八肽胆囊收缩素在猪,大鼠和豚鼠肠道的免疫组织化学定位和分布

实验采用ＡＢＣ免疫组织化学方法研究了八肽胆囊收缩素样免疫反应物质在猪、大鼠和豚鼠肠道的定位与分布,并用相邻切片免疫双标记法观察了它与５－羟色胺的关系,结果表明,ＣＣＫ－８－ＩＲ细胞主要位于肠腺的底部,少数位于绒毛上皮。节段性分布上,在猪可见于从十二指肠到结肠全长的粘膜,大鼠和豚鼠ＣＣＫ－８－ＩＲ细胞则见于从十二指肠至回肠的粘膜,但均以十二指肠密度最高;免疫双标记法证实,在三种动物肠道中均有ＣＣＫ＝     

Bombesin-like immunoreactivity in human gastrointestinal tract

In the present study the distribution and molecular characteristics of bombesin-like immunoreactivity (BLI) were studied in acid extracts of human gastrointestinal tract. The highest levels were found in the fundus, antrum, pylorus and pancreas with lower levels in the duodenum, jejunum, terminal ileum and colon. BLI was also detected in both the muscle and mucosal layers of the antrum and colon. Sephadex G-50 gel chromatography under acid dissociating conditions revealed two peaks of immunoreactivity, one in the position of synthetic porcine gastrin releasing peptide (GRP) and the second eluting with synthetic amphibian bombesin. Variations in the proportions of the two molecular forms were seen in different regions of the gut. In the stomach and pancreas greater than 70% of the BLI eluted with the GRP marker while in pylorus, jejunum and terminal ileum only 20% was present in this form. Reverse-phase ODS silica HPLC of the major antral BLI peak, utilising a methanol/trifluoroacetic acid gradient indicated that this peptide was similar to porcine GRP. We have therefore (1) demonstrated the presence and heterogeneity of bombesin-like immunoreactivity throughout the human gastrointestinal tract and (2) shown for the first time that a proportion of this BLI closely resembles porcine GRP.     

Distribution of bombesin binding sites in the rat gastrointestinal tract

In an attempt to identify potential target sites for the satiety action of bombesin (BN), the distribution and pharmacological specificity of bombesin binding sites were examined in the rat gastrointestinal tract by in vitro autoradiography utilizing (125I-Tyr4) bombesin. Specific BN binding was localized to the circular muscle level of the gastric fundus and antrum, submucosal layer of the small intestine and longitudinal and circular muscle and submucosal layers of the colon. Pharmacological studies indicated that gastrin releasing peptide (GRP), Ac-GRP20-27 and BN-like compounds, litorin and ranatensin, inhibited the binding of (125I-Tyr4)BN with high affinity while compounds which lacked COOH-terminal homology with BN demonstrated a low affinity for BN binding sites. The wide distribution of BN binding sites in the gastrointestinal tract provides a number of potential sites for the mediation of the satiety action of BN.     

Distribution and heterogeneity of immunoreactive cholecystokinin (CCK) in the mucosa of the porcine gastrointestinal tract

The concentration and molecular nature of cholecystokinin-like immunoreactivity (CCK-LI) in extracts of porcine intestinal mucosa were determined using sequence-specific radioimmunoassays. Highest CCK concentrations were measured in duodenal mucosa (258 +/- 60 pmol/g in the distal duodenum) followed by jejunal mucosa (204 +/- 36 pmol/g in the proximal jejunum) and pylorus (51 +/- 9 pmol/g). All other gastrointestinal regions proximal to the pylorus and distal to the jejunum contained less than 20 pmol/g. Pancreas contained less than 1 pmol/g. Gel chromatography in 6 M urea revealed four immunoreactive forms and this was confirmed by reverse-phase high-pressure liquid chromatography (HPLC). The predominant molecular form in acid extracts of duodenal mucosa resembled CCK-33 although high concentrations of the larger CCK form ('CCK-58') and of the form intermediate in size between CCK-33 and CCK-8 were measured. A molecular form resembling CCK-8 was the principal form in neutral extracts of the duodenum.     

