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PubMed1992

Opposite effects of cholestyramine and loxiglumide on gallbladder dynamics in humans.

The aim of this study was to conduct dose-response studies of the effect of cholestyramine, alone or in combination with a test meal, on gallbladder emptying studied by ultrasonography in 31 healthy volunteers. The role of cholecystokinin in mediating the effects of cholestyramine was studied using the cholecystokinin-receptor antagonist loxiglumide. In the absence of a test meal, cholestyramine produced a dose-dependent decrease in gallbladder volume; minimal residual volumes were 30% (2 g), 55% (4 g), and 110% (12 g) of the minimal volume produced by a test meal alone. Gallbladder volume was still only 50% of the initial volume, 24 hours after ingestion of 12 g cholestyramine. Cholestyramine also enhanced gallbladder emptying in response to the test meal (n = 7). Oral loxiglumide strongly inhibited gallbladder evacuation in response to either test meal (n = 6) or cholestyramine alone (n = 6) but partially blocked gallbladder emptying when the resin was added to the test meal (n = 12). It is concluded that (a) cholestyramine alone or in combination with a test meal produces a marked decrease in gallbladder volume and (b) the action of the resin itself on gallbladder motor function appears to be mainly, but not solely, mediated by cholecystokinin through the disinhibition of the luminal feedback mechanism between bile salts and the endogenous release of cholecystokinin.

Adult↗
PubMed1992

Cholecystokinin's role in regulation of colonic motility in health and in irritable bowel syndrome.

Colonic motor activity and plasma concentrations of cholecystokinin (CCK) both increase after oral intake of a meal. Thus, CCK had been thought to mediate the postprandial increase in colonic motor activity, which is termed gastrocolonic response. The present study used the substance loxiglumide, which acts as a specific antagonist at the CCK-A receptor, to evaluate this hypothesis. In the first set of experiments, eight healthy subjects were studied four times on separate days. A multilumen catheter was endoscopically placed with its tip lying in the descending colon. Motor activity was recorded by a low-compliance perfusion manometry system at six locations 60-45 cm from the anus. Basal activity was recorded for at least 2 hours to achieve steady-state conditions. The order of the following four experiments was randomized: (a) intravenous infusion of the CCK analogue cerulein at increasing doses (7.5, 15, 30, and 60 ng/kg.h, each given for 30 minutes); (b) intravenous cerulein plus 5 mg/kg.h loxiglumide; (c) a 1000-kcal solid/liquid meal consisting of regular German food; and (d) a meal plus 5 mg/kg.h loxiglumide. In the second set of experiments, eight patients with irritable bowel syndrome were studied twice on two separate days, and two experiments were performed n randomized order: (a) a 1000-kcal solid/liquid meal consisting of regular German food; or (b) a meal plus 5 mg/kg.h loxiglumide. The motor index was calculated as the area under contractions by a computerized system. The 1000-kcal meal markedly increased colonic motor activity. This gastrocolonic response was significantly greater in patients with irritable bowel syndrome than in healthy volunteers. Cerulein stimulated motor activity only at pharmacological doses (30-60 ng/kg.h), which resulted in plasma CCK levels markedly exceeding postprandial values. Loxiglumide abolished the effects of cerulein even at pharmacological doses. However, loxiglumide did not inhibit the gastrocolonic response to a regular meal either in healthy volunteers or in patients with irritable bowel syndrome. Loxiglumide also failed to alter the interdigestive colonic motor activity. Therefore, effects mediated by the CCK-A receptor do not play a major physiological role in the regulation of the interdigestive and postprandial motility of the left colon.

Adult↗
PubMed1992

Cephalic stimulation of gastrointestinal secretory and motor responses in humans.

