Kazutomo Inoue

Correlation between Release of Cholecystokinin and Contraction of the Gallbladder in Patients with Gallstones

The role of endogenously released cholecystokinin (CCK) in mediating gallblader (GB) contraction was evaluated in 12 normal volunteers and 24 patients with gallstones (11 additional gallstone patients were excluded because of failure of adequate ultrasonographic visualization). CCK concentrations before and after oral administration of fat (Lipomul®) were measured by a specific radioimmunoassay. CCK release was correlated with changes in GB volume determined simultaneously by ultrasonography. On the basis of gallbladder contraction and operative findings, gallstone patients were divided into “contractors” (14), “noncontractors” (6), and “hydrops” (4). Lipomul caused prompt release of CCK in normal volunteers and all groups of gallstone patients. The changes (basal to peak) in plasma CCK (pg/ml) for the different groups were as follows: normal volunteers (108 ± 9 to 200 ± 16), contractors (77 ± 10 to 128 ± 13), noncontractors (59 ± 7 to 159 ± 38), and hydrops (43 ± 5 to 113 ± 47). The total integrated output of CCK (0–60 min) was greater in normal volunteers (3975 ± 762 pg-min/ml) than in contractors (1530 ± 567 pg-min/ml). Lipomul caused similar GB contraction in normal volunteers and contractors (from basal volumes to maximal contraction); these changes were from 19.5 ± 2.3 ml to 5.6 ± 1.0 ml in normal volunteers, and from 19.6 ± 3.2 to 5.2 ± 1.0 in contractors. Plasma concentrations of CCK and GB volume were highly correlated in the 12 normal volunteers (r = −0.89, p < 0.01) and in the 14 contractors (r = −0.99, p < 0.01)), but the GB was significantly (p < 0.01) more sensitive to changes in plasma CCK in the gallstone contractors than in the normal volunteers. The authors suggest that there may be two groups of gallstone patients, noncontractors and contractors. Stasis may be important in the pathogenesis of gallstones in the noncontractors, whereas in contractors, the authors speculate that an abnormality in the CCK-gallbladder relationship (characterized by diminished CCK release and increased GB sensitivity to CCK) may be involved in the evolution of the disease.

Plasma cholecystokinin and pancreatic polypeptide response after radical pancreatoduodenectomy with Billroth I and Billroth II type of reconstruction.

This study was conducted to elucidate plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) response after pancreatoduodenectomy and to compare response of CCK and PP in patients who had pancreatoduodenectomy with Billroth I and Billroth II type of reconstruction. Basal levels of plasma CCK were significantly lower in patients who had pancreatoduodenectomy (9.6 ± 0.8 pmol/L) than in the control (preoperative patients: 14.6 ± 2.0 pmol/L) probably because of the removal of the entire duodenum due to pancreatoduodenectomy, since vagotomy, which is concomitantly brought about by pancreatoduodenectomy, does not appear to interfere with release of CCK. Significant amounts of CCK (integrated CCK: 497 ± 111 pmol-120 min/L), although less amounts than in the preoperative patients (integrated CCK: 901 ± 167 pmol-120 min/L), were still released in response to oral fatty meal after pancreatoduodenectomy. Plasma CCK response to oral fatty meal was significantly greater in patients who had pancreatoduodenectomy with Billroth I type of reconstruction (integrated CCK: 705 ± 153 pmol-120 min/L) than in patients who had pancreatoduodenectomy with Billroth II type of reconstruction (248 ± 63 pmol-120 min/L). Simultaneous measurement of plasma levels of PP revealed complete abolishment of PP response by pancreatoduodenectomy. Since PP secretion can be produced by vagal stimulation, it is most likely that the decreased PP secretion is due to vagotomy rather than removal of the duodenum and pancreas. Significant amounts of CCK released after pancreatoduodenectomy, in which the main sources of release of CCK are removed, may suggest the compensatory mechanism of the remnant upper small intestine. This study also suggests the necessity of reevaluating Billroth I type of anastomosis as a physiologic reconstruction procedure for the remnant alimentary tract after pancreatoduodenectomy.

Effects of Synthetic Human Gastric Inhibitory Polypeptide on Splanchnic Circulation in Dogs

Changes in blood flow in the celiac artery, superior mesenteric artery, and pancreas in response to an intravenous injection of synthetic human gastric inhibitory polypeptide (GIP) were determined simultaneously and continuously in anesthetized dogs, using a transit-time ultrasonic flowmeter and a laser-Doppler flowmeter. Injection of GIP significantly increased superior mesenteric arterial flow in a dose-related manner (by 9%, 43%, and 139% at 30 s after an injection at the doses of 3, 50, and 800 pmol/kg, respectively). In contrast, celiac arterial flow was not significantly altered by GIP at any of the three doses. Calculated vascular resistance in the superior mesenteric artery decreased after GIP infusion, whereas that in the celiac artery was not changed by GIP. Pancreatic blood flow decreased significantly after GIP injection at the doses of 50 and 800 pmol/kg (by 11% and 17%, respectively). Our data indicate that there is a substantial difference in the hemodynamic responses to GIP among splanchnic organs, and suggest that GIP acts specifically on the mesenteric vasculature.

Effect of natural peptide YY on pancreatic secretion and cholecystokinin release in conscious dogs

The effects of natural peptide YY on pancreatic secretion under different stimulatory conditions and on fatty acid-induced cholecystokinin release were examined in five conscious dogs with pancreatic and gastric fistulas. Intravenous infusion of natural peptide YY at 1 and 0.2 Μg/kg/hr caused 60 and 40% inhibition of secretin- and cholecystokinin-stimulated secretion, respectively, and 40–50 and 20–40% inhibition of intraduodenal oleate stimulated secretion, respectively. A significant but transient decrease in the plasma cholecystokinin level was observed in response to peptide YY under oleate stimulation. The present study demonstrates that peptide YY has a potent inhibitory effect on both exogenously and endogenously stimulated pancreatic secretion and has a mild suppressive effect on fatty acid-induced cholecystokinin release, suggesting that this peptide is an important colonic inhibitor of pancreatic secretion.

