Differential effect of cytochrome P-450 ω-hydroxylase inhibition on O2-induced constriction of arterioles in SHR with early and established hypertension

Mary Pat Kunert, Richard J. Roman, J R Falck, Julian H. Lombard

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Objective: To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 ω-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 ω-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O2 sensors. Methods: Arteriolar diameters were measured in the in situ cremaster muscle of 4-to 6- and 12-to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O2 and 21% O2 before and after P-450 enzyme inhibition. Results: The P-450 ω-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O2-induced constriction of arterioles of 12-to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O2-induced constriction of arterioles in the younger WKY, but not in the 4-to 6-week-old SHR. Conclusions: These results support the hypothesis that cytochrome P-450 4A may act as an O2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO2 in young SHR during the early development of hypertension.

Original languageEnglish (US)
Pages (from-to)435-443
Number of pages9
JournalMicrocirculation
Volume8
Issue number6
DOIs
StatePublished - 2001

Fingerprint

Arterioles
Inbred SHR Rats
Mixed Function Oxygenases
Constriction
Cytochrome P-450 Enzyme System
Hypertension
Vasoconstrictor Agents
Cytochrome P-450 CYP4A
Abdominal Muscles
Enzyme Inhibitors
Microcirculation
Arachidonic Acid
Skeletal Muscle
Salts

Keywords

  • 20-HETE
  • Autoregulation
  • Hypertension
  • Local control of blood flow
  • Microcirculation
  • Oxygen

ASJC Scopus subject areas

  • Physiology
  • Genetics
  • Cardiology and Cardiovascular Medicine

Cite this

Differential effect of cytochrome P-450 ω-hydroxylase inhibition on O2-induced constriction of arterioles in SHR with early and established hypertension. / Kunert, Mary Pat; Roman, Richard J.; Falck, J R; Lombard, Julian H.

In: Microcirculation, Vol. 8, No. 6, 2001, p. 435-443.

Research output: Contribution to journalArticle

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abstract = "Objective: To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 ω-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 ω-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O2 sensors. Methods: Arteriolar diameters were measured in the in situ cremaster muscle of 4-to 6- and 12-to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0{\%} O2 and 21{\%} O2 before and after P-450 enzyme inhibition. Results: The P-450 ω-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O2-induced constriction of arterioles of 12-to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O2-induced constriction of arterioles in the younger WKY, but not in the 4-to 6-week-old SHR. Conclusions: These results support the hypothesis that cytochrome P-450 4A may act as an O2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO2 in young SHR during the early development of hypertension.",
keywords = "20-HETE, Autoregulation, Hypertension, Local control of blood flow, Microcirculation, Oxygen",
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year = "2001",
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T1 - Differential effect of cytochrome P-450 ω-hydroxylase inhibition on O2-induced constriction of arterioles in SHR with early and established hypertension

AU - Kunert, Mary Pat

AU - Roman, Richard J.

AU - Falck, J R

AU - Lombard, Julian H.

PY - 2001

Y1 - 2001

N2 - Objective: To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 ω-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 ω-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O2 sensors. Methods: Arteriolar diameters were measured in the in situ cremaster muscle of 4-to 6- and 12-to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O2 and 21% O2 before and after P-450 enzyme inhibition. Results: The P-450 ω-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O2-induced constriction of arterioles of 12-to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O2-induced constriction of arterioles in the younger WKY, but not in the 4-to 6-week-old SHR. Conclusions: These results support the hypothesis that cytochrome P-450 4A may act as an O2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO2 in young SHR during the early development of hypertension.

AB - Objective: To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 ω-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO2 in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 ω-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O2 sensors. Methods: Arteriolar diameters were measured in the in situ cremaster muscle of 4-to 6- and 12-to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O2 and 21% O2 before and after P-450 enzyme inhibition. Results: The P-450 ω-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O2-induced constriction of arterioles of 12-to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O2-induced constriction of arterioles in the younger WKY, but not in the 4-to 6-week-old SHR. Conclusions: These results support the hypothesis that cytochrome P-450 4A may act as an O2 sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO2 in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO2 in young SHR during the early development of hypertension.

KW - 20-HETE

KW - Autoregulation

KW - Hypertension

KW - Local control of blood flow

KW - Microcirculation

KW - Oxygen

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