Brain CCKA receptors mediate the colonic motor response to feeding in dogs

The influence of central vs. peripheral administration of specific type A and type B CCK receptor antagonists (L364,718 and L365,260, respectively) on colonic motor hyperactivity induced by feeding and CCK8 was investigated in dogs with strain-gauge transducers implanted on the proximal and transverse colon. Intravenous injection of L364,718 (5 and 10 micrograms/kg) reduced by 26.2% and 80.1%, respectively, the 0-4-h postprandial increase in colonic motor index; at similar doses L365,260 had no effect. Intracerebroventricular administration of L364,718, at a dose (1 microgram/kg) not active by the IV route, significantly reduced (p less than 0.01) by 67.5% the feeding-induced colonic hyperactivity. In contrast, L365,260 (1-10 micrograms/kg ICV) injected was inactive. Increase in colonic motility produced by intravenous CCK8 infusion (1 microgram/kg/h) was suppressed by previous ICV and IV administration of L364,718 at doses of 1 and 10 micrograms/kg, respectively, while L365,260 was inactive at similar doses. It is concluded that CCK8 released after a meal is responsible for the postprandial increase in colonic motility and that these effects may be mediated through activation of central CCKA receptors.     

Inhibition of satiety by a cholecystokinin antagonist is independent of gastric emptying

The ability of a cholecystokinin antagonist Proglumide to inhibit satiety induced by intraperitoneal injections of cholecystokinin octapeptide (CCK-OP) and bombesin was examined in rats equipped with chronic gastric cannulae. Both CCK-OP and bombesin significantly suppressed sham feeding. Proglumide administered alone did not alter sham feeding but it abolished the suppression of feeding induced by CCK-OP. In contrast, Proglumide did not inhibit the effect of a low dose of bombesin, but partially inhibited satiety induced by a high dose of bombesin, thus confirming our previous findings. These results indicate that the effect of Proglumide is independent of its recently described effects on gastric emptying in rat.     

Caerulein-induced acute pancreatitis in the rat. Pancreatic secretory response to cholecystokinin.

The response of pancreatic exocrine secretion to cholecystokinin (CCK), has been studied in experimental acute pancreatitis induced in rats by supramaximal doses of caerulein. Several doses of caerulein were used (4, 20 and 40 micrograms/Kg) and each one was administered by four subcutaneous injections over 3 h at hourly intervals. Pancreatic juice was collected 9 h after the first injection. The caerulein-treated animals showed a statistically significant increase in serum amylase levels. Secretory activity of ductular cells remained unchanged in all the caerulein-treated animals, but total protein and amylase secretion decreased significantly at all the caerulein doses used, both in resting conditions and under stimulation with CCK (1.25 micrograms/Kg/h). Despite this the acinar cells of rats treated with the lowest dose of caerulein retained a certain degree of secretory function since amylase activity in pancreatic juice was greater than in other groups of rats treated with higher doses of caerulein. Moreover, the percentage of increase observed in total protein and amylase in response to CCK respect to basal secretion is similar to that of the untreated animals. At higher doses (20 and 40 micrograms/Kg) the secretory capacity in response to CCK was inhibited. Therefore CCK administration in slight acute pancreatitis could be used as a therapy since it favours the secretion of pancreatic enzymes at percentual levels similar to those of the controls.     

Endogenous CCK is not involved in the regulation of interdigestive gastrointestinal and gallbladder motility in conscious dogs.

