Healing effect of warfarin in the course of cerulein-induced acute pancreatitis in rats.

Acute pancreatitis (AP) is the most common gastrointestinal disease leading to hospitalizations and unexpected deaths. The development of AP leads to damage of the pancreatic microcirculation with a cascade of subsequent events resulting, among others, in coagulopathy. Previous research showed that anticoagulants can be important therapeutic agents. Heparin and acenocoumarol can alleviate the course of AP, as well as accelerate healing and post-inflammatory regeneration of the pancreas. The aim of this study was to determine whether warfarin, a drug with more stable effects than acenocoumarol, affects the healing and regeneration of the pancreas in the cerulein-induced AP. AP was evoked in Wistar male rats by intraperitoneal administration of cerulein. The first dose of warfarin (45, 90 or 180 µg/kg) was administered 24 hours after the first dose of cerulein and the doses of warfarin were repeated once a day in subsequent 10 days. The severity of AP was assessed immediately after the last dose of cerulein, as well as at days 1, 2, 3, 5, and 10 after AP induction. Treatment with warfarin dose-dependently increased international normalized ratio (INR) and attenuated the severity of pancreatitis in histological examination and accelerated pancreatic recovery. These effects were accompanied with a faster reduction in the AP-evoked increase in serum activity of amylase and lipase, the serum concentration of pro-inflammatory interleukin-1ß, and the plasma level of D-Dimer. In addition, treatment with warfarin decreased pancreatic weight (an index of pancreatic edema) and improved pancreatic blood flow in rats with AP. The therapeutic effect was particularly pronounced after the administration of warfarin at a dose of 90 µg/kg. We conclude that treatment with warfarin accelerated regeneration of the pancreas and recovery in the course of cerulein-induced mild-edematous acute pancreatitis.

Administration of warfarin accelerates the recovery in ischemia/reperfusion-induced acute pancreatitis.

Acute pancreatitis is associated with activation of coagulation and there is a close relationship between coagulation and the severity of this disease. Administration of anticoagulants such as heparin or acenocoumarol has shown to reduce the severity of acute pancreatitis and accelerate the recovery. The aim of the current study was to determine the impact of warfarin administration on the course of ischemia/reperfusion-induced acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. Vehicle (1 ml/dose) or warfarin (45, 90 or 180 µg/kg/dose in 1 ml of vehicle) were administered intragastrically once a day. The first dose of warfarin was given 24 h after the start of pancreatic reperfusion. The severity of acute pancreatitis was assessed 2, 5, 9 and 14 days after the beginning of pancreatic reperfusion. Treatment with warfarin reduces pancreatic damage and accelerates recovery in histological examination and this effect is accompanied by a faster reduction in serum activity of pancreatic digestive enzymes, lipase and amylase. In addition, warfarin led to an earlier decrease in serum concentration of pro-inflammatory interleukin-1ß and plasma level of D-dimer. These effects were associated with an improvement of pancreatic blood flow. We conclude that warfarin exhibits a therapeutic effect in acute pancreatitis evoked by pancreatic ischemia followed by reperfusion.

Lactate in cardiogenic shock - current understanding and clinical implications.

Adenosine triphosphate (ATP) is an essential substrate metabolite in human beings. Mitochondrial oxidative phosphorylation provides > 95% of ATP with the remainder derived from glycolysis or tricarboxylic acid cycle (TCA). In normal hearts, acetyl-CoA is synthesized from the ß-oxidation of free fatty acids (FFA) and the oxidation of pyruvate. Pyruvate is synthesized from glycolysis and can be submitted either for decarboxylation to acetyl-CoA or for dehydrogenation to lactate. Moreover, pyruvate, as well as lactate, plays a key role in aerobic glucose metabolism which is highly dependent on ubiquitous regulatory mechanisms. Many recent advances in molecular biology, genetics, and physiology have revealed new insights into the metabolic flux of lactate. The initial perception characterized by increased lactate production and accumulation in peripheral tissues in anaerobic conditions has been recently contested. The paradigm of increased lactate concentration in the anaerobic setting is discussed according to contemporary reports. Nevertheless, the clinical role of lactate as a prognostic factor in cardiovascular diseases is undisturbed, especially in the field of innovative technology of left/bi ventricular-assist devices and biochips where it reassured its diagnostic and prognostic impact on the cardiovascular system.

