CCK Infusion Research Articles

Cholecystokinin-Cholescintigraphy in Adults

Cholecystokinin-cholescintigraphy (CCK-CS) provides a physiologic, noninvasive, and quantitative method for assessing gallbladder contraction and calculation of a gallbladder ejection fraction (GBEF). At present, it is used most commonly to identify patients with suspected functional gallbladder disorder. However, the methodology of CCK infusion and normal values differ markedly among imaging centers. This document represents the consensus opinion of an interdisciplinary panel that gathered to assess the current optimal method for performing CCK-CS in adults, potential uses and limitations of CCK-CS, and questions that require further investigation. The panel recommended the use of a single, standardized, recently described CCK-CS protocol that involves infusion of 0.02 μg/kg of sincalide over 60 minutes with a normal GBEF defined as ≥38%. The panel emphasized the need for a large, multicenter, prospective clinical trial to establish the utility of CCK-CS in the diagnosis of functional gallbladder disease. Although not without controversy regarding its clinical utility, the primary indication for CCK-CS at present is the well-selected patient with suspected functional gallbladder disorder. Agreement was reached that the adoption of this standardized protocol is critical to improve how CCK-CS is used to direct patient care and will represent an improvement over the diverse methods currently in use by eliminating the current lack of uniformity and adding both reliability and credibility to the results.

Block by Nitrate Tolerance of Meal-Induced Insulin Sensitization in Conscious Rabbits

Hemodynamic nitrate tolerance has been shown to result in an insulin-resistant state. We studied whether nitrate tolerance induced by a 7-day continuous exposure to transdermal nitroglycerin influenced the meal-induced insulin sensitization phenomenon in rabbits. Changes in insulin sensitivity in response to feeding in conscious rabbits were determined by rapid insulin sensitivity test, in both nitrate-tolerant and nitrate-intolerant animals. In a separate series of experiments with anesthetized rabbits with or without nitrate tolerance, the hyperinsulinemic euglycemic glucose clamping methods was used to study the effect of intraportal infusion of cholecystokinin (CCK) on whole-body insulin sensitivity. Rabbits with normal feeding exhibited a 46 ± 6% increase in insulin sensitivity as compared with their matching fasting controls. A 7-day period of treatment with patches releasing 0.07 mg of nitroglycerin per hour yielded nitrate tolerance and a state of insulin resistance and no increase in insulin sensitivity in response to food. Intraportal infusion of CCK8 (0.3-3.0 μg/kg over 20 minutes) resulted in a dose-dependent increase in insulin sensitivity in normal but not in nitrate-tolerant, fasted anesthetized animals. Nitrate tolerance blocks both the meal-induced insulin sensitization phenomenon and the insulin-sensitizing effect of intraportal CCK.

CCK-8 induces fever-like regulated hyperthermia and symptoms of sickness behavior in mice: A biotelemetric study

In earlier studies it has been found that rats respond to intracerebroventricular (i.c.v.) injection of cholecystokinin-octapeptide (CCK-8) with a febrile response characterized by rises of heat production and core temperature together with tail-skin vasoconstriction mediated by CCK2 receptors. Biotelemetric investigations of the same species have additionally shown that CCK-induced fever is accompanied by decreased locomotor activity. Similar data for mice have not been reported so far. In the present studies C57BL/6 mice were infused i.c.v. for 3 days with CCK-8 to see effects on body core temperature, locomotor activity, food intake and body weight. Biotelemetric monitoring disclosed a rise in daylight core temperature and a fall of night-time locomotor activity both lasting beyond the time of i.c.v. infusions. Food intake was suppressed only during infusion, while a significant decrease of body weight was sustained after the end of CCK-8 infusion. It is concluded that similar to rats mice also respond to i.c.v. infusion of CCK-8 with a fever-like (regulated) hyperthermia and some components of sickness behavior as measured by biotelemetry, and thus a CCK-mediated mechanism may contribute to fever genesis also in mice.