In this study, we assessed whether endogenous CCK is involved in the regulation of interdigestive gastrointestinal and gallbladder motility in conscious dogs with force transducers chronically implanted in the gastric antrum, duodenum, jejunum and gallbladder. L364718 at a dose of 1.0 mg/kg was used as a specific and potent CCK receptor blocker, and its effect on spontaneous interdigestive motility and plasma motilin release were examined. Additionally, the contractile activity of exogenous synthetic canine motilin (20-100 ng/kg) with or without pretreatment with L364718 at a dose of 1.0 mg/kg was assessed. Whether the blocking effect of L364718 on CCK receptors was sufficient or not was verified by giving CCK-OP at a bolus dose of 10 ng/kg. As a result, cyclic changes in interdigestive motor activity and the plasma motilin concentration were not affected by pretreatment with L364718. L364718 also did not affect motilin-induced interdigestive contractile activity in the gastrointestinal tract and gallbladder. On the other hand, the effect of CCK-OP was completely abolished by pretreatment with L364718. It is concluded that endogenous CCK is not involved in the regulation of spontaneous and motilin-induced interdigestive contractions in the canine gastrointestinal tract and gallbladder.     

The effects of cholecystokinin-octapeptide and pentagastrin on electrical and motor activities of canine colonic circular muscle

The effects of cholecystokinin-octapeptide (CCK-OP) and pentagastrin on electrical and motor activities of circular muscle of the canine colon were studied with the sucrose gap technique. Additional organ bath experiments were performed to further characterize the motor response to the peptides and to elucidate their site of action. The electrical activity consisted of slow waves having an initial potential followed by a plateau potential, at a regular frequency of 4.5 cycles/min. Both peptides prolonged the duration and increased the amplitude of the plateau phase of the slow waves. Concomitantly, the slow wave frequency was reduced. In addition, CCK-OP increased spiking activity. Both spiking activity and the prolonged plateau potential generated contractile activity, prolonged phasic contraction occurring with slow waves with a prolonged plateau. In organ bath experiments, both CCK-OP and pentagastrin increased the basal tone of the muscle strips and prolonged the duration of the phasic contractions. The prolongation of the duration of the contractions was not antagonized by tetrodotoxin (TTX) and atropine. CCK-OP but not pentagastrin increased the force of contractions, this action was not affected by atropine but was reduced in the presence of TTX, suggesting that the increase in force may be partially mediated by noncholinergic excitatory nerves. The increase in basal tension by the peptides was enhanced in the presence of TTX indicating that myenteric inhibitory neurones were tonically active under our experimental conditions. The results provide the electrophysiological basis for CCK-OP and pentagastrin induced changes in colonic motility.     

Stimulation of either cholecystokinin receptor subtype reduces while antagonists potentiate or sensitize a morphine-induced excitatory response.

Cholecystokinin peptides (CCK) have been shown to antagonize many opioid-mediated effects. The present study was undertaken to determine whether peripheral injections of cholecystokinin sulphated octapeptide (CCK8), cholecystokinin tetrapeptide (CCK4), the CCK(1) (lorglumide) and the CCK(2) (PD-135,158 and LY-225910) receptor antagonists can influence a classic morphine excitatory effect, i.e. the display of Straub tail reaction in mice (STR). A total of 570 female Balb/C mice were tested. Experiment 1 was undertaken to determine whether i.p. injections of CCK8 or CCK4 can influence STR. Each animal was treated with i.p. injections of saline or CCK8 (10 and 20 nmol/kg) or CCK4 (20 and 40 nmol/kg). After 30 min all animals received an i.p. injection of morphine hydrochloride (10.0 mg/kg). The highest doses of both CCK8 (35% STR) and CCK4 (40% STR) significantly reduced STR as compared to saline (85% STR) treated mice (Fisher test; P < 0.01). In experiment 2 each animal was treated with ip injections of saline or 1.0 mg/kg lorglumide or PD-135,158 fifteen minutes before an injection of morphine at doses ranging from 1.0 to 50.0 mg/kg. In experiment 3 animals were treated with injections of saline, 0.1 or 10.0 mg/kg lorglumide or LY-225910 before an injection of a fixed MC dose (2.0 mg/kg). Both lorglumide and PD-135,158 induced a significant shift to the left in the morphine dose-response curves as well as a significant decrease in ED50 of the STR. ED50 for lorglumide was significantly lower than ED50 for PD-135,158. Both doses of lorglumide and the highest dose of LY-225910 significantly increased the percent of animals displaying STR. Experiment 4 was undertaken to determine whether repeated peripheral injections of morphine or the morphine-potentiating agents CCK(1) (lorglumide) and the CCK(2) (LY-225910) receptor antagonists can induce morphine sensitization. Each animal was treated with 5 daily i.p. injections of saline (control group), 1.5 mg/Kg morphine hydrochloride (group morphine), and 1.0 mg/Kg lorglumide (group LOR) or LY-225910 (group LY). One, two, three and four weeks after the last treatment day, all animals were challenged with one i.p. injection of morphine (1.5 mg/Kg). The morphine, LOR groups and group LY showed a significant increase in percentage of animals displaying STR. These data demonstrate that the blockade of endogenous CCK actions leads to morphine sensitization probably through both CCK receptors. The present data are consistent with the antagonistic effects of CCK and opioids in the control of morphine-induced STR. In addition, these results suggest that both CCK receptors are involved in the modulatory effects of CCK on this morphine effect.     

