acids; Humans; Male; Middle Aged; Prostaglandin Antagonists; Sputum; Thromboxane A2; Thromboxane B2

Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin-induced bronchoconstriction in aspirin-sensitive asthma, the cellular origin of the LT is not yet clear.. Urinary concentrations of leukotriene E4 (LTE4), 11-dehydrothromboxane B2, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine were measured during the 24 h following cumulative intravenous administration of increasing doses of lysine aspirin to asthmatic patients. In addition, the urinary concentrations of these metabolites were measured on 5 consecutive days in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs.. In aspirin-induced asthma patients (AIA, n=10), the basal concentration of urinary LTE4, but not the other metabolites, was significantly higher than that in aspirin-tolerant asthma patients (ATA, n=10). After intravenous aspirin provocation, the AIA group showed a 13.1-fold (geometric mean) increase in excretion of LTE4 during the first 3 h, and 9alpha,11beta-prostaglandin F2 also increased in the AIA group during the first 0-3 h and the 3-6 h collection period. Ntau-methylhistamine excretion was also increased, but to a lesser degree. Administration of aspirin caused significant suppression of 11-dehydrothromboxane B2 excretion in both the AIA and ATA groups. When the percentage of maximum increase of each metabolite from the baseline concentrations was compared between the AIA group and the ATA group, a significantly higher increase in excretion of LTE4, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine was observed in the AIA group than the ATA group. An increased excretion of LTE4 and 9alpha,11beta-prostaglandin F2 has been detected in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs.. Considering that human lung mast cells are capable of producing LTC4, prostaglandin D2, and histamine, our present results support the concept that mast cells, at least, may participate in the development of aspirin-induced asthma.

Topics: Adult; Aged; Aspirin; Asthma; Bronchial Provocation Tests; Cyclooxygenase Inhibitors; Dinoprost; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Mast Cells; Methylhistamines; Middle Aged; Sensitivity and Specificity; Thromboxane A2; Thromboxane B2; Time Factors

Circadian rhythmicity of cysteinyl leukotrienes (LTs) and thromboxane (TX)-A(2) in healthy subjects and nocturnal asthmatic patients remains a subject of controversy. The aim of this study was to investigate the contribution of these mediators to the pathogenesis of nocturnal asthma.. We measured peak expiratory flow rate, urinary concentration of LTE(4), 11-dehydro-TXB(2), and creatinine eight times every 3 h in three groups: healthy control subjects (n = 5, group A), nocturnal asthmatic patients (n = 9, group B), and nonnocturnal asthmatic subjects (n = 9, group C). To evaluate the reproducibility of the measurement of urinary LTE(4), we measured urinary LTE(4) in group A for 3 separate days.. The urinary LTE(4) concentrations from 3 to 6 AM were significantly (p < 0.05) higher than from 3 to 6 PM in both group A and group B, but not in group C. The mean levels of LTE(4) in group B and group C were significantly higher (p < 0.05) than those in group A. In group B, another small peak was observed from 6 to 9 PM. No significant day-to-day variation was observed in group A. Urinary 11-dehydro-TXB(2) values from 3 to 6 AM were significantly (p < 0.001) higher than those levels from 3 to 6 PM in all groups, and the mean levels in group B and group C were significantly higher than those in group A (p < 0.05).. Circadian rhythmicity of urinary LTE(4) with a morning peak was found in healthy control subjects and nocturnal asthmatic subjects, but not in nonnocturnal asthmatic patients. It was suggested that cysteinyl LTs rather than TXA(2) might contribute to the nocturnal worsening of asthma.

Topics: Adult; Aged; Asthma; Circadian Rhythm; Creatinine; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Reference Values; Thromboxane A2; Thromboxane B2

To investigate the role of inhaled dexamethasone on airway wall remodeling.. Asthmatic guinea pig models were established, after guinea pigs inhaled ovalbumin and dexamethasone, the thickness of airway wall was determined by contour tracing, using a digitizing pad and microcomputer. To culture airway smooth muscle cells, observe the effect of histamine, thromboxane A(2) and dexamethasone on cultured cells.. The mean thickness of airway smooth muscle in asthma group was (90 +/- 14) micrometer, greater than that of control (54 +/- 7) micrometer (P < 0.01); the airway smooth muscle layer in dexamethasone group (61 +/- 11) micrometer was thinner than that of asthma group (P < 0.01). [(3)H]-TdR incorporation in histamine group (2 950 +/- 205) counts/min was higher, comparing to that of the control (613 +/- 52) counts/min (P < 0.01); [(3)H]-TdR incorporation in dexamethasone group was (1 067 +/- 96) counts/min, lower than those of histamine group (P < 0.01).. Dexamethasone could prevent airway remodeling, and had no harmful effect on airway wall.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Cells, Cultured; Dexamethasone; Guinea Pigs; Histamine; Male; Muscle, Smooth; Ovalbumin; Respiratory System; Thromboxane A2; Thymidine; Tritium

This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.

Topics: Animals; Arachidonate 5-Lipoxygenase; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cyclooxygenase Inhibitors; Dinoprost; Dogs; Eicosanoids; Epithelial Cells; Hyperventilation; Indomethacin; Leukotrienes; Male; Muscarinic Antagonists; Receptors, Muscarinic; Thromboxane A2

The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A(2) (TXA(2)) in guinea pig models of aspects of bronchial asthma was investigated. In a novel antigen (BSA)-induced asthmatic model using passively sensitized guinea pigs, pretreatment with varying doses of indomethacin controlled the ratio of followed lipid mediators, LTC(4)/D(4)/E(4) and TXB(2), in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5-mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Furthermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD(4) or TXA(2) receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD(4) and TXA(2) receptor antagonists exhibited significant effects irrespective of the condition used. Under conditions where both mediators equally participate, a combination of both receptor antagonists showed additive inhibition. YM158, a newly synthesized and orally active dual antagonist for LTD(4) and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD(4) receptor antagonist and a TXA(2) receptor antagonist mixture. Therefore, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drugs.

Topics: Administration, Oral; Animals; Asthma; Chromones; Disease Models, Animal; Guinea Pigs; Immunization, Passive; Leukotriene Antagonists; Leukotrienes; Male; Membrane Proteins; Phenylacetates; Receptors, Leukotriene; Receptors, Thromboxane; Serum Albumin, Bovine; Sulfonamides; Tetrazoles; Thiazoles; Thromboxane A2; Thromboxane B2

Phospholipase A2 (PLA2) induces hyper-sensitivity to muscarinic agonists in airway smooth muscle in vitro. The precise mechanism of this is unknown, but might involve altered calcium homeostasis. In order to elucidate the effects of PLA2, on bovine tracheal smooth muscle contraction, isometric tension and intracellular calcium concentration ([Ca2+]i) were simultaneously measured in fura 2-loaded muscle strips. A high concentration of PLA2 (0.5 microg x mL(-1)) caused the muscle strips to contract, and this contractile response was significantly attenuated by pretreatment with indomethacin (IND; 10 microM), but not by nordihydroguaiaretic acid (NDGA; 10 microM). A low concentration of PLA2 (0.02 microg x mL(-1)) did not directly contract muscle strips. However a low concentration PLA2 significantly enhanced the threshold of the contractile response and that of the [Ca2+]i response to acetylcholine (ACh), but not that of the response to a high K+ concentration. These augmented responses to ACh returned to control levels after pretreatment with IND, a thromboxane (TX) synthetase inhibitor (OKY-046; 10 microM) or a TXA2 receptor antagonist (ONO-3708; 10 microM), but not after NDGA pretreatment. These results suggest that a low concentration of phospholipase A2 enhances smooth muscle responsiveness to acetylcholine by agonist-mediated Ca2+ mobilization facilitated by thromboxane A2. It is concluded that phospholipase A2 plays an important role in bronchial hypersensitivity involving thromboxane A2. It remains to be examined whether similar abnormalities in calcium homeostasis and muscarinic receptor function or coupling are involved in the pathogenesis of asthma.

Topics: Airway Resistance; Animals; Asthma; Bronchial Hyperreactivity; Calcium; Cattle; Homeostasis; Intracellular Fluid; Muscle, Smooth; Phospholipases A; Phospholipases A2; Thromboxane A2; Trachea

The contributions of histamine, cysteinyl leukotrienes (CysLTs) and thromboxane A2 (TXA2) to the asthmatic responses and the magnitudes of blood and lung eosinophilia at acute and chronic stages of our asthmatic model were comparatively determined. Guinea pigs were alternately sensitized/challenged by inhalation with ovalbumin+Al(OH)3 and ovalbumin, once every 2 weeks. Effects of mepyramine, pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) on the early (EAR) and/or the late asthmatic response (LAR) were assessed at the second and fourth antigen challenges. The second challenge caused EAR but not LAR. Although the EAR was decreased at the fourth challenge, a substantial LAR was seen. Both mepyramine and seratrodast inhibited the EAR at the second challenge by approximately 50%. However, at the fourth challenge, these drugs did not inhibit the EAR. The LAR at the fourth challenge was attenuated by pranlukast and seratrodast by 45% and 40%, respectively. Both the blood and lung eosinophilia were modestly and markedly induced 5 h after the second and fourth challenges, respectively. These results strongly suggest that repetition of antigen challenge induces quantitative alterations of chemical mediators participating in the asthmatic responses and a change of the body state under which eosinophils exhibit enhanced migratory activities.

