Appetite responses to high-fat diets rich in mono-unsaturated versus poly-unsaturated fats.

BACKGROUND: Modifying the type of dietary fat consumed may impact appetite, therefore having implications in weight management. OBJECTIVE: To test the effects of a 5-day, high-fat diet rich in poly-unsaturated fatty acids (PUFAs) and a diet rich in mono-unsaturated fatty acids (MUFAs) on markers of appetite. METHODS: Fifteen normal weight men participated in a randomized cross-over design with two controlled feeding trials (3d lead-in diet, pre-diet visit, 5d PUFA- or MUFA-rich diet, post-diet visit). The 5d diets (50% fat) were rich in either PUFA (25% of energy) or MUFA (25% of energy). At pre- and post-diet visits, subjects consumed breakfast and lunch test meals, rich in the FA corresponding to the 5-day diet. Fasting and postprandial subjective ratings of appetite were determined and blood draws were performed for 4h after each meal to determine changes in appetite hormones. An ad libitum buffet meal was given at the end of pre- and post-diet visits. RESULTS: Acutely, at the pre-diet visit, the PUFA-rich meal resulted in lower ghrelin (hunger hormone) (iAUC: -350.85 ±â€¯60.70 vs. -233.16 ±â€¯61.42 pg/ml/8h, for PUFA vs. MUFA, respectively; p < 0.05) and higher CCK (satiation hormone) (iAUC: 238.09 ±â€¯46.07 vs. 196.84 ±â€¯33.92 pM/8h, for PUFA vs. MUFA, respectively; p < 0.05). No other acute meal challenge differences were found. The 5d high PUFA diet resulted in lower hunger ratings (iAUC: -172.06 ±â€¯40.59 vs. -274.46 ±â€¯41.47 mm/8h, for pre-to post-diet, respectively; p < 0.05). However, energy intake, ratings of fullness, or PYY did not change from pre-to post-diet for either MUFA or PUFA, and no other changes were observed with the MUFA diet. CONCLUSIONS: Acutely, a PUFA-rich meal results in ghrelin suppression and higher CCK. After a 5-day high-fat diet, PUFAs suppressed postprandial hunger while MUFAs did not change any measures of appetite.

[Blood serum cholecystokinin and clinical-functional variability of biliary pathology].

RESULTS: Basal and stimulated serum CCK concentrations were not statistically significant differences (p > 0.05) with the control group in patients studied in the whole and in patients subgroups, formed by the diagnosis of biliary pathology and the character of gallbladder emptying. Increased stimulated CCK concentration was found in patients with symptomatic variants. Reduce of serum-cholecystokinin concentration growth (ACCK) after intake of Sorbitol was revealed in subgroup of patients with low-symptom variant. Reduced sensitivity of the gallbladder to CCK was observed in subgroups of patients with gallbladder hypokinetic dyskinesia and one with symptomatic variant of biliary pathology. CONCLUSION: The sensitivity of the gallbladder neuromuscular apparatus to CCK is associated with clinical and functional variability of the biliary pathology.

Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms.

Previous reports suggest that glucagon-like peptide (GLP-1), a peptide secreted from the distal small intestine, is an endocrine satiation signal. Nevertheless, there are conflicting reports regarding the site where circulating GLP-1 acts to reduce food intake. To test the hypothesis that vagal afferents are necessary for reduction of food intake by circulating GLP-1, we measured intake of 15% sucrose during intravenous GLP-1 infusion in intact, vagotomized, and capsaicin-treated rats. We also measured sucrose intake during intravenous infusion of cholecystokinin, a peptide known to reduce food intake via abdominal vagal afferents. We found that reduction of intake by GLP-1 was not diminished by capsaicin treatment or vagotomy. In fact, reduction of sucrose intake by our highest GLP-1 dose was enhanced in vagotomized and capsaicin-treated rats. Intravenous GLP-1 induced comparable increases of hindbrain c-Fos immunoreactivity in intact, capsaicin-treated, and vagotomized rats. Plasma concentrations of active GLP-1 in capsaicin-treated rats did not differ from those of controls during the intravenous infusions. Finally, capsaicin treatment was not associated with altered GLP-1R mRNA in the brain, but nodose ganglia GLP-1R mRNA was significantly reduced in capsaicin-treated rats. Although reduction of food intake by intraperitoneal cholecystokinin was abolished in vagotomized and capsaicin-treated rats, reduction of intake by intravenous cholecystokinin was only partially attenuated. These results indicate that vagal or capsaicin-sensitive neurons are not necessary for reduction of food intake by circulating (endocrine) GLP-1, or cholecystokinin. Vagal participation in satiation by these peptides may be limited to paracrine effects exerted near the sites of their secretion.

