Endotoxin enhances hypoxic constriction of rat aorta and pulmonary artery through induction of EDRF/NO synthase

P. Zelenkov, T. McLoughlin, Roger A Johns

Research output: Contribution to journalArticle

Abstract

The vascular response to hypoxia in endotoxin (lipopolysaccharide: LPS)- exposed rat pulmonary artery (PA) and thoracic aorta (AO) was investigated and the mechanism of the observed hypoxic responses defined. In isometric tension studies, LPS-treated AO and PA rings, with and without endothelium, demonstrated decreased (P <0.05) contractile response to phenylephrine (PE EC50), and the dose response was shifted to the right (P <0.01) compared with non-LPS treated rings. Both vessel types responded to hypoxia with a markedly increased (P <0.01) and sustained (P <0.01) constriction when preexposed to LPS. Control non-LPS rings with endothelium intact had a transient vasoconstriction in early hypoxia, which was abolished with removal of the endothelium. N(ω)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, increased the PE EC50 tension in LPS-treated rings, markedly reduced the duration and magnitude of the hypoxic vasoconstriction in LPS-treated rings, and attenuated the transient vasoconstriction seen in endothelium-intact, non-LPS rings (all P <0.05). L- Arginine reversed the L-NAME effects. Hypoxia decreased guanosine 3',5'- cyclic monophosphate (cGMP) content 54 ± 4% in all LPS and 33 ± 4% in the non-LPS intact rings (P <0.05). L-NAME reduced cGMP content 90 ± 5% in all LPS rings. Indomethacin inhibited formation of a constriction factor in aortic LPS-treated rings (P <0.01) that was endothelium dependent and unaffected by the presence of L-NAME. These data confirm that the transient hypoxic constriction seen in non-LPS-treated vascular rings is due to hypoxic inhibition of constitutive NO synthase found in endothelium and demonstrate that the inhibition by hypoxia of LPS-induced NO synthase is the primary mechanism of the enhanced and sustained hypoxic vasoconstriction seen in LPS- treated vessels.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume265
Issue number4 9-4
StatePublished - 1993
Externally publishedYes

Fingerprint

Constriction
Endotoxins
Nitric Oxide Synthase
Pulmonary Artery
Endothelium
Aorta
NG-Nitroarginine Methyl Ester
Vasoconstriction
Blood Vessels
Cyclic GMP
Phenylephrine
Thoracic Aorta
Indomethacin
Lipopolysaccharides
Arginine
Hypoxia

Keywords

  • arachidonic acid
  • endothelium-derived relaxing factor
  • hypoxia
  • indomethacin
  • lipopolysaccharide
  • N(ω)-nitro-L-arginine methyl ester
  • nitric oxide
  • nitric oxide synthase
  • sepsis
  • thoracic aorta
  • vasoconstriction

ASJC Scopus subject areas

  • Cell Biology
  • Physiology
  • Pulmonary and Respiratory Medicine

Cite this

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title = "Endotoxin enhances hypoxic constriction of rat aorta and pulmonary artery through induction of EDRF/NO synthase",
abstract = "The vascular response to hypoxia in endotoxin (lipopolysaccharide: LPS)- exposed rat pulmonary artery (PA) and thoracic aorta (AO) was investigated and the mechanism of the observed hypoxic responses defined. In isometric tension studies, LPS-treated AO and PA rings, with and without endothelium, demonstrated decreased (P <0.05) contractile response to phenylephrine (PE EC50), and the dose response was shifted to the right (P <0.01) compared with non-LPS treated rings. Both vessel types responded to hypoxia with a markedly increased (P <0.01) and sustained (P <0.01) constriction when preexposed to LPS. Control non-LPS rings with endothelium intact had a transient vasoconstriction in early hypoxia, which was abolished with removal of the endothelium. N(ω)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, increased the PE EC50 tension in LPS-treated rings, markedly reduced the duration and magnitude of the hypoxic vasoconstriction in LPS-treated rings, and attenuated the transient vasoconstriction seen in endothelium-intact, non-LPS rings (all P <0.05). L- Arginine reversed the L-NAME effects. Hypoxia decreased guanosine 3',5'- cyclic monophosphate (cGMP) content 54 ± 4{\%} in all LPS and 33 ± 4{\%} in the non-LPS intact rings (P <0.05). L-NAME reduced cGMP content 90 ± 5{\%} in all LPS rings. Indomethacin inhibited formation of a constriction factor in aortic LPS-treated rings (P <0.01) that was endothelium dependent and unaffected by the presence of L-NAME. These data confirm that the transient hypoxic constriction seen in non-LPS-treated vascular rings is due to hypoxic inhibition of constitutive NO synthase found in endothelium and demonstrate that the inhibition by hypoxia of LPS-induced NO synthase is the primary mechanism of the enhanced and sustained hypoxic vasoconstriction seen in LPS- treated vessels.",
keywords = "arachidonic acid, endothelium-derived relaxing factor, hypoxia, indomethacin, lipopolysaccharide, N(ω)-nitro-L-arginine methyl ester, nitric oxide, nitric oxide synthase, sepsis, thoracic aorta, vasoconstriction",
author = "P. Zelenkov and T. McLoughlin and Johns, {Roger A}",
year = "1993",
language = "English (US)",
volume = "265",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "4 9-4",

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TY - JOUR

T1 - Endotoxin enhances hypoxic constriction of rat aorta and pulmonary artery through induction of EDRF/NO synthase

AU - Zelenkov, P.