The trophic effect of cholecystokinin on the pancreas declines in rats on total parenteral nutrition

Total parenteral nutrition (TPN) results in atrophy of the pancreas, while cholecystokinin (CCK) can significantly stimulate the exocrine pancreas in rodents. This study was designed to examine whether CCK may improve the atrophy of the pancreas in rats on TPN treatment. Forty-eight Sprague-Dawley rats were divided into orally fed and TPN groups and were infused with CCK at a dose of 5 μg/kg/h or the CCK-receptor antagonist devazepide at a dose of 200 μg/kg/h for 10 days. Infusion of CCK caused hypercholecystokininemia (hyperCCKemia) and decreased the atrophy of the pancreas resulting from TPN. The hyperplastic response to CCK in orally fed rats was decreased in the rats given TPN. Devazepide did not influence the pancreatic variables. This study further confirmed that CCK stimulates the exocrine pancreas and decreases the atrophy of the exocrine pancreas resulting from TPN. Our present findings suggest that the trophic effect of CCK on the exocrine pancreas declines in TPN.

Effect of feeding fat or intrajugular infusion of glucagon-like peptide-1 and cholecystokinin on dry matter intake, digestibility, and digesta rate of passage in growing wethers1

A cause and effect relationship between glucagon-like peptide 1 (7, 36) amide (GLP-1) and cholecystokinin (CCK) and DMI regulation has not been established in ruminants. Three randomized complete block experiments were conducted to determine the effect of feeding fat or infusing GLP-1 or CCK intravenously on DMI, nutrient digestibility, and Cr rate of passage (using Cr(2)O(3) as a marker) in wethers. A total of 18 Targhee × Hampshire wethers (36.5 ± 2.5 kg of BW) were used, and each experiment consisted of four 21-d periods (14 d for adaptation and 7 d for infusion and sampling). Wethers allotted to the control treatments served as the controls for all 3 experiments; experiments were performed simultaneously. The basal diet was 60% concentrate and 40% forage. In Exp. 1, treatments were the control (0% added fat) and addition of 4 or 6% Ca salts of palm oil fatty acids (DM basis). Treatments in Exp. 2 and 3 were the control and 3 jugular vein infusion dosages of GLP-1 (0.052, 0.103, or 0.155 µg•kg of BW(-1)•d(-1)) or CCK (0.069, 0.138, or 0.207 µg•kg of BW(-1)•d(-1)), respectively. Increases in plasma GLP-1 and CCK concentrations during hormone infusions were comparable with increases observed when increasing amounts of fat were fed. Feeding fat and infusion of GLP-1 tended (linear, P = 0.12; quadratic, P = 0.13) to decrease DMI. Infusion of CCK did not affect (P > 0.21) DMI. Retention time of Cr in the total gastrointestinal tract decreased (linear, P < 0.01) when fat was fed, but was not affected by GLP-1 or CCK infusion. In conclusion, jugular vein infusion produced similar plasma CCK and GLP-1 concentrations as observed when fat was fed. The effects of feeding fat on DMI may be partially regulated by plasma concentration of GLP-1, but are not likely due solely to changes in a single hormone concentration.

