Effect of combined leukotriene D4 and thromboxane A2 receptor antagonist on mediator-controlled resistance in guinea pigs

Abstract The effects of YM158 (3-[(4- tert -butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl)propyl]-2′-(1 H -tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D 4 and thromboxane A 2 receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A 2 , complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D 4 and thromboxane A 2 equally participated, ED 50 values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H -1-benzopyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists.