Agonist and antagonist activities of the leukotriene analogue BAY u9773 in guinea pig lung parenchyma

Abstract

BAY u9773(6( R)-(4′-carboxyphenylthio)-5( S)-hydroxy-7( E),9( E),11( Z),14( Z)-eicosatetraenoic acid) is a leukotriene E 4 analogue used to define `atypical' receptors for cysteinyl–leukotrienes. The aims of this study were first to characterise the intrinsic properties of BAY u9773 in guinea-pig lung parenchyma in vitro and second to study the influence of BAY u9773 on the concentration–response relation for leukotriene D 4 in the same preparation. BAY u9773 in itself caused a concentration-dependent contraction, which was not inhibited by the cyclooxygenase inhibitor indomethacin nor by the 5-lipoxygenase inhibitor zileuton ( N-(1-benzo-(12)-thien-2-ylethyl)- N-hydroxyurea). The CysLT 1 receptor antagonist ICI 198,615 {(1-((2-methoxy-4-(((phenylsulfonyl)amino) carbonyl)phenyl)methyl)-1 H-indazol-6-yl)carbamic acid cyclopentyl ester} alone blocked the contractile response to BAY u9773 1 μM, whereas a combination of the TP receptor antagonist BAY u3405 ((3 R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid) and ICI 198,615 was required to block the contraction induced by BAY u9773 10 μM. Together the findings suggest that BAY u9773 acted as a CysLT 1 receptor agonist and in the higher concentration also as a TP receptor agonist. The CysLT 1 receptor antagonist ICI 198,615 partly inhibited the contractile response to leukotriene D 4. Pretreatment with BAY u9773 or leukotriene D 4, caused concentration-dependent rightward displacement of the concentration–response curve for leukotriene D 4. The inhibition by BAY u9773 was partial, and not greater than that produced by ICI 198,615. Combination of BAY u9773 and ICI 198,615 did not produce additive inhibition, suggesting that the major part of the leukotriene D 4 induced contraction in guinea pig lung parenchyma is mediated by a CysLT receptor with properties distinct from those of previously described CysLT 1 and CysLT 2 receptors.