The present study was designed (a) to investigate the cephalic phase of gastropancreatic secretion, antroduodenal motility, and regulatory peptide release in six healthy young men and (b) to assess its regulation by the cholinergic system and endogenous cholecystokinin. Sham feeding performed for 15 minutes induced a concurrent stimulation of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release that lasted for 30 minutes. Reappearance of interdigestive phases III was retarded in the post-sham-fed state. Atropine abolished secretory, motor, and pancreatic polypeptide responses to sham feeding and enhanced gastrin release. The cholecystokinin receptor antagonist loxiglumide did not attenuate pancreatic enzyme response but diminished antral motor response by 72% (P less than 0.05) and release of pancreatic polypeptide by 91% (P less than 0.05); it enhanced gastrin release and abolished retardation of reappearance of phase III with sham feeding. It is concluded that (a) there is a distinct cephalic phase of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release in humans that is primarily under cholinergic control and that (b) endogenous cholecystokinin is involved in antral motor, gastrin, and pancreatic polypeptide responses to sham feeding.

Adult↗
PubMed1992

A physiological role for cholecystokinin as a regulator of gastrin secretion.

To explore the role of cholecystokinin (CCK) in regulating gastrin secretion in humans, the effect of a CCK antagonist (loxiglumide) on meal-stimulated hormone responses was investigated. Subjects received 500 mL of a liquid test meal in the presence and absence of loxiglumide (22 mumol.kg-1.h-1). In the control experiments, both plasma gastrin and CCK levels increased postprandially. In loxiglumide-treated subjects there was a marked elevation in gastrin (area under the curve, 11,042 +/- 1493/120 min vs. 2156 +/- 281 pg/120 min) and CCK levels compared with the control experiment. These observations were confirmed in experiments with modified sham feeding and gastrin-releasing peptide stimulation in which loxiglumide pretreatment also caused a significant increase in gastrin release compared with saline (P less than 0.05). Further studies with intravenous infusion of gastrin, CCK-8, and CCK-33 with and without loxiglumide showed that the increases in CCK and gastrin during loxiglumide application cannot be explained by alterations in clearance rates. The findings of this study show that postprandial gastrin secretion is influenced by CCK and support the concept of a negative feedback control of gastrin secretion by CCK.

Adult↗
PubMed1992

Effect of loxiglumide on basal and gastrin- and bombesin-stimulated gastric acid and serum gastrin levels.

The effect of the specific cholecystokinin-receptor antagonist loxiglumide on basal and bombesin-, and gastrin 17-I-stimulated gastric acid secretion and serum gastrin levels was studied in 12 healthy subjects. Loxiglumide (10 mg.kg-1.h-1) significantly augmented basal gastric acid output from 1.8 +/- 0.3 to 3.9 +/- 0.6 mmol H+/h (P less than 0.005) but did not significantly influence integrated basal serum gastrin concentrations (2 +/- 21 vs. 32 +/- 21 pmol L-1.h-1). Both gastric acid secretion and integrated serum gastrin concentrations stimulated by bombesin infusion (92.6 pmol.kg-1.h-1) were significantly augmented by loxiglumide [from 4.0 +/- 0.3 to 10.0 +/- 1.3 mmol H+/h (P less than 0.005) and from 1251 +/- 93 to 2558 +/- 206 pmol.L-1.h-1 (P less than 0.005), respectively]. Gastric acid output and serum gastrin concentrations during infusion of 5 pmol.kg-1.h-1 of synthetic human gastrin 17-I (9.6 +/- 2.9 mmol H+/h and 1045 +/- 177 pmol.L-1.h-1) and during infusion of 15 pmol.kg-1.h-1 of gastrin 17-I (14.5 +/- 3.1 mmol H+/h and 2412 +/- 312 pmol.L-1.h-1) were not significantly influenced by loxiglumide (10.3 +/- 2.3 mmol H+/h and 1291 +/- 257 pmol.L-1.h-1 for the 5-pmol.kg-1.h-1 gastrin 17-I infusion dose with loxiglumide and 13.6 +/- 3.4 mmol H+/h and 2611 +/- 305 pmol.L-1.h-1 for the 15-pmol.kg-1.h-1 gastrin 17-I infusion dose with loxiglumide). These data indicate that endogenous cholecystokinin inhibits gastric acid secretion under basal conditions and gastrin release and gastric acid secretion during infusion of bombesin in humans and suggest that the augmented effect of loxiglumide on bombesin-stimulated gastric acid secretion may be explained largely by enhanced gastrin release.

