Effect of OKY-046, a new thromboxane A2 synthetase inhibitor, on experimental asthma in guinea pigs

The effect of OKY-046, a newly synthetized thromboxane A₂ (TxA₂) synthetase inhibitor, on IgE mediated experimental asthma in guinea pigs was investigated. Indomethacin, a cyclooxygenase inhibitor, and tranilast (N-5′), a potent anti-allergic agent, were used as comparative drugs. OKY-046 clearly improved asthmatic respiratory disorders in guinea pigs. Whereas indomethacin had no effect on the changes of asthmatic respiration, tranilast significantly inhibited the changes. OKY-046 inhibited the in vitro antigen-induced contraction of sensitized guinea pig lung parenchyma. This antigen-induced contraction was also inhibited by tranilast, but not by indomethacin. OKY-046 inhibited the contractions of lung parenchyma caused by leukotriene C₄, D₄ and E₄ (LTC₄, LTD₄ and LTE₄), but not by histamine. Indomethacin showed a biphasic action on the contractile responses caused by histamine and LTD₄ Consequently, contractions due to either agonist at low concentrations were inhibited by indomethacin, but those at high concentrations were enhanced. Tranilast inhibited the contraction of lung parenchyma induced by a low concentration of LTD₄ but not that produced by histamine. Moreover, OKY-046 inhibited an elevation of concentration of thromboxane B₂ (TxB₂) in guinea pig lung perfusate after infusion of LTC₄ but did not affect the elevation of 6-keto-PGF_1α. OKY-046 had no effect on the antigen-induced release of histamine but it inhibited the release of the slow reacting substance of anaphylaxis (SRS-A) from sensitized chopped lung tissues. Indomethacin at a high concentration inhibited the release of histamine but did not affect the release of SRS-A. Tranilast clearly inhibited the release of both mediators. These results suggest that OKY-046 inhibits IgE mediated experimental asthma in guinea pigs and that its main mechanism is related to the inhibition of LT induced contraction of airway smooth muscle and the release of SRS-A from lung tissues.