A possible involvement of thromboxane A2 and peptide leukotrienes in hyperresponsiveness of Sephadex-treated rat lung parenchyma.

An augmented contraction and elevated thromboxane (TX) B2 release were observed, when the isolated parenchyma from Sephadex-treated rats was stimulated by 5-hydroxytryptamine (5-HT). Release of peptide leukotrienes (pLTs) was also increased by the stimuli. In the Sephadex-induced hyperresponsiveness model, DP-1904, a novel TX synthetase inhibitor, at the concentrations of 3 x 10(-7) to approximately 3 x 10(-6) M, reduced the augmented contraction. Also, indomethacin (3 x 10(-6) M), a histamine H1 antagonist and AA-2414 (10(-6) M, a TXA2 antagonist, significantly attenuated the hyperresponsiveness to 5-HT. ICI-198,615 (10(-7) M), a leukotriene receptor antagonist, partially but significantly reduced the augmented contraction. In an ex vivo study, oral DP-1904 significantly inhibited both the augmented contraction and elevated TXB2 release from Sephadex-treated rat parenchyma, but did not affect the blood eosinophilia induced by Sephadex-treatment. These results suggested that the ability to synthesize newly generated lipid mediators such as TXA2 and pLTs to exogenous 5-HT was altered upward by Sephadex injection, and so could lead to augmented contraction of established hyperresponsiveness in rats.