Gallbladder Dysfunction Diagnosed by Cholescintigraphy with a Fatty Meal

To the editor, The pathogenesis of gallbladder dysfunction is not fully understood and functional assessment of gallbladder emptying cholescintigraphy is widely used as a diagnostic tool. We present a case of gallbladder dysfunction diagnosed by cholescintigraphy with fatty meal. A 36-year-old woman with Behcet's disease presented with frequent postprandial right upper quadrant pain of three weeks' duration. Each episode lasted more than 30 minutes, resulting in interruption of daily activities. On examination, she was afebrile with positive Murphy's sign. Routine blood tests were within normal limits. Abdominal ultrasonography, computed tomography scan, upper gastrointestinal endoscopy, and colonoscopy yielded negative findings. Endoscopic retrograde cholangiopancreatography showed no structural pancreatobiliary diseases or delayed contrast drainage. Then gallbladder dysfunction was suspected, we performed cholescintigraphy (CS). Gallbladder filling was noted at 60 minutes after injection of 99mTc-pyridoxyl-5-methyl-tryptophan (Fig. 1A, arrow). Then 58 g chocolate (energy 324 kcal, fat 20 g) was given to her. She developed mild right upper quadrant pain and the gallbladder was still detected 30 minutes later (Fig. 1B, arrow). Fatty meal stimulated CS disclosed a decreased gallbladder ejection fraction (GBEF) of 25%, indicating a diagnosis of gallbladder dysfunction. The patient was initially treated conservatively with motility agents, which did not improve her symptom. She underwent laparoscopic cholecystectomy, which completely resolved her symptom. She has remained well for 6 years. Fig. 1 (A) Cholescintigraphy showing gallbladder filling at 60 minutes after injecting 99mTc-pyridoxyl-5-methyl-tryptophan (arrow). (B) The gallbladder was still detectable 30 minutes after ingesting chocolate (arrow), indicating gallbladder dysfunction. Gallbladder dysfunction, also known as biliary dyskinesia, is characterized by functional alterations without structural biliary abnormalities. Although measurement of GBEF by cholecystokinin (CCK)-CS has been well established for the diagnostic criteria, the dose, dose rate, and duration of infusion of CCK has not been standardized. Recently, oral fatty meal including half-and-half milk, yolk and chocolate, which release endogenous CCK and are more physiologic cholagogue stimulants than exogenous CCK, can serve as alternative stimulants to CCK.1,2 As there are many countries where CCK is not available, CS with fatty meal has become common practice. In this case, the GBEF was calculated at 30 minutes after having fatty meal. Although the GBEF has been generally calculated at 60 minutes after having fatty meal and its normal value has been established as over 33%,3 recent studies have indicated that the GBEF at 30 minutes is also regarded as a reliable value by using percentile methodology as well as an absolute cut-off.4,5 In addition, sphincter of Oddi manometry was not performed to rule out sphincter of Oddi dysfunction (SOD) in this case, it was unlikely based on the long and unremarkable post-cholecystectomy course. In conclusion, it is emphasized that CS with fatty meal is useful in order to interpret the subgroup that will benefit from cholecystectomy. Further studies are needed to establish the utility of CS with fatty meal.

A Mechanical Model for CCK-Induced Acalculous Gallbladder Pain

This study investigates the potential correlation between acalculous biliary pain and mechanical stress during the bile-emptying phase. This study is built on the previously developed mathematical model used to estimate stress in the gallbladder wall during emptying [Li, W. G., X. Y. Luo, et al. Comput. Math. Methods Med. 9(1):27-45, 2008]. Although the total stress was correctly predicted using the previous model, the contribution from patient-specific active stress induced by the cholecystokinin (CCK) test was overlooked. In this article, we evaluate both the active and passive components of pressure in a gallbladder, which undergoes isotonic refilling, isometric contraction and emptying during the infusion of CCK. The pressure is estimated from in vivo ultrasonographical scan measurements of gallbladder emptying during CCK tests, assuming that the gallbladder is a thin ellipsoidal membrane. The passive stress is caused by the volume and shape changes during refilling at the gallbladder basal pressure, whereas the active stress arises from the pressure rise during the isometric gallbladder contraction after the CCK infusion. The effect on the stress estimates of the gallbladder to the liver is evaluated to be small by comparing numerical simulations of a gallbladder model with and without a rigid 'flat top' boundary. The model was applied to 51 subjects, and the peak total stress was found to have a strong correlation with the pain stimulated by CCK, as measured by the patient pain score questionnaires. Consistent with our previous study for a smaller sample, it is found that the success rate in predicting of CCK-induced pain is over 75%.

