Travis E. Solomon

Ethanol Diet Increases the Sensitivity of Rats to Pancreatitis Induced by Cholecystokinin Octapeptide

BACKGROUND & AIMS Although alcoholism is a major cause of pancreatitis, the pathogenesis of this disorder remains obscure. Failure to produce experimental alcoholic pancreatitis suggests that ethanol may only increase predisposition to pancreatitis. This study sought to develop a model of ethanol pancreatitis by determining if an ethanol diet sensitizes rats to pancreatitis caused by cholecystokinin octapeptide (CCK-8). METHODS Rats were fed intragastrically either control or ethanol diet for 2 or 6 weeks. The animals were then infused for 6 hours with either saline or CCK-8 at a dose of 3000 pmol. kg(-1). h(-1), which by itself did not induce pancreatitis. The following parameters were measured: serum amylase and lipase levels, pancreatic weight, inflammatory infiltration, number of apoptotic acinar cells, pancreatic messenger RNA (mRNA) expression of cytokines and chemokines, and nuclear factor (NF)-kappaB activity. RESULTS All measures of pancreatitis, as well as NF-kappaB activity and mRNA expression for tumor necrosis factor alpha, interleukin 6, monocyte chemotactic protein 1, macrophage inflammatory protein 2, and inducible nitric oxide synthase, were significantly increased only in rats treated with ethanol plus CCK-8. CONCLUSIONS An ethanol diet sensitizes rats to pancreatitis caused by CCK-8. The combined action of ethanol and CCK-8 results in NF-kappaB activation and up-regulation of proinflammatory cytokines and chemokines in the pancreas. These mechanisms may contribute to the development of alcoholic pancreatitis.

Effects of Gastrin, Proglumide, and Somatostatin on Growth of Human Colon Cancer

The effects of gastrin, proglumide (a gastrin receptor antagonist), and somatostatin on growth of human colon adenocarcinoma cell lines CX1, X56, and HT29 were examined in two experimental models. Nude mice bearing xenografts of colon cancer CX1 or X56 were treated for 14-25 days subcutaneously with saline, pentagastrin (0.5 or 1.0 mg/kg), proglumide (250 or 500 mg/kg), or somatostatin 14 (33, 100, or 300 micrograms/kg) twice daily. Tumor volume, weight, protein, and deoxyribonucleic acid were measured. HT29 cells were grown in vitro and the effects of gastrin 17, proglumide, and somatostatin on growth were evaluated by cell counts or [3H]thymidine incorporation. The larger dose of pentagastrin significantly increased tumor growth in the nude mouse (p less than 0.005) and gastrin induced a biphasic effect on deoxyribonucleic acid synthesis in tissue culture with significant increases of up to 39% (p less than 0.025). Somatostatin alone significantly inhibited tumor growth in two of the cell lines and also inhibited the gastrin-induced growth. Proglumide had no effect by itself but significantly inhibited gastrin-stimulated growth. These findings suggest that growth of some human colon cancers may be hormone-dependent.

Pancreatic Polypeptide Metabolism and Effect on Pancreatic Secretion in Dogs

In dogs with gastric and pancreatic fistulas, porcine pancreatic polypeptide (PP) was infused intravenously in doses of 50, 100, 200, 400, and 800 pmol kg-1 hr-1 in the basal state and in doses of 100, 200, and 400 pmol kg-1 hr-1 during stimulation with submaximal doses of secretin (125 ng kg-1 hr-1) plus caerulein (50 ng kg-1 hr-1). Plasma concentrations of PP were measured by radioimmunoassay, and pancreatic bicarbonate and protein outputs were monitored. The half-time for disappearance of PP was 5.5 +/- 1.0 min, the metabolic clearance rate was 25.6 +/- 1.0 ml kg-1, and the volume of distribution was 209 +/- 42 ml kg-1. Basal pancreatic flow and protein output were significantly inhibited by the lowest dose of PP tested, 50 pmol kg-1 hr-1. The lowest dose of PP significantly inhibiting stimulated pancreatic secretion was 100 pmol kg-1 hr-1 for bicarbonate output and 200 pmol kg-1 hr-1 for protein output. The mean +/- SE peak increment in PP concentration in response to a meal of meat, 210 +/- 39 pM, was greater than the mean peak increment with the 400 pmol kg-1 hr-1 dose of exogenous PP, 175 +/- 19 PM. We conclude that exogenous doses of PP that produce smaller increments in PP concentration than those seen after feeding inhibit pancreatic bicarbonate and protein secretion stimulated by secretin and caerulein. This suggests that the amount of PP released by a meal is sufficient to inhibit pancreatic secretion.

Structure and receptor binding of PYY analogs

Differences in the structure of PYY and two important analogs, PYY [3-36] and [Pro34]PYY, are evaluated. Y-receptor subtype ligand binding data are used in conjunction with structural data to develop a model for receptor subtype selective agonists. For PYY it is proposed that potent binding to Y1, Y4 and Y5 receptors requires the juxtaposition of the two termini while Y2 binding only requires the C-terminal helix. Further experiments that delineate between primary and tertiary structure contributions for receptor binding and activation are required to support the hypothesis that tertiary structure is stable enough to influence the expression of PYYs bioactivity.