Topics: Administration, Inhalation; Airway Obstruction; Aluminum Hydroxide; Animals; Antigens; Asthma; Benzoquinones; Chromones; Eosinophilia; Guinea Pigs; Heptanoic Acids; Histamine H1 Antagonists; Leukotriene Antagonists; Lung; Male; Ovalbumin; Prostaglandin Antagonists; Pyrilamine; Thromboxane A2

To investigate whether platelets are activated in asthmatics with increased release of preformed mediators and to investigate the influence of oral administration of theophylline on them.. Comparison of the intracellular free calcium concentration ([Ca2+]i) in platelets as an indicator of platelet activation, CD62P expression on platelets, and the chemokine regulated upon activation in normal T cells expressed and presumably secreted (RANTES) level in platelet-rich buffer supernatants between asthmatics and normal subjects.. The respiratory outpatient clinics, Hiroshima University, Japan.. Twenty-five normal volunteers, 19 asthmatics taking no oral drugs associated with asthma treatment (group A), and 18 asthmatics taking oral theophylline (group B).. While the resting [Ca2+]is in platelets were similar among the three groups, the [Ca2+]is in group A were significantly higher than those in normal subjects (p<0.05) and group B (p<0.01) after thrombin or 9,11-epithia-11,12-methano-thromboxane A2 (STA2) stimulation in the absence of external Ca2+. The CD62P expression level and RANTES level in group A after STA2 stimulation were significantly higher than those in normal subjects and group B (p<0.05).. We conclude that agonist-mediated activation of platelets is augmented in asthmatics resulting in enhanced release of chemokine such as RANTES, which could be suppressed by oral administration of theophylline.

Topics: Administration, Oral; Adult; Aged; Asthma; Blood Platelets; Bronchodilator Agents; Calcium; Case-Control Studies; Chemokine CCL5; Female; Gene Expression Regulation; Humans; Male; Middle Aged; P-Selectin; Platelet Activating Factor; Platelet Activation; Theophylline; Thrombin; Thromboxane A2

A marked and sustained bronchoconstriction after antigen challenge was produced in actively sensitised guinea pigs, and correlated with increments of thromboxane (TX) A2 level in both the plasma and bronchoalveolar lavage fluid. DP-1904 given orally relieved the bronchoconstriction and increase in TXA2 in a dose-dependent manner. In platelet-depleted animals, antigen-induced bronchoconstriction and TXA2 release in the plasma were significantly reduced compared to those of non-platelet-depleted animals, indicating that platelets are a major cell source of TXA2 production, the remainder originating from the other cells excluding platelets. In the platelet-deprived animal, DP-1904 showed further significant inhibition of the constriction and plasma TXA2 level, and therefore likely inhibits TXA2 synthesis of various cells, including platelets, in the bloodstream. The results suggested that TXA2 is an important mediator responsible for producing antigen-induced bronchoconstriction, and endogenously originated from various cells including platelets in guinea pigs.

Topics: Animals; Anti-Asthmatic Agents; Antigens; Asthma; Blood Platelets; Enzyme Inhibitors; Guinea Pigs; Imidazoles; Male; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

There are substantial numbers of reports showing that leukotrienes (LTs) play important roles in adult asthma. No definite evidence has been demonstrated that LTs are involved in asthma attacks in children, although it is highly expected. In this report, we demonstrated that the levels of LTB4 and LTC4 but not thromboxane B2 (TXB2), a stable metabolite of TXA2, were significantly elevated in the bronchoalveolar lavage fluid, which was obtained from intubated and mechanically ventilated children with severe asthma attacks. This is direct evidence that LTB4 and LTC4 predominantly participate in asthma attacks in pediatric patients.

Topics: Adolescent; Asthma; Child, Preschool; Female; Humans; Leukotriene B4; Leukotriene C4; Male; Thromboxane A2

We examined effects of a thromboxane A2 (TXA2) antagonist seratrodast on airway hyperresponsiveness, exhaled nitric oxide (NO), and eosinophils in induced sputum in 14 asthmatics. Subjects were administered 80 mg of seratrodast once a day for 4 weeks. Respiratory conductance (Grs) was measured by the forced oscillation method and airway responsiveness was evaluated as the inhaled dose of methacholine, which induced 35% decrease in Grs. Subjects breathed into a Teflon bag, and NO concentration in the bag was measured by a chemiluminescence analyzer. Induced sputum comprised the entire expectorate produced during a 20 min inhalation of 3% saline, and was analyzed for total and differential cell counts. Airway hyperresponsiveness was significantly decreased by seratrodast. By contrast, no differences in either exhaled NO or percentage of eosinophils in sputum were observed before or after seratrodast. We conclude that seratrodast may attenuate airway hyperresponsiveness, presumably by antagonizing TXA2 released from the inflamed airways.

Topics: Anti-Asthmatic Agents; Asthma; Benzoquinones; Bronchial Hyperreactivity; Eosinophils; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Lung; Male; Methacholine Chloride; Middle Aged; Nitric Oxide; Prostaglandin Antagonists; Respiration; Sputum; Thromboxane A2

Ultrasonically nebulized distilled water-induced bronchoconstriction (UNDW-IB) is specific to asthma. The mechanisms underlying UNDW-IB are not fully understood, and no reproducible animal model has been reported. The purpose of this study was to develop a guinea-pig model of UNDW-IB. Ultrasonically nebulized distilled water (UNDW) was inhaled 20 min after an aerosolized antigen challenge in passively sensitized and artificially ventilated guinea-pigs. UNDW was also inhaled 5 and 20 min after 0.1 mg x mL(-1) methacholine inhalation in nonsensitized animals. In addition, 0.1 mg x kg(-1) S-1452, a thromboxane A2 antagonist, or saline was given intravenously 5 min before UNDW inhalation in sensitized animals. The inhalation of UNDW caused bronchoconstriction, when inhaled 20 min after an antigen challenge in sensitized guinea-pigs. UNDW inhalation did not produce bronchoconstriction after saline inhalation in nonsensitized or sensitized guinea-pigs, or after antigen inhalation in nonsensitized animals. Methacholine-induced bronchoconstriction did not evoke UNDW-IB. Neither did S-1452 reduce the UNDW-IB. In conclusion, the guinea-pig model of ultrasonically nebulized distilled water-induced bronchoconstriction developed in this study suggests that allergic reaction, but not bronchoconstriction, can induce bronchial hyperresponsiveness to ultrasonically nebulized distilled water, and that thromboxane A2 is not involved in ultrasonically nebulized distilled water-induced bronchoconstriction.

Topics: Administration, Inhalation; Albuterol; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Disease Models, Animal; Guinea Pigs; Male; Nebulizers and Vaporizers; Reference Values; Thromboxane A2; Water

We demonstrated the effect of a novel selective type IV phosphodiesterase (PDE) IV inhibitor, T-440 (1-[1-(2-methoxyethyl)pyrid-2-one-4-yl]-2,3-bis (hydroxymethyl)-6,7-diethoxynaphthalene), on antigen- and chemical mediator-induced bronchoconstrictions in anesthetized guinea pigs in vivo. Intravenously (i.v.) administered T-440 inhibited antigen-induced bronchoconstriction dose-dependently in passively sensitized guinea pigs (ED50 = 2.3 mg/kg). Histamine-, leukotriene (LT) D4-, U-46619-, acetylcholine (ACh)-, neurokinin A- and endothelin-1-induced bronchoconstrictions were also inhibited by i.v. injected T-440. Most potent suppression was produced against the bronchoconstriction induced by LTD4 (ED50 = 0.89 microgram/kg), whereas the effect against ACh was very weak (ED50 = 1.8 mg/kg). Additionally, T-440 inhibited histamine-induced bronchoconstriction by intraduodenal and intratracheal administration (ED50 and EC50 = 1.6 mg/kg and 0.50 mg/ml, respectively). Bronchoconstrictions induced by antigen and chemical mediators were also suppressed by theophylline. However, all of these anti-spasmolytic effects of theophylline were less potent than those of T-440 (1.8-110 times). Our results indicate the importance of PDE IV in bronchodilation, and PDE IV inhibitors may have potential as anti-asthma drugs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Asthma; Bronchoconstriction; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Antagonists; Injections, Intravenous; Leukotriene D4; Male; Naphthalenes; Phosphodiesterase Inhibitors; Prostaglandin Endoperoxides, Synthetic; Pyridones; Rabbits; Thromboxane A2; Vasoconstrictor Agents