The Cholecystokin Provocation HIDA Test: Recreation of Symptoms is Superior to Ejection Fraction in Predicting Medium-Term Outcomes

BackgroundThe 99m technetium labelled hepato imino diacetic acid (HIDA) scan is widely used in the investigation of patients with typical biliary pain but whose trans-abdominal ultrasound scan (US) is normal. Although the standard measure by which the HIDA scan is deemed positive is the presence of an ejection fraction (EF) of <35% following provocation with cholecystokinin (CCK), there still remains debate as to the usefulness of this measure. The aim of this study was to compare the roles of EF and symptom provocation following CCK infusion in relation to the outcome following laparoscopic cholecystectomy (LC). More specifically, we aimed to review the resolution of symptoms for our significant population of patients with normal HIDA scan EFs for whom surgery has traditionally been deemed inappropriate. Patients and MethodsAll patients undergoing LC for a presumed diagnosis of biliary dyskinesia were identified from a prospectively maintained database. Data were collected regarding pre-operative symptoms, EF and symptom provocation during the CCK HIDA scan, histological findings, early symptomatic outcome, and medium-term follow-up. ResultsDuring the period from March 2006 to October 2009, 42 patients with biliary symptoms but a negative US were referred for assessment by a single surgeon. There were 31 women and 11 men with a mean age of 39.0±12.6 years. All underwent a CCK HIDA scan of which 17 were positive with an EF <35% and the remaining 25 were negative. All patients reported recreation of symptoms following administration of CCK. All gallbladders were delivered intact for histological assessment and all but one showed evidence of chronic cholecystitis. At each postoperative visit, approximately 2 weeks following the procedure, all patients reported resolution of symptoms. After a mean of 18.7±12.1 months symptom recurrence had been noted in only one of 42 (2.4%). ConclusionsThe CCK HIDA scan is a useful study in the investigation of acalcalous cholecystitis; however, we would suggest that recreation of symptoms following CCK provocation is superior to EF for the identification of underlying chronic cholecystitis. Indeed, a normal gallbladder ejection fraction does not necessarily rule out a biliary aetiology of symptoms for this patient population.

Effects of nutritional supplementation on the appetite and energy intake responses to IV cholecystokinin in older adults

Human aging is associated with a reduction in appetite and food intake. Increased activity of the satiety hormone, cholecystokinin (CCK), may be partly responsible. This study aimed to determine whether an increase in fat and energy intake modifies the suppressive effects of CCK-8 on appetite and energy intake. Fourteen healthy older adults completed three separate dietary periods, a 14-day and a 7-day normal diet (ND; 8272 ± 480 kJ/day; 35% fat), and a 14-day high-fat diet (HFD; 11,642 ± 414 kJ/day; 43% fat), in randomised order. Immediately following each diet, subjects received, in single-blinded fashion, a 30-min intravenous infusion of either CCK-8 (1.5 ng/kg/min) (ND-CCK, HFD-CCK) or 0.9% saline (ND-SAL), the latter following only ND. Plasma CCK concentrations, appetite responses and energy intake at a buffet meal were determined. Energy intake at the buffet meal was higher on the ND-SAL study day (3349 ± 224 kJ), when compared with either ND-CCK (3023 ± 317 kJ) or HFD-CCK (2905 ± 316 kJ). The suppression of energy intake by CCK-8 infusion did not differ between the two diets. We conclude that suppression of energy intake by exogenous CCK-8 does not appear to be attenuated by incorporation of supplemental high-energy, high-fat drinks in the diet of healthy older adults.

Sincalide-Stimulated Cholescintigraphy: What Is the Standard?

TO THE EDITOR: The article by Ziessman et al. adds to the further understanding of gallbladder physiology and the effect of cholecystokinin (CCK) stimulation ( [1][1] ). They suggest considering a 38% gallbladder ejection fraction (GBEF) as the lower limit of normal for a 0.02 μg/kg infusion of CCK

Intestinal Cholecystokinin Controls Glucose Production through a Neuronal Network

Cholecystokinin (CCK) is a peptide hormone that is released from the gut in response to nutrients such as lipids to lower food intake. Here we report that a primary increase of CCK-8, the biologically active form of CCK, in the duodenum lowers glucose production independent of changes in circulating insulin levels. Furthermore, we show that duodenal CCK-8 requires the activation of the gut CCK-A receptor and a gut-brain-liver neuronal axis to lower glucose production. Finally, duodenal CCK-8 fails to lower glucose production in the early onset of high-fat diet-induced insulin resistance. These findings reveal a role for gut CCK that lowers glucose production through a neuronal network and suggest that intestinal CCK resistance may contribute to hyperglycemia in response to high-fat feeding.

Gastric leptin plays a role in sympathetic vasomotor control via a CCK1 receptor‐dependent mechanism

Gastric‐derived leptin acts on vagal afferents and interacts with the gastrointestinal hormone cholecystokinin (CCK). This study aimed to examine the significance of these signals in cardiovascular regulation. The effect of CCK (4 μg/kg, i.v.) and close arterial (c.a.; coeliac) infusion of leptin (15 μg/kg) on (a) arterial pressure (AP) and heart rate (HR), (b) firing rate (FR) of presympathetic vasomotor rostroventrolateral medullary (RVLM) neurons, and (c) splanchnic/lumbar sympathetic nerve discharge (SSND/ LSND), was examined in anesthetised, male SD rats. Within 5 minutes, c.a. leptin reduced the FR of CCK‐inhibited RVLM neurons (‐28 + 5 %; P &lt; 0.01; n=10) but not CCK‐insensitive/activated neurons (8 + 6 %; n=6), compared to saline controls (‐1 + 2 %; n=11); i.v. leptin did not affect CCK‐inhibited neurons (2 + 4 %; n=5). Leptin (c.a.) significantly decreased AP (‐13 + 3 mmHg; P &lt; 0.05; n=16) compared to c.a. saline (‐4 + 1 mmHg; n=11) and i.v. leptin (3 + 2 mmHg; n=5) without affecting HR. The CCK1 receptor antagonist lorglumide (10 mg/kg; i.v.) abolished leptin's inhibitory effect on RVLM neurons (n=3, P &lt; 0.05). In separate experiments c.a. leptin inhibited SSND (‐9 + 2 %; P &lt; 0.05; n=7) compared to c.a. saline (2 + 3 %; n=5); LSND was unaffected. We conclude that leptin acting within the gut may exert selective sympathetic effects via a CCK1 receptor‐dependent mechanism that may involve the release of CCK.

Localization of CCK-1R in the omasum and role of CCK in the regulation of omasal contractions in sheep

The present study examined localization of cholecystokinin receptor (CCK-R) mRNA in the muscle layer of the ovine omasum and role of CCK-R type 1 (CCK-1R) in the regulation of muscle contraction of the omasum. We demonstrated that not only CCK-R type 2 (CCK-2R) mRNA but also CCK-1R mRNA is highly expressed in the muscle layer of the ovine omasum. Application of CCK-8 to muscle strips of the greater curvature of the ovine omasum at 1–100 nM induced tonic contraction in a concentration-dependent manner, and the contractile effect of CCK-8 was inhibited by both CCK-1R antagonist lorglumide (IC 50 2.7 and 7.9 μM in the longitudinal and circular muscle, respectively) and CCK-2R antagonist PD135,158 (IC 50 51.4 μM in the longitudinal muscle), indicating that not only CCK-2R but also CCK-1R is functionally expressed in the plasma membrane of smooth muscles in the omasum and mediates action of exogenous CCK. Contractile effect of intravenous infusion of CCK-8 (1–30 pmol/kg/min) on omasal contraction was also confirmed in the in vivo experiments using conscious sheep in the absence and presence of atropine infusion (14.4 nmol/kg/min), and showed that circulating CCK increases omasal electromyographic (EMG) activity at lower plasma concentration than that it inhibits ruminal contractions. Taking account of our previous results in the in vivo study using other CCK-1R antagonist, it is suggested that circulating CCK, even at normal range of plasma concentration, plays a physiological role as a regulator of omasal contractions in sheep and CCK-1R mediates the action of CCK.

