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Melatonin, an antioxidant, protects the pancreas against acute inflammation but, although this indole is released mainly at night, no study has been undertaken to determine circadian changes of plasma melatonin levels and the severity of acute pancreatitis. The aims of this study were: (a) to compare the severity of caerulein-induced pancreatitis (CIP) produced in the rat during the day and at the night, and (b) to assess the changes of plasma melatonin level and the activity of an antioxidative enzyme; superoxide dismutase (SOD), in the pancreas subjected to CIP during the day time and at night without or with administration of exogenous melatonin or its precursor; l-tryptophan. Rats were kept in 12 hr light/dark cycle. CIP was induced by subcutaneous infusion of caerulein (5 microg/kg/hr for 5 hr). Melatonin (5 or 25 mg/kg) or l-tryptophan (50 or 250 mg/kg) was given intraperitoneally 30 min prior to the start of CIP. CIP induced during the day time was confirmed by histological examination and manifested by pancreatic edema, and rises of amylase and lipase plasma activities (by 400 and 500%, respectively), whereas pancreatic SOD, pancreatic blood flow (PBF) and oxygen consumption by pancreatic tissue (VO(2)) were decreased by 70, 40 and 45%, respectively, as compared with the appropriate controls. All morphological and biochemical parameters of CIP induced at night were significantly less severe, compared with those recorded during the light phase. Plasma melatonin immunoreactivity was significantly higher during the night, than during the day, especially following administration of melatonin or its precursor, which reversed all manifestations of CIP. In conclusion, a circadian rhythm modulates the severity of CIP with a decrease of pancreatitis severity during the night compared with that at the day time and this may be due to the increased plasma level of melatonin and higher activity of SOD in the pancreas.

Background: Previous studies have shown that sensory nerves and calcitonin gene-related peptide (CGRP) affect caerulein-induced pancreatitis. The aim of this study was to examine the role of capsaicin-sensitive nerves and the impact of CGRP administration on necrotizing pancreatitis induced by ischemia/reperfusion., Material/methods: Ablation of sensory nerves was made by capsaicin 10 days before induction of pancreatitis. Acute pancreatitis was induced in rats by limitation of pancreatic blood flow (PBF) followed by reperfusion. Treatment with saline or CGRP (10 g/kg s.c.) or stimulation of sensory nerves by low doses of capsaicin (0.5 mg/kg s.c.) was performed 1 h before ischemia. After 1 h reperfusion we examined pancreatic blood flow (PBF), plasma amylase and lipase activity, plasma interleukin-1beta (IL-1beta) concentration, pancreatic DNA synthesis and morphological signs of pancreatitis., Results: Ischemia followed by 1 h reperfusion led to induction of necrotizing pancreatitis, manifested by morphological signs of pancreatic damage, decrease in pancreatic DNA synthesis and PBF, as well as an increase in plasma amylase and lipase activity and plasma IL-1beta concentration. Both, treatment with CGRP and stimulation of sensory nerves attenuated pancreatic damage. Ablation of sensory nerves enhanced I/R evoked pancreatic damage. The deleterious effect of deactivation of sensory nerves on I/R-induced pancreatitis was partly reversed by administration of CGRP prior to I/R., Conclusions: Stimulation of sensory nerves protects the pancreas against damage evoked by I/R, whereas ablation of these nerves aggravates tissue damage in the pancreas exposed to I/R. The beneficial effect of sensory nerves is partly dependent on CGRP release.

