A possible involvement of thromboxane A(2) and peptide leukotrienes in hyperresponsiveness of Sephadex-treated rat lung parenchyma

An augmented contraction and elevated thromboxane (TX) B-2 release were obs erved, when the isolated parenchyma from Sephadex-treated rats was stimulat ed by 5-hydroxytryptamine (5-HT). Release of peptide leukotrienes (pLTs) wa s also increased by the stimuli, In the Sephadex-induced hyperresponsivenes s model, DP-1904, a novel TX synthetase inhibitor, at the concentrations of 3 x 10(-7)similar to 3 x 10(-6) M, reduced the augmented contraction. Also , indomethacin (3 x 10(-6) M), a histamine H-1 antagonist and AA-2414 (10-6 M, a TXA(2) antagonist, significantly attenuated the hyperresponsiveness t o 5-HT. ICI-198,615 (10(-7) M), a leukotriene receptor antagonist, partiall y but significantly reduced the augmented contraction. In an ex vivo study, oral DP-1904 significantly inhibited both the augmented contraction and el evated TXB2 release from Sephadex-treated rat parenchyma, but did not affec t the blood eosinophilia induced by Sephadex-treatment. These results suggested that the ability to synthesize newly generated lipi d mediators such as TXA(2) and pLTs to exogenous 5-HT was altered upward by Sephadex injection, and so could lead to augmented contraction of establis hed hyperresponsiveness in rats.