CCK Infusion Research Articles

Bovine pancreatic secretion in the first week of life: potential involvement of intestinal CCK receptors

The aim of this study was to evaluate pancreatic juice secretion of calves in the first postnatal days, and determine a potential involvement of cholecystokinin (CCK) and intestinal CCK receptor in its regulation. Nine neonatal Friesian calves (five controls and four treated intraduodenally with FK480, a CCK-A receptor antagonist) were surgically fitted with a pancreatic duct catheter and a duodenal cannula before the first colostrum feeding. Collections of pancreatic juice and duodenal luminal pressure recordings were started early after recovery from anaesthesia and continued for 6 days. From day 2 or 3 of life, periodic fluctuations in pancreatic secretions were observed in concert with duodenal myoelectric motor complex (MMC) and variations in plasma pancreatic polypeptide (PP) concentrations. Intraduodenal administration of FK480 reduced pancreatic juice secretion while intravenous infusion of CCK had no effect. Immunocytochemistry indicated an association of mucosal CCK-A and -B receptors with neural components of the small intestine. In conclusion, periodic activity of the exocrine pancreas exists in neonatal calves soon after birth and local neural intestinal CCK-A receptors could be partly responsible for the modulation of neonatal calf pancreatic secretion.

H. pylori and transient lower esophageal sphincter relaxations induced by gastric distension in healthy humans

The role of Helicobacter pylori infection in the control of lower esophageal sphincter (LES) motility, especially the occurrence of transient LES relaxations (TLESRs), was studied in eight H. pylori-positive and eight H. pylori-negative healthy subjects. During endoscopy, biopsy specimens were taken from the cardia, fundus, and antrum for determinations of H. pylori status, gastritis, and proinflammatory cytokine mucosal concentrations. LES motility was monitored during three different 30-min periods: baseline, gastric distension (barostat), and gastric distension with CCK infusion. Gastric distension significantly increased the TLESR rate, whereas CCK increased the rate of distension-induced TLESRs further and reduced resting LES pressure without significant differences between infected and noninfected subjects. H. pylori status did not influence resting LES pressure or gastric compliance. Cytokine mucosal concentrations were increased in infected patients, but no correlation was found with the TLESR rate, which was also independent of inflammation at the cardia, fundus, and antrum. These results suggest that H. pylori-associated inflammation does not affect the motor events involved in the pathogenesis of gastroesophageal reflux.

Circuitry underlying antiopioid actions of cholecystokinin within the rostral ventromedial medulla.

It is now well established that the analgesic actions of opioids can be modified by "anti-analgesic" or "antiopioid" peptides, among them cholecystokinin (CCK). Although the focus of much recent work concerned with CCK-opioid interactions has been at the level of the spinal cord, CCK also acts within the brain to modify opioid analgesia. The aim of the present study was to characterize the actions of CCK in a brain region in which the circuitry mediating the analgesic actions of opioids is relatively well understood, the rostral ventromedial medulla (RVM). Single-cell recording was combined with local infusion of CCK in the RVM and systemic administration of morphine in lightly anesthetized rats. The tail-flick reflex was used as a behavioral index of nociceptive responsiveness. Two classes of RVM neurons with distinct responses to opioids have been identified. OFF cells are activated, indirectly, by morphine and mu-opioid agonists, and there is strong evidence that this activation is crucial to opioid antinociception. ON cells, thought to facilitate nociception, are directly inhibited by opioids. Cells of a third class, NEUTRAL cells, do not respond to opioids, and whether they have any role in nociceptive modulation is unknown. CCK microinjected into the RVM by itself had no effect on tail flick latency or the firing of any cell class but significantly attenuated opioid activation of OFF cells and inhibition of the tail flick. Opioid suppression of ON-cell firing was not significantly altered by CCK. Thus CCK acting within the RVM attenuates the analgesic effect of systemically administered morphine by preventing activation of the putative pain inhibiting output neurons of the RVM, the OFF cells. CCK thus differs from another antiopioid peptide, orphanin FQ/nociceptin, which interferes with opioid analgesia by potently suppressing all OFF-cell firing.