[Effect of chai qin cheng qi decoction on serum CCK-8 and calcium overload of pancreatic acinar in mice with acute pancreatitis].

OBJECTIVE: To investigate the effect of Chai Qin Cheng Qi decoction (CQCQD) on serum cholecystokinin-8 (CCK-8) and calcium overload of pancreatic acinar cells in acute pancreatitis (AP) mice. METHODS: Twenty four mice were randomly divided into control group, AP group, CQCQD group and siRNA group, each comprising 6 mice. AP mouse model was induced by intraperitoneal injection of 8% L-arginine in a dose of 4 g/kg. The AP mice in the CQCQD group were fed with 0.4 mL/100 g of Chai Qin Cheng Qi solution once every two hours. The AP mice in the siRNA group were injected intraperitoneally with CCK-siRNA in a dose of 0.88 mg/kg. The changes of serum CCK-8 and calcium concentrations in the pancreatic acinar cells and pancreatic pathology were observed 6 hours after the interventions. RESULTS: The serum CCK-8 [(3764.3 +/- 369.2) ng/mL], calcium fluorescence intensity (34.8 +/- 27.1) of pancreatic acinar cells and pancreas pathology scores (6.2 +/- 1.1) of the AP mice were significantly greater (P < 0.05) than those in the control group [(1253.5 +/- 39.5) ng/mL, 5.2 +/- 2.3, 2.8 +/- 0.4], CQCQD group [(1230.5 +/- 46.1) ng/mL, 9.6 +/- 1.6, 3.8 +/- 0.8, 4.1 +/- 0.5] and siRNA group[(1702.3 +/- 598.3) ng/mL, 7.6 +/- 2.0]. Serum CCK-8 was positively correlated with intracellular calcium concentrations (r = 0.793, P = 0.021) in pancreatic acinar cells and pancreas pathology scores (r = 0.847, P = 0.000). CONCLUSION: Acute pancreatitis in mice induced by L-arginine is associated with calcium overload in pancreatic acinar cells induced by increased serum CCK-8. CQCQD can reduce serum levels of CCK-8, alleviate calcium overload in pancreatic acinar cells, and reduce pancreas pathological changes in AP mice.

In vitro gastric emptying characteristics of konjac glucomannan with different viscosity and its effects on appetite regulation.

Konjac glucomannan (KGM) is associated with the satiety-enhancing property by imparting the food matrix with high viscosity. In the present study, rheology tests on KGM sol with different viscosities were conducted to understand its flow behavior as they presented in the mouth and stomach, and the in vitro gastric emptying characteristics of KGM were examined with a human gastric simulator. Then, their effects on subjective appetite, glycemia, and appetite-related hormones (insulin, GLP-1, PYY3-36, CCK-8, ghrelin) response were investigated by conducting a randomized, single-blind, crossover trial in 22 healthy adults (11 female and 11 male, mean age (years): 23.2 ± 2.0, BMI (kg m-2): 20.6 ± 2.1). The blood samples and ratings for subjective appetite were collected at regular time intervals after the subjects were fed with four test breakfasts (one control treatment and three experimental treatments) on four different days. An ad libitum lunch was provided to the subjects once they consumed the breakfasts and their food intake was recorded. As the viscosity increased, the gastric emptying rate was delayed despite a large part of the chyme viscosity lost during digestion. The satiating capacity of the test breakfast was significantly enhanced as its viscosity increased, the and subjects' sensation for hunger, fullness, desire-to-eat, and prospective food consumption differed significantly (p = 0.006, 0.000, 0.002, and 0.001, respectively) between the treatments. The secretion of glycemia and satiety-related hormones were beneficially modulated by the increased viscosity of the test meal but a small decrease in the ad libitum food intake was observed after the intervention of the viscous test breakfasts. Overall, elevating the meal viscosity moderately by using KGM could contribute to combating the challenge of hunger for people in the bodyweight management.