Membrane-derived lipid mediators have been considered to play a major role in pathogenesis of bronchial asthma. However, the importance of and the interactions among each mediator are still unclear. We examined the role of thromboxane A2 (TXA2) and platelet-activating factor (PAF) in immediate asthmatic response (IAR) and interactions between these lipid mediators in guinea pig airway in vivo using a specific TXA2 antagonist S-1452 and a specific PAF antagonist Y-24180. We confirmed the activity of each antagonist, as S-1452 and Y-24180 significantly and dose-dependently inhibited bronchoconstriction induced by respective agonist inhalation. S-1452 inhibited IAR but Y-24180 did not, indicating that TXA2 plays a major role in IAR but PAF does not. S-1452 significantly inhibited PAF-induced bronchoconstriction but Y-24180 did not inhibit synthesized TXA2 (STA2)-induced bronchoconstriction, showing that the bronchoconstrictive effect of PAF is at least in part dependent on secondarily released TXA2, but TXA2 does not induce PAF production.

Topics: Administration, Inhalation; Animals; Antigens; Asthma; Azepines; Bridged Bicyclo Compounds; Bronchoconstriction; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Hypersensitivity; Male; Platelet Activating Factor; Receptors, Prostaglandin; Thromboxane A2; Triazoles

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can cause the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL-8 at a dose of 0.5 or 5 micrograms/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 micrograms/ml). The IL-8 treatment significantly enhanced bronchial responsiveness to histamine in a dose-dependent manner (ANOVA P < 0.01). The provocative concentration of histamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5 micrograms/kg of IL-8 was 68.1 (GSEM 1.12) and 35.6 (GSEM 1.25) micrograms/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [GSEM, 1.14] micrograms/ml). The IL-8 treatment also induced a significant influx of neutrophils, but not eosinophils, in bronchoalveolar lavage (BAL) fluid (18.3 +/- 8.8 and 30.6 +/- 8.3% in animals treated with 0.5 and 5 micrograms/kg, respectively, of IL-8 vs 3.6 +/- 0.7% in phosphate buffered saline-(PBS)-treated animals). Furthermore, we examined the effect of the thromboxane receptor antagonist S-1452 (0.01 or 0.1 mg/kg, i.p. 24 and 1 h before anesthesia) on this IL-8 induced BHR. S-1452 significantly inhibited the BHR dose-dependently (ANOVA P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intranasal; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Fatty Acids, Monounsaturated; Guinea Pigs; Interleukin-8; Male; Neutrophils; Receptors, Prostaglandin; Thromboxane A2

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

Etodolac, which inhibits the activity of cyclooxygenase, did not affect antigen-induced contractions of the trachea and lung parenchyma of guinea pigs. Indomethacin tended to enhance antigen-induced contractions of the trachea and significantly enhanced contractions of the lung parenchyma. The inhibitory activity of AA-861, a 5-lipoxygenase inhibitor, in antigen-induced contractions of the trachea and lung parenchyma was more potent than that of ozagrel, a thromboxane A2 (TXA2) inhibitor. Thus, lipoxygenase products played a more important role than TXA2 in antigen-induced contractions of the trachea and lung parenchyma. These results suggest that the enhancement of antigen-induced contractions by indomethacin might be due to an increase in anaphylactic release of lipoxygenase products through the inhibition of cyclooxygenase. Since etodolac did not enhance antigen-induced contractions, we attempted to determine whether or not etodolac inhibits 5-lipoxygenase. Etodolac was found to have no effect on 5-lipoxygenase activity. Therefore, the low adverse effect of etodolac on antigen-induced contractions of the airway may be due to its weak inhibition of cyclooxygenase in the airway. These results suggest that etodolac would have only a very slight, if any, adverse effect on the airway in patients with asthma.

Topics: Animals; Asthma; Benzoquinones; Disease Models, Animal; Etodolac; Guinea Pigs; Immunization, Passive; Indomethacin; Isoantigens; Lipoxygenase Inhibitors; Lung; Methacrylates; Muscle Contraction; Muscle, Smooth; Rabbits; Serum Albumin, Bovine; Thromboxane A2; Trachea

1. IgG1-mediated anaphylactic bronchoconstriction was elicited by intravenous administration of antigen to guinea-pig 2 days after passive sensitization with IgG1-rich serum, and this response was not affected by heating the serum (at 56 degrees C, for 4 h). IgE-mediated bronchoconstriction, provoked 14 days after passive sensitization with IgE-rich serum, was completely abolished by the heating of the serum. 2. S-1452 (10 mg kg-1, p.o.), a selective thromboxane (Tx) A2 antagonist, significantly but incompletely suppressed the IgG1-mediated bronchoconstriction, but did not affect the IgE-mediated one, while diphenhydramine (5 mg kg-1, i.v.), a histamine antagonist, almost completely inhibited both IgG1- and IgE-mediated bronchoconstriction. 3. Pretreatment with propranolol (1 mg kg-1, i.v.), a beta-adrenergic blocker, in addition to diphenhydramine, caused a long-lasting bronchoconstriction following antigen challenge in both animal models. This histamine-independent bronchoconstriction was markedly suppressed by S-1452 at a low dose of 0.1 mg kg-1. 4. A significant increase in bronchial responsiveness to i.v. acetylcholine (ACh), compared to the prechallenge value, occurred as early as 3 min and persisted for 24 h after antigen challenge in the IgG1 model, but was not observed in the IgE model. S-1452 (10 mg kg-1, p.o.) inhibited the IgG1-mediated bronchial hyperresponsiveness, as assessed 60 min after antigen challenge. 5. A marked elevation of TxB2 levels was observed in bronchoalveolar lavage fluid (BALF) 3 min after antigen challenge in the IgG1 model, while levels were not changed in the IgE model. In contrast, the plasma TxB2 level assessed 1 min after antigen challenge was increased in both the IgGI and IgE models.6. The results indicate that the inhibition of IgGl- but not IgE-mediated bronchoconstriction by higher doses of S-1452 may result from the suppression of increased bronchial responsiveness to allergic mediators such as histamine, which is probably due to TxA2 generated in the airway lumen rather than in plasma. In both the IgGI and IgE models, plasma TxA2 appeared to contribute directly to the bronchoconstriction, its action being almost completely masked by histamine-mediated bronchoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic beta-Antagonists; Animals; Antibodies, Monoclonal; Antigens; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoconstriction; Diphenhydramine; Fatty Acids, Monounsaturated; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; Receptors, Prostaglandin; Thromboxane A2; Thromboxane B2

Synthesis and pharmacological evaluation of several compounds related to 2-[2-(1-imidazolyl)ethyl]-4-(3-pyridyl)-1(2H)-phthalazinones are described. The phenyl moiety of the phthalazinone skeleton was found to play an important role in both thromboxane A2 synthetase-inhibitory and bronchodilatory activities. Further, the 3-pyridyl group at the 4-position was shown to be necessary for in vivo thromboxane A2 synthetase-inhibitory activity.

Topics: Animals; Asthma; Bronchodilator Agents; Guinea Pigs; Imidazoles; In Vitro Techniques; Male; Phthalazines; Rabbits; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thromboxane A2; Thromboxane-A Synthase

Airway reactivity to bronchoconstrictor mediators changes with age. We studied the effects of maturational change on airway responses induced by a thromboxane A2 mimetic, U-46619 (2, 6 and 20 nmol/kg; i.v.), leukotriene D4 (0.6 and 2 nmol/kg; i.v.) or vehicle (0.9% NaCl; i.v.) in immature (196 +/- 3 g: 2 weeks) and adult guinea pigs (512 +/- 5 g: 11 weeks). In the same animals, we measured both lung resistance (RL) to monitor airflow obstruction and extravasation of Evans Blue dye (20 mg/kg) to quantify airway plasma exudation. For a comparison, changes in RL in response to acetylcholine (5, 15 and 50 nmol/kg; i.v.) were also examined in both age groups. The order of potency to induce an increase in RL did not change with age (leukotriene D4 > U-46619 > acetylcholine). In immature animals, the peak RL after U-46619 (2, 6 and 20 nmol/kg; P < 0.05, P < 0.005 and P < 0.01, respectively) and leukotriene D4 (2 nmol/kg; P < 0.01) was significantly higher than in adult animals. U-46619 and leukotriene D4 produced significant extravasation of Evans Blue dye in both immature and adult animals. The order of potency to induce extravasated dye also did not change with age (leukotriene D4 > U-46619). The amount of extravasation of Evans Blue dye after U-46619 (6 and 20 nmol/kg) and leukotriene D4 (0.6 and 2 nmol/kg) was significantly smaller in immature animals than adults at all airway levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Asthma; Blood Pressure; Capillary Permeability; Eicosanoids; Evans Blue; Guinea Pigs; Leukotriene D4; Male; Prostaglandin Endoperoxides, Synthetic; Respiratory Function Tests; Respiratory System; Thromboxane A2; Vasoconstrictor Agents

