Shigekazu Nakano

Effects of endoscopic variceal ligation on portal hypertensive gastropathy and gastric mucosal blood flow

Objective:Portal hypertensive gastropathy (PHG) has been recognized recently as a potential cause of upper gastrointestinal tract bleeding and is associated with a change in gastric hemodynamic indices in cirrhotic patients with portal hypertension. Endoscopic variceal ligation (EVL) is the treatment of choice for esophageal varices. We investigated the early effect of EVL on PHG and gastric mucosal blood flow (GMBF).Methods:We examined 35 cirrhotic patients who were treated by EVL. PHG was evaluated endoscopically and GMBF was measured by laser Doppler flowmetry before and 1 or 2 wk after EVL.Results:After EVL, only two patients (5.7%) developed severe PHG, 6 (17.1%) developed mild PHG, and 27 (77.1%) showed no change in endoscopic appearance of PHG. In those patients who developed PHG, EVL significantly decreased GMBF at the corpus (p < .05). However, no significant changes of GMBF at the corpus were noted after EVL in those patients who had no worsening of endoscopic features. EVL had no effect on GMBF at the antrum in any patients.Conclusions:Endoscopic variceal ligation is safe and does not lead, at least within 1–2 wk, to worsening of gastropathy in most cases. Our finding that gastropathy developed in the presence of reduced GMBF may suggest that PHG develops as a result of congestion caused by blockade of gastric blood drainage rather than by hyperemia.

Role of endogenous cholecystokinin and cholecystokinin-A receptors in the development of acute pancreatitis in rats

Recent studies provide significant evidence that Cholecystokinin (CCK) is involved in the induction and development of acute pancreatitis in experimental animals. However, the results obtained with specific CCK-A (peripheral) receptor antagonists are still controversial. The present studies were undertaken to evaluate the involvement of endogenous CCK and the CCK-A receptors in the development of severe acute pancreatitis induced in Otsuka Long-Evans Tokushima Fatty (OLETF) rats that have a selective defect in the CCK-A receptor. Three models of severe acute pancreatitis were induced by retrograde intraductal infusion of 4% sodium taurocholate, by the closed duodenal loop, or by a single intraperitoneal injection of 500 mg/100 g body weight of L-arginine in OLETF rats and control Long-Evans Tokushima Otsuka (LETO) rats. Plasma CCK levels rose up to 4- to 14-fold over the preloading values after the onset of acute pancreatitis in all three models in both groups of rats. However, histologic alterations as well as the magnitudes of increase in serum amylase and lipase activity and the pancreatic wet weight were significantly less in the OLETF rats than those in the LETO rats. In addition, 72 h after the onset of arginine pancreatitis, massive destruction of pancreatic parenchyma with a significant reduction in serum amylase and lipase activities and pancreatic wet weight was observed in the LETO rats, whereas these changes were not seen in OLETF rats. These results suggest that endogenous CCK and CCK-A receptors play a role in the development of severe acute pancreatitis in rats.

Acute pancreatitis with diabetic ketoacidosis associated with hypermyoglobinemia, acute renal failure, and DIC

We report a case of acute pancreatitis with diabetic ketoacidosis associated with increased serum myoglobin concentration, acute renal failure, and disseminated intravascular coagulation. A 49-year-old man suffering from diarrhea, vomiting, and somnolence was admitted to the hospital. He had had flu-like symptoms for 4 days prior to the onset of these symptoms. He was a habitual drinker and had been consuming 360 ml–900 ml of the drink “shochu” (distilled spirits containing 28% alcohol) daily for 30 years. Laboratory data on admission revealed elevated serum levels of pancreatic enzymes, including amylase, trypsin, lipase, pancreatic secretory trypsin inhibitor (PSTI), phospholipase A2 (PLA2), and elastase-1, as well as elevated levels of glucose (373 mg/dl), ketone bodies (3675 μmol/l), and myoglobin (229.8 ng/ml). Treatment with subcutaneous insulin and intravenous administration of electrolyte fluid and the systemic protease inhibitor, gabexate mesilate, was begun immediately. Early after the initiation of treatment, there was an increase in serum cretinine (4.9 mg/dl), and thrombocytopenia (15000/μl) was observed. The patient completely recovered from renal failure and acute pancreatitis, but required insulin therapy. Alcohol ingestion and dehydration are thought to have played a major role in the triggering of the acute pancreatitis, We examined the relationship among acute pancreatitis, diabetic ketoacidosis, and hypermyoglobinemia in the literature.

