Experimental evidence for a vagally mediated and cholecystokinin-independent enteropancreatic reflex.

Truncal vagotomy results in diminished pancreatic protein secretion in response to intraduodenal fat. This diminished secretion may be due, at least in part, to interruption of the vagal reflexes between the intestine and the pancreas that work independently of cholecystokinin (CCK). In five dogs with chronic pancreatic fistulas, plasma CCK concentrations and pancreatic protein secretion in response to an intestinal stimulant (intraduodenal oleate) and to two exogenous peptides (bombesin and CCK-33) were compared before and after bilateral truncal vagotomy. Vagotomy decreased integrated protein secretion by about 50% in response to intraduodenal oleate. In contrast, protein output in response to parenteral stimuli increased after vagotomy. Integrated output of CCK in response to intraduodenal oleate or to exogenous bombesin or CCK was not significantly affected by vagotomy, but release of pancreatic polypeptide was decreased significantly in response to all stimuli after truncal vagotomy. These data provide evidence that truncal vagotomy decreases pancreatic protein secretion in response to intestinal stimulants by interrupting enteropancreatic reflexes mediated by the vagus, while maintaining normal (or supranormal) sensitivity of the pancreas to endogenous and exogenous CCK.     

Evidence that the cholinergic enteropancreatic reflex may be independent of cholecystokinin release.

Studies were performed in four dogs with chronic gastric and pancreatic fistulas following intraduodenal perfusion with 10 mmole hr-1 of sodium oleate for 30 minutes. Radioimmunoassay (RIA) of plasma CCK LI was undertaken by an RIA method using labeled, desulfated CCK 8 I125 and an antiserum raised to CCK 8. The detection limit for the assay was 0.25 to 0.5 fmole and the lowest detectable plasma level was 5 to 10 fmoles ml-1. Since there was equal cross-reactivity to gastrin, a gastrin-specific assay also was employed to evaluate any changes in gastrin levels. After oleate infusion the plasma CCK increment above basal was 50 +/- 11 fmoles ml-1, with return to basal levels after 60 minutes. Administration of atropine significantly (P less than 0.01) inhibited the release of CCK in the first 20 minutes. Thereafter CCK release was not reduced. Plasma gastrin values did not change before and after oleate perfusion. Pancreatic protein output increased from 72 +/- 12 to 420 +/- 55 mg/10 min-1 after oleate administration. However, after atropinization the rise in pancreatic protein output was significantly lower (152 +/- 36 mg/10 min-1) (P less than 0.01). We have shown that, using our RIA method, there is a measurable rise in plasma CCK LI after intraduodenal oleate. After atropinization the CCK response was decreased significantly during the first 30 minutes, but was virtually unchanged during the second 30 minutes, when the fall in pancreatic protein output was most marked. We conclude that the cholinergic mechanism which plays a role in the endogenous stimulation of pancreatic protein secretion by intraduodenal oleate cannot be explained simply be decreased CCK release. This mechanism may be hormonal, distinct from secretin, or neural possibly, via activation of an enteropancreatic reflex.     

Physiologic role of cholecystokinin in the intestinal phase of pancreatic polypeptide release.

Release of pancreatic polypeptide (PP) after a meal is biphasic, with an early transient peak believed to be under cholinergic control, and a secondary, prolonged intestinal phase thought to be mediated by hormones. Endogenous release of PP was stimulated by intraduodenal oleate (6.8 mmol/hr) or by intravenous administration of pure cholecystokinin-33 (CCK-33, 0.1 micrograms/kg/hr) in five dogs. Radioimmunoassay measurements of plasma concentrations of PP and CCK-33 were compared by linear regression analysis before and after vagotomy. Correlations between plasma concentrations of PP and CCK-33 before vagotomy (r = 0.83 [oleate], r = 0.97 [IV-CCK-33]) and after vagotomy (r = 0.92 [oleate], r = 0.92 [IV-CCK-33]) were highly significant. Changes in plasma concentrations of PP relative to a particular increment in plasma CCK-33 (before vagotomy) were similar, whether stimulated by oleate or by exogenous CCK-33. After vagotomy, less PP was released relative to a change in plasma CCK-33 (stimulated by oleate or by exogenous CCK-33), but the PP response relative to a change in plasma CCK-33 induced by the two stimuli remained remarkably similar. These results provide evidence that the intestinal phase of physiologic release of PP is mediated to a large extent through release of CCK.     

Release of radioimmunologic cholecystokinin in human subjects

After the development of reliable, highly sensitive, specific radioimmunologic methods for measuring physiologic CCK concentrations in human plasma, we have been able to study the importance of CCK in the postprandial activation of pancreatic enzyme secretion. In man, food causes a threefold increase in the basal plasma CCK concentration with a peak at about 60 minutes. The highest CCK concentrations are observed after intraduodenal fat infusion. Selective proximal vagotomy results in a significant increase in basal CCK concentrations in duodenal ulcer patients without altering the postprandial CCK output. After gastric resection (Billroth I or Billroth II) an initial greater postprandial CCK output is observed. In patients with chronic pancreatic insufficiency without enzyme substitution, basal plasma CCK concentrations and the early postprandial CCK output were elevated which indicated a feedback mechanism between pancreatic enzyme secretion and CCK release from the mucosa of the upper small intestine.     

Proglumide inhibits cholecystokinin and meal-stimulated pancreatic secretion and release of pancreatic polypeptide

Exogenously administered cholecystokinin is a potent stimulant of pancreatic exocrine secretion and pancreatic polypeptide release. Release of cholecystokinin by amino acids and fats is strongly correlated with both pancreatic exocrine secretion and pancreatic polypeptide release. Despite this correlation, direct evidence that cholecystokinin is a physiologic mediator of these actions is not available. We have studied this problem in fasted dogs with chronic pancreatic fistulas by means of a specific cholecystokinin antagonist, proglumide, to inhibit the effect of cholecystokinin. Secretion, neurotensin (with secretin stimulation infusion), or cholecystokinin-octapeptide was infused intravenously, either with saline solution or with proglumide (300 mg/kg/hr). For endogenous release of cholecystokinin, intraduodenal infusions of phenylalanine and tryptophan or of sodium oleate were given with either intravenous saline solution or intravenous proglumide. Pancreatic secretion and release of cholecystokinin and pancreatic polypeptide were measured in plasma. Cholecystokinin-octapeptide stimulated pancreatic secretion of water and protein; both of these were significantly inhibited by proglumide. Intraduodenal amino acids and sodium oleate both caused significant release of cholecystokinin, which was not altered by proglumide; however, proglumide inhibited pancreatic secretion stimulated by intraduodenal amino acids and sodium oleate. Release of pancreatic polypeptide stimulated by amino acid and sodium oleate was also significantly inhibited by proglumide. Since proglumide appears to block actions of cholecystokinin, our results show that cholecystokinin is physiologically important for pancreatic secretion and for release of pancreatic polypeptide.     

Release of cholecystokinin and gallbladder contraction before and after gastrectomy.

The contraction of the gallbladder by ultrasonography and release of cholecystokinin (CCK) by specific radioimmunoassay in response to the ingestion of oral fatty meal before and 1 month after gastrectomy in five patients with early gastric cancer was studied. Before gastrectomy, basal concentrations of CCK (13.4 +/- 2.3 pmol/L) rose significantly to a maximum of 23.3 +/- 3.6 pmol/L at 20 minutes after ingestion of oral fatty meal, and remained significantly elevated during the study. Gallbladder contraction began as CCK concentrations rose, demonstrating significant correlation with plasma CCK. One month after gastrectomy, CCK showed a rapid and greater response to the ingestion of fatty meal, attaining a maximum of 53.7 +/- 7.3 pmol/L at 10 minutes, then gradually falling to basal level. The maximal contraction of the gallbladder after gastrectomy was almost the same as before gastrectomy (62.7 +/- 4.0% of original area), showing a significant correlation with plasma CCK, but refilling of the gallbladder was induced earlier with corresponding reduction of plasma CCK. Simultaneous measurement of plasma concentrations of pancreatic polypeptide revealed a fairly similar response to plasma CCK before and after gastrectomy. The release of CCK is the chief mechanism by which the ingestion of a fatty meal causes contraction of the gallbladder even after gastrectomy as well as before gastrectomy.     