Adult↗
PubMed1992

Role of circulating cholecystokinin in control of fat-induced inhibition of food intake in humans.

Cholecystokinin (CCK) has been proposed to serve as a satiety signal in animals and humans. To further explore the role of CCK in humans, the effect on satiety and eating behavior of a specific CCK-receptor antagonist, loxiglumide, that preferentially inhibits peripheral (CCK-A) receptors was investigated. In a randomized, blind, four-period latin square design, 10 subjects received intravenous saline (placebo) or loxiglumide (10 mg/kg per hour) with concomitant intrajejunal perfusions of isotonic saline or fat (containing 50% corn oil and 3% albumin). Food intake and plasma CCK concentrations were assessed, and subjects scored their feelings of hunger and fullness in paired experiments. In placebo-treated subjects, the duration of the meal was shorter during fat perfusion (30 +/- 2 minutes vs. 35 +/- 2 minutes; P less than 0.01; mean +/- SEM). The amount of food intake was reduced (361 +/- 31 g vs. 454 +/- 35 g; P less than 0.05), and fluid ingestion was inhibited (490 +/- 31 mL vs. 625 +/- 38 mL; P less than 0.01). Loxiglumide did not affect any parameter and did not change the pattern of responses. In loxiglumide-treated subjects there was a 4-5-fold elevation in plasma CCK levels. These results confirm that jejunal infusion of lipid reduces the size of the meal and stimulates early satiety. The data imply that these effects are not mediated through peripheral endogenous CCK under these conditions.

Adult↗
PubMed1994

Effect of intravenous human gastrin-releasing peptide on food intake in humans.

BACKGROUND/AIMS: Bombesin and gastrin-releasing peptide (GRP) are closely related peptides. Both have been proposed to serve as a satiety signal in animals. METHODS: To explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions. RESULTS: GRP produced a significant reduction in calorie intake (P < 0.05) but only a 19% (nonsignificant) reduction in food intake. Fluid ingestion was not affected by GRP. No overt side effects were produced by GRP, but subjects experienced d less hunger and early fullness in the premeal period during GRP infusion but not when receiving saline (P < 0.05-0.01). CONCLUSIONS: This study shows that intravenous infusions of GRP can decrease spontaneous food intake at concentrations that produce physiological effects, such as stimulation of acid or pancreatic secretion or gallbladder contraction. The data imply that GRP-like peptides can act as satiety signals in humans, confirming data previously reported in animals.

Adult↗
PubMed1994

Cholecystokinin is a negative regulator of gastric acid secretion and postprandial release of gastrin in humans.

BACKGROUND/AIMS: The role of cholecystokinin (CCK) in the regulation of gastric acid secretion is still controversial. This study examined the effect of the CCK-A receptor antagonist loxiglumide (lox) on gastrin- or CCK-induced gastric acid secretion and meal-stimulated plasma gastrin levels in a placebo-controlled study. METHODS: Acid output was studied in eight subjects who received intravenously gastrin-17 (15, 30, and 60 pmol.kg-1.h-1); gastrin-17 plus lox; cholecystokinin octapeptide (CCK-8) (15, 30, and 60 pmol.kg-1.h-1); CCK-8 plus lox; or gastrin plus CCK-8. Sham feeding-induced acid output and meal-stimulated gastrin secretion were studied during lox infusion. RESULTS: Gastrin-17 dose-dependently stimulated acid output to near-maximal levels. CCK-8 (15 pmol.kg-1.h-1) increased acid secretion 2.5-fold over basal; higher infusion rates had less or no effect. When combined with lox, CCK-8 produced a near-maximal acid response (6-fold over basal). CCK-8 together with gastrin-17 inhibited gastrin-induced acid output by 67%. Meal-stimulated plasma gastrin concentrations were elevated 3.2-fold, whereas sham feeding-induced acid secretion was not modified by lox. CONCLUSIONS: Blockade of CCK-A receptors converts CCK-8 into a potent acid secretagogue and augments postprandial gastrin secretion. A CCK-mediated stimulation of paracrine somatostatin secretion from antral and fundic D cells represents a candidate mechanism for the inhibition of the parietal and gastrin cell in humans.