Therapeutic effect of exogenous ghrelin in the healing of gingival ulcers is mediated by the release of endogenous growth hormone and insulin-like growth factor-1.

Ghrelin, an acylated 28-amino acid polypeptide, was primary isolated from the stomach, and the stomach is a main source of circulating ghrelin. Ghrelin strongly and dose-dependently stimulates release of growth hormone from the anterior pituitary, as well as increases food intake and fat deposition. Previous studies showed that ghrelin exhibits protective and therapeutic effect in different parts of the gastrointestinal system, including the oral cavity. The aim of present study was to examine the role of growth hormone and insulin-like growth factor-1 (IGF-1) in the healing of gingival ulcers. Studies were performed on rats with the intact pituitary gland and hypophysectomized rats. In anesthetized rats, chronic ulcers of the gum were induced by acetic acid. Rats were treated intraperitoneally twice a day with saline or ghrelin (4, 8 or 16 nmol/kg/dose) for six days. In pituitary-intact rats, administration of ghrelin significantly increased serum concentration of growth hormone and IGF-1 and this effect was associated with a significant increase in the healing rate of gingival ulcers. Moreover, treatment with ghrelin increased mucosal blood flow and DNA synthesis in the gum, while a local inflammation was decreased what was observed as a reduction in mucosal concentration of pro-inflammatory interleukin-1ß. Hypophysectomy decreased serum level of growth hormone below a detection limit; whereas serum concentration of IGF-1 was reduced by 90%. On the other hand, removal of the pituitary gland was without any significant effect on the healing rate of gingival ulcers or on the ulcer-induced increase in DNA synthesis and concentration of pro-inflammatory interleukin-1ß in gingival mucosa. Administration of ghrelin failed to affect serum level of growth hormone and IGF-1 in hypophysectomized rats, and was without any effect on the healing rate of gingival ulcers, mucosal blood flow, DNA synthesis or concentration of interleukin-1ß in gingival mucosa. Neither induction of gingival ulcers nor hypophysectomy nor administration of ghrelin significantly affected serum concentration of pro-inflammatory interleukin-1ß. We concluded that endogenous growth hormone and IGF-1 were involved in the therapeutic effect of exogenous ghrelin in the healing of gingival mucosa damage.

Atrial natriuretic peptide and brain natriuretic peptide changes after epicardial percutaneous left atrial appendage suture ligation using LARIAT device.

Percutaneous left atrial appendage closure is an alternative treatment for stroke and systemic thromboembolism risk reduction in non-valvular atrial fibrillation (AF). However, the neurohormonal impact of epicardial exclusion of the left atrial appendage (LAA) with the LARIAT procedure is unknown. Evaluation of changes in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels in AF patients underwent percutaneous LAA suture ligation. Sixty six patients underwent successfully percutaneous LAA suture ligation using LARIAT device. The level of ANP and BNP was measured before and 3 months after procedure. Mean ANP level before procedure was 249 ± 77 pg/mL (range from 95 pg/mL to 503 pg/mL) and mean BNP level was 481 ± 517 pg/mL (range from 34 pg/mL to 2508 pg/mL). Three months after procedure mean ANP level was 249 ± 79 pg/mL (range from 98 pg/mL to 492 pg/mL) and mean BNP level was 495 ± 526 pg/mL (range from 52 pg/mL to 2420 pg/mL). At 3 months follow up after percutaneous LAA suture ligation there were no significant differences in ANP and BNP levels.

Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis.