Release of cholecystokinin in man: correlation of blood levels with gallbladder contraction.

Although it is generally assumed that release of cholecystokinin (CCK) is the chief mechanism by which a fatty meal causes contraction of the gallbladder, measured release of CCK and gallbladder contraction have never been correlated. We have achieved this correlation in eight adult male volunteers, by means of a specific radioimmunoassay for CCK and by ultrasonographic imaging of the gallbladder. This study validates our CCK radioimmunoassay and correlates measured concentrations of CCK with changes in gallbladder size measured by ultrasonographic examination. Basal concentrations of CCK (82.6 +/- 10.4 pg/ml) rose significantly to a maximum of 411.1 +/- 79.9 pg/ml at 16 minutes after intraduodenal instillation of medium-chain triglyceride (Lipomul). Mean basal volume of the gallbladder was 34.6 cm3; maximum reduction of gallbladder volume (to one-third of original) was achieved at 18 minutes. Elevated CCK concentrations began to fall toward basal, and the gallbladder began to refill at 25 minutes. Results obtained after oral ingestion of Lipomul provide similar results. Linear regression analysis demonstrated excellent correlation between concentrations of CCK and gallbladder size during both contraction and relaxation phases. Future study of this correlation may be useful in patients with manifest dysfunction of the gallbladder, as well as in individuals known to be at risk of gallbladder disease.     

Plasma cholecystokinin response to a liquid fat meal in vagotomized patients.

Since previous studies have suggested that in patients with truncal vagotomy (TV) the plasma cholecystokinin (CCK) secretion in response to nutrients is impaired, we have measured the plasma CCK response to a liquid fat meal (250 ml 20% Intralipid) in six patients with TV and pyloroplasty. We have compared the results with those obtained in eight normal subjects, six patients with duodenal ulcer, and eight patients with highly selective vagotomy (HSV). Plasma CCK concentrations were measured by a sensitive and specific radioimmunoassay employing antibody T204 directed against the sulphated tyrosine region of CCK. Basal plasma CCK concentrations were not significantly different among the four groups studied (2.1 +/- 0.4 pmol/l in normal subjects, 2.8 +/- 0.5 pmol/l in duodenal ulcer patients, 3.1 +/- 0.5 pmol/l in patients with TV, and 2.7 +/- 0.5 pmol/l in patients with HSV). The increments in plasma CCK after ingestion of the fat meal in patients with TV (15.7 +/- 3.1 pmol/l) and HSV (14.9 +/- 1.6 pmol/l) were significantly higher (p less than 0.01) than those in normal subjects (4.8 +/- 0.9 pmol/l) and in patients with duodenal ulcer (5.5 +/- 0.6 pmol/l). Similarly, the integrated plasma CCK secretions in patients with TV (554 +/- 139 pmol/l, 120 min) and in patients with HSV (876 +/- 132 pmol/l, 120 min) were significantly increased (p less than 0.05) compared to those in normal subjects (187 +/- 29 pmol/l, 120 min) and in patients with duodenal ulcer (264 +/- 35 pmol/l, 120 min). It is concluded that patients with TV and HSV show an increased plasma CCK secretion in response to a liquid test meal.     

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 re-evaluating Billroth I type of anastomosis as a physiologic reconstruction procedure for the remnant alimentary tract after pancreatoduodenectomy.     

Effect of fat on meal-stimulated gastric and pancreatic secretion

In 5 dogs with chronic gastric and pancreatic fistulas, gastric secretion was continuously stimulated with a 10% liver extract meal, kept at a constant pH 7 by intragastric titration. After the first hour of stimulation, intraduodenal sodium oleate was infused in graded doses. Gastric acid and pancreatic secretion (volume, bicarbonate and protein) were measured. Plasma gastrin, secretin, VIP, and GIP were determined by radioimmunoassay. The liver extract meal evoked a gastric acid output of 12±1.4 mEq/30 min and a rise in plasma gastrin from 90 ± 20 to 250±50 pg/ml. Sodium oleate produced inhibition of acid secretion by 40% and 70% at doses of 8 and 16 mmol/hr, respectively. Sodium oleate produced a dose-dependent increase in volume of pancreatic juice, bicarbonate and protein output. Meal-stimulated plasma gastrin levels were not affected by sodium oleate. Plasma secretin and VIP levels remained unchanged during the infusion of sodium oleate. GIP was released by liver extract meal and, in addition, in a dose-related fashion by graded doses of sodium oleate. It is concluded that VIP and secretin are not released by fat and they are not involved in the inhibition of gastric secretion. GIP may be one of the mediators in the inhibition of gastric acid secretion by fat. The inhibition of acid secretion by fat is not mediated by suppression of gastrin release.     

