Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites. Am J Physiol Heart Circ Physiol 2000 Oct;279(4):H1526-33
Date
09/29/2000Pubmed ID
11009437DOI
10.1152/ajpheart.2000.279.4.H1526Scopus ID
2-s2.0-34447616694 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
Zhu D, Birks EK, Dawson CA, Patel M, Falck JR, Presberg K, Roman RJ, Jacobs ERAuthor
Kenneth W. Presberg MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmidesAnimals
Caproates
Cytochrome P-450 CYP4A
Cytochrome P-450 Enzyme System
Female
Hydroxyeicosatetraenoic Acids
Hypoxia
In Vitro Techniques
Male
Mixed Function Oxygenases
Phenylephrine
Pulmonary Artery
Pulmonary Circulation
Rabbits
Sulfones
Vasoconstriction
Vasoconstrictor Agents