The effects of proglumide on cholecystokinin-, bombesin-, and glucagon-induced satiety in the rat

Intraperitoneal (IP) administration of the glutaramic acid derivative proglumide inhibited satiety induced by all IP doses of cholecystokinin octapeptide (CCK-OP) in 3-hour food-deprived intact rats. Proglumide did not influence satiety when administered alone and did not inhibit satiety induced by IP glucagon. While proglumide did not inhibit satiety induced by low doses of IP bombesin, it partially and significantly inhibited the satiety effects produced by high doses of this peptide. Since bombesin is a known secretagogue for CCK in several species, these results indicate that while bombesin and CCK act independently to induce satiety, the effect induced by high doses of bombesin is mediated, in part, by the release of endogenous CCK or a structurally related peptide. Furthermore, these results illustrate that proglumide is a specific antagonist of CCK-induced satiety and is, therefore, a potentially useful tool for investigating the physiologic role of this peptide in the control of food intake.     

Proglumide fails to increase food intake after an ingested preload

Proglumide, a selective antagonist of exogenous cholecystokinin in vitro, also inhibits the reduction of food intake induced by the systemic administration of cholecystokinin octapeptide (CCK-8) in food deprived rats. On the basis of an increase in the size of a brief test meal which followed an oral preload and treatment with a single dose of proglumide, it was suggested that a role for endogenous cholecystokinin in satiety had been demonstrated. We attempted to replicate this finding and could not under very similar experimental conditions. Subsequently, we tested whether other proglumide doses would antagonize the satiating effect of a larger oral preload on test meal intake. When these results were also found to be negative, we confirmed that proglumide (at several doses) significantly antagonized the reduction in food intake induced by exogenous CCK-8 under our conditions. Since proglumide antagonized the satiating effect of exogenous CCK-8, but did not increase food intake after oral preloads that were presumed to release endogenous CCK, we conclude that a reliable satiating effect of endogenous CCK remains to be demonstrated.     

Prostaglandin hyperalgesia, V: a peripheral analgesic receptor for opiates

Prostaglandin E2 injected in the rat paw causes hyperalgesia which is antagonized by local injections of opiate and opiate antagonists. In the present investigation in rats it is shown that naloxone has an analgesic effect at doses as low as 2 micrograms/site, injected into the rat hind paw. At a dose that has no analgesic effect (1 microgram/site) naloxone antagonized the analgesia produced by either local or systemic administration of morphine. Local administration of levorphanol (50 micrograms/site) caused a 50% reduction in the intensity of the hyperalgesia induced by prostaglandin E2. A dose four times greater of its isomer, dextrorphan, had little analgesic effect. The present results support the suggestion that this peripheral analgesia is the result of an action of opiates in receptors located at the nociceptors.     