Pancreatic cancer and hypercalcemia associated with von Recklinghausen's disease

A 44-year-old man with von Recklinghausens disease was admitted to our hospital presenting with left hypochondralgia. Computed tomography showed a large mass at the body and tail of the pancreas, with metastatic liver tumors. Endoscopic retrograde pancreatography revealed an obstruction of the main pancreatic duct at the body. In the course of the illness, the patients serum calcium concentration increased gradually to 13.6 mg/dl, although bone scan with99mtechnetium demonstrated no accumulation in the bones. Serum levels of parathyroid hormone related-protein and tumor necrosis factor were also elevated. Based on these findings, he was diagnosed as having pancreatic cancer with liver metastases and humoral hypercalcemia of malignancy associated with von Recklinghausens disease. Postmortem examination revealed a solid tumor, measuring 6.0×6.0×8.0 cm, in the body and tail of the pancreas. Histologically, the tumor was moderately differentiated adenocarcinoma. The association of von Recklinghausens disease with maliganant neurogenic neoplasms is well established, whereas the association with non-neurogenic malignant neoplasm is considered to coincidental. Our current case suggests a possible relationship between von Recklinghausens disease and pancreatic cancer.

Treatment with cholecystokinin receptor antagonist loxiglumide enhances insulin response to intravenous glucose stimulation in postpancreatitic rats

Pancreatic exocrine and endocrine function in postpancreatitic rats treated with cholecystokinin (CCK) receptor antagonist loxiglumide was compared with that treated with saline and CCK octapeptide (CCK-8) or with that in normal control rats. Treatment with loxiglumide (50 mg/kg body weight), CCK-8 (2.5 micrograms/kg body weight), or saline (2.5 ml/kg body weight) was given three times a day for 6 days starting 1 day after the induction of acute pancreatitis by a 4-h subcutaneous infusion of 20 micrograms/kg body weight/h of caerulein. On day 8, pancreatic exocrine and endocrine function was simultaneously determined following an intravenous injection of a mixed solution of 0.2 g/kg body weight glucose plus 100 ng/kg body weight caerulein. Basal pancreatic juice flow was significantly increased in all of the postpancreatitic rats irrespective of the treatment, whereas the maximal juice flow in the loxiglumide- and saline-treated rats was significantly low compared with the CCK-8-treated and the control rats. Basal and the peak protein outputs in the loxiglumide-treated rats were comparable to those in saline-treated rats, but were lower than those in the control or the CCK-8-treated rats. Although serum glucose concentrations in all of the postpancreatitic rats were similar to those in the control rats, stimulated as well as basal insulin release tended to be high compared with the control rats. In particular, loxiglumide-treated rats showed the exaggerated insulin response compared with other groups of rats. These present observations indicate that administration of high dose of loxiglumide for a long period decreases pancreatic enzyme output and causes insulin resistance.

CCK administration after CCK receptor blockade accelerates recovery from cerulein-induced acute pancreatitis in rats

We examined the effects of treatment with cholecystokinin (CCK) octapeptide (CCK-8) and the CCK receptor antagonist loxiglumide on the recovery of exocrine pancreas in post-acute pancreatitic rats. Acute pancreatitis was induced in rats by intravenous infusion of 20 μgkgh cerulein for 4 h. At 24 h after the start of cerulein infusion, rats were divided into nine treatment groups: oral administration of saline (control), or oral administration of 10 or 50mgkg body weight loxiglumide twice daily for the first 3 days, followed by saline administration (Loxi-1 and Loxi-2), 10 or 50mgkg body weight loxiglumide twice daily for 6 days (Loxi-3 and Loxi-4), oral administration of saline or 10 or 50mgkg body weight loxiglumide twice daily for the first 3 days, followed by subcutaneous injection of 2.5 μgkg body weight CCK-8 twice daily for the next 3 days (CCK-1, CCK-2, and CCK-3), and subcutaneous injection of 2.5 μgkg body weight CCK-8 twice daily for 6 days (CCK-4). Pancreatic wet weight and biochemical changes were evaluated on day 8 at 12 h after the last treatment. Treatment with loxiglumide (Loxi-3 and Loxi-4) or CCK-8 for 6 days (CCK-4) or with a high dose of loxiglumide for the first 3 days (Loxi-2) significantly suppressed the recovery of pancreatic weight and DNA content compared to saline treatment or to the untreated normal control rats. However, when loxiglumide treatment was followed by 3 days of CCK-8 injections (CCK-2 and CCK-3), pancreatic protein and DNA content recovered to levels comparable to or above the control levels. The most remarkable increase in enzyme content was obtained in postpancreatitic rats treated with high-dose loxiglumide for the first 3 days, followed by CCK-8 injection (CCK-3). On the other hand, 6 days of CCK-8 treatment (CCK-4) had no significant influences on pancreatic enzyme contents. These results suggest that the most favorable strategy for the treatment of acute pancreatitis is to give high-dose loxiglumide during the early stage for only a short period, followed by CCK-8 administration.