Coagulative disorders are known to occur in acute pancreatitis and are related to the severity of this disease. Various experimental and clinical studies have shown protective and therapeutic effect of heparin in acute pancreatitis. Aim of the present study was to determine the influence of acenocoumarol, a vitamin K antagonist, on the development of acute pancreatitis. Studies were performed on male Wistar rats weighing 250 - 270 g. Acenocoumarol at the dose of 50, 100 or 150 µg/kg/dose or vehicle were administered once a day for 7 days before induction of acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. The severity of acute pancreatitis was assessed after 5-h reperfusion. Pretreatment with acenocoumarol given at the dose of 50 or 100 µg/kg/dose reduced morphological signs of acute pancreatitis. These effects were accompanied with a decrease in the pancreatitis-evoked increase in serum activity of lipase and serum concentration of pro-inflammatory interleukin-1ß. Moreover, the pancreatitis-evoked reductions in pancreatic DNA synthesis and pancreatic blood flow were partially reversed by pretreatment with acenocoumarol given at the dose of 50 and 100 µg/kg/dose. Administration of acenocoumarol at the dose of 150 µg/kg/dose did not exhibit any protective effect against ischemia/reperfusion-induced pancreatitis. We concluded that pretreatment with low doses of acenocoumarol reduces the severity of ischemia/reperfusion-induced acute pancreatitis.

Peptidyl hormones of endocrine cells origin in the gut--their discovery and physiological relevance.

In 1902 William Bayliss and Ernest Starling discovered secretin and it was the beginning of general endocrinology as well as, endocrinology of gastrointestinal tract. Ernest Starling was also a first person who introduced a term hormone for the substances which serves to transfer the information between cells of organism. Subsequent years delivered discovery of successive hormones of the digestive tract. Gastrin was discovered in 1905; whereas cholecystokinin in 1928. Ghrelin and obestatin are last hormones determined in the gastrointestinal tract and they were found in 1999 and 2006, respectively. Both above hormones are originating from the common prohormone. In 60s of past century, the biochemical structure of the gastrointestinal tract hormones was determined for the first time. Substantial progress in endocrinology of the digestive tract took place when radioimmunoassay was employed to measure of hormones concentration. Subsequently, radiolabeled hormones were used to localize hormonal receptors. Next breakthrough in the gastrointestinal tract endocrinology happened after introduction to experimental methods the cloning of complementary DNA. This method has allowed, among the others, to establish the full structure of receptors as well as, a genes coding hormones and their receptors. Discovery of genes structure allowed subsequently introducing these genes into foreign cells, what gives a chance to obtain significant amount of recombined hormones possessing species specificity. This review is presenting a history of the gastrointestinal tract endocrinology, as well as a relevance of gastrointestinal tract hormones in the regulation of body physiological activity.

Therapeutic effect of ghrelin in the course of ischemia/reperfusion-induced acute pancreatitis.

BACKGROUND: Protective effect of pretreatment with ghrelin against different forms of acute pancreatitis (AP) has been recently reported. Moreover, the healing properties of this peptide have been proved in AP evoked by cerulein. However, no studies have investigated whether the administration of ghrelin affects the course of ischemia/reperfusion-induced AP. AIM: The aim of this study was to evaluate the impact of ghrelin therapy on the course of necrotizing inflammation of the pancreas and to test its impact on peroxidation of lipids and antioxidant defense system in the acutely inflamed pancreas. METHODS: Acute inflammation of the pancreas was triggered by pancreatic ischemia which was then followed by reperfusion of the gland. Ghrelin (8 nmol/kg/dose) was administered to intraperitoneally twice daily, 24h after the initiation of AP. The impact of ghrelin on the course of necrotizing pancreatitis was evaluated between 1 and 21 days, and involved histological, functional, and biochemical analyses. RESULTS: Treatment with ghrelin ameliorated morphological signs of pancreatic damage including edema, acinar cells vacuolization, hemorrhages, acinar necrosis, leukocytic infiltration of the gland, and led to its earlier regeneration. These effects were accompanied by an improvement in pancreatic blood flow, enhanced DNA synthesis, reduced serum level of pro- inflammatory interleukin-1ß, decreased levels of malondialdehyde and an enhanced superoxide dismutase activity in pancreatic tissue. CONCLUSIONS: Ghrelin exerts a pronounced therapeutic effect against ischemia-reperfusion-induced pancreatitis. The mechanisms involved are likely multifactorial and are mediated by its anti-inflammatory, as well as anti-oxidative properties.

The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats.

Ghrelin has been primarily shown to exhibit protective and therapeutic effect in the gut. Pretreatment with ghrelin inhibits the development of acute pancreatitis and accelerates pancreatic recovery in the course of this disease. In the stomach, ghrelin reduces gastric mucosal damage induced by ethanol, stress or alendronate, as well as accelerates the healing of acetic acid-induced gastric and duodenal ulcer. The aim of present studies was to investigate the effect of pretreatment with ghrelin on the development of acetic acid-induced colitis. Studies have been performed on male Wistar rats. Animals were treated intraperitoneally with saline (control) or ghrelin (4, 8 or 16 nmol/kg/dose). Saline or ghrelin was given twice: 8 and 1 h before induction of colitis. Colitis was induced by a rectal enema with 1 ml of 4% solution of acetic acid and the severity of colitis was assessed 1 or 24 hours after induction of inflammation. Rectal administration of acetic acid induced colitis in all animals. Damage of colonic wall was seen at the macroscopic and microscopic level. This effect was accompanied by a reduction in colonic blood flow and mucosal DNA synthesis. Moreover, induction of colitis significantly increased mucosal concentration of pro-inflammatory interleukin-1ß (IL-1ß), activity of myeloperoxidase and concentration of malondialdehyde (MDA). Mucosal activity of superoxide dismutase (SOD) was reduced. Pretreatment with ghrelin reduced the area and grade of mucosal damage. This effect was accompanied by an improvement of blood flow, DNA synthesis and SOD activity in colonic mucosa. Moreover, ghrelin administration reduced mucosal concentration of IL-1ß and MDA, as well as decreased mucosal activity of myeloperoxidase. Administration of ghrelin protects the large bowel against the development of the acetic acid-induced colitis and this effect seems to be related to the ghrelin-evoked anti-inflammatory and anti-oxidative effects.

Involvement of cyclooxygenase-1 and cyclooxygenase-2 activity in the therapeutic effect of ghrelin in the course of ethanol-induced gastric ulcers in rats.

Previous studies have shown that treatment with ghrelin exhibits protective and therapeutic effects in the gut. Aim of our present investigation was to examine the influence of ghrelin administration on the healing of ethanol-induced gastric ulcers and determine the role of cyclooxygenase-1 and cyclooxygenase-2 in this effect. Our studies were performed on male Wistar rats. Gastric ulcers were induced by intragastric administration of 75% ethanol. Ghrelin alone or in combination with cyclooxygenase inhibitors was administered twice, 1 and 13 hours after ethanol application. Cyclooxygenase-1 (COX-1) inhibitor (SC-560, 10 mg/kg/dose) or COX-2 inhibitor (celecoxib, 10 mg/kg/dose) were given 30 min prior to ghrelin. Twelve or 24 hours after administration of ethanol, rats were anesthetized and experiments were terminated. The study revealed that administration of ethanol induced gastric ulcers in all animals and this effect was accompanied by the reduction in gastric blood flow and mucosal DNA synthesis. Moreover induction of gastric ulcer by ethanol significantly increased mucosal expression of mRNA for COX-2, IL-1ß and TNF-α. Treatment with ghrelin significantly accelerated gastric ulcer healing. Therapeutic effect of ghrelin was associated with significant reversion of the ulcer-evoked decrease in mucosal blood flow and DNA synthesis. Ghrelin administration also caused the reduction in mucosal expression of mRNA for IL-1ß and TNF-α. Addition of SC-560 slightly reduced the therapeutic effect of ghrelin in the healing of ethanol-induced ulcer and the ulcer area in rats treated SC-560 plus ghrelin was significantly smaller than that observed in rats treated with saline or SC-560 alone. Pretreatment with celecoxib, a COX-2 inhibitor, abolished therapeutic effect of ghrelin. We concluded that treatment with ghrelin increases healing rate of gastric ulcers evoked by ethanol and this effect is related to improvement in mucosal blood flow, an increase in mucosal cell proliferation, and reduction in mucosal expression of proinflammatory cytokines. Ghrelin is able to reverse a deleterious effect of COX-1 inhibitor on healing of ethanol-induced gastric ulcers. Activity of COX-2 is necessary for the therapeutic effect of ghrelin in healing of ethanol-induced gastric ulcers.