Gallbladder filling and response to cholecystokinin are not affected by vagotomy

We studied the effects of vagotomy on gallbladder (GB) motility in prairie dogs and humans with infusion cholescintigraphy. Twelve male prairie dogs were anesthetized and given an intravenous infusion of 120 microCi of diethyl-HIDA for 150 minutes. Images were acquired every 10 minutes. Then cholecystokinin (CCK)-8, 1.5 micrograms/kg, was given as a bolus, and images were acquired for another 30 minutes. We repeated the studies giving 300 micrograms/kg of atropine 20 minutes before administration of CCK-8. All animals underwent truncal vagotomy, and the studies were repeated 1 and 3 months later. The GB filled in a stepwise fashion; partitioning of bile varied from one 10-minute period to the next and averaged 20% +/- 2%/80% +/- 3% during the 150-minute period. Episodic partial GB emptying (ejection fraction 19% +/- 2%; intervals of 70 +/- 5 minutes) occurred during this phase. GB filling and partitioning of bile were unchanged after vagotomy. GB ejection fraction in response to CCK-8 was 69% +/- 6% in controls, 74% +/- 5% after atropine, 78% +/- 8% 4 weeks after vagotomy, and 66% +/- 6% 3 months after vagotomy. Sixteen human subjects were studied after parietal cell vagotomy (six patients) or truncal vagotomy and drainage (10 patients). GB filling average 2.5% +/- 2% per minute in patients who underwent truncal vagotomy and 3% +/- 1% per minute in patients who underwent parietal cell vagotomy. GB emptying in response to CCK-33 (0.02 U/kg/min) was 74% +/- 7% in patients who underwent truncal vagotomy and 82% +/- 4% in patients who underwent parietal cell vagotomy. Thus neither GB filling nor GB emptying in response to CCK was altered by cholinergic blockade or vagotomy.     

Correlation of cholecystokinin receptors with gallbladder contractility in patients with gallstones.

The authors have previously identified two groups of patients with gallstones: those whose gallbladders contract the same as those of normal volunteers and show an increased sensitivity to endogenous cholecystokinin (CCK) ("contractors") and those whose gallbladders are relatively unresponsive ("noncontractors"). To define the mechanism responsible for these differences in contractility, the authors have measured CCK receptors on gallbladder muscle of patients with gallstones. Twenty-three patients with gallstones and 10 healthy volunteers (controls) fasted overnight. Simultaneous plasma samples for radioimmunoassay of CCK release and ultrasonographic measurements of gallbladder volume were obtained before and at intervals for 60 minutes after ingestion of Lipomul. Patients with gallstones had cholecystectomy, and CCK receptors were determined on cell membranes from gallbladder specimens by use of radiolabeled analogs of CCK-8-SO4. Histologic sections were graded for the degree of inflammation and scarring. Thirteen patients with gallstones were identified as contractors and 10 as noncontractors. Basal gallbladder volumes were not significantly different between patients in either group. The total integrated output of CCK for contractors was 1.6 +/- 0.2 ng X min/ml compared with 5.5 +/- 1.2 ng X min/ml for controls, while the integrated output for noncontractors was 11.1 +/- 2.1 ng X min/ml. Contractors had a higher number of CCK-binding sites (27.6 +/- 6.8 fmol/mg protein) than did noncontractors (4.8 +/- 1.0 fmol/mg protein). CCK receptors in gallbladders of all patients with gallstones correlated closely with gallbladder motility (y = 1.149, x = 0.624, r = 0.7, p less than 0.001). Although contractors had more mild inflammation and scarring, 40% of noncontractors had mild inflammation and scarring; there was no correlation. A decrease in CCK receptors may be an early event in the pathogenesis of gallstone formation by causing a decrease in gallbladder motility in some patients.     

