Document Detail

Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock.
MedLine Citation:
PMID:  10966238     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: To test the effect of a continuous infusion of the nitric oxide (NO) synthase (S) inhibitor aminoethyl-isothiourea (AE-ITU) on survival time, hemodynamics, and oxygen transport in a porcine model of live group A streptococcal (GAS) sepsis. Furthermore, to examine the role of endothelin-1, histamine, and reactive oxygen species (ROS) in streptococcal shock. DESIGN: Prospective, randomized trial. SETTING: Laboratory at a university hospital. SUBJECTS: Twenty-eight pigs with an average weight of 25 kg. INTERVENTIONS: Sixteen animals received a continuous infusion of live Streptococcus pyogenes 1.3 x 10(10) colony forming units/hr: eight received fluids only, and the other eight received an intravenous infusion of AE-ITU 10 mg/kg/hr starting 30 mins before the GAS challenge. Six control pigs received AE-ITU 10 mg/kg/hr iv for 5 hrs. Another six animals received half the dose of GAS over 5 hrs. MEASUREMENTS AND MAIN RESULTS: GAS infusion caused a rapid increase in pulmonary, hepatic, and systemic vascular resistance, followed by hypotension with a 90% lethality at 4 hrs. Treatment with AE-ITU increased 4-hr survival in septic animals from 1/8 to 8/8 and 5-hr survival from 0/8 to 5/8, prevented hypotension, and increased urine output. AE-ITU attenuated the decrease in cardiac output, liver blood flow, and oxygen delivery, and hepatic arterial blood flow as a fraction of cardiac output increased (all p < .05). Plasma nitrate/nitrite levels decreased in all animals. Inducible NOS and endothelial constitutive NOS activities in liver, gut, and lung were not increased during sepsis, nor were they decreased after AE-ITU. Plasma levels of endothelin-1 and methylhistamine increased in all septic animals and were not modified by AE-ITU. AE-ITU prevented the increase in monocyte ROS production caused by GAS. In control animals, AE-ITU caused an increase in mean arterial pressure, liver blood flow, and oxygen delivery. CONCLUSIONS: In this model of porcine GAS-induced septic shock, which was not associated with enhanced NO production, infusion of the NOS inhibitor AE-ITU prolonged survival, prevented hypotension, and improved cardiac contractility, organ perfusion, and tissue oxygenation. These beneficial effects of AE-ITU might be a result of the combined effect of ROS scavenging and modulation of local NO production, thus improving the balance of vasodilator and vasoconstrictor forces and reducing oxidative stress.
T Saetre; E A Höiby; T Aspelin; G Lermark; T Egeland; T Lyberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Critical care medicine     Volume:  28     ISSN:  0090-3493     ISO Abbreviation:  Crit. Care Med.     Publication Date:  2000 Aug 
Date Detail:
Created Date:  2000-10-05     Completed Date:  2000-10-05     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0355501     Medline TA:  Crit Care Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2697-706     Citation Subset:  AIM; IM    
Research Forum, Ullevaal University Hospital, Oslo, Norway.
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MeSH Terms
Disease Models, Animal
Isothiuronium / analogs & derivatives*,  therapeutic use
Nitric Oxide / antagonists & inhibitors*
Random Allocation
Shock, Septic / drug therapy*,  mortality*,  physiopathology
Streptococcal Infections / drug therapy*,  mortality*,  physiopathology
Streptococcus pyogenes
Survival Rate
Thiourea / analogs & derivatives*,  pharmacology
Reg. No./Substance:
0/aminoethyl-isothiourea; 10102-43-9/Nitric Oxide; 22584-04-9/Isothiuronium; 2986-20-1/etiron; 62-56-6/Thiourea
Comment In:
Crit Care Med. 2000 Aug;28(8):3081-2   [PMID:  10966302 ]

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