Effect of the Cholecystokinin Receptor Antagonist Loxiglumide on Pancreatic Exocrine Function in Rats After Acute Pancreatitis

Recent studies have demonstrated that cholecystokinin (CCK) receptor antagonists not only reduce the severity of pancreatitis but also inhibit pancreatic regeneration after pancreatitis. This study was undertaken, therefore, to examine the effects of the CCK receptor antagonist loxiglumide on the exocrine pancreas when given after an episode of acute pancreatitis that was induced in rats by a 4-h subcutaneous infusion of 20 μg/kg body weight/h cerulein. Biochemical changes and secretory function in response to 100 ng/kg body weight cerulein were determined after a 6-day treatment with saline, loxiglumide (50 mg/kg body weight), or CCK-8 (2.5 μg/kg body weight), which was given three times a day starting 24 h after the induction of acute pancreatitis. In the saline-treated rats, pancreatic enzyme contents and pancreatic juice and protein output were significantly low, whereas the pancreatic weight and protein and DNA contents were comparable to those of the controls without pancreatitis. Loxiglumide treatment, although significantly decreasing protein output, had no influence on pancreatic weight, protein and DNA contents, or pancreatic juice flow but increased the amylase and lipase contents compared to those of the saline-treated postpancreatitic rats. CCK-8 treatment also had no influence on pancreatic weight or protein and DNA contents but significantly increased the pancreatic enzyme contents and pancreatic juice and protein output compared to those of the saline-treated postpancreatitic rats. These results suggest that loxiglumide does not significantly inhibit the recovery of exocrine pancreatic function but appears to accelerate the increase in pancreatic amylase and lipase contents even when given after an attack of acute pancreatitis.

Effects of Mci-727 on Pancreatic Exocrine Secretion and Acute Pancreatitis in Two Experimental Rat Models

The effects of a newly developed compound having antiulcer action, (Z)-2-(4-methylpiperazin-1-yl)-1-[4-(2-phenyl-ethyl)phenyl]-ethanone oxime hydrochloride monohydrate (MCI-727), on pancreatic exocrine secretion were studied in anesthetized rats and evaluated its preventive and therapeutic effects on acute pancreatitis in two experimental rat models. Intraduodenal administration of MCI-727 [25, 50, or 100 mg/kg body weight (wt)] stimulated a dose-dependent increase in pancreatic juice and bicarbonate output without increasing the protein output or plasma cholecystokinin concentration. MCI-727-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but not by the cholecystokinin receptor antagonist loxiglumide (50 mg/kg body wt/h) or cholinergic receptor antagonist atropine (100 μg/kg body wt/h). In rats with acute pancreatitis induced by four subcutaneous injections of 20 μg/kg body wt cerulein at hourly intervals over 3 h, MCI-727 administered orally at a dose of 100 mg/kg body wt 30 min before the first cerulein injection significantly reduced the increases in serum amylase and lipase activity and pancreatic wet weight and induced improvements in the results of histologic examination. Moreover, when given 30 min before and 90 min after the first cerulein injection, MCI-727 had even more dramatic protective effects on all these parameters. In addition, even when administered immediately after the last cerulein injection, MCI-727 effectively ameliorated all these alterations of acute pancreatitis. However, MCI-727 had no apparent beneficial effects on the biochemical and histologic alterations of acute pancreatitis in the severe form induced by retrograde intraductal injection of 1.0 ml/kg body wt of 4% sodium taurocholate. These findings suggest that oral administration of MCI-727 stimulates pancreatic exocrine secretion by endogenous secretin release and that it has therapeutic as well as preventive effects on mild forms of acute pancreatitis in rats.