Adult↗
PubMed1989

Cholecystokinin receptor antagonism of stimulated pancreatic and gastric secretion.

The effects of cholecystokinin receptor antagonist, dipentyl-3,4-dichloroproglumide (DDP), on stimulated pancreatic and gastric secretion were studied in the rat. DDP dose-dependently inhibited cholecystokinin-stimulated amylase release from dispersed acinar cells. In vivo, DDP inhibited cholecystokinin octapeptide-stimulated amylase and protein secretion. DDP also inhibited pentagastrin-stimulated gastric acid secretion in vivo. Meal-stimulated acid output was decreased by 34% (DDP 400 micrograms/kg/hr) but responsiveness to histamine or parachlorophenyl-gamma-aminobutyric acid was unchanged.

Amylases↗
PubMed1985

Selective presence of opiate receptors on intestinal circular muscle cells.

Smooth muscle cells isolated separately from the longitudinal and circular muscle layers of guinea pig and human intestine exhibited a unique pattern of response to derivatives of proenkephalin and prodynorphin present in the myenteric plexus. Receptors for other myenteric transmitters (acetylcholine, the octapeptide of cholecystokinin and substance P) capable of mediating contraction, were present on both circular and longitudinal muscle cells, whereas opiate receptors were present on circular muscle cells and selectively absent from longitudinal muscle cells in both species. The opiate myoreceptors belonged to the three main subclasses (kappa, delta and mu) and exhibited a rank order of sensitivity similar to that of opiate neuroreceptors. The distribution of these receptors parallels the distribution of opioid nerve fibers and appears to reflect the role of opioids in the regulation of neuromuscular activity.

Acetylcholine↗
PubMed1986

A novel bioassay for the NK-2 neurokinin receptor: the guinea pig gallbladder.

Although three neurokinin receptors (NK-1, NK-2, NK-3) have been identified by radioligand binding assays, only the NK-1 and NK-3 types have been found in smooth muscle bioassays. In this study, evidence is presented demonstrating functional NK-2 type receptors in the guinea pig gallbladder (GPGB). The potencies of the following neurokinins were determined in the GPGB and the guinea pig ileum (GPI): substance P (SP), physalaemin (PH), eledoisin (EL), substance K (SK) and kassinin (KA). ED50 values were determined by linear regression analysis of the dose-related increases in the force generated by each peptide. In the GPI, the rank order of potency was SP = PH = EL greater than SK = KA, indicating NK-1 selectivity. In the GPGB, the relative potencies were SK greater than KA greater than EL much greater than PH greater than SP, which is similar to that reported for the NK-2 receptor in radioligand binding assays. These findings demonstrate the NK-2 receptor tissue selectivity of the GPGB.

Animals↗
PubMed1990

Comparison of the effect of lorglumide on pancreatic growth stimulated by camostate in rat and hamster.

