title: Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites.
abstract: 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 omega- and omega1-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 omega- and omega1-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 (FI(O(2)) = 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.
authors.affiliation: Department of Physiology, Cardiovascular Research Center, Milwaukee, 53226, Wisconsin, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhu
authors.forename: E K
authors.initials: EK
authors.lastname: Birks
authors.forename: C A
authors.initials: CA
authors.lastname: Dawson
authors.forename: M
authors.initials: M
authors.lastname: Patel
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: K
authors.initials: K
authors.lastname: Presberg
authors.forename: R J
authors.initials: RJ
authors.lastname: Roman
authors.forename: E R
authors.initials: ER
authors.lastname: Jacobs
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D002208:Caproates / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation; D011817:Rabbits; D013450:Sulfones / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C415082:6-(20-propargyloxyphenyl)hexanoic acid; D000577:Amides; D002208:Caproates; D006893:Hydroxyeicosatetraenoic Acids; D013450:Sulfones; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A