Cholecystokinin octapeptide reduces myocardial fibrosis and improves cardiac remodeling in post myocardial infarction rats.

BACKGROUND/AIMS: Myocardial infarction (MI) increases myocardial fibrosis (MF) and subsequent cardiac remodeling. Cholecystokinin octapeptide (CCK-8) is expressed in cardiomyocytes and plays an important role in cardiovascular regulation. In this study, we intend to use a rat model of myocardial infarction to evaluate the effects of CCK-8 on myocardial fibrosis and cardiac remodeling. METHODS: Male Sprague-Dawley rats were separated into 3 groups: sham operation, MI + NaCl, and MI + CCK-8. All rats were subjected to left coronary artery ligation to induce MI or sham operation and then treated with CCK-8 or saline for 28 days. After 4 weeks, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E and Masson's Trichrome-stained sections. The levels of BNP, CCK-8 in the plasma of all rats were detected by ELISA; RNA sequencing (RNA-seq) analysis was also adapted to detect differentially expressed genes in myocardial tissues of each group. Myocardial expression of fibrosis markers was analyzed by western blotting, immunohistochemistry and qRT-PCR. RESULTS: CCK-8 was demonstrated to improve left ventricular function and results of H&E staining, Masson's trichrome staining, immunohistochemistry and western blotting showed that CCK-8 attenuated MF. Gene expression profiles of the left ventricles were analysed by RNA-seq and validated by qRT-PCR. Cardiac fibrosis genes were downregulated by CCK-8 in the left ventricle. SIGNIFICANCE: CCK-8 can alleviate fibrosis in the noninfarcted regions and delay the left ventricular remodeling and the progress of heart failure in a MI rat model.

Effect of viscosity on appetite and gastro-intestinal hormones.

In previous studies we showed that higher viscosity resulted in lower ad libitum intake and that eating rate is an important factor. In this study we aimed to explore the effect of viscosity on the gastro-intestinal hormones ghrelin, CCK-8 and GLP-1. Thirty-two subjects (22+/-2 y, BMI 21.9+/-2.2 kg/m(2)) participated in this cross-over study. Subjects received a fixed amount of a chocolate flavored milk-based liquid or semi-solid product similar in energy density and macronutrient composition. Before intake and 15, 30, 60 and 90 min thereafter, appetite was rated and blood was drawn to determine glucose, CCK-8, active ghrelin, desacyl ghrelin and GLP-1 concentrations. After the last blood withdrawal, subjects were offered a chocolate cake meal to consume ad libitum. In the appetite ratings we observed a small effect showing that the semi-solid product is apparently considered as more satisfying than the liquid. There was a significant product effect for fullness (p 0.03), desire to eat (p 0.04), appetite something sweet (p 0.002) and prospective consumption (p 0.0009). We observed no clear effect of viscosity on gastro-intestinal hormones. Only for desacyl ghrelin there was a significant product effect (p 0.004). Concentrations were consistently higher after intake of the semi-solid product. Ad libitum intake of the chocolate cake was 102+/-55 g after the liquid and 96+/-46 g after the semi-solid product (ns). The results of our study show a similar response of the gastro-intestinal hormones CCK-8, ghrelin and GLP-1 after a fixed preload of a liquid and semi-solid product similar in energy- and macronutrient composition.