We conducted a 14 day experiment in which we administered camostate (a trypsin inhibitor) and cholecystokinin alone or in combination with lorglumide, a cholecystokinin receptor antagonist, to both rats and hamsters. Plasma cholecystokinin levels were 21.7 +/- 3.2 pM and 19.6 +/- 2.5 pM with camostate, 16.3 +/- 2.4 pM and 14.8 +/- 2.2 pM with exogenous cholecystokinin, and 3.7 +/- 0.4 pM and 4.2 +/- 1.0 pM in control experiments in rats and hamsters, respectively. Both cholecystokinin and camostate were found to promote pancreatic growth in rats (18 +/- 4 and 111 +/- 7%, respectively) and hamsters (76 +/- 18 and 61 +/- 12%, respectively). Although lorglumide caused a decrease of this effect of camostate in both rats (78 +/- 5%) and hamsters (25 +/- 10%), it only became significant in rats. We therefore conclude that there are important interspecies differences in the role cholecystokinin plays in mediating the trophic effects of trypsin inhibitors on the pancreas.

Animals↗
PubMed1990

Effects of lorglumide on gastrin- and peptone-stimulated gastric acid secretion in rats.

This study in rats demonstrates that gastric acid secretion stimulated by infusion of gastrin 17-I yielding plasma concentrations in the physiological range is almost abolished by the cholecystokinin-receptor antagonist lorglumide. Furthermore, lorglumide also inhibited intragastric peptone stimulated gastric acid secretion by 43%. When compared to peptone stimulation with a saline background infusion, lorglumide infusion inhibited peptone stimulated gastric acid secretion only significantly in the late (20 to 30 minutes) part of stimulation, while the initial part (0 to 10 and 10 to 20 minutes) was not significantly inhibited by lorglumide. Both peptone stimulation and gastrin infusion significantly augmented serum gastrin concentrations, which were not significantly influenced by lorglumide. The serum gastrin concentrations achieved during gastrin infusion were higher than during peptone stimulation, however the differences were not statistically significant. It is concluded that lorglumide abolishes gastrin stimulated gastric acid secretion in rats, but only partly (43%) inhibits peptone-meal stimulated gastric acid secretion. In contrast to the gastrin infusion experiments, where lorglumide abolishes acid secretion during the entire study period, the compound inhibits gastric acid secretion more effectively towards the end of peptone stimulation than in the beginning.

Animals↗
PubMed1992

Direct contractile effect of motilin on isolated smooth muscle cells of guinea pig small intestine.

We examined the direct effect of motilin on longitudinal and circular smooth muscle cells isolated from the guinea pig small intestine. In addition, the effects of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate hydrochloride (TMB-8, an inhibitor of intracellular Ca(2+)-release), verapamil (a voltage-dependent Ca(2+)-channel blocker), and removal of extracellular Ca2+ were investigated to evaluate the role of intracellular Ca2+ stores and extracellular Ca2+ on the muscle contraction induced by motilin. The effects of atropine (a muscarinic receptor antagonist), spantide (a substance P receptor antagonist) and loxiglumide (a CCK-receptor antagonist) were also examined to determine whether the motilin-induced contraction was independent of those receptors. Motilin induced a contraction of the longitudinal and circular smooth muscle cells in a dose-dependent manner with the maximal effect attained after 30 seconds of incubation. The ED50 values were 0.3 nM and 0.05 nM, respectively. TMB-8 suppressed completely the motilin-induced contraction of both types of smooth muscle cells. Verapamil had only a slight suppressive effect. Removal of extracellular Ca2+ did not have any significant influence on motilin-induced contraction. The contractile response to motilin was not affected by atropine, spantide or loxiglumide. Our findings showed that:1) motilin has a direct contractile effect on both longitudinal and circular smooth muscle cells; 2) this contractile effect is not evoked via muscarinic, substance P or CCK receptors, and 3) the intracellular release of Ca2+ plays an important role in the contractile response to motilin on both types of smooth muscle cells.

Animals↗
PubMed1987

Effect of a cholecystokinin antagonist on some effects of diazepam.

Dose responses were evaluated for the effects of diazepam alone or together with the cholecystokinin receptor antagonist CR 1409 on pentetrazole-induced convulsions, motor performance and spontaneous motor activity. The results obtained showed that the cholecytokinin antagonist potentiated the effects of diazepam on motor performance and the anticonvulsant activity of diazepam, while it did not affect spontaneous motor activity. The data presented are consistent with a role for cholecystokinin in some effects of diazepam.

