Effect of thromboxane synthase inhibitor, CS-518, on propranolol-induced bronchoconstriction in guinea pigs

beta-adrenoreceptor antagonists, such as propranolol, can provoke severe br onchoconstriction in asthmatic subjects. Recently we developed an animal mo del of propranolol-induced bronchoconstriction and investigated the involve ment of chemical mediators in this reaction. The purpose of this study was to elucidate the role of thromboxane A(2) in the development of propranolol -induced bronchoconstriction after allergic bronchoconstriction. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine h ydrochloride and were then artificially ventilated Propranolol at a concent ration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challeng e. A potent and selective thromboxane A(2) synthase inhibitor; CS-518, in d oses of 0.01, 0.1 and 1 mg/kg and vehicle were administered intravenously 1 5 min after the antigen challenge. Another study was performed in naive gui nea pigs; ascending doses of methacholine (12.5, 25, 50, 100 and 200 mu g/m l) were inhaled for 20 sec at 5-min intervals, 10 min after intravenous adm inistration of CS-518. Propranolol inhaled 20 min after the antigen challen ge caused bronchoconstriction in sensitized guinea pigs. CS-518 administere d 15 min after the antigen challenge significantly inhibited propranolol-in duced bronchoconstriction in a dose-dependent manner; while CS-518 did not influence the dose-dependent response to inhaled methacholine in naive guin ea pigs. We conclude that thromboxane A(2) contributes to the development o f propranolol-induced bronchoconstriction following allergic reaction in ou r guinea pig model.