Role of lipoxygenase, cyclooxygenase and cytochrome P-450 metabolites in contractions of isolated guinea pig pulmonary venules induced by hypoxia and anoxia.

Arachidonic acid metabolites, notably leukotrienes (LTs), have been postulated to play a role in hypoxic pulmonary vasoconstriction. In the present study, we examined the contribution of arachidonic acid metabolites, via the cyclooxygenase, 5-lipoxygenase and cytochrome P-450 monooxygenase pathways, to the hypoxia (25 +/- 3 torr)- and anoxia (0 +/- 2 torr)-induced contractions of isolated pulmonary venules. Neither the cyclooxygenase inhibitors indomethacin (5 microM) or ibuprofen (10 microM) nor the 5-lipoxygenase inhibitors nordihydroguaiaretic acid (5 microM) or U 60257B (10 microM) affected the contractile responses. Similarly, the LT receptor antagonists FPL 57231 (3 microM) or LY 163443 (1 microM), at concentrations that inhibited LT-induced venular contractions, did not significantly affect the responses to hypoxia or anoxia. In fact, anoxia suppressed spontaneous LT release from the venules. The cytochrome P-450 inhibitor SKF-525A (500 microM) nonselectively depressed venular contractions induced by decreased PO2 and pharmacological agents. Induction of the cytochrome P-450 monooxygenase system with beta-naphthoflavone did not alter venular contractions induced by hypoxia or anoxia. Contractions of isolated guinea pig pulmonary venules elicited by decreased PO2 are not mediated by 5-lipoxygenase or cyclooxygenase metabolites. Furthermore, the data do not support a role for cytochrome P-450 metabolites of endogenous substrates in these contractions.