Effect of resistant wheat starch on subjective appetite and food intake in healthy adults.

OBJECTIVE: The aim of this study was to determine the effect of replacing standard wheat flour (SWF) with resistant wheat starch (RWS) on markers of appetite and food intake in healthy adults. METHODS: A randomized, single-blind, crossover study was conducted with 27 healthy adults (ages 23 ± 2 y with a body mass index of 23.0 ± 3.0 kg/m2). After an overnight fast, muffins that contained only SWF or muffins in which 40% of the SWF was replaced with RWS were consumed as part of the breakfast meal. Appetite questionnaires and plasma samples were collected before the test meal and at 10 time points after meal consumption. An ad libitum meal was provided 240 min after breakfast, and the amount eaten was recorded. Food intake was recorded over the remainder of the day using a diet diary, and appetite was measured hourly using appetite questionnaires. Plasma was assayed to measure biomarkers of satiety and glycemia. RESULTS: Replacing SWF with RWS had no effect on subjective appetite or energy intake at the lunch meal (P > 0.05). Total daily energy intake (including the breakfast meal) was reduced by 179 kcal when participants consumed the RWS muffins (P = 0.05). Replacing SWF with RWS reduced plasma insulin (P < 0.05) but had no effect on plasma glucose, cholecystokinin, glucagon-like peptide-1, or peptide YY3-36 concentration (P > 0.05). CONCLUSIONS: These results indicate that replacing SWF with RWS decreases plasma insulin concentration and reduces energy intake over a 24-h period.

Subclinical exocrine pancreatic dysfunction resulting from decreased cholecystokinin secretion in the presence of intestinal villous atrophy.

UNLABELLED: The aim of this study was to evaluate the concept that pancreatic dysfunction in patients having gluten sensitivity (celiac disease [CD]) or cow's milk protein enteropathy (CMPE) may result from the lack of pancreatic enzyme stimulation in the absence or decrease of cholecystokinin (CCK) secretion caused by villous atrophy. PATIENTS AND METHODS: The following parameters were measured: plasma CCK in response to a fatty meal and human pancreatic fecal elastase in 24 patients with CD while on gluten-free diet and after gluten provocation and in 12 patients with CMPE at diagnosis and after a 6-month period of cow's milk-free diet. Intestinal mucosa morphology was examined by small bowel biopsy. Sixty-three controls having no organic gastrointestinal problems were investigated once at the time of diagnostic evaluation. RESULTS: Fasting CCK, obtained at a time when patients with CD or CMPE had normal intestinal mucosa, was significantly different from postprandial and comparable to that of the control group. Fasting CCK obtained from patients with villous atrophy was also statistically different, but not significantly, from the postprandial. Fasting and postprandial plasma CCK and fecal pancreatic elastase values from patients having normal intestinal mucosa were significantly higher than those obtained from patients with villous atrophy. Significant correlation of intestinal mucosa morphology and CCK with fecal elastase concentration was documented. CONCLUSION: Exocrine pancreatic dysfunction in individuals having villous atrophy may be the consequence of decreased CCK secretion. Cholecystokinin and pancreatic secretion is restored to normal, with intestinal mucosa regeneration.

[The effect and mechanism of cholecystokinin octapeptide induced-gastric dysmotility on bile regurgitation during stress].

