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The influence of a load of L-arginine on serum amino acids and pancreatic apoptosis/proliferation and ATP levels in the rat
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
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.
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2004 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 29, no 4, 113-120 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:

Administration of high doses of amino acids like ethionine, methionine, and arginine causes pancreatic tissue damage. The initial mechanism behind these effects is not known. The aim of this study was to show the early effects of a load of L-arginine on programed cell death/proliferation and ATP levels in the pancreas.

METHODS:

We analyzed in rats the effects of intraperitoneal administration of L-arginine on serum amino acids, pancreatic cell apoptosis/proliferation, and ATP levels at 8, 16, and 24 hours. Serum amino acid concentrations were measured with HPLC, tissue ATP was measured fluorometrically, apoptosis was studied with caspase-3 activity and histone-associated DNA-fragments, and proliferation was studied with thymidine autoradiography.

RESULTS:

After a load of l-arginine, there were initially increased serum levels of L-arginine and L-citrulline, but these fell below control levels after 24 hours as well as amino acids in the glutamate family (ornithine, proline, histidine, and glutamine). Initially, increased ATP levels in the pancreatic tissue returned to control levels at 24 hours. The acinar cells proliferation was suppressed and the apoptosis rate strongly increased at 16 and 24 hours. Pancreatic histology showed vacuole formation in the acinar cells at 8 hours. At 16 hours, there was less vacuolization, but apoptotic bodies were seen, and at 24 hours there was cell degeneration but no necrosis.

CONCLUSIONS:

After a load of l-arginine, amino acid metabolism causes a high ATP production in the pancreatic tissue that may cause mitochondrial initiation of cell death.

Place, publisher, year, edition, pages
2004. Vol. 29, no 4, 113-120 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-23748PubMedID: 15502637Local ID: 3258OAI: oai:DiVA.org:liu-23748DiVA: diva2:244063
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-01Bibliographically 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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 866
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved
2. 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, LenaSandström, PerSundqvist, TommySmeds, StaffanGasslander, ThomasSvanvik, Joar

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