Gastric emptying in response to IAPP and CCK in rats with subdiaphragmatic afferent vagotomy

In the subdiaphragmatic vagal deafferentation procedure (SDA), the afferent fibers of the vagus are surgically severed unilaterally where they enter the brain stem. The technique includes a subdiaphragmal truncal vagotomy performed on the contralateral side. This procedure has been used to study the control of food intake, but it has not been used previously to investigate the role of vagal afferent fibers in the control of gastric emptying (GE). The current experiment studied the effect of SDA on the inhibition of GE by islet amyloid polypeptide (IAPP or amylin) and cholecystokinin (CCK) in awake, unrestrained rats with gastric cannulas. The experimental group underwent subdiaphragmatic vagal deafferentation; the control group had sham operations. All rats received 20-min intravenous infusions of IAPP (1, 3, 9, 27, and 81 pmol/kg/min), CCK (3, 30 and 90 pmol/kg/min), and normal saline in random order. Gastric emptying of saline was measured by the phenol red method during the last 5 min of each infusion period. CCK dose-dependently inhibited gastric emptying in both the control and SDA animals. The inhibition of GE by CCK was significantly attenuated by SDA ( p < 0.01). IAPP also inhibited gastric emptying dose-dependently, but the difference between the SDA and control groups was not significant. The current experiment, which used a different methodology than previous studies, provides support for the hypothesis that the inhibition of gastric emptying by CCK, but not by IAPP, is mediated partly by afferent vagal fibers.

Gallbladder dyskinesia

The most appropriate means to diagnose and manage patients with suspected gallbladder dyskinesia remain contentious. A major problem relates to difficulties in clearly identifying the features that characterize biliary-like pain. Conflicting reports in the literature regarding whether symptoms alone are reliable predictors of pain relief after cholecystectomy in patients with suspected gallbladder dysfunction underscore the perceived need by clinicians for a reliable test to help confirm a clinical suspicion of gallbladder dysfunction before cholecystectomy. Most studies report use of cholecystokinin-cholescintigraphy (CCK-CS) with calculation of gallbladder ejection fraction in predicting symptom outcome after cholecystectomy in patients with suspected gallbladder dyskinesia. However, quality evidence is lacking, thereby precluding a definitive recommendation regarding its use. Nevertheless, CCK-CS may be useful when performed using a slow infusion of CCK in a well-selected patient population. Based on our clinical experience and interpretation of the literature, we currently suggest consideration of cholecystectomy to our patients based on high clinical suspicion. This is performed after adequate follow-up with trials of pharmacologic therapies and exclusion of other disease entities and counseling the patient on postoperative expectations. Clearly, a large, prospective, controlled study is needed with patients meeting the Rome definition of gallbladder dyskinesia, randomized to surgery or no surgery, and using standardized CCK-CS methods and outcome measures with long-term follow-up. This study would help us better understand the pathophysiology and optimal management of this clinically challenging condition.

A high-fat diet raises fasting plasma CCK but does not affect upper gut motility, PYY, and ghrelin, or energy intake during CCK-8 infusion in lean men