Laparoscopic Cholecystectomy for Acalculous Gallbladder Disease

Use of laparoscopic cholecystectomy (LC) to treat patients with symptoms due to gallstone disease is well established. However, use of LC for patients with acalculous gallbladder disease remains controversial. In this study, we examined the use of hepatobiliary iminodiacetic acid (HIDA) scans with cholecystokinin (CCK) infusion to identify patients with acalculous gallbladder disease who would benefit from LC. From December 1991 to February 1997, 4480 patients underwent cholecystectomy at Baylor University Medical Center, including 72 patients who underwent LC for acalculous disease following preoperative HIDA scan. We retrospectively analyzed their preoperative symptoms and workup. Follow-up was obtained by telephone questionnaire in 59 of 72 patients (82%). Overall, 48 of 59 patients (82%) reported an excellent outcome following LC. We found no significant difference in outcome in patients who underwent HIDA scan with CCK infusion, regardless of gallbladder ejection fraction or exacerbation of symptoms caused by the infusion. Preoperative symptom complex was also not predictive of postoperative outcome. LC is an effective treatment for patients with acalculous gallbladder disease. A preoperative HIDA scan with CCK infusion does not accurately predict treatment success or failure. Patients with a normal ejection fraction and absence of symptoms from a HIDA scan can still have excellent relief of symptoms after LC.

In vivo changes in the intestinal reflexes and the response to CCK in the inflamed small intestine of the rat.

Functional motor changes and morphological alterations have been associated with intestinal inflammation. The aim of our study was to evaluate functional alterations of intestinal reflexes and of the responses to CCK in the Trichinella spiralis model of intestinal inflammation. Rats were prepared with strain gauges and electrodes in the small intestine to evaluate spontaneous motor activity, the ascending contraction of the peristaltic reflex, and the motor responses to CCK-8 infusion. Infected animals showed increased motor activity at the duodenum and jejunum but not at the ileum. Ascending contraction was increased in both duodenum and ileum. Ascending excitation after N(omega)-nitro-L-arginine was still increased as well as the residual response after atropine. Response to CCK-8 during intestinal inflammation was changed in the jejunum, in which it turned from the inhibition shown in healthy animals to excitation. NADPH-diaphorase staining did not show any changes between distribution and density of positive neurons in either healthy or infected animals. In conclusion, intestinal inflammation induces functional changes in the motor activity that could explain the abnormal motor responses observed in inflammatory disorders.

Differential effects of neurotensin and cholecystokinin on intestinal microcirculation after ischemia-reperfusion.

We investigated the effect of neurotensin and cholecystokinin (CCK) on intestinal microcirculation after ischemia-reperfusion. Ischemia was induced in Wistar rats by occlusion of the superior mesenteric artery for 40 min. Ten minutes before reperfusion, infusion of either neurotensin or CCK was started. Afterwards, the microhemodynamics of the jejunum were examined by means of intravital microscopy. Ischemia-reperfusion decreased functional capillary density from 873.4+/-18.1 to 362.5+/-8.3 cm(-1) and red blood cell velocity from 0.49+/-0.03 to 0.34+/-0.02 mm/s. Furthermore, leukocyte-endothelium interaction was increased. Neurotensin infusion significantly increased functional capillary density to 483.2+/-9.0 cm(-1) and red blood cell velocity to 0.69+/-0.01 mm/s in the mucosal capillaries compared with ischemic controls. Despite the amelioration of villus perfusion, the number of non-perfused villi significantly increased (11.8+/-3.6%) compared with ischemic controls. CCK infusion also resulted in a significant increase of functional capillary density (535.2+/-7.4 cm(-1)) and red blood cell velocity (0.67+/-0.01 mm/s). In contrast to neurotensin, the number of non-perfused villi was not increased (5.8+/-2.2%). We conclude that neurotensin further aggravates perfusion inhomogeneity and stasis when administered during the ischemic period. In contrast, CCK has no negative influence on perfusion homogeneity after ischemia-reperfusion. It may be superior to neurotensin in the reconstitution of normal microvascular perfusion patterns after ischemia-reperfusion.

Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through CCK(A) receptors.

It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in Sprague-Dawley rats was recorded. Intravenous infusion of CCK-8 (0.1-1 nmol) suppressed the efferent activity. The effect of CCK-8 was significantly reduced in animals with total subdiaphragmatic vagotomy in comparison to those with partial vagotomy. Intravenous infusion of CCK(A) receptor antagonist L-364,718 (1-100x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8, but the CCK(B) receptor antagonist L-365,260 (1-100x10(-6) g) did not in the conditions of either partial or total vagotomy. Intracisternal infusion of L-364,718 (1x10(-6) g) blocked the response of vagal efferent activity to 0.1 nmol CCK-8 i.v. Infusion of exogenous CCK-8 did not affect the activity of supradiaphragmatic vagal afferents. The results suggest that the effect of systemically administered CCK-8 on vagal efferent activity is mediated by both peripherally (subdiaphragmatically) and centrally localized CCK(A) receptors.

4668 Is magnetic resonance cholangio-pancreatography with cholecystokinin useful in identifying patients with sphincter of oddi dysfunction?

Sphincter of Oddi manometry (SOM) is the standard method of diagnosing SOD. SOM is invasive, can be technically difficult and associated with complications. MRCP with CCK stimulation may provide useful information relating to sphincter of Oddi function. AIM: Evaluate the sensitivity/specificity of CCK-MRCP in predicting the results of SOM in patients with clinically suspected SOD (type III). METHOD: Data from consecutive patients referred for SOM who had CCK-MRCP prior to SOM were analyzed. All MRCP studies were reported by one radiologist who was blinded to the findings of SOM. Patients with prior therapy to the papilla or known pancreaticobiliary malignancy or stricture were excluded. Equivocal/failed MRCP or SOM were excluded from analysis. SOM was performed using a standard 5 F perfused, aspirating catheter (Wilson-Cook, Winston-Salem, NC); SOD was diagnosed if the mean pressure from two leads was greater or equal to 40 mmHg. MRCP was performed with oblique coronal singleshot breath-hold, 5cm slabs (8000/150//135), FOV-24 cm. Scans were performed before and 20 mins after initiation of the CCK infusion (0.02mcg/Kg, in 6ml saline, 0.1ml/sec). CCK-MRCP was abnormal if the common bile duct increased in diameter post-CCK. RESULTS: Of 25 patients (mean age 38yrs., range7-74yrs, M/F=5/20), 18 biliary and 18 pancreatic SOM studies were analyzed; CCK-MRCP was inadequate in 2 patients. Of all 12 patients, CCK MRCP was abnormal in 4 of 6 patients with abnormal biliary SOM (sensitivity 67%) and was normal in 7 of 12 patients with normal biliary SOM (specificity 58%). Of the 5 patients with an intact gallbladder, CCK-MRCP was normal in all 3 patients with normal biliary SOM and abnormal in both patients with abnormal biliary SOM. The sensitivity and specificity of CCK-MRCP in predicting abnormal biliary SOM in post- cholecystectomy patients was 50% and 44 % respectively. There was no association between pancreatic SOM and CCK-MRCP. CONCLUSION: 1] The overall sensitivity and specificity of CCK-MRCP in predicting abnormal biliary SOM was 67% and 58% respectively. 2] The sensitivity and specificity were 100% in the small sub-group of 5 patients with the gallbladder in situ. This study is on-going to further evaluate these novel findings.