Long-lasting bronchial hyperresponsiveness to i.v. acetylcholine was observed in actively sensitized guinea-pigs after aerosol ovalbumin exposure. The response became significant at 7 h post-challenge and persisted for at least 120 h compared to the response of unsensitized animals. Pretreatment of animals with the specific thromboxane A2 receptor antagonist, S-1452 (calcium (1R,2S,3S,4S)-(5Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1] hept-2-yl)hept-5-enoate dihydrate), almost completely inhibited the onset of bronchial hyperresponsiveness, as assessed at 24 and 120 h post-challenge. However, it was ineffective when administered at 1 h post-challenge or 2 h before assessment of bronchial responsiveness. Lung vascular injury occurred transiently immediately after antigen challenge, the kinetics of injury being associated with those for the production of thromboxane B2 in bronchoalveolar lavage fluid. The vascular injury was dramatically suppressed by pretreatment with S-1452. These findings suggest that acutely generated thromboxane A2 plays an important role in the pathogenesis of antigen-induced long-lasting bronchial hyperresponsiveness, probably by producing vascular damage in the lungs.

Topics: Acetylcholine; Administration, Inhalation; Aerosols; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelium, Vascular; Fatty Acids, Monounsaturated; Guinea Pigs; Immunization; Injections, Intravenous; Lung; Male; Ovalbumin; Prostaglandins; Pulmonary Artery; Receptors, Prostaglandin; Thromboxane A2

Although it is well recognized that beta-blockers can induce bronchoconstriction only in patients with asthma, mechanisms of the bronchoconstriction are not well known. We hypothesize that bronchoconstriction induced by beta-blockers may result from inflammatory mediators released by allergic reactions. In this study, we developed a guinea pig model for propranolol-induced bronchoconstriction (PIB) after antigen inhalation and investigated the effect of specific thromboxane (TXA2) receptor antagonists, S-1452 and ONO NT-126, on PIB in passively sensitized and artificially ventilated guinea pigs to determine whether TXA2 is involved in PIB. Propranolol caused bronchoconstriction with 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. On the other hand, propranolol did not produce bronchoconstriction after antigen provocation in nonsensitized guinea pigs or after saline provocation in sensitized animals. Pretreatment of the animals with S-1452 in doses of 0.01 and 0.1 mg/kg and ONO NT-126 in doses of 1.0 and 10 micrograms/kg injected intravenously 15 min after antigen challenge as well as before antigen challenge reduced PIB in a dose-dependent manner. Bronchoconstriction caused by methacholine did not induce PIB. These results suggest that TXA2 has an important role in the pathophysiology of the PIB that develops after the allergic bronchoconstriction.

Topics: Administration, Inhalation; Analysis of Variance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Provocation Tests; Constriction, Pathologic; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Hypersensitivity; Inflammation; Injections, Intravenous; Male; Methacholine Chloride; Premedication; Propranolol; Receptors, Prostaglandin; Thromboxane A2; Time Factors

We established an experimental model of late asthmatic response (LAR) using conscious guinea pigs actively sensitized by antigen aerosol inhalation. In actively sensitized guinea pigs, antigen challenge by aerosol inhalation caused an immediate increase in specific airway resistance (SRaw) (immediate airway response; IAR) followed by a LAR which occurred 4 to 8 hr after antigen challenge. SRaw in the challenged animals was still increased 23 hr after antigen challenge. Examination of bronchoalveolar lavage (BAL) fluid and histology of the lungs revealed increases in eosinophils and neutrophils during LAR. The beta-2 agonist salbutamol inhibited only IAR and not LAR. Dexamethasone inhibited LAR but not IAR. A low dose of theophylline had little effect on both IAR and LAR. A novel thromboxane A2 (TXA2) receptor antagonist, AA-2414, orally administered before antigen challenge dose-dependently inhibited both IAR and LAR, and oral administration of AA-2414 after the IAR inhibited LAR. Also, thromboxane synthetase inhibitors, CV-4151 and OKY-046, reduced both IAR and LAR. Salbutamol significantly reduced the increase in neutrophils in BAL fluid, and dexamethasone significantly reduced the increase in eosinophils and neutrophils in BAL fluid. Theophylline also reduced the increase in eosinophils in BAL fluid. However, AA-2414 did not inhibit the accumulation of these inflammatory cells in BAL fluid or the airway tissues. These results suggest that asthmatic responses in guinea pigs are similar to those in asthmatic subjects and that TXA2 plays an important role in both IAR and LAR but not in inflammatory cell infiltration in this model of allergic asthma.

Topics: Acetylcholine; Airway Resistance; Animals; Antibodies; Asthma; Benzoquinones; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Fatty Acids, Monounsaturated; Guinea Pigs; Heptanoic Acids; Leukocytes; Male; Methacrylates; Ovalbumin; Pyridines; Theophylline; Thromboxane A2

The human thromboxane A2 receptor (TXA2-R)-coding gene was introduced into Chinese hamster ovary cells and a cell line (TCHO-25) stably expressing TXA2-R, at a level of 3 x 10(5)/cell, was obtained. An anti-asthmatic agent AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid] competitively inhibited the specific binding of a TXA2 mimic ([3H]U-46619) to the TCHO-25 cells, with an IC50 of 6.0 x 10(-8) M, indicating that the drug is an antagonist of human TXA2-R. The TCHO-25 cells offer a tool for the screening and characterization of human TXA2-R antagonists.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Benzoquinones; Binding, Competitive; CHO Cells; Cloning, Molecular; Cricetinae; Guinea Pigs; Heptanoic Acids; Humans; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Plasmids; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Thromboxane A2; Trachea

The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a thromboxane A2 synthase inhibitor, on eosinophil accumulation and activation were investigated in an experimental asthmatic guinea pig model and several cellular models. In the in vivo studies, CS-518 inhibited the biphasic eosinophil accumulation in the bronchoalveolar lavage fluid, potently in the early phase, but less potently in the delayed phase. On the other hand, even at the lower dose, CS-518 completely inhibited the hypodensity of eosinophils in the delayed phase. In the in vitro studies, CS-518 suppressed thromboxane A2 production and potentiated prostaglandin I2 production from guinea pig eosinophils. Moreover, CS-518 and prostaglandin I2 suppressed chemotaxis, peroxidase release and superoxide generation in guinea pig eosinophils. In addition, the present studies provide further support for the possibility that thromboxane A2 and prostaglandin I2, which are produced in bronchoalveolar tissue and within eosinophils, are involved in modulation of eosinophil function and suggest that CS-518 is a potent inhibitor of eosinophil activation.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Eosinophils; Epoprostenol; Guinea Pigs; In Vitro Techniques; Male; Peroxidases; Platelet Activating Factor; Pulmonary Alveoli; Superoxides; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

The study revealed the relation of bronchial asthma (bacterial variant) clinical pattern to plasma levels of PGF2 alpha, 6-keto-PGF1 alpha and TxB2. In remission of the disease the above indices are lower. Severe asthma remission is characterized by higher levels of 6-keto-PGF1 alpha and TxB2 than moderate asthma one, demonstrates a tendency to growing PGF2 alpha levels. A rise in PGF2 alpha and TxB2 in manifest asthma points to their participation in bronchospasm formation suggesting an active role of these bronchoconstrictors in asthma pathogenesis. Higher levels of 6-keto-PGF1 alpha are of a compensary nature in the pathogenesis of PGF2 alpha and TxB2 bronchoconstrictory action, and of damaging nature contributing to the formation of bronchial mucosa edema and bronchial gland hypersecretion.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Asthma; Dinoprost; Female; Humans; Male; Middle Aged; Remission Induction; Severity of Illness Index; Thromboxane A2