Antagonistic effects of naloxone on CCK-octapeptide induced satiety and rumino-reticular hypomotility in sheep

Continuous intracerebroventricular (ICV) infusion of CCK-octapeptide (CCK8) was performed in ewes fitted with a permanent cannula into the lateral cerebral ventricle and Nichrome electrodes on the reticulum in order to record its electrical activity. In the first series of experiments, subsequently repeated in 12 h fasted animals, CCK8 was infused during the first hour of a 3 hour period of feeding at 2.5, 5 and 10 ng.kg-1.min-1. The same series of infusion were performed 20 min after ICV injection of 2.4 and 10 micrograms.kg-1 of naloxone. CCK8 reduced significantly in a dose related manner the food intake (r = 0.95; P less than 0.01) and the frequency of cyclic spike bursts associated to biphasic contractions of the reticulum observed during feeding (r = 0.89; P less than 0.01). At 5 and 10 ng.kg-1.min-1, the reduction of food intake reached 46.2 and 52.6% during the period of infusion; the basal and stimulated (feeding) frequency of reticular contractions were nearly halved. Previous ICV administration of naloxone (2.4 micrograms.kg-1) partially blocked the effects of CCK8 infusion on both food intake (72%) and reticular frequency (54% basal, 67% stimulated). The CCK8 induced effects on both food intake and frequency of reticular contraction were completely abolished after a previous 10 micrograms.kg-1 injection of naloxone. These results suggest that the central effects of CCK8 on feeding behavior and forestomach motility involve similar central structures and are mediated through opiate receptor structures.     

In vitro effect of calcitonin on guinea pig gallbladder

Calcitonin (CT) is a 32 amino acidic polypeptide hormone which has been found in almost all species and whose effects are mainly concerned with calcium and phosphorous homeostasis. Three preparations are employed for therapeutic uses: salmon (sCT), porcine (pCT) and human CT (hCT). The sCT is the most powerful one and in human volunteers a strong relaxing effect has been shown on gallbladder (GB) basal volume and emptying in response to a meal, intraduodenal instillation of a liquid meal and i.v. cholecystokinin (CCK) infusion. Our study was aimed at investigating if a direct sCT effect could be demonstrated on smooth muscle strips from guinea pig GBs "in vitro" (organ bath). Isometric contractions were measured in response to maximal doses of acetylcholine (ACh: 10(-4) M), KCl (80 mM) and cholecystokinin octapeptide (CCK-OP: 10(-6) M), in absence and in presence of four doses of sCT (1 x 10(-9), 1 x 10(-8), 1 x 10(-7) and 1 x 10(-6) M). sCT did not affect the initial strip basal tone. ACh, CCK-OP and KCl caused, as expected, a powerful contraction of the strips, but no effect was shown when each of the sCT doses was administered before ACh (1.28+ 0.69 SEM without sCT vs 1.28g+ 0.69 with sCT; n = 6) and CCK-OP (1.46g+ 0.19 without sCT vs 1.46g+ 0.19 with sCT; n = 8) or 5 min after the induced KCl contraction. On the basis of these preliminary results, we conclude that no evidence of a direct sCT effect was found on guinea pig GBs when considering either basal smooth muscle tone or isometric contraction in response to ACh, KCl and CCK-OP. Further studies are therefore required to clarify the influence of CT on GB dynamics in vivo and to elucidate its the physiological significance.     

Pituitary adenylate cyclase activating polypeptide stimulates gallbladder motility in conscious dogs.