缩胆囊素和促胰液素对豚鼠离体胃平滑肌运动的影响

用８个肌槽同时记录豚鼠胃不同部位肌条的收缩活动,以观察八肽缩胆囊素（ＣＣＫ－８）和促胰液素的影响。结果表明：ＣＣＫ－８能（１）增高各部位纵行肌和环行肌的张力;（２）加快胃体纵行肌,胃窦纵行肌、环行肌和幽门环行肌的收缩频率;（３）增大胃窦环行肌收缩波平均振幅和（４）增加幽门环行肌收缩波运动指数,但减少胃体和胃窦纵行肌收缩波平均振幅。上述作用均不能被阿托品和消炎病所阻断。而促胰液素对各部位肌条的收缩活动没有明显的影响。     

Different affinity states of CCK(1) receptors on pancreatic acini and gastric smooth muscle in the rat.

It has recently been shown that--after chronic cholecystokinin (CCK) treatment--an adaptation of pancreatic secretory but not gastric motor function does occur. Recent studies indicate that the CCK(1)-receptor exists in two (i.e. high and low) affinity states, which could be distinguished by the CCK-analogue JMV-180. CCK occupancy of high and low affinity sites is thought to be related to the initiation of different intracellular events and consequent biological responses. Affinity states of CCK(1)-receptors on pancreas and gastrointestinal (GI) smooth muscle could be different and this can offer an explanation for the different effects of CCK on pancreatic and gastric growth. We therefore studied the affinity states of CCK(1)-receptors on isolated rat pancreatic acini and gastric smooth muscle preparations. When acini were incubated with increasing concentrations of CCK-8, a biphasic (i.e. stimulation followed by inhibition) effect on amylase release was observed. JMV-180 caused only stimulation of enzyme release and combined JMV-180 and CCK stimulation (at submaximal doses) resulted in an additive secretory response. CCK-8 induced contractions of pyloric, antral and fundic muscle in a concentration-dependent manner. The response was monophasic, reaching a plateau. JMV-180 had only a very weak effect on these preparations. On the contrary, it inhibited CCK-induced contractions in a competitive manner, the concentration-response curve to CCK being shifted to the right by the CCK analogue. Our data suggest that the affinity states of CCK(1)-receptors on rat pancreatic and gastric tissue are different. On pancreatic acini CCK(1)-receptors exist in both high- and low-affinity states whose occupation is followed by the sequence of intracellular events leading to growth. In contrast, occupation of low affinity receptors (the only ones present in the GI smooth muscle) does not lead to cell proliferation. This difference therefore explains the different adaptive response of the pancreas and the stomach to chronic CCK administration. Furthermore, different affinity states of CCK(1)-receptors may mediate different functions of the digestive tract.     

Distribution of prostaglandin E2 binding sites in the porcine gastrointestinal tract

Binding of biologically active ³H-PGE₂ to particulate fractions of porcine gastrointestinal mucosa and muscle was investigated. Specific binding activity was detected in the 2500 xg and 30,000 xg sedimentation fractions of mucosa from esophagus, fundus, antrum, duodenum, ileum and colon, as well as in serosal muscle taken from the antrum, ileum, and colon. Optimal binding (> 40 fmol/mg protein) was observed in the 30,000 xg fraction of fundic mucosa incubated at pH 5.0. The characteristics of ³H-PGE₂ binding were variable in the remainder of the gastrointestinal tract although binding in these tissues was significantly less (0.2 to 15 fmol/mg protein) than that observed in the fundic mucosa. These data suggest that the cellular and/or subcellular site of PG binding is not uniform throughout the gastrointestinal tract. In fundic mucosa removal of the surface epithelial layer by scraping did not significantly alter the total binding activity for PGE. This result suggests that in gastric secretory mucosa optimal binding activity for PGE₂ occurs within the gastric pits deep to the surface epithelium.     