The anti-asthmatic effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a specific thromboxane A2 (TXA2) synthase inhibitor, were investigated in the ovalbumin-sensitized guinea pig asthmatic model. Although CS-518 slightly inhibited (about 25%) whole bronchoconstriction, it significantly inhibited the antigen-induced bronchoconstriction mediated by slow-reacting substance of anaphylaxis (SRS-A), which was not reduced by chlorpheniramine, a histamine H1 antagonist. On the other hand, indomethacin, a cyclooxygenase inhibitor, potentiated the SRS-A-mediated constriction. CS-518 strongly, and indomethacin slightly, suppressed the leukotriene D4-induced bronchoconstriction. CS-518 clearly inhibited the antigen-induced airway hyperresponsiveness, but this compound had no effect on the airway hyperresponsiveness induced by U-46619, a TXA2-mimetic agent, and propranolol. These results suggest that CS-518 suppresses the development of bronchoconstriction and airway hyperresponsiveness in asthmatic models by inhibition of TXA2 synthesis with the concomitant increase in bronchodilating prostaglandins such as prostaglandin E2 and prostaglandin I2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Chlorpheniramine; Disease Models, Animal; Guinea Pigs; Indomethacin; Male; Methacrylates; Ovalbumin; Propranolol; Prostaglandin Endoperoxides, Synthetic; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

The effect of the specific thromboxane (Tx)A2 receptor antagonist, BAY u 3405 on the late asthmatic response (LAR) was investigated in guinea pigs which are sensitized actively with Ascaris suum antigen. Respiratory resistance (Rrs) of awake guinea pigs was measured by 30 Hz oscillation method for 6 hours after antigen challenge. %Rrs was calculated as the increase rate of Rrs to baseline Rrs (pre-challenge value). Ten mg/kg of BAY u 3405 or vehicle (0.5% methyl cellulose) was administered orally after the end of immediate asthmatic response, i.e., 2 hours after antigen challenge. %Rrs of the control group at 4 and 5 hours after antigen challenge were 101.4 +/- 27.5% and 77.5 +/- 19.9%, respectively. Those of the BAY group were 32.5 +/- 6.2% and 23.5 +/- 5.0%, respectively. %Rrs of the BAY group were significantly lower than those of the control group at both timings (p < 0.05). No significant difference was shown between the BAY group and the control group in the results of the bronchoalveolar lavage (BAL) 4 hours after challenge. Concerning the results of BAL at 6 hours after challenge, the total cell count and its segment, eosinophils count and lymphocytes count in the BAY group were 274.9 +/- 70.5, 62.5 +/- 13.1, 11.3 +/- 3.3 (x 10(5) cells), respectively, resulting in significantly smaller numbers (each p < 0.05) than those in the control group which were 491.9 +/- 55.1, 198.6 +/- 43.9, 32.1 +/- 7.3 (x 10(5) cells), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Airway Resistance; Animals; Asthma; Bronchoalveolar Lavage Fluid; Carbazoles; Guinea Pigs; Leukocyte Count; Lung; Male; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

Thromboxane A2 (TxA2) has been implicated in airway responses to allergen and in the bronchial hyperresponsiveness observed in asthma. Furthermore a TxA2 receptor antagonist and a TxA2 synthase inhibitor inhibit plasma exudation in airways induced by inhaled platelet-activating factor. To evaluate whether TxA2 has any direct effect on plasma exudation in the airways, we studied the effect of a stable TxA2 mimetic (U-46619; 2, 20, and 200 nmol/kg iv) on lung resistance (RL) and Evans blue dye extravasation (marker of plasma albumin; 20 mg/kg iv) at the airway levels of trachea, main bronchi, and proximal and distal intrapulmonary airways in anesthetized, tracheostomized, and mechanically ventilated guinea pigs. Injection of U-46619 produced an immediate and marked dose-dependent increase in RL, which peaked at approximately 30 s. At the highest dose of U-46619, we also observed a later increase in RL, starting at approximately 3 min and reaching a second peak at approximately 8 min. Mean systemic blood pressure increased in a dose-dependent manner [maximum 82 +/- 8 (SE) mmHg]. U-46619 also produces dose-dependent plasma exudation, measured as Evans blue dye extravasation, at all airway levels as well as into the tracheal lumen. Airway responses to U-46619 (200 nmol/kg iv) were abolished in animals pretreated with the TxA2 receptor antagonist ICI-192605 (0.5 mg/kg iv). We conclude that U-46619, despite being a vasoconstrictor, is potent in inducing plasma exudation in airways and that this effect is mediated via a TxA2 receptor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Asthma; Dioxanes; Exudates and Transudates; Guinea Pigs; Plasma; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Receptors, Prostaglandin; Receptors, Thromboxane; Respiratory Physiological Phenomena; Respiratory System; Thromboxane A2; Vasoconstrictor Agents

We examined the effect of a potent thromboxane (Tx) A2 receptor antagonist, calcium (1R, 2S, 3S, 4S)-(5Z)-7-(((phenylsulfonyl)amino)bicyclo[2.2.1] hept-2-yl)-5-heptenoate dihydrate (S-1452), on antigen- and various allergic-spasmogen-induced contractions of guinea pig lung parenchymal strips and on the increase in insufflation pressure, an index of bronchoconstriction, in anesthetized guinea pigs. In isolated guinea pig lung parenchymal strips, S-1452 showed competitive antagonism of the contractile activity of U-46619, a TxA2 mimetic, with a pA2 value of 8.9. The compound also inhibited the contraction induced by prostaglandin (PG) D2 and PGF2 alpha, but a TxA2 synthetase inhibitor, OKY-046, did not. In contrast, both drugs inhibited not only leukotriene (LT) D4-induced contraction but also antigen-induced contraction in the presence of a histamine antagonist. In anesthetized guinea pigs, oral administration of S-1452 markedly inhibited the bronchoconstrictions induced by intravenous injection of U-46619, PGD2, PGF2 alpha, LTD4 and platelet-activating factor (PAF) with ED50 values of 0.006, 0.031, 0.112, 0.033 and 0.115 mg/kg, respectively, but OKY-046 inhibited only that by LTD4 and PAF. Additionally, bronchoconstriction following intravenous injection of antigen was almost completely suppressed by S-1452 (0.1 mg/kg) and partially by OKY-046 (300 mg/kg) in passively sensitized guinea pigs which were treated with diphenydramine and propranolol. The inhibitory effect of S-1452 against U-46619-induced broncho-constriction persisted up to 7 h after oral administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Asthma; Bridged Bicyclo Compounds; Bronchoconstriction; Fatty Acids, Monounsaturated; Guinea Pigs; In Vitro Techniques; Lung; Male; Methacrylates; Muscle Contraction; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Thromboxane A2

In the present study, we investigated (1) whether airway responsiveness to inhaled histamine-aerosol could be induced during 7-d exposure of guinea pigs to 4 ppm NO2 and, if so, (2) whether thromboxane A2 may be involved in such increase. Female Hartley guinea pigs were divided into 6 groups (n = 15/group). Three groups were exposed to filtered air and the other 3 groups were exposed to NO2 for 1, 3, or 7 d (24 h/d). Baseline specific airway resistance (SRaw0) did not change significantly after exposure to 4 ppm NO2 or air. Airway responsiveness was determined 1 wk before the beginning of exposure and on the day of termination of the exposure. Prior to exposure to NO2, the EC200His, the concentrations of inhaled histamine necessary to double SRawNaCl (SRaw after inhalation of 0.9% NaCl), were 1.07 +/- 0.20, 1.30 +/- 0.20, and 1.01 +/- 0.18 mM for the 3 groups later given NO2 for 1, 3, and 7 d, respectively. Following exposure to NO2 for 1, 3, or 7 d, EC200His values were 1.42 +/- 0.25, 0.66 +/- 0.10 (p < .05), and 1.05 +/- 0.22 mM, respectively. These results show that 7-d exposure to 4 ppm NO2 induced a significant increase in airway responsiveness on d 3. Exposure to air had no significant effect on the airway responsiveness. This transient hyperresponsiveness was inhibited by a specific inhibitor of thromboxane synthetase, OKY 046. These results indicated that (1) a lower concentration (4 ppm) of NO2 than that previously reported can induce transient hyperresponsiveness in guinea pigs during appropriate long-term exposure, and (2) thromboxane A2 may play an important role in this transient airway hyperresponsiveness.

Topics: Administration, Inhalation; Air Pollutants; Airway Resistance; Animals; Asthma; Bronchial Hyperreactivity; Drug Hypersensitivity; Female; Guinea Pigs; Histamine; Lung; Methacrylates; Nitrogen Dioxide; Thromboxane A2; Thromboxane-A Synthase; Time Factors

Effects of a thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) were investigated in anesthetized, artificially ventilated guinea pigs in order to examine the role of the cyclooxygenase pathway in bronchial hyperresponsiveness. Pretreatment with aerosolized OKY-046 significantly inhibited the bronchial hyperresponsiveness to histamine, but pretreatment with intravenous indomethacin showed a tendency to potentiate bronchial hyperresponsiveness. These results suggest that subthreshold concentration of thromboxane A2 contributes to bronchial hyperresponsiveness through activating the cyclooxygenase pathway including thromboxane A2 synthesis, and that the released cyclooxygenase products have an inhibitory effect on the bronchial hyperresponsiveness in guinea pigs.

