cyclic-gmp and Pancreatitis

Acute pancreatitis (AP) is an inflammatory disorder with a high mortality rate. Cilostazol is a selective phosphodiesterase-3 inhibitor drug that is commonly used as an antiplatelet, antithrombotic, and vasodilator drug. It exhibits antioxidant, anti-inflammatory, and anti-apoptotic activities, but its effect on AP has not been fully elucidated yet. The present study aimed to investigate the effects of cilostazol on L-arginine-induced AP and the possible protective mechanisms. A rat model of AP was established by a single i.p. injection of 3-g/kg L-arginine on day 13 of the experiment. The treated groups received a single daily oral dose of either 100 or 300 mg/kg/day for 14 consecutive days. Rats with AP showed histopathological changes of pancreatic tissue injury together with increased serum amylase enzyme activity and decreased serum insulin, pancreatic adiponectin, and cGMP levels. Moreover, AP rats showed increased pancreatic inflammatory biomarker (TNF-α, VCAM-1, and MPO) levels with decreased anti-inflammatory IL-10 levels. In addition, oxidative stress biomarkers (MDA and NO) were increased in AP with decreased antioxidant SOD activity and GSH level. Moreover, HO-1 immunostaining was increased in the AP group. Cilostazol pretreatment reversed the histopathological change; decreased the amylase activity and the levels of TNF-α, VCAM-1, and MPO; and increased the levels of insulin, adiponectin, cGMP, cAMP, and IL-10. Moreover, cilostazol decreased MDA and NO but increased SOD and GSH. Lastly, cilostazol increased the HO-1 immunostaining more than in the AP group. These data suggest that cilostazol protects against L-arginine-induced AP, which may be related to an increase in cGMP, cAMP, and upregulation of HO-1 with subsequent anti-inflammatory and antioxidant properties.

Topics: Animals; Arginine; Cilostazol; Cyclic AMP; Cyclic GMP; Heme Oxygenase (Decyclizing); Male; Oxidative Stress; Pancreatitis; Phosphodiesterase 3 Inhibitors; Rats; Rats, Wistar

The role of nitric oxide (NO) in the human pancreas and in pancreatitis still remains controversial. Furthermore, conflicting conclusions have been reached by different laboratories about the localization of the NO-generating enzyme (NO synthase, NOS) in the pancreas. Here, we investigated the co-expression of NOS with enzymes involved in regulation of NO signalling in the normal human pancreas and in pancreatitis. We found that the whole NO signalling machinery was up-regulated in pancreatitis, especially within the exocrine compartment. Furthermore, the exocrine parenchymal cells revealed higher levels of oxidative stress markers, nitrotyrosine and 8-hydroxyguanosine, in pancreatitis, which reflects the exceptional susceptibility of the exocrine parenchyma to oxidative stress. This study provides a direct link between oxidative stress and the enzymatic control of the NO bioavailability at the cellular level and endows with further insight into fundamental mechanisms underlying pancreatic disorders associated with disruptions in the L-arginine-NO-cGMP signalling enzyme cascade.

Topics: Aged; Arginine; Biomarkers; Case-Control Studies; Cyclic GMP; Female; Fluorescent Antibody Technique; Guanosine; Humans; Immunoenzyme Techniques; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Pancreas; Pancreatitis; Signal Transduction; Tyrosine

It has been widely shown that preconditioning, inducing heat shock proteins, can protect against experimentally induced pancreatitis. Solid evidence indicates that HSP70 plays a central role in this context, possibly by inhibition of premature intracellular trypsinogen activation. Current preconditioning protocols such as whole body hyperthermia are, however, quite strenuous and clinically not applicable. There is little data on other means to induce pancreatic HSPs such as pharmacologic pretreatment.However, in models of ischemic liver reperfusion injury, it has been demonstrated that atrial natriuretic peptide (ANP) can be used for such pharmacologic preconditioning. Evidence indicates that ANP exerts its protective effects via increased cGMP levels, activation of heat shock transcription factor (HSF) and, increased protein levels of HSP70. Pancreatic acinar cells express ANP receptors and respond to ANP treatment with increased cGMP levels. We have, therefore, investigated whether intravenous ANP pretreatment could be used to protect the pancreas against experimental pancreatitis. When given 20 minutes prior to pancreatitis induction, ANP pretreatment had no effect on cerulein-induced pancreatitis. In contrast, 24 hours after preconditioning, induction of HSP70 protein expression and protection against experimental pancreatitis were found. However, controls treated with NaCl without ANP showed a similar response. This indicates that stress caused by general anesthesia and jugular vein catheterization can be sufficient for preconditioning while ANP, in contrast to models of ischemic liver reperfusion injury, does not confer additional protection.