In various organs, including heart, kidneys, brain, liver and stomach, preconditioning by brief exposure to ischemia protects the organ against damage evoked by subsequent severe ischemia. This study has been undertaken to check whether two brief ischemic periods protect the pancreas against severe ischemia/reperfusion-induced pancreatitis and, if so, what is the role of sensory and vagal nerves in this phenomenon. In male Wistar rats, the ischemic preconditioning of the pancreas was performed by clamping of celiac artery (2 x 5 min with 5 min interval). Thirty minutes after preconditioning or sham operation, the ischemia/reperfusion-induced pancreatitis was evoked by clamping of inferior splenic artery for 30 min using microvascular clips, followed by 1 h reperfusion. Sensory nerves ablation was induced 10 days before final experiments by capsaicin. Truncal vagotomy was performed 1 week before the experiment. Exposure to regular 30-min pancreatic ischemia followed by 1 h reperfusion led to the development of acute hemorrhagic pancreatitis. Ischemic preconditioning, applied prior to induction of pancreatitis, caused the reduction in plasma lipase, plasma interleukin-1beta and histological signs of pancreatic damage, as well as attenuated the reduction in pancreatic blood flow and DNA synthesis. Ablation of sensory nerves by capsaicin caused an aggravation of ischemia/reperfusion-induced pancreatic damage and attenuated a protective effect of ischemic preconditioning. Noxious effect of sensory nerves ablation on the pancreas was accompanied by the reduction in pancreatic blood flow and an increase in plasma interleukin-1beta. Similar but less pronounced deleterious effect on the pancreas was observed after vagotomy. We conclude that: (1) pancreatic ischemic preconditioning reduces the severity of ischemia/reperfusion-induced pancreatitis; (2) this effect seems to be related, at least in part, to the improvement of pancreatic blood flow and the reduction in the release of proinflammatory interleukin-1beta; (3) sensory and vagal nerves are involved in protective effect of ischemic preconditioning against pancreatic damage.

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.

Background: Helicobacter pylori (Hp) infection is involved in various gastroduodenal pathologies. Also, the potential role of Hp infection has been proposed in several extragastroduodenal disorders, such as cardiovascular, skin or immunological diseases. The role of Hp infection in acute pancreatitis has not been tested. The aim of this study was to determine the influence of Hp infection on the course of acute ischemia/reperfusion-induced pancreatitis in rats., Methods: Inoculation with CagA- and VacA-positive Hp or administration of vehicle were performed after visceral ischemia. Visceral ischemia was evoked by clamping of the celiac artery for 30 min. Four weeks later, after full recovery from primary ischemia-induced damage, acute pancreatitis was evoked by limitation of pancreatic blood flow (PBF) in the splenic artery for 30 min using microvascular clips. Rats were sacrificed 1 h or 1, 3, 5, 10, and 21 days after removal of the vascular clips. Hp infection was assessed by the urease test and gastric histology., Results: In Hp-negative rats ischemia followed by reperfusion caused acute pancreatitis as manifested by a reduction in PBF and pancreatic DNA synthesis, as well as by increases in plasma amylase, lipase, interleukin-1beta (IL-1beta) and interleukin-10 (IL-10). The morphological features of pancreatic tissue showed necrosis, strongly pronounced edema, hemorrhages and leukocyte infiltration. The maximal intensity of pancreatic damage was observed between the 1st and 3rd day of reperfusion, then pancreatic tissue underwent regeneration. Hp infection resulted in a significant reduction in PBF and an aggravation of pancreatic ischemia 1 h and 3 and 5 days after reperfusion. Plasma amylase in Hp-infected rats was significantly higher than in Hp-negative animals 1 h and 1 and 3 days after ischemia, whereas in lipase this significant difference was observed between the 1st and 3rd day. DNA synthesis in Hp-positive rats was additionally reduced 1 h and 3 and 5 days after ischemia. Also ischemia evoked an increase in serum IL-1beta and IL-10, and morphological manifestations of pancreatitis were additionally enhanced by Hp infection., Conclusions: (1) Hp infection increases the severity of ischemia-induced pancreatitis; (2) Hp infection increases production of pro-inflammatory IL-1beta, and (3) Hp infection aggravates disturbances in pancreatic microcirculation in acute pancreatitis., (Copyright 2002 S. Karger AG, Basel and IAP)