Topics: Aerosols; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Dose-Response Relationship, Drug; Guinea Pigs; Indomethacin; Male; Methacrylates; Thromboxane A2

Prostaglandin D2 (PGD2) and thromboxane A2 (TXA2) have been suggested to play important roles in the pathogenesis of bronchial asthma. In the present study, effects of i.v.-administration of PGD2 on bronchial hyperresponsiveness in guinea pigs were investigated by the measurement of dynamic compliance and dynamic respiratory resistance with formulae which can exclude the effects of changes of the airway wall thickness. With these formulae, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of PGD2 induced airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was enhanced with the administration of PGD2. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of PGD2 administration.

Topics: Airway Resistance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Edema; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Infusions, Intravenous; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin D2; Thromboxane A2

Thromboxane A2(TxA2) has been implicated in the pathogenesis of airway hyperresponsiveness. The effects of inhaled TxA2 on human airway function have not been studied because of its short half-life. U46619 is a chemical that mimics the effects of TxA2. The purpose of this study was to evaluate the effects of inhaled U46619 on human airway function and methacholine airway responsiveness. Airway responsiveness to methacholine and U46619 was measured in 19 subjects (13 asthmatic and six normal) and expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). On one day, methacholine alone was inhaled. On a second day, U46619 was inhaled, then 1 h later methacholine was inhaled. On a third day, U46619 was inhaled, then repeated 1 h later. In six subjects, the effects of isotonic saline or a subthreshold concentration of histamine or U46619 were examined on methacholine airway responsiveness. U46619 was 178 times more potent as a bronchoconstrictor than was methacholine. Airway responsiveness to methacholine was correlated to airway responsiveness to U46619 (r = 0.87, p = 0.001). Subthreshold concentrations of U46619, but not of histamine, increased methacholine airway responsiveness. The mean maximal fall in FEV1 after inhaled methacholine was 13.2% (SEM, 3.4%) after saline, 12.4% (SEM, 2.4%) after histamine, and 25.7% (SEM, 2.0%) after U46619 (p = 0.0004). This effect lasted less than 1 h. There was no tachyphylaxis to repeated inhalations of U46619. These results indicate that in human subjects inhaled U46619 is a potent bronchoconstrictor that, when present in the airways, can cause airway hyperresponsiveness to inhaled methacholine in asthmatic subjects.

Topics: Aerosols; Asthma; Blood Pressure; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Female; Heart Rate; Humans; Male; Methacholine Chloride; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2

A study was made of the effect of ketotifen on the concentration of leukotriene B4, prostacyclin and thromboxane A2 in the liquid of bronchoalveolar lavage and on external respiration and cellular immunity during 4 weeks of the treatment of patients with infection-dependent bronchial asthma and chronic obstructive bronchitis. Inclusion of ketotifen into the treatment of patients with bronchial obstruction exerts a stimulating action on the suppressor component of T-cell immunity, leads to a decrease of the content of leukotriene B4 and thromboxane A2 in the lavage liquid, which is accompanied by positive shifts in the clinical course of the broncho-obstructive syndrome. Ketotifen turned out most effective in patients with an initially low content of the subpopulation of T suppressors and with high concentrations of leukotriene B4 and thromboxane A2 in the liquid of bronchoalveolar lavage.

Topics: Adult; Asthma; Bronchi; Bronchitis; Bronchoalveolar Lavage Fluid; Chronic Disease; Eicosanoids; Epoprostenol; Female; Humans; Ketotifen; Leukotriene B4; Male; Middle Aged; Thromboxane A2

Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.

Topics: Administration, Inhalation; Adult; Airway Resistance; Asthma; Bronchoconstrictor Agents; Eicosanoids; Endothelium, Vascular; Epoprostenol; Female; Humans; Leukotriene E4; Leukotrienes; Male; Methacholine Compounds; Platelet Activating Factor; Prostaglandins; SRS-A; Stimulation, Chemical; Thromboxane A2

Effects of a thromboxane A2 receptor antagonist (S-1452) on bronchoconstriction induced by inhaled leukotriene C4 and a leukotriene receptor antagonist (AS-35) on bronchoconstriction caused by inhalation of a thromboxane A2 mimetic (STA2) were studied in anesthetized, artificially ventilated guinea pigs in order to examine the interaction of thromboxane A2 and leukotrienes in airways. 0.01-1.0 mu g/ml of leukotriene C4 and 0.1-1.0 mu g/ml of STA 2 inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at the airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with inhaled S-1452 (0.01, 0.033 mg/ml) significantly reduced the airway responses produced by 0.01,0.033,0.1,0.33 and 1.0 mu g/ml of leukotriene C4 in a dose dependent manner. While pretreatment with inhaled AS-35 (1mg) did not affect the STA2 dose-response curve. These findings suggest that leukotriene C4 activates thromboxane A2 generation while thromboxane A2 does not influence 5-lipoxygenase pathway in the airways.

Topics: Administration, Inhalation; Animals; Asthma; Bridged Bicyclo Compounds; Bronchoconstriction; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Male; Pyridines; Pyrimidines; Pyrimidinones; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; Tetrazoles; Thromboxane A2

Upon comparison of functional activity of platelets and their response to aspirin in 20 subjects with aspirin bronchial asthma, 19 patients with non-aspirin bronchial asthma and 21 healthy controls it was found out that in aspirin asthma platelet count is elevated, their response to aggregation inductors enhances while to aspirin is abnormal, plasmic thromboxane level is reduced. Aspirin asthma patients are believed to have a specific platelet defect.

Topics: Aspirin; Asthma; Epoprostenol; Humans; In Vitro Techniques; Platelet Aggregation; Platelet Count; Platelet Function Tests; Stimulation, Chemical; Thromboxane A2

Thromboxane A2 (TXA2) has been suggested to play an important role in the pathogenesis of bronchial asthma. In this study the effects of intravenous administration of TXA2 on bronchial smooth muscle in guinea-pigs were investigated by measuring dynamic compliance and dynamic respiratory resistance, using a formula to exclude the effects of differences in airway wall thickness. Using this formula, the ratio of bronchial smooth muscle constriction by histamine can be estimated as an index of bronchial hyperresponsiveness. Administration of TXA2 did not induce airway wall edema. The ratio of bronchial smooth muscle constriction by histamine was significantly (p less than 0.01) enhanced by the administration of TXA2. Moreover, TXA2 antagonists, ONO-NT-126 and ONO-8809, inhibited the effect of TXA2 administration. These results suggest that TXA2 is an important mediator affecting bronchial hyperresponsiveness.

Topics: Airway Resistance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Lung Compliance; Muscle Contraction; Muscle, Smooth; Thromboxane A2

Thromboxane A2 is a potent bronchial smooth muscle spasmogen in vitro, and it has been implicated in airway inflammation and in the genesis of bronchial hyperresponsiveness in asthma. We have examined the urinary excretion of a variety of products derived from thromboxane A2 (thromboxane B2, 2,3-dinor, and 11-dehydro-thromboxane B2) and prostacyclin (6-oxo-PGF1 alpha and 2,3-dinor-6-oxo-PGF1 alpha) using gas chromatography-mass spectrometry in patients admitted acutely to hospital with severe asthma and in atopic volunteers after bronchial antigen challenge. Urinary excretion of all thromboxane-derived products was markedly increased in a number of patients with severe acute asthma compared with that in a nonsmoking control population, in some cases approaching those previously described in myocardial infarction: TXB2, 31.6 +/- 12.0 versus 6.5 +/- 0.9; 2,3-dinor-TXB2, 79.0 +/- 19.2 versus 29.5 +/- 2.7; and 11-dehydro-TXB2, 234.3 +/- 65.3 versus 25.0 +/- 2.1 ng/mmol creatinine (p less than 0.001). Urinary prostacyclin-derived products were also significantly raised in acute asthma. In contrast, after inhaled allergen challenge in atopic volunteers, which caused significant bronchoconstriction, urinary excretion of thromboxane-derived products was not significantly elevated: TXB2, 5.6 +/- 1.1 versus 5.7 +/- 1.0; 2,3-dinor-TXB2, 41.2 +/- 12.5 versus 28.5 +/- 6.9; and 11-dehydro-TXB2, 69.8 +/- 17.6 versus 39.7 +/- 11.2 ng/mmol creatinine. In a separate experiment, less than 2% of exogenously administered TXB2 to the airway appeared as urinary thromboxane-derived products, suggesting that production of greater than or equal to 1 microgram of TXA2 in vivo would be required to increase urinary thromboxane excretion twofold.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Aged; Allergens; Asthma; Bronchial Provocation Tests; Female; Humans; Male; Middle Aged; Prostaglandins; Thromboxane A2

