Inhibition of the production of nitric oxide and vasodilator prostaglandins attenuates the cardiovascular response to bacterial endotoxin in adrenalectomized rats

Csaba Szabo, C. Thiemermann, J. R. Vane

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Bacterial lipopolysaccharide (LPS) is the toxic moiety of the gram-negative bacterial outer membrane which is responsible for many of the pathophysiological events that occur during endotoxic shock. Here we investigate the hypothesis that endogenous glucocorticoids modulate the formation of nitric oxide (NO) and of vasodilator cyclooxygenase metabolites in response to LPS. Intravenous administration of a small dose of Escherichia coli LPS (0.1 mg kg-1) to normal Wistar rats caused a moderate fall in blood pressure, and 120 min of endotoxaemia was not associated with an attenuation of the rise in blood pressure elicited by intravenous injection of noradrenaline (NA; vascular hyporeactivity). When adrenalectomized (ADX) rats, which lack endogenous glucocorticoids, were subjected to the same dose of LPS, they developed a much more severe form of circulatory shock, which was characterized by a profound fall in blood pressure and a vascular hyporeactivity to NA. Both hypotension and vascular hyporeactivity were prevented by pre-treatment with dexamethasone. Inhibition of NO biosynthesis with N(G)-methyl-L-arginine significantly attenuated the hypotension and the vascular hyporeactivity to NA caused by LPS in ADX rats. Similarly, the cyclooxygenase inhibitor indomethacin significantly attenuated the circulatory failure elicited by LPS in the ADX rats. Interestingly, 120 min of endotoxaemia resulted in a de novo biosynthesis of an induced isoform of NO synthase in the lungs of ADX, but not normal Wistar, rats. This induction of NO synthase was prevented by dexamethasone pre-treatment. We conclude that the severe, delayed circulatory failure (hypotension and vascular hyporeactivity to NA) seen in ADX rats subjected to LPS is mediated by an enhanced formation of NO and vasodilator cyclooxygenase metabolites, presumably prostacyclin. These findings support the hypothesis that endogenous glucocorticoids ameliorate the induction of NO synthase and cyclooxygenase in response to inflammatory stimuli such as cytokines or endotoxin.

Original languageEnglish (US)
Pages (from-to)233-238
Number of pages6
JournalProceedings of the Royal Society B: Biological Sciences
Volume253
Issue number1338
StatePublished - 1993
Externally publishedYes

Fingerprint

vasodilator agents
nitric oxide
endotoxins
Vasodilator Agents
Endotoxins
lipopolysaccharides
prostaglandins
Prostaglandins
Lipopolysaccharides
Rats
Nitric Oxide
blood vessels
prostaglandin synthase
rats
hypotension
Blood pressure
Prostaglandin-Endoperoxide Synthases
glucocorticoids
nitric oxide synthase
Nitric Oxide Synthase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Agricultural and Biological Sciences (miscellaneous)

Cite this

@article{6e463989fdaf43a59f88f4c4facca21c,
title = "Inhibition of the production of nitric oxide and vasodilator prostaglandins attenuates the cardiovascular response to bacterial endotoxin in adrenalectomized rats",
abstract = "Bacterial lipopolysaccharide (LPS) is the toxic moiety of the gram-negative bacterial outer membrane which is responsible for many of the pathophysiological events that occur during endotoxic shock. Here we investigate the hypothesis that endogenous glucocorticoids modulate the formation of nitric oxide (NO) and of vasodilator cyclooxygenase metabolites in response to LPS. Intravenous administration of a small dose of Escherichia coli LPS (0.1 mg kg-1) to normal Wistar rats caused a moderate fall in blood pressure, and 120 min of endotoxaemia was not associated with an attenuation of the rise in blood pressure elicited by intravenous injection of noradrenaline (NA; vascular hyporeactivity). When adrenalectomized (ADX) rats, which lack endogenous glucocorticoids, were subjected to the same dose of LPS, they developed a much more severe form of circulatory shock, which was characterized by a profound fall in blood pressure and a vascular hyporeactivity to NA. Both hypotension and vascular hyporeactivity were prevented by pre-treatment with dexamethasone. Inhibition of NO biosynthesis with N(G)-methyl-L-arginine significantly attenuated the hypotension and the vascular hyporeactivity to NA caused by LPS in ADX rats. Similarly, the cyclooxygenase inhibitor indomethacin significantly attenuated the circulatory failure elicited by LPS in the ADX rats. Interestingly, 120 min of endotoxaemia resulted in a de novo biosynthesis of an induced isoform of NO synthase in the lungs of ADX, but not normal Wistar, rats. This induction of NO synthase was prevented by dexamethasone pre-treatment. We conclude that the severe, delayed circulatory failure (hypotension and vascular hyporeactivity to NA) seen in ADX rats subjected to LPS is mediated by an enhanced formation of NO and vasodilator cyclooxygenase metabolites, presumably prostacyclin. These findings support the hypothesis that endogenous glucocorticoids ameliorate the induction of NO synthase and cyclooxygenase in response to inflammatory stimuli such as cytokines or endotoxin.",
author = "Csaba Szabo and C. Thiemermann and Vane, {J. R.}",
year = "1993",
language = "English (US)",
volume = "253",
pages = "233--238",
journal = "Philosophical Transactions of the Royal Society B: Biological Sciences",
issn = "0962-8436",
publisher = "Royal Society of London",
number = "1338",

}

TY - JOUR

T1 - Inhibition of the production of nitric oxide and vasodilator prostaglandins attenuates the cardiovascular response to bacterial endotoxin in adrenalectomized rats

AU - Szabo, Csaba

AU - Thiemermann, C.

