Depletion of serum L-arginine in patients with acute pancreatitis.

INTRODUCTION: Acute pancreatitis may be initiated by interference with the pancreatic outflow to the duodenum. This flow is normally regulated by reflex relaxation of the sphincter of Oddi in which nitric oxide is an important mediator. AIM: To test the hypothesis that acute pancreatitis involves a depletion in serum L-arginine resulting in impaired production of nitric oxide. METHODS: We measured serum L-arginine and L-citrulline and urinary nitrite/nitrate concentrations 1 to 3 days after the onset of symptoms in 11 patients with gallstone pancreatitis, 10 patients with alcoholic pancreatitis, and 6 patients with idiopathic pancreatitis. We compared their results with those from control groups of 13 healthy blood donors, 9 patients fasting before hernia operations, 8 patients with acute cholecystitis, and 9 alcoholic subjects but no pancreatitis. Serum arginine and citrulline concentrations were measured with high performance liquid chromatography, and urinary nitrite/nitrate spectrophotometrically. RESULTS: Patients with acute pancreatitis, of whatever cause, had lower serum L-arginine and L-citrulline concentrations than controls. Patients with gallstone and idiopathic pancreatitis also have reduced urinary concentrations of nitrite and nitrate but this was not seen in patients with alcoholic pancreatitis. CONCLUSIONS: L-arginine and L-citrulline concentrations are depleted in the serum of patients with acute pancreatitis. Reduced urinary nitrite and nitrate in gallstone pancreatitis indicate that there is a defect formation of nitric oxide. This may cause a functional obstruction of the outflow of pancreatic juice to the duodenum and so may be involved in the pathophysiology of acute pancreatitis.

Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor.

Inappropriate activation of the mineralocorticoid receptor (MR) results in renal sodium retention and potassium loss in patients with liver cirrhosis. Recent evidence suggested that this MR activation is, at least in part, a result of bile acid-dependent reduction in 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) activity, an enzyme preventing cortisol-dependent activation of MR by converting cortisol to cortisone. Here, we investigated the molecular mechanisms underlying bile acid-mediated MR activation. Analysis of urinary bile acids from 12 patients with biliary obstruction revealed highly elevated concentrations of chenodeoxycholic acid (CDCA), cholic acid (CA), and deoxycholic acid (DCA), with average concentrations of 50-80 microm. Although CDCA and DCA both mediated nuclear translocation of MR in the absence of 11 beta HSD2 and steroids in transiently expressing HEK-293 cells, the transcriptional activity of MR was not stimulated. In contrast, CDCA and DCA both inhibited 11 beta HSD2 with IC(50) values of 22 and 38 microm, respectively and caused cortisol-dependent nuclear translocation and increased transcriptional activity of MR. LCA, the bile acid that most efficiently inhibited 11 beta HSD2, was present at very low concentrations in cholestatic patients, whereas the weak inhibitor CA did not cause MR activation. In conclusion, these findings indicate that CDCA, and to a lesser extent DCA, by inhibiting 11 beta HSD2, mediate cortisol-dependent nuclear translocation and transcriptional activation of MR and are responsible at least for a part of the sodium retention and potassium excretion observed in patients with biliary obstruction.

The mechanism of increased renal clearance of amylase in acute pancreatitis.

Amylase isoenzymes, separated by polyacrylamide gel electrophoresis, were measures in 25 normal persons (mean amylase to creatinine clearance ratio 3.0%), 15 patients with acute pancreatitis (mean clearance ratio 9.5%, P less than 0.0001), and 6 patients with hyperamylasemia due to common duct stones (mean clearance ratio 4.1%). Two isoamylases (P1, P2) resembling pancreatic isoenzymes and three isoamylases (S1, S2, S3) resembling salivary isoenzymes appeared regularly in normal serum and urine. Salivary amylases predominated in serum, but pancreatic amylases predominated in urine. This finding is consistent with renal clearance of pancreatic amylases exceeding that of salivary amylases under normal conditions. In patients with pancreatitis or common duct stones, essentially all of the increased amylase activity in serum and urine was due to pancreatic isoamylases (P1 and P2) in their normal proportions. No new or altered amylase isoenzymes were detected. The fraction of pancreatic amylases in the serum or urine was identical for the two diseases. Whereas the difference in amylase to creatinine clearance ratios observed between the two groups of patients is not a function of different amylase isoenzymes presented to the kidney, we conclude that the increased amylase clearance in acute pancreatitis is caused by an alteration of renal transfer of amylase, either at the glomerulus or tubule.