Ghrelin accelerates the healing of oral ulcers in non-sialoadenectomized and sialoadenectomized rats.

UNLABELLED: Ghrelin exhibits protective and therapeutic effect in different parts of the gastrointestinal tract. The aim of the present study was to examine the influence of ghrelin administration on the healing of oral ulcers in rats with intact salivary gland and in sialoadenectomized rats. Gingival and lingual ulcers were induced by acetic acid. After induction of ulcers, rats were treated with saline or ghrelin for six days. In rats with intact salivary glands and induction of oral ulcers, administration of ghrelin significantly increased the healing rate of these ulcers. This result was associated with a significant increase in mucosal blood flow and cell proliferation, and a decrease in concentration of pro-inflammatory interleukin-1ß in gingival and lingual mucosa. Sialoadenectomy decreased cell proliferation and increased concentration of pro-inflammatory interleukin-1ß in oral mucosa, as well as reduced the healing rate of gingival and lingual ulcers. Administration of ghrelin reversed deleterious effect of sialoadenectomy and increased the healing rate of oral ulcers above a value observed in rats with intact salivary glands. CONCLUSIONS: Treatment with ghrelin accelerates healing of oral ulcers in salivary glands-intact rat, as well as in rats with reduced salivary secretion evoked by sialoadenectomy. Mechanisms of beneficial effects of ghrelin administration involve an increase in mucosal blood flow and cell proliferation, as well as a reduction in local inflammation.

Heparin inhibits protective effect of ischemic preconditioning in ischemia/reperfusion-induced acute pancreatitis.

UNLABELLED: Previous studies have shown that pancreatic ischemic preconditioning or heparin, applied before induction of acute pancreatitis inhibit the development of this disease and accelerate pancreatic recovery. The aim of the study was to determine the influence of treatment with heparin on protective effect of ischemic preconditioning (IP) in ischemia/reperfusion-induced acute pancreatitis. Heparin was administered twice, before and during induction of acute pancreatitis. IP was performed by short-term clamping of celiac artery, 30 min before induction of acute pancreatitis. Acute pancreatitis was induced in rats by clamping of inferior splenic artery for 30 min followed by reperfusion. Rats were sacrificed after 6-h and 24-h reperfusion. RESULTS: IP applied alone caused a mild pancreatic damage associated with a limited increase in plasma amylase activity, concentration of pro-inflammatory interleukin-1ß and plasma level of D-dimer. Pretreatment with heparin or IP applied alone reduced the severity of acute pancreatitis. Both these procedures caused a similar reduction in plasma lipase, amylase and interleukin-1ß, as well as in histological signs of pancreatic damage. These changes were associated with partial reversion of the pancreatitis-evoked fall of pancreatic blood flow and DNA synthesis. Combination of heparin plus IP reduced the protective effect of heparin or IP applied alone. It was manifested by an increase in pancreatic damage and plasma level of lipase, amylase and interleukin-1ß, as well as by reduction in pancreatic DNA synthesis and plasma concentration of D-dimer and interleukin-10. CONCLUSIONS: heparin abolishes the protective effect of ischemic preconditioning in ischemia reperfusion-induced pancreatitis. This observation suggests that initial clot formation is necessary to induce pancreatic protection by IP.

Role of sensory nerves in gastroprotective effect of anandamide in rats.

