Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites

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

Research output: Contribution to journalArticle

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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 (FI(O2) = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline profusion 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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume279
Issue number4 48-4
StatePublished - 2000

Fingerprint

Vasoconstriction
Cytochrome P-450 CYP4A
Lung
Pulmonary Artery
Rabbits
Pressure
Phenylephrine
Perfusion
Mixed Function Oxygenases
Arachidonic Acid
Blood Vessels
Gases
Microsomes
Ventilation
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Proteins
DDMS

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

Daling, Z., Birks, E. K., Dawson, C. A., Patel, M., Falck, J. R., Presberg, K., ... Jacobs, E. R. (2000). Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites. American Journal of Physiology - Heart and Circulatory Physiology, 279(4 48-4).

Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites. / Daling, Zhu; Birks, Eric K.; Dawson, Christopher A.; Patel, Monica; Falck, J R; Presberg, Kenneth; Roman, Richard J.; Jacobs, Elizabeth R.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 279, No. 4 48-4, 2000.

Research output: Contribution to journalArticle

Daling, Z, Birks, EK, Dawson, CA, Patel, M, Falck, JR, Presberg, K, Roman, RJ & Jacobs, ER 2000, 'Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites', American Journal of Physiology - Heart and Circulatory Physiology, vol. 279, no. 4 48-4.
Daling, Zhu ; Birks, Eric K. ; Dawson, Christopher A. ; Patel, Monica ; Falck, J R ; Presberg, Kenneth ; Roman, Richard J. ; Jacobs, Elizabeth R. / Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites. In: American Journal of Physiology - Heart and Circulatory Physiology. 2000 ; Vol. 279, No. 4 48-4.
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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 (FI(O2) = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline profusion 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.",
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AU - Daling, Zhu

AU - Birks, Eric K.

AU - Dawson, Christopher A.

AU - Patel, Monica

AU - Falck, J R

AU - Presberg, Kenneth

AU - Roman, Richard J.

AU - Jacobs, Elizabeth R.

PY - 2000

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N2 - 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 (FI(O2) = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline profusion 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.

AB - 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 (FI(O2) = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline profusion 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.

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KW - Pulmonary vascular tone

KW - Vasodilator

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