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.
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D003911:Dextrans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000502:physiology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology*