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1 Department of Physiology, Cardiovascular Research Center, and 2 Department of Medicine, Medical College of Wisconsin, Milwaukee, 53226; 3 Department of Physiology, Clement Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53295; and 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75325
20-Hydroxyeicosatetraenoic
acid (20-HETE) is a cytochrome P-450 4A (CYP4A)
metabolite of arachidonic acid (AA) in human and rabbit lung
microsomes and is a dilator of isolated human pulmonary arteries
(PA). However, little is known regarding the contribution of
P-450 metabolites to pulmonary vascular tone. We examined
1) the effect of two mechanistically distinct 
- and
1-hydroxylase inhibitors on perfusion pressures in isolated
rabbit lungs ventilated with normoxic or hypoxic gases, 2)
changes in rabbit PA ring tone elicited by 20-HETE or - and
1-hydroxylase inhibitors, and 3) expression of CYP4A
protein in lung tissue. A modest increase in perfusion pressure
(55 ± 11% above normoxic conditions) was observed in isolated
perfused lungs during ventilation with hypoxic gas
(FIO2 = 0.05). Inhibitors of 20-HETE
synthesis, 17-oxydecanoic acid (17-ODYA) or
N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline perfusion pressure above that of
vehicle and amplified hypoxia-induced increases in perfusion pressures by 92 ± 11% and 105 ± 11% over baseline pressures,
respectively. 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-propargyloxyphenyl)hexanoic acid (PPOH),
an epoxygenase inhibitor, blunted contraction to PE. Conversion of AA
into 20-HETE was blocked by 17-ODYA, DDMS, and hypoxia. CYP4A
immunospecific protein confirms expression of CYP4A in male rabbit lung
tissue. Our data suggest that endogenously produced 20-HETE
could modify rabbit pulmonary vascular tone, particularly under hypoxic conditions.
cytochrome P-450 4A; -hydroxylase inhibitor; pulmonary vascular tone; vasodilator; eicosanoid metabolism; arachidonic acid
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