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The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
Department of Surgery, Vrinnevi Hospital, Norrköping, Sweden.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
2002 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 106, no 1-3, 97-104 p.Article in journal (Refereed) Published
Abstract [en]

Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by Nω-nitro-l-arginine (l-NNA) reduced the urinary excretion of NO2/NO3 and raised serum l-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO2/NO3. The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, l-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of l-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.

Place, publisher, year, edition, pages
2002. Vol. 106, no 1-3, 97-104 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25029DOI: 10.1016/S0167-0115(02)00056-3Local ID: 9452OAI: oai:DiVA.org:liu-25029DiVA: diva2:245355
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
In thesis
1. The influence of nitric oxide and cholecystokinin on tissue homeostasis in exocrine pancreas: an experimental study in rats
Open this publication in new window or tab >>The influence of nitric oxide and cholecystokinin on tissue homeostasis in exocrine pancreas: an experimental study in rats
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Growth of the pancreas is stimulated by cholecystokinin (CCK) in rats. Nitric oxide (NO), which is synthesized from the amino acid L-arginine by NO-synthases (NOS), interferes with CCK in modulating the pancreatic secretion. Both pro- and anti-apoptotic influences of NO have been observed in other tissues, but its importance for pancreatic tissue homeostasis has not been studied.

Cell proliferation and death rates were studied in the rat pancreas during different experimental conditions. CCK-octapeptide (CCK-8) was given in different doses either intermittently or continuously for three days and the pancreatic growth response was studied. Exogenous CCK-8 caused dose-dependent pancreatic atrophy when given intermittently and hyperplasia when given continuously.

The influence of NO on cell death and proliferation was studied during: 1) basal conditions, 2) CCK-8 induced hyperplasia, and 3) CCK-8 induced atrophy. The NO level was manipulated either by NOS inhibition (L-NNA) or by exogenous NO supply (SNAP). NO-metabolism was assessed in the basal situation by analysis of nitrite/nitrate excretion in urine (which was decreased by L-NNA and increased by SNAP), and L-arginine in serum (which increased by L-NNA) and L-citrulline in serum.

1) During basal conditions NOS inhibition (NO↓) increased apoptosis and decreased cell proliferation.

2) During CCK-8 induced hyperplasia NOS inhibition (NO↓) increased both apoptosis and cell proliferation. The apoptosis dominated as indicated by decreased DNA content. SNAP administration (NO↑) did neither influence apoptosis nor cell proliferation.

3) During CCK-8 induced atrophy (DNA↓, apoptosis↑, cell proliferation↑, and cytoplasmic vacuolization) NOS inhibition further increased apoptosis, reduced cell proliferation and abolished vacuole formation. SNAP administration (NO↑) decreased the DNA content, and increased both apoptosis and cell proliferation. The vacuole formation was still present. Hence, NO influences both the basal and the disturbed homeostasis in hyperplastic and atrophic rat pancreatic tissue.

Early events of a load of L-arginine, known to induce pancreatitis within 48 hrs, was studied at 8, 16 and 24 hrs by analysis of serum L-arginine and L-citrulline, pancreatic tissue ATP, apoptosis and cell proliferation. The initially increased serum L-arginine and L-citrulline decreased to levels below control at 24 hrs. Administration of L-arginine was correlated to a biphasic ATP production and formation of small vacuoles (mitochondrial swelling) in the acinar cells, most prominent at 8 hrs and followed by a gradually increased apoptosis rate. The cell proliferation decreased. At 24 hrs there was pronounced cell degeneration, but no evident necrosis. Another 20 amino acids in serum were also analysed at 24 hrs. Twelve amino acids (including the 'glutamate family') were significantly reduced. After an L-arginine load the augmented A TP production correlates to the initiation of pancreatic cell death. The disturbed amino acid metabolism seems to be of importance for development of experimental pancreatitis.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 67 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 846
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22407 (URN)1619 (Local ID)91-7373-820-4 (ISBN)1619 (Archive number)1619 (OAI)
Public defence
2004-05-06, Elsa Brändströmsalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-01Bibliographically approved

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Trulsson, LenaGasslander, ThomasSundqvist, TommySvanvik, Joar

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