There is evidence from studies in animals that the effects of both fat and CCK on gastrointestinal function and energy intake are attenuated by consumption of a high-fat diet. In humans, the effects of exogenous CCK-8 on antropyloroduodenal motility, plasma CCK, peptide YY (PYY), and ghrelin concentrations, appetite, and energy intake are attenuated by a high-fat diet. Ten healthy lean males consumed isocaloric diets (~15,400 kJ per day), containing either 44% (high-fat, HF) or 9% (low-fat, LF) fat, for 21 days in single-blind, randomized, cross-over fashion. Immediately following each diet (i.e., on day 22), subjects received a 45-min intravenous infusion of CCK-8 (2 ng.kg(-1).min(-1)), and effects on antropyloroduodenal motility, plasma CCK, PYY, ghrelin concentrations, hunger, and fullness were determined. Thirty minutes after commencement of the infusion, subjects were offered a buffet-style meal, from which energy intake (in kilojoules) was quantified. Body weight was unaffected by the diets. Fasting CCK (P < 0.05), but not PYY and ghrelin, concentrations were greater following the HF, compared with the LF, diet. Infusion of CCK-8 stimulated pyloric pressures (P < 0.01) and suppressed antral and duodenal pressures (P < 0.05), with no difference between the diets. Energy intake also did not differ between the diets. Short-term consumption of a HF diet increases fasting plasma CCK concentrations but does not affect upper gut motility, PYY and ghrelin, or energy intake during CCK-8 infusion, in a dose of 2 ng.kg(-1).min(-1), in healthy males.

EFFECT OF RENIN-ANGIOTENSIN SYSTEM ON REGULATION OF PANCREATIC SECRETION IN CONSCIOUS RATS

Background/Aim: Although previous studies have shown the presence of renin-angiotensin system (RAS) in the pancreas, the effect of RAS on regulation of pancreatic secretion has remained controversial. In the present study, we therefore investigated the effect of RAS on pancreatic secretion by using valsartan, a specific angiotensin II receptor blocker in conscious rats. Method: Male Wistar rats prepared with pancreatic, bilialy, duodenal, and intravenous cannulas were used in the study. Valsartan at a dose of 0, 1, 5, or 25 mg/kg was administrated into the duodenum, and volume of pancreatic fluid and protein output were determined for 4 hours. In addition, to examine the mechanism of action of RAS on pancreatic secretion, perivagal application of capsaicin (1 mg/rat) or intravenous infusion of atropine (100 μg/kg/hr) was conducted and then pancreatic secretion was examined after administration of valsartan at 25 mg/kg. Furthermore, to examine the influence of RAS on CCK or secretin-stimulated pancreatic secretion, valsartan at 25mg/kg was administrated and then pancreatic secretion was examined during intravenous infusion of CCK or secretin. Results: Pancreatic fluid secretion, but not protein output significantly decreased after administration of valsartan at 5 and 25 mg/kg. Perivagal application of capsaicin and intravenous infusion of atropine completely abolished the decrease in the pancreatic fluid secretion by valsartan. Valsartan at 25 mg/kg did not exert any effects on the CCK or secretin-stimulated pancreatic secretion. Conclusion: Present results suggest that pancreatic RAS participates in the stimulation of basal pancreatic fluid secretion via cholinergic pathway and has no influence on CCK or secretin-stimulated pancreatic secretion in conscious rats.

Dose-dependent effects of cholecystokinin-8 (CCK-8) on pyloric motility, appetite and energy intake.

CCK suppresses appetite and modulates gastrointestinal motility, however, the relationship between these parameters remains unclear. Furthermore, the effects of CCK on appetite may be due to nausea caused by supraphysiological CCK concentrations. We hypothesised that CCK would have dose-dependent effects on pyloric motility and appetite, in the absence of nausea. Healthy males (23±1 years; BMI 23±0.5 kg/m 2 ) were studied on 4 occasions in double-blind, randomised fashion. Appetite and pyloric pressures were measured during 120-min intravenous infusions of (i) saline (control), or CCK-8 at (ii) 0.33 (‘CCK0.33’), (iii) 0.66 (‘CCK0.66’) or (iv) 2 (‘CCK2’) ng/kg/min. At 90 min energy intake at a buffet meal was quantified. There was an effect of treatment on scores for desire-to-eat ( P <0.05). All CCK infusions decreased desire-to-eat when compared with control ( P <0.05), and their effects were dose-related ( R =0.7, P =0.05). No infusion-induced nausea. There was a treatment-by-time interaction for the number of isolated pyloric pressure waves (IPPWs) ( P =0.001). All CCK infusions increased IPPWs when compared with control; CCK0.66 and CCK2 between 0 and 90 min ( P <0.01), and CCK0.33 between 0 and 45 min ( P <0.05). Mean energy intake was less following both CCK0.66 (3630±550 kJ) and CCK2 (3319±359 kJ) when compared with control (3974±491 kJ). There was an inverse relationship between desire-to-eat and IPPWs ( R =−0.7, P <0.05), and a trend for a positive relationship between desire-to-eat and energy intake ( R =0.53, P =0.09). In conclusion (i) intravenous CCK has dose-related effects on pyloric motility and appetite, in the absence of nausea, and (ii) the stimulation of IPPWs may be a determinant of appetite suppression.