Delayed plasma cholecystokinin and gallbladder responses to intestinal fat in patients with Billroth I and II gastrectomy

This study was undertaken to examine the intestinal phase of cholecystokinin (CCK) secretion and gallbladder contraction in patients who had undergone partial gastrectomy. Plasma CCK concentrations, measured by radioimmunoassay, and gallbladder contraction, measured by cholescintigraphy, were studied after intestinal administration of fat. Fasting plasma CCK concentrations were in the same range in nine patients who had undergone Billroth I gastrectomy (1.0 +/- 0.2 pmol/L), in nine patients who had undergone Billroth II gastrectomy (1.4 +/- 0.2 pmol/L), and in nine normal subjects (1.5 +/- 0.4 pmol/L). The peak increments in plasma CCK after intestinal fat were significantly (p less than 0.05) lower in patients with partial gastrectomy (5.4 +/- 0.6 pmol/L) compared with normal subjects (7.9 +/- 0.8 pmol/L). The integrated plasma CCK secretion was significantly (p less than 0.01 to p less than 0.05) reduced during the first 30 minutes in patients after Billroth I (74 +/- 11 pmol/1.30 min) and Billroth II gastrectomy (51 +/- 11 pmol/1.30 min) compared with normal subjects (122 +/- 18 pmol/1.30 min). Similarly, the start of gallbladder emptying was significantly (p less than 0.05) delayed in patients after partial gastrectomy. After 1 hour, however, the integrated plasma CCK response and gallbladder emptying were in the same range in Billroth I patients (186 +/- 34 pmol/1.60 min, 60% +/- 7%), Billroth II patients (175 +/- 17 pmol/1.60 min, 63% +/- 7%) and normal subjects (190 +/- 18 pmol/1.60 min, 55% +/- 6%). It is concluded that in patients who have undergone partial gastrectomy plasma CCK and gallbladder responses to intestinal fat are significantly delayed but reach normal levels beyond 30 minutes.     

Bile inhibits release of cholecystokinin and neurotensin

We have investigated the effect of bile on fat-stimulated release and basal plasma levels of cholecystokinin-33/39 (CCK) and neurotensin in six awake dogs prepared with chronic gastric and duodenal cannulas. Experimental bile diversion was achieved by catheterization of the common bile duct through the duodenal cannula; the gallbladder was undisturbed. Bile diversion significantly enhanced the release of both CCK and neurotensin that was stimulated by intraduodenal (ID) infusion of a triglyceride suspension (corn oil) (0.5 gm/kg-hr). The integrated release with ID triglyceride (ng [0 to 90 min]/ml) for CCK was control 5.58 +/- 0.83, bile diversion 14.47 +/- 2.81, bile excess 1.68 +/- 0.56, and for neurotensin was control 0.35 +/- 0.19, bile diversion 1.26 +/- 0.35, and bile excess 0.45 +/- 0.31. ID infusion of excessive bile (bile collected during bile diversion) significantly inhibited both the release and basal levels of CCK. Bile diversion alone did not modify plasma levels of CCK or neurotensin. We conclude that: endogenous bile exerts a negative feedback effect on release of CCK and neurotensin induced by triglyceride and on basal plasma levels of CCK; bile is unnecessary for the stimulation of endocrine cells in the intestinal mucosa by dietary fat; and measured basal levels of CCK and neurotensin represent a real amount of circulating peptide in the fasting state, that is, the basal levels are real and not artifactual.     

Evidence for a pyloro-cholecystic reflex for gallbladder contraction.

