Inhibitory effects of OKY-046·HCl, a selective thromboxane (TX) A₂ synthetase inhibitor, on platelet activating factor (PAF)-induced airway hyperresponsiveness in guinea pigs

Abstract

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 μg/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-PGF_1α in BALF were found. (2) There were no changes in the number of leukocytes; the activities of alkaline phosphatase, N-acetyl-β-D-glucosaminidase, and lactate dehydrogenase; and the LTC₄/D₄/E₄ in BALF. (3) In bronchus-lung preparations, PAF (1 μg/min) also caused the AHR and increased TXB₂ generation. OKY-046·HCl (100 μg/min) inhibited the AHR and TXB₂ generation. (4) PAF (1 μg/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.