Previous studies have shown that stimulation of cannabinoid 1 (CB1) receptor protects the gastric mucosa against stress-induced lesion. Aim of the present study was to examine the influence of anandamide on lipid peroxidation and antioxidant defense system in gastric mucosa and the role of sensory nerves in gastroprotective effects of cannabinoids. Studies were performed on rats with intact or ablated sensory nerves (by neurotoxic doses of capsaicin). Gastric lesions were induced by water immersion and restrain stress (WRS). Anandamide was administered at the dose of 0.3, 1.5 or 3.0 µmol/kg, 30 min before exposure to WRS. CB1 receptor antagonist, AM251 (4.0 µmol/kg) was administered 40 min before WRS. WRS induced gastric lesions associated with the decrease in gastric blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD). Serum level of interleukin-1ß (IL-1ß) and mucosal level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were increased. Administration of anandamide reduced the ulcers area, generation of MDA+4-HNE and serum level of IL-1ß, and this effect was associated with the reduction in the WRS-induced decrease in gastric mucosal blood flow, mucosal DNA synthesis and SOD activity. Ablation of sensory nerves increased the area of ulcers, serum level of IL-1ß and mucosal content of MDA+4-HNE, whereas mucosal DNA synthesis, SOD activity and blood flow were additionally decreased. In rats with ablation of sensory nerves, administration of anandamide at the high doses (1.5 and 3.0 µmol/kg) partly reduced deleterious effect of WRS on gastric mucosa, but this effect was weaker than in animals with intact sensory nerves. Low dose of anandamide (0.3 µmol/kg) was ineffective in the protection of gastric mucosa against the WRS-induced lesions in rats with ablation of sensory nerves. In rats with intact sensory nerves and exposed to WRS, administration of AM251 exhibited deleterious effect. In rats with ablation of sensory nerves and exposed to WRS, AM251 failed to affect mucosal injury in the stomach. We conclude that anandamide reduces the mucosal oxidative stress and exhibits gastroprotective effect against WRS-induced ulcers. These effects are partly mediated by sensory nerves.

Role of hormonal axis, growth hormone - IGF-1, in the therapeutic effect of ghrelin in the course of cerulein-induced acute pancreatitis.

Ghrelin is a ligand for growth hormone secretagogue receptor and stimulates release of growth hormone (GH). Recent studies have shown that treatment with ghrelin exhibits protective and therapeutic effect in the course of experimental pancreatitis. The aim of present study was to examine the role of GH and insulin-like growth factor-1 (IGF-1) in these effects. Acute pancreatitis was induced by cerulein. Study was performed on pituitary-intact hypophysectomized rats. Ghrelin was administered twice a day at the dose of 8 nmol/kg/dose. IGF-1 was given twice a day at the dose of 20 nmol/kg/dose. The severity of acute pancreatitis was assessed 0 h or 1, 2, 3, 5 and 10 days after the last dose of cerulein. Administration of cerulein led to the development of acute edematous pancreatitis. In pituitary-intact rats, treatment with ghrelin reduced biochemical indexes of the severity of acute pancreatitis and morphological signs of pancreatic damage, leading to faster regeneration of the pancreas reduction in serum concentration of pro-inflammatory interleukin-1ß and decrease in serum activity of amylase and lipase. These effects were accompanied with an improvement of pancreatic blood flow and an increase in pancreatic DNA synthesis. Hypophysectomy delayed the healing of the pancreas and abolished the therapeutic effect of ghrelin. In hypophysectomized rats with pancreatitis, treatment with IGF-1 exhibits therapeutic effect similar to that observed in ghrelin-treated rats with the intact pituitary. We conclude that therapeutic effect of ghrelin in cerulein-induced pancreatitis is indirect and depends on the release of GH and IGF-1.

Therapeutic effect of ghrelin in the course of cerulein-induced acute pancreatitis in rats.

Recent studies have shown that pretreatment with ghrelin exhibits protective effect in the gut. Administration of ghrelin reduces gastric mucosal damage, as well as inhibits the development of experimental pancreatitis. However, this protective effect requires administration of ghrelin before gastric or pancreatic damage and thus has a limited clinical value. The aim of present study was to assess the influence of ghrelin administered after development of acute pancreatitis on the course of this disease. Acute pancreatitis was induced by cerulein. Ghrelin was administered twice a day for 1, 2, 4, 6 or 9 days at the dose of 4, 8 or 16 nmol/kg/dose. The first dose of ghrelin was given 24 hours after last injection of cerulein. The severity of acute pancreatitis was assessed between 0 h and 10 days after cessation of cerulein administration. Administration of caerulein led to the development of acute edematous pancreatitis and maximal severity of this disease was observed 24 hours after induction of pancreatitis. Treatment with ghrelin reduced morphological signs of pancreatic damage such as pancreatic edema, leukocyte infiltration and vacuolization of acinar cells, and led to earlier regeneration of the pancreas. Also biochemical indexes of the severity of acute pancreatitis, serum activity of lipase and amylase were significantly reduced in animals treated with ghrelin. These effects were accompanied by an increase in the pancreatic DNA synthesis and a decrease in serum level of pro-inflammatory interleukin-1b. Administration of ghrelin improved pancreatic blood flow in rats with acute pancreatitis. We conclude that: (1) treatment with ghrelin exhibits therapeutic effect in caerulein-induced experimental acute pancreatitis; (2) this effect is related, at least in part, to the improvement of pancreatic blood flow, reduction in proinflammatory interleukin-1beta and stimulation of pancreatic cell proliferation.

