Kenji Okubo

Vagal efferent nerve-dependent inhibitory action of pancreatic polypeptide and peptide YY in conscious rats: comparison with somatostatin

The release of pancreatic polypeptide (PP) and peptide YY (PYY) is regulated by the vagal nerve, and the inhibitory effect of these peptides on pancreatic exocrine secretion shows indirectly via a neural mechanism. To determine the role of the vagal nerve on the inhibitory action of these peptides on the pancreas, we compared the effect on the pancreatic response to bile and pancreatic juice diversion in conscious rats with and without vagotomy. We also studied this response in rats treated with capsaicin, because bile-pancreatic juice diversion is the most potent endogenous stimulation of pancreatic secretion in conscious rats. In addition, since somatostatin potently inhibits of pancreatic enzyme secretion, the effects of PP and PYY were compared with somatostatin. An intravenous infusion of 2.5 nmol/kg per h of PP and PYY significantly inhibited the pancreatic responses of bile and pancreatic juice diversion in animals with an intact vagal nerve and in those treated with capsaicin, whereas the same dose of peptides failed to inhibit pancreatic secretion in vagotomized rats. Somatostatin inhibited pancreatic secretion under all conditions tested. We concluded that the inhibitory action of PP and PYY on pancreatic secretion is fully mediated by the vagal efferent nerve although other multiple mechanisms are involved for the inhibitory action of somatostatin.

Effect of long-term exercise under restricted-feeding on intestinal content of cholecystokinin and on the pancreas in aging rats

The effects of exercise (5000 m/day running from 100 to 600 days of age) on the cholecystokinin (CCK) content in the proximal intestine, and the enzyme and insulin contents of the pancreas were examined in food-restricted rats. Food restriction decreased the body weight and the wet weights of the pancreas and proximal intestine but not the wet weight of the stomach. Food restriction also decreased the chymotrypsin content of the pancreas but not its amylase content. The contents of enzymes in the pancreas were not affected by exercise. The insulin content of the pancreas was lower in lean rats produced by food restriction and/or exercise than in controls. Exercise increased the wet weight of the proximal intestine and the CCK content of the intestine. The increase in the CCK content may be due to compensational change in the efficiency of digestion of luminal nutrients induced by exercise.

Effects of pancreatic duct ligation and aging on acute taurocholate-induced pancreatitis. Experiments in the perfused pancreas in rats.

SummaryConclusionWhen taurocholate was injected into the common bile duct, high ductal pressure due to ligation of the pancreatic duct did not produce more damage in the pancreas of both old rats and young adult rats, and levels of pancreatic enzymes in portal venous effluent were lower in old rats than in younger ratsBackgroundThe effects of ligation of the pancreatic, duct and aging on acute pancreatitis caused by taurocholate are still unclear.MethodsYoung adult and old male Wistar rats were used. Six hours after ligation of the common bile duct in both the duodenum and liver hilus, rats were killed and the pancreata were perfused. Taurocholate or normal saline was injected retrogradely into the common bile duct. The levels of amylase and lipase in the portal venous effluent were determined as markers of damage to the pancreas. The pancreas was also histologically examined after the perfusion experiments using an Image Analysis System.Results(1) A nonsignificant elevation of pancreatic enzymes was found in portal venous effluent by the retrograde injection of saline into the common bile duct. Injection of taurocholate caused a marked elevation of enzymes in the effluent for the first 30 min after injection, which then gradually decreased. (2) Basal levels of pancreatic enzymes were significantly higher in the ligation group than in the nonligation group. Injection of saline into the common bile duct had no apparent effect on enzymes in the effluent. In contrast, taurocholate injection into the common bile duct produced a marked increase in enzymes in the portal venous effluent. However, no significant difference was found between the ligation group and the nonligation group. (3) Similar findings were obtained when old rats were used. (4) Although basal levels of enzymes were almost the same in nonligated old and young adult rats, taurocholate injection into the pancreatic duct in old rats resulted in a significant depression of enzymes compared to that in young adult rats. In the ligation group, pancreatic enzymes in the portal venous effluent following taurocholate injection tended to be lower in old rats than in young adult rats. The results were histologically supported in that various degrees of fibrosis were found in the pancreata of old rats.

Evidence for the effect of aging on tissue contents of gastrin, cholecystokinin and somatostatin in the rat.