Pharmacological examination of cholecystokinin (CCK-8)-induced contractile activity in the rat isolated pylorus

The actions of cholecystokinin (CCK) in the production of a satiety-like state have been suggested to be mediated via receptors for CCK which are located in the pylorus. We investigated the actions of CCK and other pharmacological agents upon the isolated rat pylorus in vitro. We used the change in isometric tension of the tissue preparation (contraction amplitude) as the measure of the effects of the pharmacological agents. Cholecystokinin COOH-terminal octapeptide (CCK-8) was observed to elicit contraction in a dose-dependent manner, with the half-maximal dose (ED50) in the vicinity of 1 nM. Rapid desensitization to CCK was observed. The contraction amplitude was atropine-independent, and was not significantly antagonized by a wide variety of other pharmacological agents. The Na+-channel blocker tetrodotoxin was without effect upon contractile amplitude, as was the K+-channel blocker 4-aminopyridine, except at very high concentrations. Neurotensin, bombesin, and the substance P and bombesin antagonist spantide all elicited contraction in the isolated tissue; neurotensin had a similar potency to CCK-8 and bombesin was 10-15-fold less potent than CCK-8. Unsulfated CCK-8 was at least 170-fold less potent than sulfated CCK-8 and tetragastrin was at least 500-fold less potent than CCK-8. These results suggest that pyloric CCK receptors, which appear to have a pharmacological profile typical of peripheral CCK receptors, may have a physiological role in the peptidergic control of gastric emptying in the rat.     

Biologically active gastrin/CCK-related peptides in the stomach of a reptile, Crocodylus niloticus; Identified and characterized by immunochemical methods

We have used immunochemical, chromatographic, and bioassay techniques to characterize peptides related to gastrin and CCK, from the stomach of the reptile Crocodylus niloticus. By immunocytochemistry gastrin/CCK-like peptides were localized in specific mucosal cells of the pylorus and in the duodenum. Boiling water extracts of pyloric antrum cross reacted with four antisera specific for the C-terminal region of gastrin or CCK, but estimates of concentration varied between antisera. Antisera specific for the N-terminus of heptadecapeptide gastrin (G17), intact G17, or the amphibian CCK-like peptide caerulein did not cross react with the crocodile extracts. Gel filtration of the extracts on Sephadex G50 resolved one major peak eluting significantly before G17 or CCK8, suggesting larger molecular size, whereas ion exchange on DE52 cellulose resolved two major immunoreactive peaks, both eluting before G17, indicating that they are less acidic. The more acidic of the two peptides stimulated gastric acid secretion in the rat, but had no CCK-like actions on the rat pancreas. Thus crocodile antrum contains gastrin-like peptides, which are however clearly distinguishable from any of the known mammalian forms of gastrin and CCK.     

Gastrointestinal hormones cause rapid c-Met receptor down-regulation by a novel mechanism involving clathrin-mediated endocytosis and a lysosome-dependent mechanism

The activated c-Met receptor has potent effects on normal tissues and tumors. c-Met levels are regulated by hepatocyte growth factor (HGF); however, it is unknown if they can be regulated by gastrointestinal (GI) hormones. c-Met is found in many GI tissues/tumors that possess GI hormone receptors. We studied the effect of GI hormones on c-Met in rat pancreatic acini, which possess both receptors. CCK-8, carbachol, and bombesin, but not VIP/secretin, decreased c-Met. CCK-8 caused rapid and potent c-Met down-regulation and abolished HGF-induced c-Met and Gab1 tyrosine phosphorylation, while stimulating c-Met serine phosphorylation. The effect of cholecystokinin (CCK) was also seen in intact acini using immunofluorescence, in a biotinylated fraction representing membrane proteins, in single acinar cells, in Panc-1 tumor cells, and in vivo in rats injected with CCK. CCK-8 did not decrease cell viability or overall responsiveness. GF109203X, thapsigargin, or their combination partially reversed the effect of CCK-8. In contrast to HGF-induced c-Met down-regulation, the effect of CCK was decreased by a lysosome inhibitor (concanamycin) but not the proteasome inhibitor lactacystin. Inhibitors of clathrin-mediated endocytosis blocked the effect of CCK. HGF but not CCK-8 caused c-Met ubiquitination. These results show CCK and other GI hormones can cause rapid c-Met down-regulation, which occurs by a novel mechanism. These results could be important for c-Met regulation in normal as well as in neoplastic tissue in the GI tract.     