Response of Rat Exocrine Pancreas to High-Fat and High-Carbohydrate Diets

Intake of diets with high fat content is a risk factor for acute pancreatitis and pancreatic cancer. The underlying mechanisms leading to the development of these diseases due to high fat intake are currently unknown. The current study was designed in rats to determine the physiologic and pathological consequences of a highfat diet that contained excess amounts of cottonseed oil or a high-carbohydrate diet that contained high amounts of sucrose on the exocrine pancreas. Rats were maintained on the diets for 4 weeks, and a cannula was inserted into the right jugular vein and one into the pancreatic duct for collection of pancreatic juice. Volume of the pancreatic juice and concentrations of amylase, lipase, and trypsinogen in the pancreatic juice were measured before and after infusions of CCK-8. Results showed that basal and CCK-stimulated pancreatic outputs of volume, amylase and lipase but not trypsinogen, were significantly elevated in intact rats given a high-fat diet when compared with rats given a high-carbohydrate diet. Forty-eight hours later, rats were sacrificed, and parts of the pancreas were removed for isolation of pancreatic acinar cells and for histopathologic studies. Pancreatic acini isolated from rats on a high-fat diet showed significantly lower basal and CCK-stimulated amylase release when compared with those on a high-carbohydrate diet. Histology of the pancreas of rats on a high-carbohydrate diet appeared normal; however, the pancreas of rats on high-fat diet showed significant alterations in exocrine pancreas. These results showed abnormalities in the exocrine pancreas of rats on a high-fat diet, that were not found in rats on a high-carbohydrate diet; further, they support the contention that a high-fat diet has a deleterious effect on the pancreas.

Selective exocytosis of zymogen granules induces non-parallel secretion in short-term cholecystokinin-stimulated rats.

Parallel studies on pancreatic enzyme secretion and zymogen granule enzyme composition have been carried out in rats subjected to infusion of cholecystokinin (CCK) (1.25 microgram/kg per h) over 30 min. Flow cytometric analysis showed a significant decrease in the mean value of granule size after CCK stimulation. The amount of trypsinogen stored in each individual zymogen granule was significantly lower at 30 min of CCK infusion, but no variation in intragranular amylase content was observed. As a result, the amylase/trypsinogen ratio was significantly increased in the zymogen granules that remained in the pancreas of rats stimulated with CCK for 30 min. A significantly greater proportion of trypsin than amylase was secreted after 30 min CCK infusion. Our results support the existence of different types of granules loaded with different proportions of enzymes. We conclude that short-term CCK stimulation induces the selective release of large granules containing a high proportion of trypsinogen, which leads to a non-parallelism of enzyme secretion.

Role of CCK-A receptor in the regulation of pancreatic bicarbonate secretion in conscious rats: a study in naturally occurring CCK-A receptor gene knockout rats.

Whether cholecystokinin (CCK) has a direct action on duct cells and the role of CCK-A receptor in bicarbonate secretion were examined by comparing the results obtained from OLETF (CCK-A receptor-deficient rats) and control (LETO) rats. Rats were prepared with cannulae for draining bile and pancreatic juice separately, with two duodenal cannulae and an external jugular vein cannula. The experiments were conducted without anesthesia. The responses of bicarbonate secretion to intravenous infusion of CCK, acetyl-beta-methylcholine (Ach), and 2-deoxy-D-glucose (2DG), and to intraduodenal infusion of HCl and a liquid meal were examined. To examine the synergistic effect between CCK and secretin, the effect of CCK during a background secretin infusion was examined in LETO rats. CCK did not stimulate bicarbonate secretion in either strain, nor in LETO rats with secretin infusion. When gastric acid secretion was prevented by administration of omeprazole, Ach did not increase bicarbonate secretion, but 2DG did in both strains. Intraduodenal infusion of HCI and a liquid meal significantly increased bicarbonate secretion in both strains; however, the responses were much less in OLETF than LETO rats. In conclusion, intravenous injection of CCK did not stimulate bicarbonate secretion, and the lack of CCK-A receptor decreased bicarbonate secretion in response to luminal stimulants.

Effect of Insulin and Glucose on Basal and Cholecystokinin-Stimulated Exocrine Pancreatic Secretion in Humans

Pancreaticobiliary secretion is reduced during acute hyperglycemia. In nondiabetics, this inhibitory effect also may result from hyperinsulinemia. Therefore we investigated the effects of acute hyperglycemia and euglycemic hyperinsulinemia on basal and cholecystokinin (CCK)-stimulated pancreaticobiliary secretion. Nine healthy volunteers (age, 22-52 years) were studied on three occasions in random order during (a) intravenous saline (control), (b) hyperglycemic hyperinsulinemic clamping (HG; plasma glucose at 15 mM), and (c) euglycemic hyperinsulinemic clamping (HI; plasma insulin at 150 mU/L, glucose at 4-5 mM). Duodenal outputs of bilirubin, amylase, trypsin, and bicarbonate were measured under basal conditions and during CCK infusion (0.25 and 0.5 IDU/kg/h). Basal pancreaticobiliary secretion was significantly (p < 0.05) reduced during both HG and HI. During low-dose CCK stimulation, HG significantly (p < 0.05) reduced bilirubin and trypsin output compared with control. In contrast, HI did not significantly reduce pancreatic enzyme and bilirubin output during low-dose CCK infusion. During high-dose CCK infusion, neither HI nor HG influenced pancreatic enzyme and bilirubin output. Pancreatic bicarbonate output was not influenced by CCK and remained significantly (p < 0.05) reduced during HI and HG compared with control. It is concluded that during both acute hyperglycemia and euglycemic hyperinsulinemia, basal pancreaticobiliary secretion is significantly reduced. CCK-stimulated pancreatic enzyme and bilirubin output is significantly reduced only during hyperglycemia. The inhibitory effect of hyperglycemia on pancreaticobiliary secretion in healthy volunteers may occur independent of insulin.

Regional effects of cholecystokinin octapeptide on colonic phasic and tonic motility in healthy humans.

The aim of this study was to assess in nine healthy subjects the effects of CCK octapeptide (CCK-8) on colonic tonic activity, measured by a barostat, and phasic activity, measured by manometry. On 2 consecutive days, recordings were performed in the unprepared proximal and distal colons during intravenous infusion of saline and CCK-8 at 5, 20, and 40 ng. kg-1. h-1. In the proximal colon CCK-8 induced, at the 20 and 40 ng. kg-1. h-1 doses, a tonic relaxation with an increase in barostat bag volume to 156 +/- 25 and 157 +/- 19% of basal (P < 0.01) and a decrease in phasic activity to 72 +/- 7 and 76 +/- 7% of basal (P < 0.01). In the distal colon, CCK-8 induced, at the 20 and 40 ng. kg-1. h-1 doses, a tonic relaxation (increase in intrabag volume to 133 +/- 12 and 149 +/- 15%, respectively; P < 0.01), whereas phasic activity increased (128 +/- 8 and 132 +/- 6%, respectively; P < 0.01). Effects of CCK-8 on tonic and phasic activities are different according to the colonic segment. Because meals induce colonic tonic contraction, our results suggest that CCK, as a hormone, is not an important mediator of the response of the colon to feeding in humans.

Sphincter of Oddi manometry before and after laparoscopic cholecystectomy.

In animal studies cholecystectomy has been found to alter the normal effect of cholecystokinin (CCK) on sphincter of Oddi (SO) function. This could be of importance with regard to the development of postcholecystectomy biliary pain. We therefore investigated the effect of laparoscopic cholecystectomy on SO motility before and after infusion with CCK. A prospective study of SO motility, under basal conditions and during CCK (ceruletide) infusion, was carried out in eight women with uncomplicated gallstone disease, before and after laparoscopic cholecystectomy. Laparoscopic cholecystectomy increased common bile duct pressure (P = 0.01) and decreased the frequency of phasic contractions (P=0.05). However, the inhibitory effect of CCK was preserved as infusion of CCK was associated with a significant reduction in SO phasic amplitude and frequency, both before and after cholecystectomy. Following laparoscopic cholecystectomy an indisputable inhibitory effect of CCK in the SO was found. Common bile duct pressure increased and minor modifications in basal SO motility were seen.

Cholecystokinin affects gastric emptying and stomach motility in the rainbow trout Oncorhynchus mykiss.

In this study, we describe new methods for recording gastric emptying and in vivo measurements of intragastric pressure in fish. Using these methods, we investigated the effects of the sulphated octapeptide of cholecystokinin (CCK8) on gastric emptying and on stomach motility in vivo and in vitro. Gastric emptying of 99Tcm-labelled food was measured in swimming fish by using a gamma camera, counting consecutive 2.5 min periods for 18-42 h. After 20 h, 55.3+/-4.0 % of the labelled food remained in the stomach of the control fish (mean s.e.m., N=9). Vascular infusion of CCK8 (25 pmol kg-1 h-1) delayed gastric emptying so that 70.4+/-4.8 % of the labelled food remained in the stomach after 20 h (N=8). Gastric pressure changes in vivo were measured using a balloon surgically fitted into the cardiac or pyloric part of the stomach. In the cardiac part, intra-arterial infusion of CCK8 at 0.1 nmol kg-1 h-1 resulted in a decrease in the frequency and amplitude of rhythmic contractions, while higher doses started/increased contractions. Atropine blocked much of the basal contractile activity, but did not influence the CCK8-induced inhibition of contractile activity. The pyloric part of the stomach was unaffected by intra-arterial infusion of CCK8 or atropine. In vitro perfusion of the stomach (with a balloon placed in the cardiac part to record motility) with CCK8 at high concentrations (10(-7 )mol l-1 and above) augmented the spontaneous contractions, while lower concentrations had inconsistent effects. In addition, CCK8 (10(-7) to 10(-6 )mol l-1) decreased the amplitude of spontaneous contractions in longitudinal strip preparations, usually in combination with an increase in the resting tension. The decrease in amplitude was not affected by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester hydrochloride (L-NAME; 10(-4 )mol l-1). Depending on the concentration and experimental arrangement, CCK8 had either inhibitory or excitatory effects on the cardiac stomach, suggesting the possible presence of different types of CCK receptor. We conclude that the predominant effect of CCK8 in vivo may be a slowing down of gastric emptying, presumably coinciding with a release of bile into the duodenum.

Effect of acute hyperglycemia on basal, secretin and secretin + cholecystokinin stimulated exocrine pancreatic secretion in humans

Pancreatico-biliary secretion is reduced during acute hyperglycemia. We investigated whether alterations in pancreatico-biliary flow or volume output are responsible for the observed reduction in duodenal output of pancreatic enzymes and bilirubin during hyperglycemia. Eight healthy subjects were studied on two occasions during normoglycemia and hyperglycemia (15 mmol/l). Pancreatico-biliary output was measured by aspiration using a recovery marker under basal conditions (60 min), during secretin infusion (0.1 CU/kg.h) for 60 min and during secretin + CCK (0.5 IDU/kg.h) infusion for 60 min. Secretin was infused to stimulate pancreatico-biliary flow and volume output. Secretin significantly (P < 0.005–P < 0.05) increased volume and bicarbonate output and CCK significantly (P < 0.01) increased the output of bilirubin, pancreatic enzymes, bicarbonate and volume, both during normoglycemia and hyperglycemia. During hyperglycemia basal, secretin stimulated and secretin + CCK stimulated total pancreatico-biliary output were significantly (P < 0.005–P < 0.05) reduced compared to normoglycemia. The incremental outputs, however, were not significantly different between hyper- and normoglycemia. Pancreatic volume output was significantly (P < 0.05) reduced during hyperglycemia compared to normoglycemia under basal conditions (31 ± 16 ml/h versus 132 ± 33 ml/h) during secretin infusion (130 ± 17 ml/h versus 200 ± 34 ml/h) and during secretin + CCK infusion (370 ± 39 ml/h versus 573 ± 82 ml/h). Plasma PP levels were significantly (P < 0.05) reduced during hyperglycemia. It is concluded that 1) hyperglycemia significantly reduces basal pancreatico-biliary output 2) the incremental pancreaticobiliary output in response to secretin or secretin + CCK infusion is not significantly affected during hyperglycemia, 3) a reduction in volume output contributes to the inhibitory effect of hyperglycemia on pancreatico-biliary secretion, 4) hyperglycemia reduces PP secretion suggesting vagal-cholinergic inhibition of pancreatico-biliary secretion and volume during hyperglycemia.

Physiological role of cholecystokinin in gastroprotection in humans

Objective: Cholecystokinin (CCK) is able to protect gastric mucosa against acute injury in experimental animals but little is known about the role of this hormone in maintaining mucosal integrity in humans. This double-blind, placebo controlled study was performed in 16 healthy volunteers. It describes the effects of CCK-8 infused intravenously (i.v.) at physiological doses and endogenous CCK released by intraduodenal (i.d.) oleate on gastric mucosal damage, as brought about by ethanol without or with pretreatment with loxiglumide, a selective CCK-A receptor antagonist. Methods: CCK-8 was infused i.v. 30 min before and throughout the study or i.d. oleate was instilled through a separate duodenal tube. Thirty minutes after the start of i.v. infusion of CCK or i.d. oleate instillation, 100 ml of 50% ethanol spray was applied to the gastric mucosa using an endoscope. Gastroscopy was performed and mucosal lesions were quantified using modified Lanza score. Gastric biopsies were taken from oxyntic mucosa for histological evaluation and gastric content was aspirated for radioimmunoassay of somatostatin. Results: In placebo-treated subjects ethanol caused endoscopic damage, with an average score of 2.8 ± 0.2. Histologically, a widespread disruption of surface epithelium and deep hemorrhagic necrotic lesions were observed. Pretreatment with CCK or i.d. oleate markedly reduced the endoscopic lesion score to 0.7 ± 0.1 and 0.3 ± 0.1, respectively, and in both cases this reduction was accompanied by a significant rise in plasma CCK. Histologically, surface epithelium was still disrupted but deep necrotic lesions were absent. Gastric content collected before and after CCK or oleate showed a several-fold increase of luminally released somatostatin. Conclusions: Pretreatment with loxiglumide abolished the protective effects of i.v. CCK-8 and i.d. oleate on mucosal lesions induced by ethanol and prevented the rise in intragastric somatostatin, but failed to affect the increments in plasma CCK. Endogenous CCK plays a physiological role in the maintenance of mucosal integrity. This occurs through activation of CCK-A receptors and is associated with an increased gastric luminal release of somatostatin.

Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion

GREENOUGH, A., G. COLE, J. LEWIS, A. LOCKTON, J. E. BLUNDELL. Untangling the effects of hunger, anxiety, and nausea on energy intake during i.v. cholecystokinin octapeptide (CCK-8) infusion. PHYSIOL BEHAV 65(2) 303–310, 1998.— Infusions of cholecystokinin (CCK) may exert their effects on appetite by inducing feelings of nausea or anxiety. In this double blind, placebo controlled crossover study, the impact of these effects on appetite were examined. Fifteen male subjects received a 20 min i.v. infusion of cholecystokinin octapeptide (CCK-8) (4 ng/kg/min) or saline. The infusion commenced 20 min after a soup preload and 10 min before an ad libitum test meal. Visual analogue scales of appetite and mood were measured over 3 h, and subjects were instructed to report any other sensations they experienced over this time. CCK-8 significantly reduced premeal hunger, elevated premeal anxiety, and reduced energy intake at the ad libitum test meal. Meal duration and rate of eating (kcal/min) were also significantly reduced after CCK-8. After the smaller meal with CCK-8, hunger rose quickly to a higher level than with placebo. The return of hunger was commensurate with the smaller amount of energy consumed and indicated that CCK did not exert an enduring effect on hunger suppression. A significant correlation was found between the reduction in energy intake and hunger (r = 0.75 p < 0.01), but not with anxiety (r = 0.15 not significant). Analyses were performed separately on subjects who did ( n = 8), or did not ( n = 7) report gastrointestinal disturbance. Energy intake was reduced by 56.6% and 44.6%, respectively. These results indicate that, although feelings of anxiety and nausea may accompany CCK infusions, they are not necessary for the effects of CCK on appetite. These data provide support for a role of CCK in satiety.