The changes associated with aging in the tissue concentrations of cholecystokinin, somatostatin and gastrin in young (7-month-old), middle-aged (13-month-old) and old (25-26-month-old) rats were investigated. The concentrations and total contents of somatostatin and gastrin significantly decreased in the antrum in 13- and 25-26-month-old rats compared with the young controls. The cholecystokinin concentration in the proximal intestine and its total content significantly increased in the old rats. Somatostatin concentrations in the intestine and cerebral cortex did not change with age. Cholecystokinin content in the cerebral cortex decreased in old rats because of the decrease of tissue wet weight. We conclude that the effects of aging on the changes of peptide concentrations in tissues vary depending on peptide specie and in different tissues studied.

Mechanisms of stimulatory effect of neuromedin C on pancreatic exocrine secretion in conscious rats

The mechanisms of the stimulatory effect of the bombesin-like peptide neuromedin C on pancreatic exocrine secretion were examined in conscious rats. Rats were prepared with cannulae draining bile and pancreatic juice separately. Intravenous infusion of 0.35 nmol/kg/h of neuromedin C significantly increased the secretions of pancreatic bicarbonate and protein, and transiently increased the plasma cholecystokinin (CCK) concentration. The increase in pancreatic secretion persisted for 90 min, whereas the increase in plasma CCK was observed only after 15 and 30 min from the beginning of neuromedin C infusion. Intravenous infusion of CR-1409, a specific CCK-receptor antagonist, inhibited, but did not abolish, the protein secretion stimulated by neuromedin C. Intraduodenal infusion of a potent proton pump inhibitor, omeprazole, suppressed, but did not abolish, protein secretion induced by neuromedin C. Omeprazole abolished the increase in bicarbonate secretion produced by neuromedin C. These results indicate that neuromedin C induces release of CCK and that its induction of pancreatic hypersecretion is due to both its direct effect and CCK. The results also suggest that gastric hypersecretion may have a role in the bicarbonate hypersecretion induced by neuromedin C.

Different response of brain cholecystokinin content to intragastric administration of trypsin inhibitor (camostate) in young and old rats

The tissue concentrations of cholecystokinin in the intestine and the brain in young (4-8-month-old), and old (26-29-month-old) rats before and after intragastric administration of synthetic trypsin inhibitor (camostate) were examined. The total cholecystokinin content in the proximal intestine was significantly higher in old rats, whereas that in the brain was similar in young and old rats. Intragastric administration of camostate significantly increased the plasma cholecystokinin concentration and decreased the intestinal cholecystokinin content in both young and old rats. It also decreased the cholecystokinin content in the brain of old rats but not of young rats. These results suggest that the effect of aging on changes in the tissue content of cholecystokinin varies in different tissues.

Secretory capacity of pancreatic protein during luminal feedback regulation in conscious rats

Pancreatic exocrine secretion in conscious rats is regulated by bile and pancreatic juice in the proximal intestine (luminal feedback regulation), and bile-pancreatic juice diversion from the intestine results in cholecystokinin (CCK) release and pancreatic hypersecretion. Pancreatic protein secretion increases to a maximum 60-90 min after bile-pancreatic juice diversion, and then decreases slightly to a steady level of two times the basal level. Change in plasma CCK concentration parallels protein secretion. In this study, the mechanism of the decreases of protein secretion and CCK concentration was examined by stimulation with various species of peptides having different stimulatory mechanisms. Cannulae for draining bile and pancreatic juice separately and a duodenal cannula and extrajugular vein cannula were inserted into male Wistar rats. Four days later, basal levels in a 90-min period were determined, bile and pancreatic juice were diverted for 90 min, and then either secretin (1.2 nmol/kg/h), CCK-8 (25 and 100 pmol/kg/h), neuromedin C (350 pmol/kg/h and 3.5 nmol/kg/h), or CCK-JMV-180 (200 nmol/kg/h) was infused intravenously for 60 min. Infusion of secretin significantly increased protein secretion and prevented its decrease after its maximum induced by bile-pancreatic juice diversion. The plasma CCK concentrations were not increased further by neuromedin C. In conclusion, pancreatic exocrine secretion and CCK release in conscious rats are maximally stimulated by luminal feedback regulation that the decrease after maximal protein output may be due to limitation of secretory capacity and/or desensitization of acinar cells.