Cholecystokinin-8 increases Fos-like immunoreactivity in the brainstem and myenteric neurons of rats through CCK1 receptors

To examine the role of cholecystokinin1 receptor (CCK1) in the activation of brainstem and myenteric neurons by CCK, we compared the ability of exogenous CCK-8 to induce Fos-like immunoreactivity (Fos-LI) in these neurons in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, lacking CCK1 receptors, and Long-Evans Tokushima Otsuka (LETO) controls. Five groups (n=4 rats per group) of OLETF rats, and five LETO control groups, were injected intraperitoneally (IP) with 5, 10, 20, and 40 microg/kg CCK-8 or saline. Forty-micrometer brainstem sections containing the area postrema, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus, and myenteric neurons of the duodenum, jejunum, and ileum underwent a diaminobenzidine reaction enhanced with nickel to reveal Fos-LI. CCK-8 did not increase Fos-LI in any of the tested neurons in the OLETF rats. CCK-8 increased Fos-LI in the brainstem of the LETO rats in a dose dependent manner. In the LETO rats only 40 microg/kg CCK-8 increased Fos-LI in the myenteric plexus of the jejunum. This study demonstrates that CCK-8 activates the brainstem and myenteric neurons through the CCK1 receptor.     

Different affinity states of CCK1 receptors on pancreatic acini and gastric smooth muscle in the rat

It has recently been shown that—after chronic cholecystokinin (CCK) treatment—an adaptation of pancreatic secretory but not gastric motor function does occur. Recent studies indicate that the CCK₁-receptor exists in two (i.e. high and low) affinity states, which could be distinguished by the CCK-analogue JMV-180. CCK occupancy of high and low affinity sites is thought to be related to the initiation of different intracellular events and consequent biological responses. Affinity states of CCK₁-receptors on pancreas and gastrointestinal (GI) smooth muscle could be different and this can offer an explanation for the different effects of CCK on pancreatic and gastric growth. We therefore studied the affinity states of CCK₁-receptors on isolated rat pancreatic acini and gastric smooth muscle preparations. When acini were incubated with increasing concentrations of CCK-8, a biphasic (i.e. stimulation followed by inhibition) effect on amylase release was observed. JMV-180 caused only stimulation of enzyme release and combined JMV-180 and CCK stimulation (at submaximal doses) resulted in an additive secretory response. CCK-8 induced contractions of pyloric, antral and fundic muscle in a concentration-dependent manner. The response was monophasic, reaching a plateau. JMV-180 had only a very weak effect on these preparations. On the contrary, it inhibited CCK-induced contractions in a competitive manner, the concentration–response curve to CCK being shifted to the right by the CCK analogue. Our data suggest that the affinity states of CCK₁-receptors on rat pancreatic and gastric tissue are different. On pancreatic acini CCK₁-receptors exist in both high- and low-affinity states whose occupation is followed by the sequence of intracellular events leading to growth. In contrast, occupation of low affinity receptors (the only ones present in the GI smooth muscle) does not lead to cell proliferation. This difference therefore explains the different adaptive response of the pancreas and the stomach to chronic CCK administration. Furthermore, different affinity states of CCK₁-receptors may mediate different functions of the digestive tract.     

Both afferent and efferent nerves are implicated in cholecytokinin motor actions in the small intestine of the rat.

Cholecystokinin (CCK) regulates intestinal motility after being released by several luminal nutrients. However the mechanism of action of CCK is still not well known. The aim of our study was to establish the mechanism of action of CCK in the rat intestine using an in vivo model and focusing on the nervous pathways involved in the response as well as type of receptors. Anesthetized rats were prepared with two strain-gauges, in duodenum and jejunum, to record circular muscle motor activity. A group of animals was also prepared with a catheter to infuse capsaicin inside the duodenum. Responses to CCK-octapeptide (CCK-8) as well as to CCK agonists were studied. CCK-8 was also infused after CCK antagonists, atropine, hexamethonium or L-nitroarginine. Results show that duodenal response to CCK-8 is excitatory although inhibitory responses can be induced by gastrin. In the jejunum, CCK-8 induces an inhibitory response that is mediated by both CCK-A and -B receptors. Excitatory responses to CCK-8 are due to stimulation of preganglionic receptors while inhibitory responses are NO mediated through stimulation of postganglionic CCK-B receptors. Capsaicin locally applied in duodenal mucosa significantly decreased CCK-8 response, whereas mucosal exposure to lidocaine completely blocked CCK-8 response. In conclusion our results show that CCK response varies along the intestine according to the predominance of excitatory or inhibitory efferent innervation. Moreover, CCK-8 actions are mediated through both extrinsic and intrinsic afferent fibres.     