We studied the effect of graded antral distension on gallbladder contraction both when gastrin release was promoted (alkaline distension) and when gastrin release was blocked (acid distension) in five dogs provided with innervated antral pouch, chronic bile fistula and gastric fistula. Graded distension of the antrum caused graded gallbladder contraction as evidenced by bilirubin output even when gastrin release was completely suppressed. This nongastrin mechanism of gallbladder contraction is abolished by parenteral atropine and by transthoracic truncal vagotomy. These observations provide evidence for a cholinergic, pyloro-cholecystic reflex for gallbladder contraction that is dependent on intact long vagal pathways. Similar reflex mechanisms have been shown to be initiated by antral distension and to cause pancreatic enzyme secretion (pyloro-pancreatic reflex) or acid secretion from the oxyntic gland area of the stomach (pyloro-oxyntic reflex). It would appear, therefore, that the antrum plays a central role in the integration of upper gastrointestinal function not only through the hormone gastrin but also through neural reflex mechanisms.     

Correlation between gallbladder size and release of cholecystokinin after oral magnesium sulfate in man

In order to determine the effect of oral magnesium sulfate on gallbladder contraction and release of cholecystokinin (CCK) in man, magnesium sulfate (25 g in 100 ml distilled water) was given by mouth to five fasting adult male volunteers. Plasma samples were collected for measurement of CCK by a specific radioimmunoassay. Gallbladder volumes were determined from sonograms obtained from a phased-array real-time ultrasound scanner. Basal concentrations of CCK (82.2 ± 10.1 pg/ml) increased significantly at 20 minutes after oral magnesium sulfate (113.8 ± 7.1 pg/ml), and reached a maximal value at 50 minutes (150.0 ± 42.0 pg/ml). The mean basal volume of the gallbladder was 30.8 ± 5.3 cm³ and maximum reduction of gallbladder volume (to one third of original) was achieved at 50 minutes after ingestion of magnesium sulfate. Linear regression analysis showed a close correlation (r = -0.9337) between plasma concentrations of CCK and gallbladder size in response to magnesium sulfate. Oral magnesium sulfate also caused a significant increase in serum gastrin (from basal of 51.4 ± 9.9 pg/ml to 69.8 ± 15.5 pg/ml at 5 min); there was no significant correlation between gastrin release and gallbladder contraction. This study provides direct evidence that the mechanism of magnesium sulfate-stimulated gallbladder contraction occurs through the release of CCK, and shows a close correlation between CCK release and contraction of the gallbladder.     

Comparison of cholecystokinin release and gallbladder emptying in men and in women at estrogen and progesterone phases of the menstrual cycle

Why are gallstones more common in women than in men? To investigate this, we measured gallbladder emptying (by ultrasonography) and release of endogenous cholecystokinin (CCK) (by specific radioimmunoassay) in eight men and nine women in response to ingestion of corn oil (1 gm/kg). Each woman was studied on the fourteenth and twenty-first day of her menstrual cycle, estimated to be the estrogen (women [E] ) and progesterone (women [P] ) peaks, respectively. Fasting plasma concentrations of CCK were significantly higher in women (E) (135 +/- 7 pg/ml) than in men (99 +/- 13 pg/ml) but not significantly higher than in women (P) (113 +/- 11 pg/ml). The peak increase in CCK concentration over basal concentration and the integrated release of CCK were not significantly different from one group to another. Men had a larger fasting gallbladder volume (GBV) (21.4 +/- 3.2 ml) than did women (E) (12.4 +/- 2.1 ml) and women (P) (14.2 +/- 2.1 ml) and emptied more GBV in response to fat than did the women. The residual GBV and fractional emptying after ingestion of corn oil were not different among the three groups. Measurements of plasma CCK and GBV during the contraction phase were highly correlated in all groups. It appears, from these data, that the increased prevalence of gallstones in women relative to men cannot be explained on the basis of significant differences either in release of CCK or in gallbladder motility. Linear regression lines that were developed indicated that the mean change in GBV relative to a given change in plasma CCK was significantly higher in men than in women. Differences between men and women in this hormonal-motility relationship may contribute to the incidence of gallstones in premenopausal women.     

