Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock

Details

Serval ID
serval:BIB_16A672477A21
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock
Journal
American Journal of Respiratory and Critical Care Medicine
Author(s)
Rosselet  A., Feihl  F., Markert  M., Gnaegi  A., Perret  C., Liaudet  L.
ISSN
1073-449X (Print)
Publication state
Published
Issued date
01/1998
Volume
157
Number
1
Pages
162-70
Notes
Comparative Study
Journal Article --- Old month value: Jan
Abstract
S-methyl-isothiourea (SMT) is a potent inhibitor of NO synthase (NOS) with relative selectivity towards the inducible isoform (iNOS). We compared SMT and norepinephrine for the treatment of experimental endotoxic shock. Anesthetized rats challenged intravenously with lipopolysaccharide (LPS), 10 mg/kg, were treated after 1 h with a 4-h infusion of norepinephrine (titrated to maintain blood pressure within baseline values), SMT at low dose (0.1 mg x kg-1 x h-1), or at high dose (1 mg x kg-1 x h-1), or an equivalent volume of saline (2 ml x kg-1 x h-1). In saline-treated animals, LPS increased plasma nitrate and produced hypotension, low cardiac output (CO), lactic acidosis, and signs of liver and kidney dysfunction. Norepinephrine maintained blood pressure (BP) and reduced the fall in CO, without affecting lactic acidosis, organ dysfunction, and nitrate accumulation. The latter was dose-dependently blunted by SMT. Treatment with this agent prevented hypotension, through systemic vasoconstriction with the high dose and a maintained CO with the low dose. Low, but not high, dose SMT blunted lactic acidosis. Both doses reduced the signs of renal, but not liver, dysfunction. In additional studies, we obtained evidence that, in contrast with the high dose, SMT at low dose did not interfere with the function of constitutive NOS. These findings suggest a potential advantage of selective iNOS inhibition over standard adrenergic support in the therapy of septic shock.
Keywords
Animals Blood Gas Analysis Disease Models, Animal Dose-Response Relationship, Drug Drug Evaluation, Preclinical Hemodynamic Processes/drug effects Infusions, Intravenous Isothiuronium/*analogs & derivatives/therapeutic use Lipopolysaccharides Male Nitrates/blood Nitric Oxide Synthase/*antagonists & inhibitors Nitric Oxide Synthase Type II Norepinephrine/*therapeutic use Random Allocation Rats Rats, Wistar Shock, Septic/*drug therapy/metabolism/physiopathology Vasoconstrictor Agents/*therapeutic use
Pubmed
Web of science
Create date
25/01/2008 9:38
Last modification date
20/08/2019 12:46
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