Messenger RNA levels and binding sites of muscarinic acetylcholine receptors in gastrointestinal muscle layers from healthy dairy cows

Acetylcholine interacts with muscarinic receptors (M) to mediate gastrointestinal (GI) smooth muscle contractions. We have compared mRNA levels and binding sites of M(1)to M(5) in muscle tissues from fundus abomasi, pylorus, ileum, cecum, proximal loop of the ascending colon (PLAC), and external loop of the spiral colon (ELSC) of healthy dairy cows. The mRNA levels were measured by quantitative RT-PCR. The inhibition of [(3)H]-QNB (1-quinuclidinyl-[phenyl-4-(3)H]-benzilate) binding by M antagonists [atropine (M(1 - 5)), pirenzepine (M(1)), methoctramine (M(2)), 4-DAMP (M(3)), and tropicamide (M(4))] was used to identify receptors at the functional level. Maximal binding (B(max)) was determined through saturation binding with atropine as a competitor. The mRNA levels of M(1), M(2), M(3), and M(5) represented 0.2, 48, 50, and 1.8%, respectively, of the total M population, whereas mRNA of M(4) was undetectable. The mRNA levels of M(2) and of M(3) in the ileum were lower (P < 0.05) than in other GI locations, which were similar among each other. Atropine, pirenzepine, methoctramine, and 4-DAMP inhibited [(3)H]-QNB binding according to an either low- or high-affinity receptor pattern, whereas tropicamide had no effect on [(3)H]-QNB binding. The [(3)H]-QNB binding was dose-dependent and saturable. B(max) in fundus, pylorus, and PLAC was lower (P < 0.05) than in the ELSC, and in the pylorus lower (P < 0.05) than in the ileum. B(max) and mRNA levels were negatively correlated (r = -0.3; P < 0.05). In conclusion, densities of M are different among GI locations, suggesting variable importance of M for digestive functions along the GI tract.     

Effects of cholecystokinin-8 induced gastric dysmotility on bile regurgitation during stress and molecular mechanisms

OBJECTIVE: To illustrate the existence of bile regurgitation under stress condition, and explore the possible effects and related mechanism of changes of plasma cholecystokinin octapeptide (CCK-8) and intragastric pH on stress-induced bile regurgitation in rats. METHODS: (1) Changes in plasma CCK-8 and gastric bile concentration were respectively measured by using radioimmunoassay (RIA) method while simultaneously calculating gastric ulcer index (UI) 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 group, plasma CCK-8 and gastric bile concentration significantly increased during stress (p<0.01) and both simultaneously reached the peak at the time point of 2 h after stress; UI and intragastric pH apparently increased (p<0.01); (2) Significant changes to CCK-8S were found in the mean contractile amplitude and frequency of circular muscle (CM) and longitudinal muscle (LM) of gastric antrum and pylorus; (3) CCK-8S-evoked significant increase in [Ca(2+)]i (p<0.01) could be suppressed by CCK-A receptor (CCK-AR) antagonist; whereas a small but significant increase was still elicited by CCK-8S under condition of the removal of extracellular calcium or by given nifidipine; (4) CCK-8S-intensified calcium current (I(CaL)) apparently inhibited by respective administration of nifidipine, Ca(2+)-ATPase inhibitors or calcium dependent chloride channel (I(Cl-Ca)) blocker (p<0.01). CONCLUSION: 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 (VDCC) through the activation of calcium dependent chloride channels.     

Effect of CCK-8 on myoelectrical activity of the gastrointestinal tract in the conscious miniature pig

In conscious miniature pigs, with implanted electrodes in the wall of the antrum pylori, duodenum, jejunum, and ileum, the influence of IV infusions of CCK-8 (17.5 and 175 pM/kg/min) on gastrointestinal myoelectrical activity was measured. Although both doses under study induced a decrease in antral spike activity, only the higher dose resulted in an overall decrease in integrated myoelectrical activity. In the ileum both doses augmented spiking activity during the infusion, but inhibited electrical activity after the end of the infusion. No response was observed in the duodenum and jejunum. The experiments demonstrate the overall inhibitory effect of CCK-8 on antral electrical activity and its stimulatory influence on ileal smooth muscle.     

