Document Detail


Type II nitric oxide synthase activity is cardio-protective in experimental sepsis.
MedLine Citation:
PMID:  12860479     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Overproduction of nitric oxide (NO) via the induction of NO synthase (NOS) II is implicated in the pathogenesis of the refractory hypotension that characterizes septic shock. However, clinical trials of nonselective NOS inhibitors have failed to afford a mortality benefit in patients with sepsis, and in those with depressed left ventricular function, death rates were increased. Such observations have led to the suggestion that a selective inhibitor of NOSII would be more effective in treating septic shock, although precisely how NO modulates cardiac function in these circumstances remains unclear. We therefore used an isolated ejecting rodent heart model to study the effects of NO and experimental sepsis (endotoxin 20 mg kg i.p.) on cardiac functions. Coronary flow and cardiac output and ventricular functions were reduced by LPS, effects that were partially obviated by supplementation of perfusate with the NO substrate, L-arginine. These improvements were partially blocked by the selective NOSII inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400W) and further reduced by the combined NOSI, II and III inhibitor L-nitro L-arginine methyl ester (L-NAME). These findings suggest that NOSII is cardio-protective in the heart in sepsis and explain why its inhibition in man led to increased mortality in a subpopulation of patients.
Authors:
Suzanna Price; Jane A Mitchell; Peter B Anning; Timothy W Evans
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  European journal of pharmacology     Volume:  472     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-07-15     Completed Date:  2004-04-23     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  111-8     Citation Subset:  IM    
Affiliation:
Unit of Critical Care Medicine, Imperial College School of Medicine, Royal Brompton Hospital, Dovehouse Street, London SW3 6LY, UK.
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MeSH Terms
Descriptor/Qualifier:
Amidines / pharmacology
Animals
Benzylamines / pharmacology
Cardiotonic Agents / antagonists & inhibitors,  metabolism*
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Heart / drug effects,  physiopathology*
Heart Function Tests
Lipopolysaccharides / toxicity
Male
Myocardium / enzymology*
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide Synthase / antagonists & inhibitors,  metabolism*
Nitric Oxide Synthase Type II
Rats
Rats, Wistar
Sepsis* / enzymology,  physiopathology
Chemical
Reg. No./Substance:
0/Amidines; 0/Benzylamines; 0/Cardiotonic Agents; 0/Enzyme Inhibitors; 0/Lipopolysaccharides; 0/N-(3-(aminomethyl)benzyl)acetamidine; 50903-99-6/NG-Nitroarginine Methyl Ester; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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