OBJECTIVE: To illustrate the existence of bile regurgitation under stress condition, and explore the possible effects and related mechanism of changes of cholecystokinin octapeptide (CCK-8) on stress-induced bile regurgitation in rats. METHODS: (1) Changes in plasma CCK-8 and gastric bile concentration were measured by using radioimmunoassay while simultaneously calculating gastric ulcer index and intragastric pH; (2) Each isolated gastric strips were suspended in a tissue chamber to record the contractile responses by polyphysiograph; (3) The responsiveness of gastric smooth muscle cells (SMCs) to sulfated cholecystokinin octapeptide (CCK-8S) were examined using fura-2-loaded microfluorimetric measurement of intracellular calcium concentration ([Ca(2+)] i); (4) The current of L-type calcium channels (I(CaL)) of SMCs were recorded by patch-clamp techniques. RESULTS: (1) Compared with the normal control, plasma CCK-8 [from (2.23 +/- 0.88) pmol/L to (10.80 +/- 3.82) pmol/L] and gastric bile concentration [from (37.93 +/- 23.76) micromol/L to (1316.00 +/- 197.36) micromol/L] significantly increased during the stress (P < 0.01) and both simultaneously reached the peak at the time point of 2 h after stress; ulcer index (from 0.62 +/- 0.23 to 32.01 +/- 16.11) and intragastric pH (from 1.06 +/- 1.20 to 5.29 +/- 1.25) apparently increased (P < 0.01); (2) Significant changes to CCK-8S were found in the mean contractile amplitude and frequency of circular muscle and longitudinal muscle of gastric antrum and pylorus; (3) CCK-8S-evoked significant increase in [Ca(2+)] i [from (65.8 +/- 7.4) nmol/L to (472.1 +/- 35.6) nmol/L, P < 0.01] could be suppressed by CCK-A receptor antagonist; whereas a small but significant increases were still elicited by CCK-8S under condition of the removal of extracellular calcium; (4) CCK-8S-intensified calcium current I(Ca-L) [from (-56.42 +/- 6.57) pA to (-88.54 +/- 5.71) pA, P < 0.01)] apparently inhibited by respective administration of nifedipine, Ca(2+)-ATPase inhibitors or calcium dependent chloride channel blocker (P < 0.01). CONCLUSIONS: Gastric mucosal damage induced by bile regurgitation is closely connected with gastric antrum and pylorus dysmotility evoked by CCK-8 during the stress. CCK-8S-evoked [Ca(2+)] i increase in gastric antrum and pylorus SMC depends on the release of intracellular calcium stores which activates L-type voltage-dependent calcium channels through the activation of calcium dependent chloride channels.

Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans.

CONTEXT: CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited. OBJECTIVE: First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size). PARTICIPANTS AND DESIGN: Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8 kg/m(2)) in a university research centre. Plasma was collected preprandially and for 180 min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180 min before an ad libitum lunch was provided. RESULTS: CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F(1,15)=14.737, p<0.01). Profiles of hunger/fullness did not differ between conditions (F(1,15)=0.505, p=0.488; F(1,15)=2.277, p=0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925 kJ; t(14)=0.201, p=0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size. CONCLUSIONS: These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach.

Altered concentrations of appetite regulators may contribute to the development and maintenance of HIV-associated wasting.

OBJECTIVE: To examine the relation of circulating appetite neuropeptides, CCK-8 sulphate (CCK-8s) and beta-endorphin, and the tumour necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNFR) to the anorexia and wasting associated with HIV-infection. DESIGN: Cross-sectional analysis. SETTING: A university-based HIV/AIDS ambulatory clinic in Madrid, Spain. PARTICIPANTS: Thirty-six randomly selected AIDS patients without concomitant diseases or secondary infections were classified into two groups: 19 patients with wasting and 17 with normal body weight, and 18 healthy controls. MEASUREMENTS: Nutritional status was evaluated by anthropometry, laboratory parameters and self-report of appetite. Plasma levels of TNF-alpha and sTNFR proteins p55 (sTNFR-p55) and p75 (sTNFR-p75) were determined by enzyme immunoassay, whereas CCK-8s and beta-endorphin levels were measured by radioimmunoassay. RESULTS: AIDS patients with wasting had significantly higher plasma concentrations of CCK-8s, but lower levels of beta-endorphin when compared to well-nourished AIDS patients (P < 0.01) or controls (P < 0.001). Mean levels of TNF-alpha, and sTNFR-p55 and sTNFR-p75 were greater in AIDS patients with wasting than in asymptomatic AIDS patients or in controls. No significant association was observed between any of these circulating peptides and the parameters of malnutrition. CONCLUSIONS: An activation of the TNF system, together with reciprocal changes in plasma concentrations of two neuropeptides with opposing appetite regulation, that is increased concentrations of CCK-8s but lower levels of beta-endorphin, are associated with the presence of HIV wasting. We hypothesize that these changes may contribute to the development of HIV wasting by producing a pathological inhibition of appetite.