Effect of colectomy on cholecystokinin and gastrin release.

Studies were conducted to determine the effect of resection of the colon on the release of cholecystokinin (CCK) and gastrin. A standard food stimulation test was performed in five dogs. Peripheral blood samples were collected for future measurement of CCK and gastrin by specific radipimmunoassay. Each dog underwent subtotal colectomy with side-to-end ileoproctostomy. The food stimulation test was repeated at approximately weekly intervals for eight weeks after colectomy. Basal plasma CCK levels of 139 ± 21 pg/ml before colectomy did not change after colectomy. Total amount of CCK released after food was increased significantly at both four (5.94 ± 0.78 ng min/ml) and eight (13.00 ± 2.72 ng min/ml) weeks after colectomy in comparison with that observed prior to colectomy (2.94 ± 0.54 ng min/ml). Basal serum gastrin levels of 28 ± 9 pg/ml did not change significantly after colectomy. Total amount of gastrin released after food was increased significantly at both two (8651 ± 2294 pg min/ml) and three (6940 ± 1426 pg min/ml) weeks after operation, but at none of the later weeks. The precolectomy output, used for comparison, was 5608 ± 1346 pg min/ml. It was concluded that resection of the colon leads to an increase in release of CCK and gastrin after food stimulation. This finding provides further evidence that the colon contains a factor that inhibits the release of CCK and gastrin, and that the colon functions as an endocrine organ.

Pancreatic secretion and the release of cholecystokinin after a meal in dogs with and without exclusion of pancreatic juice.

Pancreatic secretion and plasma levels of cholecystokinin-33/39 (CCK) were measured for 5 h after a meal in dogs with and without exclusion of pancreatic juice. Significant and prolonged increases in pancreatic secretion and plasma CCK levels were observed irrespective of pancreatic juice exclusion. The integrated responses of pancreatic protein output (2.6 +/- 0.6 g/300 min), plasma CCK (1.3 +/- 0.5 nmol.l-1 .300 min) with exclusion of pancreatic juice showed no significant differences from those without exclusion (2.8 +/- 0.3 g/300 min and 1.3 +/- 0.3 nmol.l-1.300 min for protein output and CCK, respectively). These results suggest that the CCK-mediated feedback mechanism of pancreatic enzyme secretion does not work, at least not in the postprandial state in dogs.

Effect of synthetic chicken and porcine vasoactive intestinal peptide on pancreatic blood flow in dogs

Studies were conducted in dogs to determine the effect of synthetic chicken and porcine vasoactive intestinal peptide on blood flow and exocrine secretion of the pancreas and on systemic arterial pressure. The stimulatory effect of synthetic chicken vasoactive intestinal peptide on blood flow and exocrine secretion of the pancreas was almost similar to that observed after synthetic porcine vasoactive intestinal peptide stimulation, whereas, synthetic chicken vasoactive intestinal peptide retained only approximately two thirds of the potency of synthetic porcine vasoactive intestinal peptide in its effect on lowering systemic arterial pressure. This study suggests that an increase in exocrine pancreatic secretion may be related to an increase in pancreatic blood flow in response to vasoactive intestinal peptide. This study leads us to speculate that total amounts of splanchnic organ blood flow increased in response to porcine vasoactive intestinal peptide are much more greater than those after chicken vasoactive intestinal peptide stimulation, although we cannot exclude the possibility that porcine vasoactive intestinal peptide may be much more potent in its effect on vasodilations in peripheral systemic vessels in comparison with chicken vasoactive intestinal peptide.

Effect of synthetic physalaemin on splanchnic circulation in dogs.

Physalaemin has been reported as one of the most potent vasodilator and hypotensive peptides (1-4). In spite of these studies, however, the effect of the peptide on splanchnic circulation is not known precisely. In the present study, the effect of synthetic physalaemin on superior mesenteric arterial blood flow, portal venous blood flow and pancreatic capillary blood flow was investigated in dogs. Dose dependent increases of superior mesenteric arterial blood flow and portal venous blood flow were induced in response to physalaemin (0.1-10.0 ng/kg). Superior mesenteric arterial blood flow and portal venous blood flow attained maximal increases of 77 +/- 8.9% and 70 +/- 8.6%, respectively, at a dose of 5 ng/kg. Physalaemin caused a dose-related decrease in systemic arterial blood pressure. Pancreatic capillary blood flow did not show significant change with the administration of physalaemin. These data suggest that physalaemin may play some physiological roles in the regulation of splanchnic circulation.

Total small bowel resection inhibited bombesin-stimulated release of cholecystokinin and pancreatic polypeptide in anesthetized cats.

In anesthetized cats, immunoreactive cholecystokinin (CCK), pancreatic polypeptide (PP), and gastrin were released in response to bombesin both before and after small bowel resection. Total small bowel resection significantly decreased bombesin-stimulated release of cholecystokinin and pancreatic polypeptide without affecting the release of gastrin. Integrated analysis showed that CCK, pancreatic polypeptide, and gastrin were released in significant quantities after small bowel resection. The results show that total small bowel resection caused significant inhibition of bombesin-stimulated release of cholecystokinin and pancreatic polypeptide; in contrast, gastrin release remained unaffected. The data further indicate that extra bowel sources of cholecystokinin exist in cats and the release of CCK from those sources occurred following bombesin stimulation.