Inhibition of pancreatic secretion in man by cigarette smoking

Cigarette smoking has been linked to an elevated incidence of duodenal ulcer disease in smokers, although the mechanism is unclear. In 23 young normal subjects single or double secretin tests were performed during non-smoking and smoking periods. Cigarette smoking inhibited the secretion of pancreatic juice and bicarbonate in light smokers (< one pack/day for < three years). Heavy smokers (> one pack/day for > three years) exhibited depressed pancreatic secretory rates during non-smoking periods. Inhibition of pancreatic alkaline secretion by cigarette smoking could be the link between the habit and duodenal ulcer disease.

Effects of selective cholecystokinin antagonists L364,718 and L365,260 on food intake in rats

The selective type A and B cholecystokinin (CCK) receptor antagonists L364,718 and L365,260 were used to identify the receptor subtype that mediates the satiety effect of endogenous CCK. Male rats (n = 12-13/group), fed ground rat chow ad lib, received L364,718 (0, 1, 10, 100, or 1000 micrograms/kg IP) or L365,260 (0, 0.1, 1, 10, 100, 1000, or 10,000 micrograms/kg IP) 2 h after lights off, and food intake was measured 1.5, 3.5, and 5.5 h later. L364,718 significantly stimulated 1.5-h food intake by more than 40% at 10 micrograms/kg and higher doses; cumulative intake at 3.5 and 5.5 h remained elevated by about 20% at 1000 and 100 micrograms/kg of L364,718, respectively. In contrast, L365,260 had no significant stimulatory effect on feeding at any dose. The potency of L365,260 for antagonizing gastrin-stimulated gastric acid secretion was examined in unanesthetized rats. Male rats (n = 14), prepared with gastric and jugular vein cannulas, received doubling doses of gastrin (G-171) (0.16-5 nmol/kg/h IV), each dose for 30 min, and gastric juice was collected for each 30-min period. G-171 stimulated gastric acid output dose dependently; the minimal effective dose was 0.16 nmol/kg/h, while maximal output (5-fold above basal) occurred at 5 nmol/kg/h. L365,260 (0, 1, 10, 100, 1000, or 10,000 micrograms/kg IV), administered 30 min before continuous infusion of G-171 (1.25 or 5 nmol/kg/h), significantly inhibited acid output only at 10,000 micrograms/kg; cumulative 60-min output was decreased by 60%. These results suggest that CCK acts at CCK-A receptors to produce satiety during the dark period in ad lib-feeding rats.

Cholecystokinin octapeptide releases growth hormone from the pituitary in vitro.

Abstract Cholecystokinin-octapeptide (CCK-8)(10−6 to 10−8M) produced a marked increase in growth hormone (GH) release from incubated rat anterior pituitary quarters and from cultured GH3 pituitary tumor cells. Although several CCK-8 analogues also caused GH release, bombesin, secretin and pancreatic polypeptide had no effect on GH secretion in vitro . In the GH3 cell line, CCK-8 (10−7M) reversed the inhibitory effect of somatostatin (10−5M) on GH release. As CCK immunoreactivity has been demonstrated to be present in the hypothalamus, these results suggest that CCK-8 may be a physiologically important growth hormone releasing factor.

Effect of gastric inhibitory polypeptide on pentagastrin-stimulated acid secretion in man

Eight male subjects were given pentagastrin by intravenous infusion in doses of 25, 74, 222, 667, and 2000 ng/kg/hr, each dose for 30 min. On another day the same subjects were given the same doses of pentagastrin while gastric inhibitory polypeptide (GIP) was being infused intravenously in a dose of 2 μg/kg/hr. At the 222 ng/kg/hr dose of pentagastrin, acid output was significantly lower with GIP; at all other doses of pentagastrin, acid output did not differ significantly in tests with and without GIP. Pepsin output in the tests with and without GIP did not differ significantly at any dose of pentagastrin. Plasma concentration of GIP, measured by radioimmunoassay, showed a mean±SE plateau level of 7.4±1.4 ng/ml during GIP infusion and 0.4±0.1 ng/ml peak level after a standard meal. We conclude that the increase in blood concentration of GIP produced by feeding is probably inadequate to cause significant inhibition of gastric acid or pepsin secretion in man.

Effects of Nicotine on Gastrointestinal Secretions

The effect of nicotine on gastric, pancreatic, and hepatic exocrine secretions was assessed in conscious dogs prepared with various combinations of Heidenhain pouch, gastric, pancreatic, and biliary fistulas. The alkaloid was infused in doses corresponding to amounts absorbed from smoking up to four cigarettes in 1 hr. In the pancreas, nicotine inhibited the secretin-stimulated secretion of both fluid and bicarbonate, and the degree of inhibition was dose-related. Spontaneous biliary secretion of bicarbonate was also depressed by the drug. Nicotine did not alter gastric secretion of acid, gastric mucosal blood flow, or the mucosal barrier to hydrogen or sodium ions. These findings provide a possible link between cigarette smoking and duodenal ulcer formation. Specifically, the nicotine from cigarette smoke may inhibit pancreatic and hepatic bicarbonate secretion in man, thereby depriving the duodenum of the alkaline secretion it needs to neutralize gastric acid adequately.

The effects of thyrotropin releasing hormone (TRH) on the gastrointestinal tract

Abstract Thyrotropin-releasing hormone (TRH) immunoreactivity is distributed throughout the gastrointestinal tract and the pancreas. We have studied the effect of TRH on several gastrointestinal functions in intact, unanesthetized dogs. Intravenous TRH stimulated gastric action potentials (p