AU - McLoughlin, T.

AU - Johns, Roger A

PY - 1993

Y1 - 1993

N2 - The vascular response to hypoxia in endotoxin (lipopolysaccharide: LPS)- exposed rat pulmonary artery (PA) and thoracic aorta (AO) was investigated and the mechanism of the observed hypoxic responses defined. In isometric tension studies, LPS-treated AO and PA rings, with and without endothelium, demonstrated decreased (P <0.05) contractile response to phenylephrine (PE EC50), and the dose response was shifted to the right (P <0.01) compared with non-LPS treated rings. Both vessel types responded to hypoxia with a markedly increased (P <0.01) and sustained (P <0.01) constriction when preexposed to LPS. Control non-LPS rings with endothelium intact had a transient vasoconstriction in early hypoxia, which was abolished with removal of the endothelium. N(ω)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, increased the PE EC50 tension in LPS-treated rings, markedly reduced the duration and magnitude of the hypoxic vasoconstriction in LPS-treated rings, and attenuated the transient vasoconstriction seen in endothelium-intact, non-LPS rings (all P <0.05). L- Arginine reversed the L-NAME effects. Hypoxia decreased guanosine 3',5'- cyclic monophosphate (cGMP) content 54 ± 4% in all LPS and 33 ± 4% in the non-LPS intact rings (P <0.05). L-NAME reduced cGMP content 90 ± 5% in all LPS rings. Indomethacin inhibited formation of a constriction factor in aortic LPS-treated rings (P <0.01) that was endothelium dependent and unaffected by the presence of L-NAME. These data confirm that the transient hypoxic constriction seen in non-LPS-treated vascular rings is due to hypoxic inhibition of constitutive NO synthase found in endothelium and demonstrate that the inhibition by hypoxia of LPS-induced NO synthase is the primary mechanism of the enhanced and sustained hypoxic vasoconstriction seen in LPS- treated vessels.

AB - The vascular response to hypoxia in endotoxin (lipopolysaccharide: LPS)- exposed rat pulmonary artery (PA) and thoracic aorta (AO) was investigated and the mechanism of the observed hypoxic responses defined. In isometric tension studies, LPS-treated AO and PA rings, with and without endothelium, demonstrated decreased (P <0.05) contractile response to phenylephrine (PE EC50), and the dose response was shifted to the right (P <0.01) compared with non-LPS treated rings. Both vessel types responded to hypoxia with a markedly increased (P <0.01) and sustained (P <0.01) constriction when preexposed to LPS. Control non-LPS rings with endothelium intact had a transient vasoconstriction in early hypoxia, which was abolished with removal of the endothelium. N(ω)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, increased the PE EC50 tension in LPS-treated rings, markedly reduced the duration and magnitude of the hypoxic vasoconstriction in LPS-treated rings, and attenuated the transient vasoconstriction seen in endothelium-intact, non-LPS rings (all P <0.05). L- Arginine reversed the L-NAME effects. Hypoxia decreased guanosine 3',5'- cyclic monophosphate (cGMP) content 54 ± 4% in all LPS and 33 ± 4% in the non-LPS intact rings (P <0.05). L-NAME reduced cGMP content 90 ± 5% in all LPS rings. Indomethacin inhibited formation of a constriction factor in aortic LPS-treated rings (P <0.01) that was endothelium dependent and unaffected by the presence of L-NAME. These data confirm that the transient hypoxic constriction seen in non-LPS-treated vascular rings is due to hypoxic inhibition of constitutive NO synthase found in endothelium and demonstrate that the inhibition by hypoxia of LPS-induced NO synthase is the primary mechanism of the enhanced and sustained hypoxic vasoconstriction seen in LPS- treated vessels.

KW - arachidonic acid

KW - endothelium-derived relaxing factor

KW - hypoxia

KW - indomethacin

KW - lipopolysaccharide

KW - N(ω)-nitro-L-arginine methyl ester

KW - nitric oxide

KW - nitric oxide synthase

KW - sepsis

KW - thoracic aorta

KW - vasoconstriction

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M3 - Article

VL - 265

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 4 9-4

ER -