Mechanisms of increased lower esophageal sphincter pressure following intraduodenal peptone infusion in dogs

Peptone perfusion of the excluded duodenum in dogs is associated with an increase in lower esophageal sphincter pressure (LESP). This study investigates the role of cholinergic, adrenergic, and hormonal mediators in the response of the LES to intraduodenal peptone infusion. Adult dogs underwent duodenal exclusion via a Roux-en-Y pylorojejunostomy with formation of a mucocutaneous fistula. Manometric measurements of LESP and radioimmunoassay determinations of gastrin and pancreatic polypeptide (PP) blood levels were made at rest and at 15-min intervals following peptone infusion of the excluded duodenum. In control experiments, peptone infusion resulted in an increase in mean LESP at all time intervals (P less than 0.05). PP blood levels increased significantly, while gastrin levels remained unchanged. Both truncal vagotomy and pretreatment with atropine blocked the changes in LESP. PP release in response to peptone was accentuated in vagotomized dogs, while atropine suppressed the release of PP following peptone infusion. Treatment with 6-hydroxydopamine did not affect the increase in either LESP or PP blood levels observed in controls. Intravenous somatostatin suppressed the release of PP following intraduodenal peptone, but did not block the lower esophageal sphincter response. This data indicates that the increase in LESP seen following intraduodenal peptone infusion is centrally mediated and dependent on vagal innervation and cholinergic neurotransmission.     

Effect of total biliary diversion (cholecysto-jejuno-cystostomy) on gut hormone release and pancreatic structure in dogs

In order to elucidate the effect to total biliary diversion (TBD) on gut hormone release and pancreatic structure, we performed cholecysto-jejuno-cystostomy (CJC) in 6 mongrel dogs using a small interposed intestinal segment between the gallbladder and the urinary bladder with ligation of the common bile duct. Twelve weeks after CJC, CJC was converted into cholecysto-jejuno-duodenostomy (CJD) to normalize luminal bile flow. Fat rich meal loading tests were carried out before and after these procedures. Plasma concentrations of GI hormones (CCK, PP, GIP) were measured by radioimmunoassay and morphological changes of the pancreas were evaluated by light and electron microscopic study. CJC significantly enhanced the basal levels and fat-stimulated release of both CCK and PP, however after CJD, these changes returned to the normal levels. Following CJC, fat-stimulated GIP release was completely inhibited, but recovered after CJD. Following CJC, hypertrophy of pancreatic acinar cells with profuse and dilated rough endoplasmic reticulum was observed, while after CJD this change returned to the pre-operative state. These results suggest that a feedback regulation may exist between luminal bile flow and CCK secretion, and pancreatic hypertrophy after TBD is, at least partly, due to the increased plasma CCK levels.     

Effect of bombesin on plasma cholecystokinin in normal persons and gastrectomized patients measured by sequence-specific radioimmunoassays

Since bombesin is known to stimulate pancreatic enzyme secretion and gallbladder contraction, we have measured plasma cholecystokinin (CCK) concentrations during bombesin infusion using sequence-specific radioimmunoassays. Antibody 1703 binds to COOH terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulfated tyrosine region of CCK. In nine normal persons infusion of increasing doses of bombesin (2.4, 6, 18, and 60 pmol/kg X 20 min) induced dose-related integrated plasma CCK responses (58.5 +/- 9.7, 70.5 +/- 12.2, 79.5 +/- 11.1, and 101.4 +/- 15.4 pmol/L X 20 min [antibody 1703] and 50.4 +/- 11.9, 62.0 +/- 13.4, 74.7 +/- 9.2, and 116.1 +/- 11.3 pmol/L X 20 min [antibody T204]). Infusion of 60 pmol bombesin/kg X 20 min in eight patients with partial gastrectomy resulted in similar increases in plasma CCK (8.1 +/- 1.8 pmol/L, antibody 1703; 9.5 +/- 2.0 pmol/L, antibody T204) as in eight normal control subjects (6.5 +/- 0.9 pmol/L, antibody 1703; 8.8 +/- 1.0 pmol/L, antibody T204). During infusion of bombesin, plasma gastrin levels increased from 16.7 +/- 1.4 to 49.6 +/- 8.1 pmol/L (P less than 0.005) in the normal persons, while there was no significant change in plasma gastrin levels in gastrectomized patients. Bombesin did not significantly influence gastric acid secretion in three patients with partial gastrectomy studied. It is concluded that infusion of bombesin releases CCK in humans by a gastrin-independent mechanism.