Topics: Anesthesia, General; Animals; Atrial Natriuretic Factor; Blood Pressure; Catheterization, Peripheral; Cyclic GMP; HSP70 Heat-Shock Proteins; Jugular Veins; Male; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley

Nineteen patients with acute pancreatitis were examined for the activity of LDH, NADH-tetrazolium oxidoreductase, acid phosphatase, the content of calcium salts, cAMP and cGMP in biopsy tissue of the pancreas; pancreatic enzymes and bicarbonates in the duodenal contents and pancreatic juice. The activity of enzymes participating in oxidative metabolism in epithelial cells of the intact pancreas appeared elevated. During the development of destructive changes in the pancreatic parenchyma, the processes of intracellular oxidation get inhibited, the enzymes go out into the intercellular space, calcium transport gets impaired, and acid phosphatase is activated. It has been found that in acute destructive pancreatitis, primarily impaired are epithelial cells of the islets, followed by the impairment of the epithelium of the acini and at the last moment of that of the excretory ducts. The data obtained enable one to regard cyclonucleotides, calcium, pancreatic enzymes and lysosomal hydrolases as pathogenetic elements of acute pancreatitis.

Topics: Acute Disease; Adult; Cyclic AMP; Cyclic GMP; Glycolysis; Humans; Middle Aged; Oxidation-Reduction; Pancreas; Pancreatitis

Previous studies have shown that when atrial natriuretic peptide (ANF) is given to anaesthetized dogs with hypovolemic acute pancreatitis, it will produce a diuresis and natriuresis but will not elevate the glomerular filtration rate (GFR). When the same dose of peptide is given to dogs equally hypovolemic (hemorrhage) but without pancreatitis, a brisk increment in GFR occurs. GFR will, however, rise in dogs with pancreatitis in response to other peptides, such as glucagon. In these studies we assessed cGMP excretion as a marker for ANF effect in both normal anaesthetized dogs and dogs with acute experimental pancreatitis. In each group, urinary output and sodium excretion increased significantly, but GFR rose only in the control group. Urinary excretion of cGMP rose equally and dramatically in both control and experimental animals. We conclude that GFR is prevented from rising in dogs with experimental pancreatitis following ANF, but this effect does not depend on depressed cGMP generation.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Female; Glomerular Filtration Rate; Infusions, Intravenous; Male; Pancreatitis; Shock

The content of pancreatic enzymes, cyclic nucleotides and prostaglandins (PG) in the duodenal contents was measured in 77 patients with chronic pancreatitis and in 20 healthy individuals. Pancreatitis exacerbation was attended by a decrease in enzymatic activity, in bicarbonate, cAMP and cGMP production. The content of PGE in pancreatic secretion remained normal, that of PGF2 alpha was elevated. Stimulation of the exocrine part of the pancreas by means of euphylline, pentagastrin and calcium was accompanied by the rise of the content of cyclic nucleotides rather than of PG. Suppression of enzymatic secretion by contrykal was followed by the reduction in the content of the cyclic nucleotides and PGE. The data suggest that cyclic nucleotides and PG are involved in the mechanism by which the external secretion of the pancreas is impaired in patients with chronic pancreatitis.

Topics: Adult; Amylases; Chronic Disease; Cyclic AMP; Cyclic GMP; Dinoprost; Female; Humans; Lipase; Male; Middle Aged; Pancreas; Pancreatic Juice; Pancreatitis; Prostaglandins E; Trypsin

Patients with chronic recurrent pancreatitis were examined for the blood content of insulin, glucagon, somatostatin (SS), somatotropin (STH), cAMP and cGMP. The blood content of insulin, glucagon and STH was normal, that of SS and cAMP elevated, and that of cGMP lowered. In severe pancreatitis, the endocrine part of the pancreas was activated. The relationship was established between the level of amylasemia and the activity of islet cells and the blood content of cGMP. The compensatory importance of hypersecretion of SS and glucagon for pancreatitis exacerbation is demonstrated. The role of cyclic nucleotides in the pancreatic activity is discussed.

Topics: Adult; Aged; Chronic Disease; Cyclic AMP; Cyclic GMP; Female; Glucagon; Growth Hormone; Humans; Insulin; Male; Middle Aged; Pancreatic Hormones; Pancreatitis; Recurrence; Somatostatin