AU - Vane, J. R.

PY - 1993

Y1 - 1993

N2 - Bacterial lipopolysaccharide (LPS) is the toxic moiety of the gram-negative bacterial outer membrane which is responsible for many of the pathophysiological events that occur during endotoxic shock. Here we investigate the hypothesis that endogenous glucocorticoids modulate the formation of nitric oxide (NO) and of vasodilator cyclooxygenase metabolites in response to LPS. Intravenous administration of a small dose of Escherichia coli LPS (0.1 mg kg-1) to normal Wistar rats caused a moderate fall in blood pressure, and 120 min of endotoxaemia was not associated with an attenuation of the rise in blood pressure elicited by intravenous injection of noradrenaline (NA; vascular hyporeactivity). When adrenalectomized (ADX) rats, which lack endogenous glucocorticoids, were subjected to the same dose of LPS, they developed a much more severe form of circulatory shock, which was characterized by a profound fall in blood pressure and a vascular hyporeactivity to NA. Both hypotension and vascular hyporeactivity were prevented by pre-treatment with dexamethasone. Inhibition of NO biosynthesis with N(G)-methyl-L-arginine significantly attenuated the hypotension and the vascular hyporeactivity to NA caused by LPS in ADX rats. Similarly, the cyclooxygenase inhibitor indomethacin significantly attenuated the circulatory failure elicited by LPS in the ADX rats. Interestingly, 120 min of endotoxaemia resulted in a de novo biosynthesis of an induced isoform of NO synthase in the lungs of ADX, but not normal Wistar, rats. This induction of NO synthase was prevented by dexamethasone pre-treatment. We conclude that the severe, delayed circulatory failure (hypotension and vascular hyporeactivity to NA) seen in ADX rats subjected to LPS is mediated by an enhanced formation of NO and vasodilator cyclooxygenase metabolites, presumably prostacyclin. These findings support the hypothesis that endogenous glucocorticoids ameliorate the induction of NO synthase and cyclooxygenase in response to inflammatory stimuli such as cytokines or endotoxin.

AB - Bacterial lipopolysaccharide (LPS) is the toxic moiety of the gram-negative bacterial outer membrane which is responsible for many of the pathophysiological events that occur during endotoxic shock. Here we investigate the hypothesis that endogenous glucocorticoids modulate the formation of nitric oxide (NO) and of vasodilator cyclooxygenase metabolites in response to LPS. Intravenous administration of a small dose of Escherichia coli LPS (0.1 mg kg-1) to normal Wistar rats caused a moderate fall in blood pressure, and 120 min of endotoxaemia was not associated with an attenuation of the rise in blood pressure elicited by intravenous injection of noradrenaline (NA; vascular hyporeactivity). When adrenalectomized (ADX) rats, which lack endogenous glucocorticoids, were subjected to the same dose of LPS, they developed a much more severe form of circulatory shock, which was characterized by a profound fall in blood pressure and a vascular hyporeactivity to NA. Both hypotension and vascular hyporeactivity were prevented by pre-treatment with dexamethasone. Inhibition of NO biosynthesis with N(G)-methyl-L-arginine significantly attenuated the hypotension and the vascular hyporeactivity to NA caused by LPS in ADX rats. Similarly, the cyclooxygenase inhibitor indomethacin significantly attenuated the circulatory failure elicited by LPS in the ADX rats. Interestingly, 120 min of endotoxaemia resulted in a de novo biosynthesis of an induced isoform of NO synthase in the lungs of ADX, but not normal Wistar, rats. This induction of NO synthase was prevented by dexamethasone pre-treatment. We conclude that the severe, delayed circulatory failure (hypotension and vascular hyporeactivity to NA) seen in ADX rats subjected to LPS is mediated by an enhanced formation of NO and vasodilator cyclooxygenase metabolites, presumably prostacyclin. These findings support the hypothesis that endogenous glucocorticoids ameliorate the induction of NO synthase and cyclooxygenase in response to inflammatory stimuli such as cytokines or endotoxin.

UR - http://www.scopus.com/inward/record.url?scp=0027492010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027492010&partnerID=8YFLogxK

M3 - Article

C2 - 7694300

AN - SCOPUS:0027492010

VL - 253

SP - 233

EP - 238

JO - Philosophical Transactions of the Royal Society B: Biological Sciences

JF - Philosophical Transactions of the Royal Society B: Biological Sciences

SN - 0962-8436

IS - 1338

ER -