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Nitric oxide and extravasation in endotoxaemia: an experimental study
Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-27523Local ID: 12179ISBN: 91-7373-170-6 (print)OAI: oai:DiVA.org:liu-27523DiVA: diva2:248075
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
List of papers
1. Intravenous endotoxin does not increase tissue extravasation of albumin in rats
Open this publication in new window or tab >>Intravenous endotoxin does not increase tissue extravasation of albumin in rats
1998 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 42, no 8, 966-973 p.Article in journal (Refereed) Published
Abstract [en]

Background: It is unclear whether activation of the inducible nitric oxide synthase (iNOS) increases or decreases the extravasation of plasma.

Methods: Chloralose anaesthetised male Wistar rats received E. coli lipopolysacharide (LPS), 3 mg kg-1 i.v., or the corresponding volume of saline, 3 or 5 h before the end of the experiment. Mean arterial pressure (MAP) and heart rate (HR) were recorded. Tissue clearance of radio-labelled albumin, during the last 2 h of each experiment, was determined by a double-isotope method. In separate animals, the serum concentration of nitrite and nitrate was determined, 5 h after LPS or the solvent.

Main Results: LPS initially decreased MAP and lastingly increased HR. In the 3-h LPS animals (n=8), tissue plasma clearance was lower in the heart and calf muscle and increased only in diaphragm, compared to corresponding control animals (n=8). In the 5-h LPS rats, clearance was lowered (n=8) in the entire gastrointestinal tract and in testes, compared to controls (n=8). The serum nitrite/nitrate concentration was higher in animals given LPS (n=6) than in controls (n=6).

Conclusion: After LPS, tissue clearance of albumin was not increased in any major tissue, in spite of increased serum levels of NO end products. Apparently, after activation of iNOS, the augmented release of NO is not necessarily associated with increased albumin extravasation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81416 (URN)10.1111/j.1399-6576.1998.tb05357.x (DOI)
Available from: 2012-09-13 Created: 2012-09-13 Last updated: 2017-12-07Bibliographically approved
2. Aminoguanidine does not influence tissue extravasation of albumin in endotoxaemic rats
Open this publication in new window or tab >>Aminoguanidine does not influence tissue extravasation of albumin in endotoxaemic rats
2001 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 45, no 1, 112-118 p.Article in journal (Refereed) Published
Abstract [en]

Background: It is generally maintained that protein and fluid are lost from the circulation under septic conditions. The role played by an increased production of nitric oxide, by the inducible nitric oxide synthase (iNOS), in this process is unclear.

Methods: Chloralose anaesthetised male Wistar rats received E. coli lipopolysaccharide (LPS), 3 mg kg−1 i.v., and were studied for 5 h. Mean arterial pressure (MAP) and heart rate (HR) were monitored and haematocrit (Hct) was determined intermittently. Tissue plasma volume and tissue clearances of radiolabelled albumin over the last 2 h of the experiment were determined by a double-isotope method. In 8 rats, 2 h after LPS, aminoguanidine, an iNOS selective blocker, was given i.v. at a dose of 5 mg kg−1. This was followed by a continuous infusion for the duration of the experiment; altogether 20 mg kg−1 was administered. In the control group (n=8), a corresponding volume of saline was infused.

Results: Aminoguanidine did not significantly influence Hct, MAP and HR, as evidenced by inter-group comparisons (Mann-Whitney test). Tissue plasma clearances of albumin and tissue plasma volume were similar in both groups.

Conclusion: Aminoguanidine at 20 mg kg−1 did not reverse the haemodynamic changes induced by LPS. Neither did the drug affect the tissue plasma clearance of albumin or the tissue plasma volume.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26995 (URN)10.1034/j.1399-6576.2001.450117.x (DOI)11631 (Local ID)11631 (Archive number)11631 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Effective inhibition of nitric oxide production by aminoguanidine does not reverse hypotension in endotoxaemic rats
Open this publication in new window or tab >>Effective inhibition of nitric oxide production by aminoguanidine does not reverse hypotension in endotoxaemic rats
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26996 (URN)10.1034/j.1399-6576.2002.460104.x (DOI)11632 (Local ID)11632 (Archive number)11632 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Nitric oxide does not cause extravasation in endotoxemic rats
Open this publication in new window or tab >>Nitric oxide does not cause extravasation in endotoxemic rats
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.

Keyword
albumin, endotoxin, immunohistochemistry, lipopolysaccharide, nitric oxide, nitric oxide synthase, rats, tissue plasma clearance, water
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31547 (URN)10.1097/01.ta.0000171988.56193.a6 (DOI)17348 (Local ID)17348 (Archive number)17348 (OAI)
Note

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: 2017-12-13Bibliographically approved

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