Pretreatment with obestatin inhibits the development of cerulein-induced pancreatitis.

Obestatin is a peptide derived from the proghrelin, a common prohormone for ghrelin and obestatin. Obestatin, like the ghrelin has been originally extracted from rat stomach, and the stomach seems to be a major source of circulating obestatin. Previous studies have shown that administration of ghrelin exhibits protective effect in the pancreas, inhibiting the development of acute pancreatitis. Recent study has shown that obestatin promotes survival of beta-cells and pancreatic islets. Aim of the present study was to investigate the influence of obestatin administration on the development of cerulein-induced pancreatitis. Studies were performed on male Wistar rats. Acute pancreatitis was induced by cerulein given intraperitoneally 5 times at a dose of 50 microg/kg/dose with 1-h intervals. Obestatin was injected twice intraperitoneally at the dose of 4, 8 or 16 nmol/kg/dose. In control saline-treated rats, obestatin was without effect on pancreatic morphology, serum activity of pancreatic enzymes, serum level of pro-inflammatory interleukin-1beta or pancreatic cells proliferation. In animals with induction of acute pancreatitis, morphological examination showed that administration of obestatin decreased pancreatic leukocyte infiltration and vacuolization of acinar cells. These effects were accompanied by reduction in the pancreatitis-evoked increase in serum level of pancreatic digestive enzymes, lipase amylase and poly-C ribonuclease. Obestatin administered at the highest dose of 16 nmo/kg/dose reduced serum activity of these enzymes by 33, 42 and 44%, respectively. Also serum concentration of pro-inflammatory interleukin-1beta was decreased by obestatin in rats with acute pancreatitis; whereas the pancreatitis-evoked decrease in pancreatic blood flow and pancreatic DNA synthesis was partially reversed. Administration of obestatin reduces the severity of cerulein-induced acute pancreatitis. This effect is related, at least in part, to the improvement of pancreatic blood flow and reduction in proinflammatory interleukin-1beta release.

Treatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in rats.

UNLABELLED: Recent studies have shown that ghrelin exhibits gastroprotective effects. The aim of present study was to examine the influence of ghrelin administration on the healing of chronic gastric and duodenal ulcers and to evaluate the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this process. In pituitary-intact or hypophysectomized rats, chronic gastric and duodenal ulcers were induced by acetic acid. After induction of ulcers, rats were treated intraperitoneally twice a day with saline, ghrelin (4, 8 or 16 nmol/kg/dose) or IGF-1 (20 nmol/kg/dose) for six or ten days. In animals with intact pituitary, treatment with ghrelin increased serum level of GH and IGF-1. These effects were accompanied by the increase in mucosal cell proliferation, mucosal blood flow and healing rate of gastric and duodenal ulcers. After hypophysectomy, the significant increase in serum level of endogenous ghrelin was observed, but the healing of gastric and duodenal ulcers was delayed. This effect was accompanied by a significant decrease in serum concentration of endogenous GH and IGF-1, and reduction in mucosal blood flow and DNA synthesis. In hypophysectomized rats, administration of exogenous ghrelin was without any effect on serum level of GH and IGF-1, healing rate of gastroduodenal ulcers or mucosal cell proliferation. In contrast to this effect, administration of IGF-1 increased mucosal cell proliferation, healing rate of gastroduodenal ulcers and mucosal blood flow in hypophysectomized rats. CONCLUSION: Treatment with ghrelin accelerates healing of chronic gastroduodenal ulcers and this effect is mediated by the release of endogenous GH and IGF-1.