The satiating effect of CCK-33 is produced by hormonal and paracrine mechanisms, but CCK-8 acts through only a paracrine mechanism in the rat.

The satiating potencies of exogenous cholecystokinin-8 (CCK-8) and cholecystokinin-33 (CCK-33) depend on route of administration: the peptides are equipotent after ip administration, but CCK-33 is significantly more potent than CCK-8 after infusion into the hepatic portal vein (hpv). This suggests that CCK-33 has a hormonal and paracrine mode of action, while CCK-8 has only a paracrine mode of action. This hypothesis was confirmed in rats with abdominal vagotomies that spared the hepatic proper nerves: CCK-33 ip decreased 30-min intake of 10% sucrose significantly, but CCK-8 did not (Eisen et al., 2005). To test the hypothesis further, we prepared 7 male rats with chronic hpv catheters and abdominal vagotomies that spared the hepatic proper and gastroduodenal nerves. HPV infusions of CCK-33, CCK-8, or saline began 5 min before and continued for the first 7.8 min of 30-min access to sweetened condensed milk. The largest dose of CCK-33 (26.4 μg/kg) decreased intake >80%, but an equimolar dose of CCK-8 (8 μg/kg) did not (

Supramaximal CCK-58 does not induce pancreatitis in the rat: role of pancreatic water secretion

In contrast to supramaximal CCK-8 or caerulein, acute or prolonged supraphysiological levels of endogenous CCK-58 do not cause pancreatitis. Compared with CCK-8, CCK-58 is a much stronger stimulant of pancreatic chloride and water secretion, equivalent to maximally effective secretin, but with a chloride-to-bicarbonate ratio characteristic of acinar fluid. Because supraphysiological endogenous CCK does not cause pancreatitis and because coadministration of secretin ameliorated caerulein- or CCK-8-induced pancreatitis, coincident with restoring pancreatic water secretion, we hypothesized that supramaximal CCK-58 would not induce pancreatitis. Conscious rats were infused intravenously with 2 or 4 nmol x kg(-1) x h(-1) of CCK-8 or synthetic rat CCK-58 for 6 h, and pancreases were examined for morphological and biochemical indexes of acute pancreatitis. A second group was treated as above while monitoring pancreatic protein and water secretion. CCK-8 at 2 nmol x kg(-1) x h(-1) caused severe edematous pancreatitis as evidenced by morphological and biochemical criteria. CCK-58 at this dose had minimal or no effect on these indexes. CCK-58 at 4 nmol x kg(-1) x h(-1) increased some indexes of pancreatic damage but less than either the 2 or 4 nmol x kg(-1) x h(-1) dose of CCK-8. Pancreatic water and protein secretion were nearly or completely abolished within 3 h of onset of CCK-8 infusion, whereas water and protein secretion were maintained near basal levels in CCK-58-treated rats. We hypothesize that supramaximal CCK-58 does not induce pancreatitis because it maintains pancreatic acinar chloride and water secretion, which are essential for exocytosis of activated zymogens. We conclude that CCK-58 may be a valuable tool for investigating events that trigger pancreatitis.