Influence of Hyperglycemia on the Satiating Effect of CCK in Humans

In the present study the effects of intraduodenal (i.d.) fat (endogenous CCK) and of CCK infusion on satiety were studied during normo- and hyperglycemic conditions. Eight healthy subjects participated in two protocols consisting of two experiments each. First protocol: (a) normoglycemia (control) with i.d. emulsified fat (i.d. fat) infusion, (b) acute hyperglycemia (HG) with plasma glucose levels stabilized at 15 mmol/L and i.d. fat infusion. In the second protocol the effect of exogenous cholecystokinin (CCK) on satiety was studied during normo- and hyperglycemia. Intraduodenal fat (Intralipid 10%) was infused at a dose of 1 g/h via a nasoduodenal tube in the first protocol, whereas in the second protocol CCK-33 was infused intravenously at a dose of 0.5 IDU/kg·h. Satiety was scored using visual analog scales (VAS). Plasma CCK levels were determined at regular intervals. During infusion of i.d. fat and i.v. CCK the VAS scores of wish to eat, hunger, and prospective feeding decreased significantly ( p < 0.05) in the normoglycemic experiments. During hyperglycemia satiety did not significantly change in the basal period; however, the scores of wish to eat, hunger, and prospective feeding increased significantly ( p < 0.05) when i.d. fat or i.v. CCK was administered. Plasma CCK levels in the basal and the stimulated period were not significantly different between normo- and hyperglycemia. In summary, the present study shows that in healthy humans volunteers 1) during normoglycemic conditions satiety can be induced by very low dose of i.d. fat and by CCK infusion, 2) during hyperglycemia the effect of i.d. fat and CCK on satiety are reversed, resulting in increased appetite.

Fat-induced changes of the integrity of rat exocrine pancreas measured in vivo and in vitro

Adaptation of exocrine pancreas by dietary fats and its resulting effects on morphology and function of the exocrine pancreas remain controversial. In this study we have examined the influence of dietary fats on pancreatic pathophysiology by examining the basal and stimulated pancreatic secretion of enzymes in response to high fat (HFD) and no fat (NFD) diets. Methods: Male Sprague Dawley rats (N=10) were fed ad libitum with high fat diets containing 45% fat (vegetable oil) and 29% carbohydrates. An identical group was fed with diets containing 58% carbohydrates but no fat. The animals were maintained in screen bottomed cages at 22°C on a 12 hr light-dark cycle with free access to water. After four weeks, the animals were fasted for 24 hrs, anesthetized, bile pancreatic duct was cannulated to collect pancreatic juice. Bile pancreatic juice was collected for 30 min before and after infusion of CCK for 30 min via the jugular vein. The animals were maintained for additional 24 hrs with recirculation of pancreatic juice to the duodenum and then sacrificed to isolate pancreatic acini by collagenase digestion. Amylase content and release in response to CCK-8 by isolated acini were measured. Histopathologic studies of pancreas, fixed in 10% buffered formalin, were evaluated by light microscopy. Results: Outputs of enzymes (amylase, lipase and trypsinogen) in bile pancreatic juice of rats on high fat diets under basal and stimulated conditions were significantly higher than that of rats on no fat diet. Amylase release measured in isolated acini of rats on high fat diet in response to CCK-8 was significantly lower than that of rats on no-fat diet. Histopathology revealed significant difference in cellular changes (cytoplasmic vacuolation; swelling and pyknosis) in rats on high fat diet. Conclusions: Dietary fats, especially high fat, alters pancreatic morphology and function. The results indicate that high fat diets enhanced the outputs of enzymes in bile pancreatic juice, down regulated CCK stimulated amylase response in isolated pancreatic acini and induced cellular injury.