Protective and therapeutic effect of heparin in acute pancreatitis.

UNLABELLED: The initiation and progression of acute pancreatitis is associated with disturbances in pancreatic microcirculatory. Microcirculatory disorders contribute to multiorgan dysfunction syndrome in the course of acute pancreatitis. The aim of this study was to determine the influence of heparin administration on the development and the course of ischemia/reperfusion-induced pancreatitis. METHODS: Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. In the first series of studies, heparin was administered 0.5 h before induction of acute pancreatitis and the severity of acute pancreatitis was assessed after 6-h reperfusion. In the second series of studies, heparin was administered twice a day, starting 24 h after the initiation of reperfusion. In both series of studies, heparin was administered subcutaneously at the dose of 150 U/kg. RESULTS: Treatment with heparin, before induction of pancreatitis, inhibits the development of morphological signs of acute pancreatitis and reduced the pancreatitis-evoked increase in plasma level of pancreatic enzymes and pro-inflammatory interleukin-1beta. These effects have been accompanied with improvement of pancreatic blood flow, pancreatic DNA synthesis and reduction in plasma concentration of D-dimer. Administration of heparin after induction of acute pancreatitis accelerates normalization of pancreatic histology, and reduces biochemical markers of the severity of acute pancreatitis. These effects have been accompanied with the improvement of pancreatic circulation, increase in APTT and reduction in plasma D-dimer level. CONCLUSIONS: Treatment with heparin inhibits the development of ischemia/reperfusion-induced pancreatitis and accelerates pancreatic regeneration in the course of this disease.

Ischemic preconditioning of the hindlimb or kidney does not attenuate the severity of acute ischemia/reperfusion-induced pancreatitis in rats.

UNLABELLED: Ischemic preconditioning of several organs, including the pancreas has been shown to protect these organs from injury evoked by subsequent exposure to severe ischemia followed by reperfusion. Moreover, it has been shown that ischemic preconditioning of distant organs such as the kidney, intestine or limb may protect the heart as effectively as cardiac preconditioning itself. This study was designed to determine whether ischemic preconditioning of the kidney or hindlimb protects the pancreas against ischemia/reperfusion-induced pancreatitis. METHODS: In male Wistar rats, remote ischemic preconditioning of the pancreas was performed by clamping of right femoral or renal artery twice for 5 min with 5 min interval. Direct ischemic preconditioning was performed by clamping of celiac artery. Thirty min after ischemic preconditioning or sham-operation, acute pancreatitis was induced by clamping of inferior splenic artery for 30 min followed by reperfusion. After 6, 12 h or 1, 2, 3, 5 or 9 days of reperfusion the experiment was ended. Secretory studies were performed 2 h after exposure to direct or remote ischemic preconditioning of the pancreas in conscious rats with chronic pancreatic fistula. RESULTS: Direct ischemic preconditioning of the pancreas applied alone reduced pancreatic exocrine secretion; whereas ischemic preconditioning of the hindlimb or kidney was without effect on pancreatic secretion. Direct ischemic preconditioning of the pancreas attenuated the severity of acute pancreatitis. It was found as a reduction in the pancreatitis-evoked increase in serum activity of lipase and amylase, a decrease in serum concentration of pro-inflammatory interleukin-1beta, diminution of histological signs of pancreatic damage, as well as, an improvement of pancreatic blood flow and DNA synthesis. Remote ischemic preconditioning of the pancreas evoked by short-lasting ischemia of the hindlimb or kidney was without any protective effect in ischemia/reperfusion-induced pancreatitis. Moreover, this procedure led to a significant increase in serum activity of lipase and amylase, and enhanced the morphological signs of pancreatic damage. CONCLUSION: In contrast to direct ischemic preconditioning, remote ischemic preconditioning of the pancreas is without effect on pancreatic exocrine secretion and does not reduce the severity of ischemia/reperfusion-induced pancreatitis.