Cholecystokinin does not stimulate prosomatostatin-derived peptides in man.

In man, plasma cholecystokinin (CCK) and somatostatin-28 (S-28) levels increase after ingestion of a mixed meal. Both peptides originate from the gastrointestinal tract. In supra- and periphysiological doses, CCK stimulates the release of somatostatin-14 from in vitro pancreatic islets and gastric cells and increases circulating somatostatin-like immunoreactivity in dogs, leading to the conjecture that CCK regulates somatostatin-like immunoreactivity secretion. Nonetheless, whether CCK is responsible in part for the meal-induced rise in S-28 in man has not been established. Therefore, the present study was designed to determine if CCK, at both physiological and supraphysiological concentrations, increases the circulating levels of prosomatostatin (proS)-derived peptides in humans. On 3 separate days, five healthy men ate a mixed liquid meal or received iv infusions of CCK at rates of 18 or 38 pmol/kg.h. Plasma levels of pro-S-derived peptides, including pro-S, S-14, S-13, S-28, and CCK, were measured. Basal CCK levels averaged 0.9 +/- 0.1 pmol/L and increased after the meal to a peak level of 5.4 +/- 1.5 pmol/L and averaged 3.1 +/- 1.2 pmol/L over 90 min. The mean basal levels of pro-S, S-14, and S-13, measured collectively, was 6.1 +/- 0.4 pmol/L eq S14 and was unaltered by food intake. The S-28 level was 6.7 +/- 0.6 pmol/L and rose to a zenith of 13.1 +/- 3.3 pmol/L by 90 min. Infusion of CCK at 18 and 38 pmol/kg.h produced steady state plasma CCK levels of 4.1 +/- 1.1 and 9.9 +/- 1.5 pmol/L, respectively. Basal levels of pro-S-derived peptides were unaltered during the infusion of either the low or high dose of CCK. We conclude that CCK by itself is not a physiological signal to the release of pro-S-derived peptides in man.

Effect of exogenous cholecystokinin (CCK)-8 on food intake and plasma CCK, leptin, and insulin concentrations in older and young adults: evidence for increased CCK activity as a cause of the anorexia of aging.

Healthy aging is associated with reductions in appetite and food intake--the so-called anorexia of aging, which may predispose to protein-energy malnutrition. One possible cause of the anorexia of aging is an increased satiating effect of cholecystokinin (CCK). To investigate the impact of aging on the satiating effects of CCK, 12 young and 12 older healthy subjects received 25-min iv infusions of saline (control) and CCK-8, 1 ng/kg per min or 3 ng/k per min, on 3 separate days before a test meal. Older subjects ate less than young subjects, and food intake was suppressed 21.6% by CCK-8, compared with the control day (P < 0.05). The suppression of energy intake by CCK-8 in older subjects was twice that in young subjects (32 +/- 6% vs. 16 +/- 6% SEM, P < 0.05) and was related to plasma CCK-8 concentrations, which were higher at baseline (P < 0.05) and increased more during CCK-8 infusions in older than young subjects (P < 0.01). The extent of suppression of food intake per given rise in plasma CCK-8 concentrations did not differ between the two age groups (P = 0.35). Endogenous CCK concentrations were higher at baseline in older subjects (P < 0.001) and decreased during the CCK-8 but not control infusions (P < 0.01), suggesting that CCK suppresses its own release. Plasma leptin concentrations were not affected by CCK infusion, whereas postprandial insulin concentrations were lowered and the peak postprandial glucose concentration was delayed but not affected by CCK-8 infusion. Because older people retain their sensitivity to the satiating effects of exogenous CCK and plasma endogenous CCK concentrations are higher in older people, increased CCK activity may contribute to the anorexia of aging.