Changes in gastric endocrine cells in Balb/c mice bearing CT-26 carcinoma cells: an immunohistochemical study

The distribution and density of gastric endocrine cells in Balb/c mice bearing CT-26 carcinoma cells were studied immunohistochemically employing specific antisera against serotonin, somatostatin, glucagon, gastrin, cholecystokinin (CCK)-8 and human pancreatic polypeptide (hPP). The animals were divided into two groups, a non-implanted sham group and a CT-26 carcinoma cell-implanted group. Samples were collected from two regions of the stomach (fundus and pylorus) at 28 days after implantation of the medium or the CT-26 cells (1x10(5) cells/mouse). Five of the 6 types of immunoreactive (IR) cells were identified, with only the hPP IR cells not being detected. The regional distribution of the gastric endocrine cells in the CT-26 implanted group was similar to that of the non-implanted sham group. However, the endocrine cells were significantly decreased in the CT-26-implanted group as compared to those of the non-implanted sham group. Serotonin- and somatostatin-IR cells in the fundus and pylorus , and gastrin- and CCK-8-IR cells in the pylorus of the CT-26 implanted groups were significantly decreased compared to those of the sham group. In addition, glucagon-IR cells were restricted only to the fundus of the sham animals. hPP-IR cells were not detected in either the T-26 implanted- or the non-implanted group. Since endocrine cells are the anatomical units responsible for the production of gut hormones, a change in their density may reflect a change in their capacity to produce such hormones. Implantation of the tumor cell mass induced severe quantitative changes in gastric endocrine cell density, an abnormality which may contribute to the development of gastrointestinal symptoms, such as anorexia and indigestion, frequently encountered in cancer patients.     

Distribution of gastrin and CCK cells in the rat gastrointestinal tract

Summary Gastrin and cholecystokinin (CCK) cells of the rat gastrointestinal tract have been studied by immunocytochemistry and radioimmunoanalysis. With antisera directed against the COOH-terminal tetrapeptide sequence, which is common to gastrin and CCK, three distinct endocrine cell types are detected. One of the cell types predominates in the antrum, is scarce in the rest of the gut and corresponds to the gastrin cell. The second cell type is virtually confined to the duodenum and jejunum and corresponds to the CCK cell. The third cell type occurs disseminated in the small intestines, predominates in the ileum, and reacts with COOH-terminus-specific antisera only following diethylpyrocarbonate and not following formaldehyde fixation. It is possible that the third cell type stores a third member of the gastrin-CCK family of gut hormones.     

蓝狐消化道内分泌细胞的免疫组化研究

蓝狐又名北极狐(Alopex lagopus),属于食肉目(Carnivora),犬科(Canidae),北极狐属(Alopex).     

Role of cholecystokinin in the intestinal phase of pancreatic circulation in dogs

The regulatory mechanisms of postprandial pancreatic hyperemia are not well characterized. The aim of this study is to clarify the role of cholecystokinin (CCK) in the intestinal phase of pancreatic circulation. Pancreatic, gastric, and intestinal blood flows were measured by ultrasound transit-time blood flowmeters in five conscious dogs. Pancreatic and gastric secretion and blood pressure were also monitored. Synthetic CCK octapeptide (CCK-8) or gastrin heptadecapeptide (gastrin-17) was infused intravenously, and milk was infused into the duodenum with or without loxiglumide, a specific CCK-A receptor antagonist. CCK-8 induced dose-related increases of pancreatic, but not gastric or intestinal, blood flow and protein secretion without affecting systemic blood pressure. Gastrin-17 did not affect pancreatic blood flow. An intraduodenal infusion of milk increased pancreatic and intestinal blood flows and pancreatic protein secretion. Loxiglumide completely inhibited pancreatic blood flow and protein responses to CCK-8 and milk but not the intestinal blood flow response. CCK is a potent and specific pancreatic vasodilator, with its effect mediated by CCK-A receptors. CCK plays an important role in the regulation of the intestinal phase of the pancreatic circulation in dogs.