Animals↗
PubMedDate not supplied

Role of serotonin in the discriminative stimulus properties of mescaline.

Rats were trained to discriminate intraperitoneally administered mescaline from saline in a two-lever operant chamber for food reinforcement. Reward was contingent upon responses made greater than 15 sec apart (DRL-15) on the appropriate lever paired with either drug or saline administration. Following the establishment of discriminative response control by mescaline, the animals were tested for stimulus generalization produced by mescaline after: (a) blockade of periphreral and central serotonin (5-HT) receptors with cinanserin, methysergide, or cyproheptadine; (b) blockade of peripheral 5-HT receptors with xylamidine tosylate; and (c) depletion of brain 5-HT with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA). The results show that all three central 5-HT antagonists greatly reduced the discriminability of mescaline while the peripheral antagonist, xylamidine tosylate, was without effect. Furthermore, these agents at the doses employed did not effect the discriminability of saline. Depletion of 5-HT with PCPA potentiated the effects of a sub-threshold dose of mescaline and slightly reduced the discriminability of saline. The results indicate that mescaline produces its discriminative stimulus properties by directly stimulating central serotonergic receptors.

Animals↗
PubMed1978

Role of peripheral mechanisms in the behavioral effects of 5-hydroxytryptophan.

The effects of 5-hydroxytryptophan (5-HTP) were studied in rats trained to press a lever under a fixed-ratio (Fr-32) schedule of water presentation. d-, l-and d,l-5-HTP all decreased responding in a dose-related manner. The levo isomer (12.5-25 mg/kg) was twice as potent as the racemic form (25-50 mg/kg) in this respect. Moderate doses of d-5-HTP (less than 100 mg/kg) did not affect responding, whereas 200 mg/kg produced almost complete suppression. The response decrement produced by 25 mg/kg l-5-HTP was completely antagonized by pretreatment with either 50 mg/kg or 400 mg/kg of the decarboxylase inhibitor, benserazide (Ro4-4602). The specific peripheral decarboxylase inhibitor, carbidopa (MK-486) (50 mg/kg) and the peripheral serotonergic antagonist, xylamidine tosylate (1 mg/kg) also antagonized the effects of 25 mg/kg l-5-HTP. These results suggest that at least some of the behavioral effects of 5-HTP are due to increases in levels or turnover of 5-HTP in peripheral serotonergic neuronal systems.

5-Hydroxytryptophan↗
PubMed1986

Pizotifen (BC-105) attenuates orienting and Pavlovian heart rate conditioning in rabbits.

The cardiac component of the orienting reflex (OR) was elicited in rabbits by 75 dB, 4-sec duration tones of either 304 or 1216 Hz. The conditioned cardiac response was also studied using the same tones and paraorbital electric shock as conditioned and unconditioned stimuli, respectively, using a differential Pavlovian conditioning paradigm. Subcutaneous injections of the central 5-HT antagonist pizotifen (BC-105), the peripheral 5-HT antagonist xylamidine, the central 5-HT agonist d-lysergic acid diethylamide (LSD), and LSD in conjunction with BC-105 were administered 15 min prior to behavioral assessment. Both the heart rate (HR) conditioned response (CR) and the OR consisted of bradycardia. BC-105 attenuated, but xylamidine had no effect on, OR habituation. LSD reduced the magnitude of the OR, an effect which was blocked by BC-105. BC-105 also produced a dose-related attenuation of the bradycardiac HR CR; however, xylamidine had no effect on HR conditioning, suggesting that the attenuation of the HR CR by BC-105 was central rather than peripheral in origin. LSD potentiated the bradycardiac HR CR, but BC-105 in conjunction with LSD attenuated this response. These results suggest that central 5-HT neurons may modulate the magnitude of bradycardiac responses during orienting and aversive Pavlovian conditioning.

Animals↗