Effect of a thromboxane A 2 synthetase inhibitor (OKY-046 · HCl) on airway hyperresponsiveness in guinea pigs

Abstract

We studied the effect of (E)-3-[p-1HH-imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046 · HCl), a specific thromboxane (TX) A 2 synthetase inhibitor, on airway hyperresponsiveness of guinea pigs. OKY-046 · HCl (30–100 mg/kg, intraduodenally (i.d.) or orally (p.o.)) suppressed dose dependently the airway hyperresponsiveness to acetylcholine (ACh) induced by formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF) and repetitive antigen. OKY-046 · HCl (100 mg/kg) also inhibited the increase in TXB 2 in bronchoalveolar lavage fluid (BALF) induced by FMLP, PAF and antigen. Aspirin 10 or 30 mg/kg i.d. or p.o.) suppressed the airway hyperresponsiveness induced by FMLP and PAF but not by antigen. Azelastine (10 mg/kg i.d.) was ineffective on PAF- and antigen-induced airway hyperresponsiveness. TXA 2 mimetic drugs caused airway hyperresponsiveness that was not inhibited by OKY-046 · HCl (30 mg/kg i.v.). Furthermore, OKY-046 · HCl showed no effect on propranolol- and physostigmine-induced airway hyperresponsiveness which did not accompany TXB 2 generation in BALF. The number of eosinophils in BALF increased after FMLP exposure, an effect which was not inhibited by OKY-046 · HCl. These results suggest that OKY-046 · HCl inhibits airway hyperresponsiveness by suppressing TXA 2 generation. We suggest that OKY-046 · HCl will be a new antiasthmatic drug.