ono-nt-126 and Asthma

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

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 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