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness is specific to asthma, we examined the effects of a selective thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in patients with bronchial asthma and chronic bronchitis. The provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and after oral administration of OKY-046 and indomethacin in eight asthmatic and 10 bronchitic subjects. Baseline FEV1 value was not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in bronchitic subjects. On the other hand, PC20-FEV1 was not altered by indomethacin in all subjects. It was concluded that the involvement of thromboxane A2 in bronchial hyperresponsiveness may be specific to asthma.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Bronchitis; Chronic Disease; Female; Humans; Male; Methacholine Chloride; Methacholine Compounds; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness (BHR) is specific to asthma, we examined the effects of a selective inhibitor of thromboxane synthetase (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in normal subjects and patients with chronic bronchitis, diffuse bronchiectasis, and intrinsic bronchial asthma. The provocative concentration of methacholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) was measured before and after oral administration of OKY-046 (2,600 mg over four days) and indomethacin (450 mg over three days) in ten normal, ten bronchitic, nine bronchiectatic, and eight asthmatic subjects, respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in normal, bronchitic, or bronchiectatic subjects. On the other hand, PC20-FEV1 increased significantly (p less than 0.005) from 2.19 to 8.13 mg/ml after indomethacin in bronchiectatic subjects, but not in normal, bronchitic, or asthmatic subjects. We conclude that the involvement of thromboxane A2 in BHR may be specific to asthma, and bronchial responsiveness of bronchiectasis may be potentiated by inflammatory release of bronchoconstrictor prostaglandins except for thromboxane A2. Further studies using thromboxane A2 receptor antagonists are needed to confirm the conclusion.

Topics: Acrylates; Asthma; Bronchi; Bronchial Provocation Tests; Bronchiectasis; Bronchitis; Female; Forced Expiratory Volume; Humans; Indomethacin; Male; Methacholine Chloride; Methacholine Compounds; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane-A Synthase; Vital Capacity

We studied the inhibitory effects of OKY-046.HCl on PAF-induced airway hyperresponsiveness (AHR) in guinea pigs. 1) Inhalation of PAF (1 or 10 micrograms/ml) caused AHR to acetylcholine (ACh) aerosol and increased TXB2 generation in broncho-alveolar lavage fluid (BALF) at 30 min and 60 min, but the AHR and the TXB2 generation disappeared at 2 hr. OKY-046.HCl (100 mg/kg, intraduodenally) inhibited the AHR, which was accompanied by its inhibition of the TXB2 generation. However, no changes of 6-keto-PGF1 alpha in BALF were found. 2) There were no changes in the number of leukocytes; the activities of alkaline phosphatase, N-acetyl-beta-D-glucosaminidase, and lactate dehydrogenase; and the LTC4/D4/E4 in BALF. 3) In bronchus-lung preparations, PAF (1 microgram/min) also caused the AHR and increased TXB2 generation. OKY-046.HCl (100 micrograms/min) inhibited the AHR and TXB2 generation. 4) PAF (1 microgram/ml) evoked TXB2 generation in BALF from normal guinea pigs. OKY-046.HCl (10(-4)M) inhibited its increase. 5) Stable TXA2 (STA2, 1 ng/ml) inhalation also caused AHR to ACh at 30 min. STA2 (0.45 ng/min) also caused the AHR in bronchus-lung preparations. These results suggest that OKY-046.HCl can inhibit PAF-induced AHR by suppressing the generation of TXA2. We also supposed that TXA2 is released from lung parenchyma, airway epithelium and cell components in BALF.

Topics: Acrylates; Animals; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; In Vitro Techniques; Male; Methacrylates; Platelet Activating Factor; Thromboxane A2; Thromboxane-A Synthase

To elucidate the possible involvement of thromboxane A2 (TxA2) in airway hyperresponsiveness, we examined the effect of OKY-046, a potent and selective inhibitor of TxA2 synthetase, on airway hyperresponsiveness induced by ozone exposure in dogs. Ozone exposure (3 ppm, 2 hr) markedly increased airway responsiveness to inhaled methacholine without affecting basal respiratory resistance. Although ozone also caused a slight but significant increase in neutrophil number in the bronchoalveolar lavage fluid, there was no correlation between the level of airway hyperresponsiveness and increased neutrophil number. Although OKY-046 significantly inhibited the increases in airway hyperresponsiveness in a dose-dependent manner at doses ranging from 100 to 300 mg/kg, p.o., the compound did not affect the basal airway responsiveness and respiratory resistance at 300 mg/kg, p.o. Inhalation of the subthreshold concentration (i.e., the highest dose which did not cause bronchoconstriction) of STA2 (a stable TxA2 mimetic agent) elicited a significant increase in airway responsiveness to methacholine. These results suggest that TxA2 may play a role in mediating ozone-induced airway hyperresponsiveness. However, the accumulation of neutrophils in the airway lumen may not be essential for the development of airway hyperresponsiveness.

Topics: Acrylates; Animals; Asthma; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Methacrylates; Ozone; Thromboxane A2; Thromboxane-A Synthase

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Animals; Asthma; Biphenyl Compounds; Bronchi; Dinoprost; Guinea Pigs; Heptanoic Acids; Histamine; Humans; Male; Methacholine Compounds; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

LG 30435 is a new quarternary phenothiazine derivative with H1-antihistaminic and antimuscarinic properties. The ability of LG 30435 to prevent changes in respiratory mechanics, induced by different mediators and the immunological reaction, was monitored together with biological and radioimmunological determination of circulating thromboxane-A2 (TxA2) in anaesthetized guinea-pigs. LG 30435 dose-dependently reduces the bronchoconstriction and TxA2 generation caused by different stimuli such as histamine, acetylcholine, leukotriene C4 (LTC4) and PAF-acether. In addition i.v. and aerosol administration of LG 30435 causes a dose-dependent reduction of the increase in airway resistance and TxA2 generation induced by ovalbumin challenge in actively sensitized animals. LG 30435 infused at different concentrations through the isolated guinea-pig lungs inhibits the TxB2 generation caused by different anaphylactic mediators, but not by arachidonic acid. These data, which further substantiate the bronchodilator activity of LG 30435 against a variety of stimuli and demonstrate its protective properties on lung anaphylaxis, suggest that this compound has a potential therapeutic value in the treatment of asthma.

Topics: Anaphylaxis; Animals; Asthma; Bronchial Spasm; Bronchodilator Agents; Dose-Response Relationship, Drug; Guinea Pigs; Male; Phenothiazines; Respiratory Mechanics; Thromboxane A2

We have demonstrated that PGF2 alpha potentiates airway contraction in vitro and suggested that this response may be mediated by TxA2. We have localized the site of action of PGF2 alpha to a point distal to the parasympathetic ganglion and shown that it is a specific effect since PGD2 produces no similar potentiation. The mechanism of the potentiation may be by a direct alteration in smooth muscle sensitivity induced by TxA2 (Fig. 4). In our previous studies we have been able to induce hyperresponsiveness in vivo (Berend et al., 1986) but no increased responsiveness in vitro (Armour et al., 1987b). In vivo airway hyperresponsiveness may depend on the presence of a mediator like TxA2 which has a short half-life, is produced by continual stimulation of inflammatory cells and which is "washed out" in vitro once the source of stimulation is removed. The fact that we can demonstrate an increase in sensitivity in vitro using PGF2 alpha or a TxA2 analogue, combined with the fact that both mediators are released from a variety of inflammatory cells suggests that one or both of these agents may mediate part of the increased responsiveness observed in asthma.

