Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites

20-Hydroxy-eicosatetraenoic acid (20-HETE) is a cytochrome P-450 4A (CYP4A) metabolite of arachidonic acid (AA) in human and rabbit lung microsomes an d is a dilator of isolated human pulmonary arteries (PA). However, little i s known regarding the contribution of P-450 metabolites to pulmonary vascul ar tone. We examined 1) the effect of two mechanistically distinct omega- a nd omega 1-hydroxylase inhibitors on perfusion pressures in isolated rabbit lungs ventilated with normoxic or hypoxic gases, 2) changes in rabbit PA r ing tone elicited by 20-HETE or omega- and omega 1-hydroxylase inhibitors, and 3) expression of CYP4A protein in lung tissue. A modest increase in per fusion pressure (55 +/- 11% above normoxic conditions) was observed in isol ated perfused lungs during ventilation with hypoxic gas (FIO2 = 0.05). Inhi bitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfo nyl-12,12-dibromododec-11-enamide (DDMS), increased baseline perfusion pres sure above that of vehicle and amplified hypoxia-induced increases in perfu sion pressures by 92 +/- 11% and 105 +/- 11% over baseline pressures, respe ctively. 20-HETE relaxed phenylephrine (PE)-constricted PA rings. Treatment with 17-ODYA enhanced PE-induced contraction of PA rings, consistent with inhibition of a product that promotes arterial relaxation, whereas 6-(20-pr opargyloxyphenyl) hexanoic acid (PPOH), an epoxygenase inhibitor, blunted c ontraction to PE. Conversion of AA into 20-HETE was blocked by 17-ODYA, DDM S, and hypoxia. CYP4A immunospecific protein confirms expression of CYP4A i n male rabbit lung tissue. Our data suggest that endogenously produced 20-H ETE could modify rabbit pulmonary vascular tone, particularly under hypoxic conditions.