Lymphocyte cholecystokinin concentrations in panic disorder.

Since cholecystokinin (CCK) is known to be anxiogenic in experimental animals and to induce panic attacks in humans, lymphocyte CCK-8 concentrations were measured in 15 patients with panic disorder and 15 age- and sex-matched healthy subjects. The patients' levels were measured again after a 30-day course of alprazolam therapy, 1.5 mg/day. The CCK-8 concentrations were significantly lower in the patients than in the control subjects and did not change after alprazolam therapy. There was no correlation between the peptide values and levels of anxiety or frequency and severity of panic attacks.

Aging and panicogenic response to cholecystokinin tetrapeptide: an examination of the cholecystokinin system.

Older age is associated with diminished symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). We hypothesized that circulating concentrations of endogenous CCK-4 and/or CCK-8 are increased in later life, possibly due to decreased enzymatic degradation, and that this is associated with desensitization of CCK-B receptors. The study group consisted of 20 healthy subjects aged 18-30 years and 20 healthy subjects aged 65-85 years. The two groups were compared on fasting basal plasma concentrations of CCK-4, sulfated CCK-8 (CCK-8s) and nonsulfated CCK-8 (CCK-8 ns), and on binding capacity of lymphocyte CCK-B receptors. Under single-blind (to subject) conditions, subjects were then administered an intravenous bolus of placebo, followed 50 min later by an intravenous bolus of 50 micro g of CCK-4. Plasma concentrations of total CCK (CCK(T)) were measured 2 min before and 2, 5, 10, and 15 min after each injection. Compared with younger subjects, older subjects had a significantly higher basal plasma concentration of CCK-8s and significantly diminished binding capacity of CCK-B receptors. Following injection of placebo, plasma CCK(T) concentrations did not significantly change from baseline in either age group, but the elderly had significantly higher concentrations than the young at 2, 5, and 10 min. Following injection of CCK-4, the plasma concentration of CCK(T) was highest at 2 min and declined after that. The elderly had significantly higher CCK(T) concentrations (ie. a slower decline in CCK(T)) than the young at 5, 10, and 15 min. These findings are consistent with our hypothesis and suggest that age-related changes in the CCK system could contribute to the diminished panicogenic response to exogenous CCK-4 in older persons.

Comparison of fatty meal and intravenous cholecystokinin infusion for gallbladder ejection fraction.

UNLABELLED: Gallbladder ejection fraction (GBEF) measured with a fatty meal (half-and-half milk) was compared with that measured with 2 equal sequential intravenous infusions of cholecystokinin (CCK-8) in a paired study of healthy subjects. METHODS: GBEF was measured by (99m)Tc-hepatic iminodiacetic acid cholescintigraphy in 13 healthy subjects. Each subject received 2 sequential doses of CCK-8 (3 ng/kg/min for 10 min) on day 1, followed by, on day 2, a 240-mL (8 oz) fatty meal (half-and-half milk) per 70 kg of body weight. RESULTS: The mean +/- SD GBEF of 53.6% +/- 20.2% with fatty meal was significantly lower than the mean of 75.8% +/- 16.3% (P < 0.01) with the first dose of CCK-8 and 71.3% +/- 17.4% (P < 0.05) with the second dose. Fatty meal GBEF varied widely, from 23.5% to 91.8%. Percentile rankings of the fatty meal GBEF were determined as the preferred methodology for reporting results. Latent and ejection periods were significantly longer with fatty meal than with either dose of CCK-8. CONCLUSION: GBEF measured with fatty meal can serve as an alternative method to intravenous injection of CCK-8 when the hormone is no longer available for clinical use. The measurement of GBEF with fatty meal requires careful attention to the details of the meal and the measurement time sequence.