Topics: Animals; Asthma; Bronchi; Bronchial Spasm; Carbachol; Dinoprost; Histamine; Muscle, Smooth; Prostaglandins F; Rabbits; Thromboxane A2; Trachea

To determine whether thromboxane A2 (TXA2) participates in allergen-induced asthmatic responses, we measured plasma TXB2 levels during allergen-induced immediate and late asthmatic responses (IAR and LAR) in atopic asthmatics. We also examined the effect of a TXA2 synthetase inhibitor, OKY-046, on the responses. Plasma TXB2 levels increased in both IAR and LAR, being 2.2 times higher in LAR than in IAR. Plasma TXB2 levels in LAR reached the peak 4 hours after allergen challenge when FEV1 had just begun to decrease in LAR. OKY-046 inhibited both IAR and LAR with decreased plasma TXB2 levels. We conclude that TXA2 is produced in allergen-induced asthmatic responses and participates in the responses, especially in inducing LAR.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Thromboxane A2; Thromboxane-A Synthase; Time Factors

1. In studies of rabbit airway smooth muscle, differences in mechanical responses to acetylcholine, histamine and high K+ in intact muscles, and in Ca2+ sensitivity in skinned muscles, have been examined in tissue taken from 5 different regions of the airway. Interactions between prostaglandin F2 alpha and epithio-thromboxane A2 and the above spasmogenic agencies were also studied. 2. Mechanical responses to histamine (10 microM) and to 128 mM K+ were smallest in trachea and were largest in 3rd and 4th order bronchi. In all regions, spasm evoked by 10 microM acetylcholine was greater than that evoked by 10 microM histamine or 128 mM K+. 3. In the third and fourth branches of the rabbit right middle bronchus, contractions evoked by 10 microM acetylcholine, 10 microM histamine and 128 mM K+ showed similar amplitudes of phasic response. In Ca2+-free solution containing 2 mM EGTA, the phasic components of the acetylcholine- or histamine-induced contraction remained unchanged in comparison with that observed in Krebs solution, but the phasic and tonic components of the K+-induced contraction and the tonic changes induced by acetylcholine and histamine were abolished. 4. Two subtypes of the histamine receptor, excitatory H1- and inhibitory H2- receptors were detected on the bronchial smooth muscle. The H1-induced contraction was mediated by release of stored Ca2+ together with activation of Ca2+ influx relatively insensitive to Ca2+ antagonists. 5. The -log(EC50) values for acetylcholine and histamine (in the presence of cimetidine and atropine) were 6.11 +/- 0.11 and 5.33 +/- 0.08, respectively, in the third branch of right middle bronchus. These values were similar to those observed for trachea. 6. Prostaglandin F2. (10 microM) and 9,11-epithio-11,12-methano-thromboxane A2 (0.1 microM) neither provoked nor enhanced the contractions evoked by any stimulants. 7. No difference was observed between the Ca2+ sensitivity of chemically skinned muscle from the trachea and that of muscle from the third branch of the right middle bronchus. 8. Regional differences in the response to histamine and acetylcholine observed in airway smooth muscles are discussed and it is concluded that these may be due to differences in receptor numbers.

Topics: Acetylcholine; Animals; Asthma; Bronchi; Histamine; In Vitro Techniques; Indomethacin; Male; Muscle Contraction; Muscle, Smooth; Nifedipine; Potassium; Prostaglandins F; Rabbits; Thromboxane A2; Trachea

Topics: Arachidonic Acid; Arachidonic Acids; Aspirin; Asthma; Blood Platelets; Humans; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane A2; Thromboxanes

In a child with primary thrombocythaemia, observations have been made over a period of five years, during which, transient apparently thrombotic events occurred in the central nervous system on several occasions. Spontaneous platelet aggregation was noted and deaggregation took place even after exposure to ADP in vitro. Associated findings included pronounced elevation in plasma levels of 6-keto-PGF1 alpha and 6-keto-PGE1, the latter described for the first time. Production of 12-HETE by platelets was markedly reduced, probably reflecting lipoxygenase deficiency which has been reported in other myeloproliferative disorders. It has been suggested that 12-HETE is a natural inhibitor of thromboxane synthetase, so the further finding of enormous generation of TxA2, measured as TxB2, by this patient's platelets may be explicable. It is suggested that the increase in TxA2 is responsible for spontaneous platelet aggregation. In response to these massive events, there is a production of 6-keto-PGE1 which in turn, promotes platelet deaggregation. Administration of aspirin resulted in symptomatic relief and complete inhibition of TxB2 production.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Alprostadil; Arachidonate 12-Lipoxygenase; Aspirin; Asthma; Blood Platelets; Child; Eosinophilia; Humans; Hydroxyeicosatetraenoic Acids; Male; Platelet Aggregation; Thrombocytosis; Thromboxane A2

The effect of lung macrophages stimulated with calcium ionophore on parasympathetic contractile response of canine bronchial rings was studied. Macrophages augmented the contraction induced by electrical field stimulation, an effect that was inhibited by indomethacin and by SQ29548, a thromboxane A2 receptor antagonist, but had no effect on the contractile response to exogenous acetylcholine. These results suggest that macrophage-derived thromboxane A2 facilitates cholinergic neurotransmission prejunctionally in airway smooth muscle.

Topics: Animals; Asthma; Bridged Bicyclo Compounds, Heterocyclic; Bronchi; Dogs; Electric Stimulation; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Indomethacin; Macrophages; Muscle Contraction; Parasympathetic Nervous System; Thromboxane A2

Since inhibition of cyclooxygenase precipitates asthmatic attacks in patients with aspirin idiosyncrasy, we have evaluated the effects of pharmacologic inhibition of thromboxane A2 (TXA2) synthetase, next to cyclooxygenase enzyme in arachidonic acid cascade. Sixteen patients with aspirin-induced asthma received increasing doses on 3 days (25 to 400 mg) of an imidazole derivative, OKY-046, which specifically blocks TXA2 synthetase. Twenty-three healthy control subjects received a single dose of 400 mg of OKY-046. In both patients and control subjects, the inhibitor at a dose of 400 mg produced (1) a pronounced fall in thromboxane B2 serum levels, (2) a rise in serum 6-keto-prostaglandin F1 alpha, and (3) a depression in platelet aggregability to arachidonic acid and adenosine diphosphate. The drug, however, neither precipitated attacks of asthma nor impaired pulmonary function tests throughout a 24-hour observation period. Five patients, but none of the control subjects, developed transient nasal congestion about 1 hour after taking the drug. Thus, inhibition of TXA2 synthetase, contrary to inhibition of cyclooxygenase, does not affect bronchopulmonary function in patients with asthma and aspirin intolerance.

Topics: Acrylates; Adult; Aspirin; Asthma; Female; Humans; Male; Methacrylates; Middle Aged; Respiratory Function Tests; Thromboxane A2

Topics: Acetylcholine; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Asthma; Bronchi; Bronchial Provocation Tests; Female; Forced Expiratory Volume; Humans; Indomethacin; Male; Middle Aged; Thromboxane A2

Topics: Asthma; Bronchial Provocation Tests; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Thromboxane A2

A 57 year old white woman is reported who developed a myocardial infarction during an attack of allergic asthma and was subsequently found to have a normal coronary arteriogram. The literature on myocardial ischemia and infarction associated with structurally normal coronary arteries is reviewed with particular reference to prostaglandin production, histamine release, platelet activation and the induction of coronary vasospasm. A hypothesis is constructed to explain asthma induced myocardial infarction in terms of interrelated pathogenetic mechanisms.

Topics: Asthma; Coronary Angiography; Coronary Vasospasm; Electrocardiography; Epoprostenol; Female; Histamine Release; Humans; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane A2

Upon a specific allergic reaction mediators released from mast cells found free in the bronchial lumen or in the epithelial surface loosen the interepithelial cell tight-junctions allowing the entrance of more allergen to deeper mast cells. The primary and secondary mediators thereby generated induce further increased vascular permeability which leads to the entrance of plasma proteins and platelets. The other immediate responses induced by mediator release are smooth muscle constriction, mucus secretion and leukocyte chemoattraction. Vagal afferent and reflex efferent stimulation are induced by histamine and probably other mediators which might contribute both to the bronchospasm as well as mucous gland secretion. Subacute responses include increased cellular infiltrates, mucosal edema, desquamation, basement membrane thickening, goblet cell hyperplasia and mucus secretion. These responses may occur because of the continued release of primary and secondary mediators as well as effects caused by the mast cell granule matrix-derived factors. It can thus be seen that many of the pathologic features of asthma may be attributed to mast cell degranulation.

Topics: Airway Obstruction; Asthma; Bradykinin; Capillary Permeability; Histamine; Humans; Leukotriene E4; Mast Cells; Mucus; Muscle Contraction; Muscle, Smooth; Prostaglandins; SRS-A; Thromboxane A2

Since it has been suggested that aspirin-induced asthma is due to inhibition of prostaglandin (PG) biosynthesis, the present investigation was undertaken to determine whether tartrazine would display a similar profile. Use was made of the exquisite sensitivity of blood platelets, both in humans and in rats, to aggregating substances generated from arachidonic acid during PG biosynthesis and of the ability of aspirin to inhibit aggregation and generation of those substances. Failure to affect aggregation by arachidonic acid as well as the accompanying formation of thromboxane A2, demonstrates that neither tartrazine nor its metabolite sulfanilic acid inhibit platelet PG synthesis. It seems unlikely that tartrazine-induced asthma results from inhibition of PG biosynthesis.

Topics: Aspirin; Asthma; Azo Compounds; Blood Platelets; Humans; Platelet Aggregation; Prostaglandins; Sulfanilic Acids; Tartrazine; Thromboxane A2

Topics: Aspirin; Asthma; Depression, Chemical; Epoprostenol; Humans; Prostaglandins; Prostaglandins E; Thromboxane A2