Effect of thromboxane synthase inhibitor, CS-518, on propranolol-induced bronchoconstriction in guinea pigs.
Beta-adrenoreceptor antagonists, such as propranolol, can provoke severe bronchoconstriction in asthmatic subjects. Recently we developed an animal model of propranolol-induced bronchoconstriction and investigated the involvement of chemical mediators in this reaction. The purpose of this study was to elucidate the role of thromboxane A2 in the development of propranolol-induced bronchoconstriction after allergic bronchoconstriction. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride and were then artificially ventilated. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. A potent and selective thromboxane A2 synthase inhibitor, CS-518, in doses of 0.01, 0.1 and 1 mg/kg and vehicle were administered intravenously 15 min after the antigen challenge. Another study was performed in naive guinea pigs; ascending doses of methacholine (12.5, 25, 50, 100 and 200 microg/ml) were inhaled for 20 sec at 5-min intervals, 10 min after intravenous administration of CS-518. Propranolol inhaled 20 min after the antigen challenge caused bronchoconstriction in sensitized guinea pigs. CS-518 administered 15 min after the antigen challenge significantly inhibited propranolol-induced bronchoconstriction in a dose-dependent manner, while CS-518 did not influence the dose-dependent response to inhaled methacholine in naive guinea pigs. We conclude that thromboxane A2 contributes to the development of propranolol-induced bronchoconstriction following allergic reaction in our guinea pig model.
Ishiura
Y
Y
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
Fujimura
M
M
Myou
S
S
Amemiya
T
T
Nobata
K
K
Liu
Q
Q
Yamamori
C
C
Matsuda
T
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D007116:Immunization, Passive; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D011433:Propranolol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D012121:Respiration, Artificial; D013876:Thiophenes / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D013876:Thiophenes; D016210:Methacholine Chloride; C055806:RS 5186; D013928:Thromboxane A2; D011433:Propranolol; D013930:Thromboxane-A Synthase