Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites

Daling Zhu, Eric K. Birks, Christopher A. Dawson, Monica Patel, J R Falck, Kenneth Presberg, Richard J. Roman, Elizabeth R. Jacobs

Research output: Contribution to journalArticle

50 Scopus citations

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 ω- and ω1-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 ω- and ω1-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.

Original languageEnglish (US)
Pages (from-to)H1526-H1533
JournalAmerican Journal of Physiology
Volume279
Issue number4 PART 2
StatePublished - Oct 1 2000

Keywords

  • Arachidonic acid
  • Cytochrome P-450 4A
  • Eicosanoid metabolism
  • Pulmonary vascular tone
  • Vasodilator
  • ω-hydroxylase inhibitor

ASJC Scopus subject areas

  • Physiology (medical)

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