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Effective inhibition of nitric oxide production by aminoguanidine does not reverse hypotension in endotoxaemic rats
Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences.
Department of Clinical Pharmacology, Sahlgrenska University Hospital, Sweden.
Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences.
2002 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 46, no 1, 17-23 p.Article in journal (Refereed) Published
Abstract [en]

Background: Excess production of nitric oxide (NO) by the inducible NO synthase (iNOS) has been implicated in the pathophysiology of septic shock. Using methaemoglobin (metHb) and the stable NO metabolite nitrate as markers of NO formation, we assessed the effect of iNOS blockade by aminoguanidine (AG) on hypotension and NO formation in endotoxaemic rats.

Methods: In 32 male Wistar rats under chloralose anaesthesia, MetHb (at 15 and 330 min, respectively) and plasma nitrate (at 330 min) were determined. Mean arterial pressure, heart rate and haematocrit were monitored. The LPS group (n=8) received bacterial endotoxin (LPS), 3 mg kg−1 i.v. and was subsequently monitored for 5 h. At 2 h after LPS, the LPS+AG20 group (n=8) received AG, 5 mg kg−1, and 5 mg kg−1 h−1 for the remaining 3 h. The LPS+AG100 group (n=8) instead received 25 mg kg−1, followed by 25 mg kg−1 h−1. The NaCl group (n=8) was given corresponding volumes of isotonic saline.

Results: AG decreased the LPS-induced rise in plasma nitrate by about 50% in the LPS+AG20 group. MetHb levels, however, were not appreciably reduced by this dose. Both NO metabolites reached control levels after the higher dose of AG. LPS caused a progressive decrease in haematocrit. AG did not influence the LPS-induced hypotension, tachycardia or haemodilution.

Conclusion: AG inhibited NO formation in a dose-dependent way. Yet, AG had no haemodynamic effects, suggesting a minor cardiovascular influence of iNOS in this endotoxin model, in parallel to what has been found in microbial sepsis.

Place, publisher, year, edition, pages
2002. Vol. 46, no 1, 17-23 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26996DOI: 10.1034/j.1399-6576.2002.460104.xLocal ID: 11632OAI: oai:DiVA.org:liu-26996DiVA: diva2:247547
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically 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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 728
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-13Bibliographically approved

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