Sexual activity increases plasma concentrations of cholecystokinin octapeptide and offsets hunger in male rats.

Male rats deprived of food for 48 h ignored food pellets immediately after ejaculating with a sexually receptive female rat as did males tested 5 min after i.p. injection of 5 micrograms cholecystokinin octapeptide (CCK-8) or males which had consumed food pellets for 1 h. The concentration of CCK-8 in plasma was increased to comparable levels (10.1 +/- 3.8 (S.E.M.); 11.3 +/- 3.7 and 7.2 +/- 0.5 pmol/l respectively, compared with 1.2 +/- 0.3 pmol/l for NaCl-injected controls) under each of these conditions, whereas the concentration of gastrin increased only after food consumption (18.4 +/- 3.8; 17.7 +/- 5.4 and 54.3 +/- 7.0 pmol/l respectively, compared with 21.5 +/- 2.1 pmol/l for NaCl-injected controls). The effect of ejaculation on the latency to starting to eat was partially reversed by i.p. injection of 50 mg of the CCK-8 antagonist proglumide, but neither treatment with proglumide or CCK-8 nor consumption of food affected the display of sexual behaviour. The results support the suggestion that CCK-8 is a 'satiety peptide' in the rat.

Plasma concentrations of cholecystokinin octapeptide and food intake in male rats treated with cholecystokinin octapeptide.

Intraperitoneal injection of 5 micrograms cholecystokinin octapeptide (CCK-8) into male rats deprived of food for 48 h produced a transient (less than 15 min) increase in plasma levels of CCK-8 but suppressed food intake for an extended period (45 min). Plasma concentrations of CCK-8 after i.p. injection of CCK-8 were raised to levels which were fairly comparable to those after feeding. Intracerebroventricular (i.c.v.) injection of the CCK antagonist proglumide (100 micrograms) reversed the effect of CCK-8 on food intake, while i.p. injection of proglumide (100 micrograms) did not have this effect. Feeding increased the plasma concentrations of somatostatin and gastrin but not of oxytocin, and somatostatin and oxytocin but not gastrin were released in response to i.p. injection of CCK-8. However, neither somatostatin nor oxytocin affected food intake, and their release in response to CCK-8 was unaffected by i.c.v. injection of proglumide. These results support the suggestion that CCK-8 is a physiological 'satiety' peptide, which can affect food intake in rats by mechanisms involving both peripheral and central CCK receptors.

Development of a sensitive and specific assay system for cholecystokinin tetrapeptide.

Cholecystokinin is a gastrointestinal and neuropeptide which has been implicated in a wide range of physiological and behavioral processes. We have developed a sensitive and specific assay system to measure the various forms of cholecystokinin (CCK) in human plasma. This 3-step system involves i) extraction of CCK fragments from plasma using reverse phase chromatography; ii) separation of peptides by high performance liquid chromatography; and iii) detection and quantification of peptides with a double-antibody radioimmunoassay, using an antibody raised against cholecystokinin tetrapeptide (CCK-4) coupled to thyroglobulin and 125I Bolton-Hunter CCK-4 as tracer. The antibody detects CCK-4, sulfated CCK-8 (CCK-8S) and nonsulfated CCK-8 (CCK-8ns) with equal affinity. The lower limit of detection is 2.7 fmol, with an ED50 of 10.6 +/- 2.2 fmol. Mean CCK-like immunoreactivity (CCK-LI) in the plasma of 12 healthy subjects was determined to be 12.9 +/- 2.1 pM CCK-4 equivalents. Concentrations of each individual peptide in plasma were determined to be 1.0 +/- 0.2 pM, 3.4 +/- 0.8 pM and 1.9 +/- 0.4 pM for CCK-4, CCK-8s and CCK-8ns respectively.