We investigated whether pituitary adenylate cyclase activating polypeptide (PA-CAP27 and PACAP38) had any effect on gallbladder motility in conscious dogs, in which force transducers were chronically implanted in the gastric antrum, duodenum and gallbladder. PACAP27 and PACAP38 were administered intravenously during the digestive and interdigestive states at doses of 30, 100 and 300 pmol/kg. By way of comparison, cholecystokinin octapeptide (CCK-OP) was administrated at doses of 3, 9 and 27 pmol/kg. As a result, each peptide evoked transient and tonic contractions both in the digestive and interdigestive states, and the effect on the motor index was dose dependent. PACAP27 and PACAP38 were 0.11 +/- 0.03 and 0.04 +/- 0.01 as potent as CCK-OP in the digestive state, and 0.18 +/- 0.04 and 0.02 +/- 0.01 in the interdigestive state, respectively, on a molar basis. Although PACAP27 and PACAP38 belong to the vasoactive intestinal polypeptide (VIP) family, intravenous administration of 300 pmol/kg of VIP had no effect on interdigestive gallbladder motility, but on the other hand inhibited gallbladder motility in the digestive state. The contractile effects of PACAP27 and PACAP38 were almost completely abolished by pretreatment with atropine or hexamethonium, but not with L364718. An in vitro study using canine gallbladder strips showed that PACAP27 and PACAP38 had no effect on spontaneous gallbladder motor activity evoked by electric field stimulation, CCK-OP or acetylcholine. It was concluded that PACAP27 and PACAP38 stimulate gallbladder motility in conscious dogs through a preganglionic cholinergic mechanism.     

The source of calcium for CCK-induced contraction of the guinea-pig gall bladder.

The sources of calcium for cholecystokinin octapeptide (CCK-OP)-induced gallbladder smooth muscle contraction are considered both extracellular and intracellular, but the relative need for intracellular calcium especially at low, physiological concentrations is not clear. To better define the calcium sources responsible for guinea-pig gallbladder contractions in vitro, we inhibited calcium influx using the calcium channel blocker, methoxyverapamil, and a calcium-free Krebs' solution. Availability and release of intracellular calcium stores were depleted by strontium substitution and ryanodine. CCK-OP was compared to bethanechol and potassium chloride (KCl). Preventing calcium influx with 10(-5) M methoxyverapamil depressed the responses to CCK-OP, bethanechol and KCl. Methoxyverapamil, however, had little effect on the time-dependent generation of tension to CCK-OP, but significantly reduced the response to bethanechol and KCl, each at ED50. The duration of the contractile response in the calcium-free Krebs' solution to CCK-OP was longer than that for bethanechol. Strontium (2.5 mM) significantly attenuated the response to CCK-OP and bethanechol, but not to KCl. Ryanodine significantly reduced contractions induced by CCK-OP but not for bethanechol, both at low dose ED25. These results indicate that contraction of the guinea-pig gallbladder induced by CCK-OP, bethanechol and KCl requires extracellular calcium influx. Further, the initiation and maintenance of contraction by CCK-OP and bethanechol necessitates calcium mobilisation from intracellular stores. CCK-OP may have a greater penchant for these calcium stores, particularly at physiological doses.     

