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Highly selective iNOS inhibition and sphincter of Oddi motility in the Australian possum
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 General and Digestive Surgery, Centre for Neuroscience and the Centre for Digestive Sciences, Flinders Medical Centre, Flinders University, Adelaide, South Australia, 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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2004 (English)In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 181, no 3, 321-331 p.Article in journal (Refereed) Published
Abstract [en]

Aim:  Inducible nitric oxide synthase (iNOS) plays a major role in acute pancreatitis. Selective inhibitors of iNOS are being developed as therapeutic agents. Sphincter of Oddi (SO) dysfunction may cause pancreatitis and nitric oxide is necessary for SO relaxation. A new highly selective iNOS inhibitor, AR-C102222AA (AR-C), is evaluated together with the established iNOS inhibitor, l-N6-(1-iminoethyl)lysine (l-NIL), and the selective neuronal nitric oxide synthase (nNOS) blocker S-methyl-l-thiocitrulline (SMTC).

Methods:  In anaesthetized Australian Brush-tailed possums, the effect of topical, i.v. or i.a. administration of these drugs was evaluated on spontaneous SO motility, blood pressure (BP) and pancreatic vascular perfusion. SO motility was recorded by manometry and pancreatic vascular perfusion by laser Doppler fluxmetry. Also, the effect of SMTC and AR-C on electrical field stimulation (EFS)-induced non-cholinergic non-adrenergic (NANC) SO relaxation in vitro was evaluated.

Results:  Infusion of AR-C (0.1–30 μmol kg−1) increased SO contraction frequency (P = 0.026) only at the two highest doses. l-NIL infusion (0.15 to 14.7 μmol kg−1) also increased SO contraction frequency at 8.8 μmol kg−1 (P < 0.05) and reduced SO contraction amplitude at the two highest doses (P < 0.05). SMTC injections (0.5 nmol–2.4 μmol) produced a dose-dependent increase in SO contraction frequency (P = 0.009), but no effect was seen on the other parameters. In vitro SMTC (40–400 μm) inhibited EFS-induced NANC relaxation in a dose-dependent manner (P < 0.0005). In contrast AR-C (10–500 μm) had no effect on EFS-induced NANC relaxation (P > 0.05).

Conclusions:  At low doses, AR-C does not effect SO motility or EFS-induced NO mediated relaxation. However, high doses of AR-C and L-NIL in vivo influenced SO motility by inhibiting nNOS activity and these effects need be considered in relation to therapeutic doses of this agent.

Place, publisher, year, edition, pages
2004. Vol. 181, no 3, 321-331 p.
Keyword [en]
Inducible nitric oxide synthase, Nitric oxide, Sphincter of Oddi motility
National Category
Natural Sciences
URN: urn:nbn:se:liu:diva-45702DOI: 10.1111/j.1365-201X.2004.01296.xOAI: diva2:266598
Available from: 2009-10-11 Created: 2009-10-11 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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