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 (10⁻⁶m), NDGA (10⁻⁵m) or staurosporine (3×10⁻⁸m). AII (3×10⁻⁷m), hypoxia (4% O₂) or PDBu (10⁻⁸m) each significantly potentiated the contractions evoked by Et-1. Indomethacin (10⁻⁶m) virtually abolished the effect of AII, hypoxia or PDBu. NDGA (10⁻⁵m) reversed the potentiating effect of both AII and hypoxia and partially reversed PDBu-evoked enhancement of Et-1-mediated responses. Staurosporine (3×10⁻⁸m) 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.