The role of cyclooxygenase and 5-lipoxygenase metabolites in potentiated endothelin-1-evoked contractions in bovine bronchi.
We have previously shown that angiotensin II (AII) potentiates responses evoked by endothelin-1 (Et-1). In the present study, the additional ability of hypoxia or phorbol 12, 13-dibutyrate (PDBu) to evoke hyperreactivity was examined. In addition, the role of cyclooxygenase and 5-lipoxygenase metabolites of arachidonic acid in the potentiation evoked by AII, hypoxia or PDBu was studied, using indomethacin and nordihydroguaiaretic acid (NDGA). The involvement of protein kinase C in the enhanced response was examined using staurosporine. Contractions were measured isometrically from rings of bovine bronchi. Contractions evoked by Et-1 alone were unaltered by indomethacin (10(-6)M), NDGA (10(-5)M) or staurosporine (3 x 10(-8)M). AII (3 x 10(-7)M), hypoxia (4% O2) or PDBu (10(-8)M) each significantly potentiated the contractions evoked by Et-1. Indomethacin (10(-6)M) virtually abolished the effect of AII, hypoxia or PDBu. NDGA (10(-5)M) reversed the potentiating effect of both AII and hypoxia and partially reversed PDBu-evoked enhancement of Et-1-mediated responses. Staurosporine (3 x 10(-8)M) abolished the ability of AII or PDBu, but not hypoxia, to enhance Et-1-mediated contractions. In conclusion, AII, hypoxia and PDBu evoke hyperresponsiveness which is mediated by prostanoids and/or leukotrienes, the precise nature of which remains to be elucidated. Differences in the ability of staurosporine to reverse AII- and hypoxia-induced hyperreactivity suggests, however, that these conditions may generate different eicosanoids.
Nally
J E
JE
Department of Biological Sciences, Glasgow Caledonian University, Scotland.
Bunton
D C
DC
Martin
D
D
Thomson
N C
NC
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000201:enzymology; D002417:Cattle; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D009637:Masoprocol; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D019311:Staurosporine; D007213:Indomethacin