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Nitric oxide does not cause extravasation in endotoxemic rats
Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
2005 (English)In: Journal of Trauma, ISSN 0022-5282, E-ISSN 1529-8809, Vol. 58, no 5, 1047-1054 p.Article in journal (Refereed) Published
Abstract [en]

Background: Nitric oxide (NO) formed from inducible NO synthase (iNOS) is assumed to promote vascular permeability in sepsis and endotoxemia.

Methods: Thirty-seven anesthetized rats were examined for the effects of endotoxin. After randomization, 17 animals had lipopolysaccharide (LPS) administered and 20 rats served as controls and were given the corresponding volume of saline. The observation period was 5 hours after administration of endotoxin. Mean arterial blood pressure, heart rate, and hematocrit were recorded in all animals, and transcapillary exchange of albumin, tissue water content, immunohistochemistry for nitric oxide synthase, and blood gases were investigated in subsets of animals.

Results: When anesthetized rats were studied for 5 hours after endotoxin (LPS), the sequestration of albumin decreased in the intestine (double-isotope method) and there was no increased water content (freeze-drying technique) when the elevated tissue plasma volume of the LPS-treated rats was corrected for. Immunohistochemical methods showed a similar distribution and intensity of staining for endothelial NOS and neuronal NOS in LPS and control groups. In the lung of the LPS-treated rats, there was a significantly larger number of infiltrating, inflammatory cells staining for iNOS. There was no iNOS demonstrated in vascular structures or heart.

Conclusion: At 5 hours after LPS, there was no increased loss of water or albumin from the circulation. This challenges the notion that NO causes vascular damage in endotoxemia and extravasation as an obligatory sequela to endotoxemia.

Place, publisher, year, edition, pages
2005. Vol. 58, no 5, 1047-1054 p.
Keyword [en]
albumin, endotoxin, immunohistochemistry, lipopolysaccharide, nitric oxide, nitric oxide synthase, rats, tissue plasma clearance, water
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-31547DOI: 10.1097/01.ta.0000171988.56193.a6Local ID: 17348OAI: diva2:252370

On the day of the defence day the status of this article was a manuscript.

Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-13Bibliographically approved
In thesis
1. Nitric oxide and extravasation in endotoxaemia: an experimental study
Open this publication in new window or tab >>Nitric oxide and extravasation in endotoxaemia: an experimental study
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Despite advances in intensive care the mortality of patients in septic shock is still high. In early stages the condition is characterised by circulatory failure that is a consequence of myocardial depression, vasodilatation with decreased sensitivity to catecholamine stimulation and increased loss of protein and fluid from the circulation. For each of these components nitric oxide (NO) has been proposed as a mediator. In the thesis focus is on extravasation and the influence of NO on this.

Methods: As a model of sepsis chloralose anaesthetised rats were subjected to endotoxaernia induced by E. coli lipopolysaccharide (LPS) 3 mg kg-1 i.v. Mean arterial pressure (MAP), heart rate (HR) and haematocrit (Hct) were followed. NO synthesis was evaluated by the detection of methaemoglobin (metHb), nitrite and nitrate in blood. Extravasation was investigated by a double isotope method of labelled albumin (albumin clearance) and by the determination of extravascular water. The effects of endotoxaemia were studied for 3 or, in the majority of cases, 5 h. To evaluate, the involvement of inducible nitric oxide synthase (iNOS) aminoguanidine (AG), an inhibitor of iNOS was employed. Finally, the presence of iNOS in several tissues was investigated by immunohistochemistry.

Main Results: LPS increased formation of NO metabolites. Initially after LPS MAP was decreased and HR elevated. Het was decreased over the 5 h observation period. After LPS the leakage of albumin, as evidenced by albumin clearance, was decreased in several vascular beds, mostly in the gastrointestinal tract. Extravascular water was not increased in any tissue. AG had no influence on circulatory changes to LPS or on albumin clearance despite the inhibition of NO synthesis as indicated by metHb and nitrate. iNOS was present in several tissues of LPS treated as well as control rats but not in the heart or in any vessels; only in the lung was there a significant increase of iNOS positive inflammatory cells after LPS as compared to controls.

Conclusion: In this rat model of endotoxaemia LPS increased the formation of NO and induced circulatory changes commonly seen in rat endotoxaernia. Yet there were no signs of increased extravasation, on the contrary results are compatible with decreased or unchanged losses of fluid and albumin. It is proposed that this result is depending on changed microvascular haemodynamics. It also shows that increased NO formation does not necessarily lead to increased extravasation and indicates that NO could  protect against extravasation in endotoxaemia or at least be neutral for the process. It also points to the importance of carefully evaluating the experimental models used in the study of endotoxaemia.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2002. 85 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 728
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-27523 (URN)12179 (Local ID)91-7373-170-6 (ISBN)12179 (Archive number)12179 (OAI)
Public defence
2002-05-03, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-13Bibliographically approved

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