Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock

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

Research output: Contribution to journalArticle

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Abstract

1. The role of an enhanced formation of nitric oxide (NO) and the relative importance of the constitutive and inducible NO synthase (NOS) for the development of immediate (within 60 min) and delayed (at 180 min) vascular hyporeactivity to noradrenaline was investigated in a model of circulatory shock induced by endotoxin (lipopolysaccharide; LPS) in the rat. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate. In addition, the calcium-dependent and calcium-independent NOS activity was measured ex vivo by the conversion of [3H]-arginine to [3H]-citrulline in homogenates from several organs obtained from vehicle- and LPS-treated rats. 3. E. coli LPS (10 mg kg-1, i.v. bolus) caused a rapid (within 5 min) and sustained fall in MAP. At 30 and 60 min after LPS, pressor responses to noradrenaline (0.3, 1 or 3 μg kg-1, i.v.) were significantly reduced. The pressor responses were restored by N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mg kg-1, i.v. at 60 min), a potent inhibitor of NO synthesis. In contrast, L-NAME did not potentiate the noradrenaline-induced pressor responses in control animals. 4. Dexamethasone (3 mg kg-1, i.v., 60 min prior to LPS), a potent inhibitor of the induction of NOS, did not alter initial MAP or pressor responses to noradrenaline in control rats, but significantly attenuated the LPS-induced fall in MAP at 15 to 60 min after LPS. Dexamethasone did not influence the development of the LPS-induced immediate (within 60 min) hyporeactivity to noradrenaline. However, dexamethasone pretreatment prevented the hypotension and vascular hyporeactivity at 180 min. 5. At 60 min after LPS a moderate increase in the activity of a calcium-independent (inducible) NOS activity was detected in the aorta, but not in any of the other tissues studied. However, at 180 min after LPS, a significant NOS induction was observed in the lung, liver, spleen, mesentery, heart and aorta. This NOS induction was substantially prevented by pretreatment with dexamethasone. 6. These results suggest that the immediate hypotension and vascular hyporeactivity to noradrenaline in endotoxin shock is caused by an enhanced formation of NO due to activation of the constitutive enzyme. The delayed hypotension and vascular hyporeactivity, however, is due to enhanced NO formation by the LPS-induced enzyme.

Original languageEnglish (US)
Pages (from-to)786-792
Number of pages7
JournalBritish Journal of Pharmacology
Volume108
Issue number3
StatePublished - 1993
Externally publishedYes

Fingerprint

Endotoxins
Nitric Oxide Synthase
Shock
Norepinephrine
Arterial Pressure
Nitric Oxide
Dexamethasone
NG-Nitroarginine Methyl Ester
Hypotension
Calcium
Aorta
Citrulline
Enzyme Activation
Mesentery
Nitric Oxide Synthase Type II
Blood Vessels
Lipopolysaccharides
Arginine
Wistar Rats
Spleen

Keywords

  • Catecholamines
  • Circulatory shock
  • Hypotension
  • In vivo
  • Lipopolysaccharide
  • Nitric oxide synthase
  • Rat

ASJC Scopus subject areas

  • Pharmacology

Cite this

Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. / Szabo, Csaba; Mitchell, J. A.; Thiemermann, C.; Vane, J. R.

In: British Journal of Pharmacology, Vol. 108, No. 3, 1993, p. 786-792.

Research output: Contribution to journalArticle

Szabo, Csaba ; Mitchell, J. A. ; Thiemermann, C. ; Vane, J. R. / Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. In: British Journal of Pharmacology. 1993 ; Vol. 108, No. 3. pp. 786-792.
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N2 - 1. The role of an enhanced formation of nitric oxide (NO) and the relative importance of the constitutive and inducible NO synthase (NOS) for the development of immediate (within 60 min) and delayed (at 180 min) vascular hyporeactivity to noradrenaline was investigated in a model of circulatory shock induced by endotoxin (lipopolysaccharide; LPS) in the rat. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate. In addition, the calcium-dependent and calcium-independent NOS activity was measured ex vivo by the conversion of [3H]-arginine to [3H]-citrulline in homogenates from several organs obtained from vehicle- and LPS-treated rats. 3. E. coli LPS (10 mg kg-1, i.v. bolus) caused a rapid (within 5 min) and sustained fall in MAP. At 30 and 60 min after LPS, pressor responses to noradrenaline (0.3, 1 or 3 μg kg-1, i.v.) were significantly reduced. The pressor responses were restored by N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mg kg-1, i.v. at 60 min), a potent inhibitor of NO synthesis. In contrast, L-NAME did not potentiate the noradrenaline-induced pressor responses in control animals. 4. Dexamethasone (3 mg kg-1, i.v., 60 min prior to LPS), a potent inhibitor of the induction of NOS, did not alter initial MAP or pressor responses to noradrenaline in control rats, but significantly attenuated the LPS-induced fall in MAP at 15 to 60 min after LPS. Dexamethasone did not influence the development of the LPS-induced immediate (within 60 min) hyporeactivity to noradrenaline. However, dexamethasone pretreatment prevented the hypotension and vascular hyporeactivity at 180 min. 5. At 60 min after LPS a moderate increase in the activity of a calcium-independent (inducible) NOS activity was detected in the aorta, but not in any of the other tissues studied. However, at 180 min after LPS, a significant NOS induction was observed in the lung, liver, spleen, mesentery, heart and aorta. This NOS induction was substantially prevented by pretreatment with dexamethasone. 6. These results suggest that the immediate hypotension and vascular hyporeactivity to noradrenaline in endotoxin shock is caused by an enhanced formation of NO due to activation of the constitutive enzyme. The delayed hypotension and vascular hyporeactivity, however, is due to enhanced NO formation by the LPS-induced enzyme.

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