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Highly selective inhibition of inducible nitric oxide synthase ameliorates experimental acute pancreatitis
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
Department of General and Digestive Surgery, Centre for Neuroscience and the Centre for Digestive Sciences, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia.
Department of Anatomical Pathology, Flinders Medical Centre, Flinders University of South Australia, Adelaide, SA, Australia.
Department of General and Digestive Surgery, Centre for Neuroscience and the Centre for Digestive Sciences, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia.
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2005 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 30, no 1, 10-15 p.Article in journal (Refereed) Published
Abstract [en]


Inducible nitric oxide synthase (iNOS) activity is increased in experimental acute pancreatitis. The aim of this study was to evaluate treatment with the selective iNOS inhibitors AR-C (AR-C102222AA) and L-NIL (L-N6-(1-iminoethyl)-lysine) in experimental acute pancreatitis.


Acute pancreatitis was induced in anesthetized Australian possums by topical administration of carbachol on the sphincter of Oddi. AR-C treatment was 2 intravenous infusions (2.5 micromol/kg over 15 minutes) at 2 and 4 hours after acute pancreatitis induction. L-NIL treatment was an intraarterial infusion (1 mg/kg/h) from 2 hours after acute pancreatitis induction. At 8 hours, pancreatic tissue was harvested and inflammation assessed (histologic score). Blood samples were collected for plasma amylase, lipase, and amino acid levels. Blood pressure, central venous pressure, supplementary fluids, and urine output were monitored.


Treatment with AR-C or L-NIL reduced the plasma levels of amylase and the volume of supplementary fluids and improved the histological score (all P < 0.05). In animals with acute pancreatitis, plasma arginine levels were reduced (P < 0.05), while citrulline and ornithine levels increased (P < 0.05), consistent with increased nitric oxide production. Treatment with AR-C ameliorated the reduced arginine level.


Treatment with AR-C or L-NIL, commencing 2 hours after the induction of acute pancreatitis, has significant and beneficial effects in experimental acute pancreatitis in Australian possums.

Place, publisher, year, edition, pages
2005. Vol. 30, no 1, 10-15 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-30807PubMedID: 15632690Local ID: 16434OAI: diva2:251630
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-26Bibliographically approved
In thesis
1. Nitric oxide, arginine and acute pancreatitis
Open this publication in new window or tab >>Nitric oxide, arginine and acute pancreatitis
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute pancreatitis is a serious inflammatory condition which is managed symptomatically as there is no causal treatment to offer. The main background causes are alcohol abuse and gallstone disease. The inducing factors lead to a premature activation of pancreatic enzymes in the acinar cells and their subsequent release into the pancreatic tissue. This activates the inflammatory cascade leading to reduced pancreatic vascular perfusion, cellular necrosis and in some cases systemic disease. Nitric oxide (NO) and the by-product citrulline are synthesised from the amino acid L-arginine by NO-synthases (NOS), which exist in three isoforms. Two are constitutive, being necessary for relaxation of vascular myogenic cells (eN OS) or for the relaxation of the sphincter of Oddi, (nNOS). The third, iNOS, is activated mainly during inflammation, producing high concentrations of NO, which may be harmful.

We demonstrate that patients with acute pancreatitis, whatever the cause, have reduced sermn levels of arginine and citrulline, indicating a disturbed NO metabolism with possible negative effects on the outflow of pancreatic juice and on pancreatic blood perfusion. One possible reason for the reduced sermn levels could be an early high NO production via the iNOS route consuming L-arginine. Inhibition of iNOS may improve this imbalance and reduce the inflammation.

In experimental studies, low doses of selective iNOS inhibition do not interfere with blood pressure, pancreatic vascular perfusion or the sphincter of Oddi in vivo. However, in high doses both in vivo and in vitro, the inhibitor stimulates the sphincter muscle by interfering with nNOS, indicating that high doses are harmful.

The iNOS inhibitor was used in an experimental study of acute pancreatitis, and we showed that treatment with selective iNOS inhibition, two hours after induction, reduced inflammation in the pancreatic tissue and the need for fluid, stabilised blood pressure and improved the amino acid balance.

High doses of L-arginine cause necrotising acute pancreatitis in rats within 48 hours. Sermn arginine and citrulline increased at 8 hours, but fell below control levels, at 24 hours. An early increase in pancreatic ATP dropped to control level at 24 hours. The ATP production correlated with histological swelling of mitochondria, seen as vacuole formation, followed by an increased apoptotic activity. Cell proliferation decreased. Full amino acid analysis at 24 hours showed reduction in 14 out of 22 amino acids, including the glutamate family. The process with apoptosis and the reduction of ATP, cell proliferation and amino acids precedes the development of inflammation and necrosis.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 75 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 866
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-24031 (URN)3587 (Local ID)91-7373-842-5 (ISBN)3587 (Archive number)3587 (OAI)
Public defence
2004-11-18, Elsa Brändströmsalen, Hälsouniversitetet, Linköpings, 09:00 (Swedish)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved

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