Profound duodenogastric reflux causes pancreatic growth in rats.

Abstract

Although duodenogastric reflux is a physiological event, excessive reflux may be a pathogenetic factor in several diseases ofthe foregut, including cancer. Long term profound duodenogastric reflux produces pancreatic and gastric tumours in rats. The trophic effect of surgically induced duodenogastric reflux on the pancreas was investigated and the mechanisms involved were examined. Rats with profound reflux from a split gastroenterostomy were compared with sham operated and unoperated controls after two and six weeks. In the six week experiment, one reflux and one sham group were given the cholecystokinin (CCK) receptor antagonist devazepide (25 nmollkg/h). Duodenogastric reflux caused a significant increase in pancreatic weight, DNA, and plasma CCK and gastrin concentrations at both two and six weeks. Devazepide substantially reduced the pancreatic weight increase after six weeks but did not abolish it completely. CCK and gastrin were not affected by devazepide. These results suggest that CCK is largely responsible for the pancreatic growth induced by reflux but another factor may also be involved. The trophic effect of duodenogastric reflux may contribute to the increased incidence of pancreatic cancer reported after gastric surgery. (Gut 1995; 36: 137-141) Keywords: duodenogastric reflux, pancreatic growth. model was used to investigate the short term effects of pronounced duodenogastric reflux on pancreatic growth in the rat, and to evaluate the role of CCK in this process. MethodsMale Wistar rats weighing 175-200 g (Sasco Inc, Omaha, Nebraska, USA), were used in the study. They were housed individually and fed standard pelleted rat chow with free access to water. DESIGN OF THE STUDYExperiment I To investigate possible growth effects of duodenogastric reflux on the pancreas, a group of rats with a split gastrojejunostomy (n= 10) were compared with sham operated rats (n=8) and unoperated controls (n=8), two weeks after surgery.Experiment II The effects of duodenogastric reflux were studied six weeks after surgery. Seventeen animals had a split gastrojejunostomy performed and eight of these also received the specific CCK receptor antagonist devazepide (also called MK329, Merck Sharp & Dohme).20 These were compared with sham operated rats with and without devazepide (n=6 and n=7, respectively) and unoperated controls (n= 5).

Effects of Profound Duodenogastric Reflux on the Foregut in Rats

“…Excessive DGR has been seen after gastric sur gery [24,25] and cholecystectomy [26,27], but also occurs without prior foregut surgery [4,5,28], In man, DGR has been implicated as a contributing factor in the pathogene sis of a variety of foregut diseases including gastric and duodenal ulcers [ 1 ], esophagitis [5,7] and Barrett's esoph agus [29]. Moreover, it has been suggested that DGR may induce premalignant changes in the gastric and esophage al mucosa [3,8] and DGR has been implicated as a cause of gastric stump cancer [2,3], In rats, reflux of pancraticoduodenal secretions, but not bile, causes adenocarcinoma of the stomach [2] and enhances the effect of carcinogens in the esophagus [8], It has previously been shown that the split gastrojejunostomy causes a rise in plasma CCK and gastrin and produces pancreatic growth in rats [10,11], Furthermore, long-term profound DGR in rats has been shown to produce pancreatic tumors [9], The mechanism responsible for the pancreatic growth is of interest since epidemiological studies in humans have suggested pre vious gastric surgery as a risk factor for pancreatic cancer [14][15][16], Thus DGR contributes to a variety of gastroin testinal diseases through mechanisms which have as yet not been identified.…”

“…The split gastrojejunostomy was performed as previously de scribed [11], Surgery was performed after an overnight fast and the animals were deprived of water for 24 h and of food for 48 h after the procedure. The proximal jejunum was divided approximately 2 cm distal to the ligament of Treitz and the afferent loop was anasto mosed to the greater curvature of the stomach 2-3 mm distal to the squamocolumnar junction.…”

Long-Term Effects on the Regulation of Pancreatic Secretion after Gastric Surgery

“…Rats display trophic changes in the pancreas after increased duodenogastric reflux [7]. Duodenogastric reflux is a well-known problem after BII resection in man.…”

“…Changes in the mixture of enzymes and gastric and intestinal contents could theoretically lead to a disturbed feedback regulation of pancreatic secretion. Increased duodenogastric reflux has, in rats, also been shown to cause pancreatic growth [6, 7]. It is known from animal experiments that increased levels of cholecystokinin (CCK) can induce preneoplastic and neoplastic changes in the gland, especially in the presence of carcinogens [8, 9, 10].…”

The effects of chronic bile reflux on the gastric mucosa of rats

“…It was also reported that bile reflux could cause hypergastrinemia (26,30,33,34) and inhibit the release of somatostatin (35). Decreased serum levels of somatostatin increased the severity of the symptoms of hypergastrinemia, and in return, hypergastrinemia could increase bile reflux (36).…”