[Effect of OKY-046 on airway hyperresponsiveness induced by ozone in dogs].
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.
Nambu
F
F
First Department of Internal Medicine, School of Medicine, Showa University, Tokyo, Japan.
Imai
T
T
Adachi
M
M
Takahashi
T
T
D000179:Acrylates / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008689:Methacrylates / Q000494:pharmacology / Q000627:therapeutic use*; D010126:Ozone; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D008689:Methacrylates; D013928:Thromboxane A2; D010126:Ozone; D013930:Thromboxane-A Synthase; C034364:ozagrel