Mechanism of action of neurotensin at the ileocecal sphincter region

Neurotensin, a neuropeptide identified in the distal small intestine, plays an unclear role in ileocecal sphincter regional function. The purpose of this study was to determine the effect and mechanism of action of neurotensin on the feline ileocecal sphincter (ICS), proximal colon, and distal ileum. Intraluminal pressures were recorded at these sites in anesthetized cats after superior mesenteric artery injection of neurotensin. Dose dependent tonic and phasic contractions were seen at all sites. Peak pressure responses were seen at the maximal dose used and were greater for the ICS than the distal ileum and the proximal colon. The threshold dose for peak pressures for neurotensin was 0.05 microgram/kg for all sites with the maximal peak pressures occurring at the maximal dose used (100 micrograms/kg). The motility index (MI [number of contractions x mean amplitude of contractions]) was determined for three minutes before and after neurotensin injection. The change in the motility index after neurotensin increased at doses above 0.05 micrograms/kg for the ileum and the ICS and 0.25 microgram/kg for the colon. Maximal responses for the motility index were seen at 1 microgram/kg for the distal ileum, and 10 micrograms/kg for the ICS and the proximal colon, with the greatest response seen at the ICS. Neurotensin-induced ICS relaxation was seen at 1 microgram/kg (50 +/- 10%, p less than 0.01) in 33% of cats. The contractile responses of the distal ileum and the proximal colon were not inhibited by naloxone, trimethaphan, tetrodotoxin, or atropine. The ICS contractile response was decreased by tetrodotoxin by 53%, p less than 0.05. The alpha 2 antagonist, yohimbine reduced the neurotensin induced ICS contraction from 31.6 +/- 3.4 to 21.9 +/- 3.3 mm Hg, p less than 0.05. Prazosin had no effect on neurotensin-induced contractions. In the presence of cimetidine and diphenhydramine, trimethaphan did not affect the neurotensin-induced contractile response at all three sites. However, neurotensin inhibited contractions induced by trimethaphan alone at all three sites. Conclusions: 1. Neurotensin causes a dose-dependent contractile response at the distal ileum, ICS, and proximal colon. 2. Neurotensin has an inhibitory effect at all three sites. 3. The contractile response at the distal ileum and the proximal colon is mediated via smooth muscle receptors. 4. The contractile response of neurotensin at the ICS is mediated partly via alpha 2 receptors and partly via smooth muscle receptors.     

The incidence of giant spike bursts and repetitive bursts of action potentials in the ovine small bowel before and after cholecystokinin administration

Giant spike bursts (GSBs) or giant contractions (GCs) and repetitive bursts of action potentials (RBAPs) are less common motility patterns as compared to the migrating motor complex (MMC), fed pattern or minute rhythm. They are present in small and large intestines in various animal species. Their occurrence in ruminants has not been satisfactorily evidenced. Thus, the aim of this study was to present the incidence of these patterns in the ovine small bowel before and after different doses of cholecystokinin octapeptide (CCK-OP) and cerulein as well as to demonstrate the motor correlates of RBAPs.Six sheep equipped with electrodes in the antrum and entire small intestine and with duodenal strain gauge force transducer were used. In fasted and non-fasted animals, continuous myoelectrical and motor recordings were performed before and after the slow injection of cholecystokinin octapeptide (20, 200 and 2000 ng/kg i.v.) and cerulein (1, 10 and 100 ng/kg i.v.) during phase 2 MMC. The incidence of GSBs and RBAPs was assessed and these patterns arrived before and after Cholecystokinin (CCK). During the control period RBAPs were most frequently observed in the ileum. GSBs and RBAPs were induced by the highest dose of the hormones. RBAPs exhibited the motor correlates and their tonic component was more pronounced following CCK-OP and cerulein injection.It is concluded that GSBs and RBAPs occur in the small intestine and the administration of CCK peptides further increases their incidence.     

Effects of novel 5-HT1A receptor antagonists on measures of postsynaptic 5-HT1A receptor activation in vivo

The effects of two putative 5-HT_1A antagonists, 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) and 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-flourobenzamido]ethyl]piperazine (p-MPPF), were examined in vivo in two tests of postsynaptic 5-HT_1A receptor activation, hypothermia and reciprocal forepaw treading, in the rat. Both p-MPPI (10 mg/Kg, I.p.) and p-MPPF (10 mg/Kg, I.p.) antagonized the hypothermia induced by the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/Kg, S.c.). Neither p-MPPI nor p-MPPF administered alone at a dose of 10 mg/kg (i.p.) induced hypothermia. Similarly, both p-MPPI (10 mg/Kg, I.p.) and p-MPPF (2.5 mg/Kg, I.p.) completely antagonized 8-OH-DPAT (2 mg/Kg, S.c.)-induced forepaw treading in rats pretreated with reserpine (1 mg/Kg, S.c., 18–24 hours prior to the experiment). p-MPPI and p-MPPF, at doses of 10 mg/kg (i.p.) did not induce forepaw treading in reserpine pretreated animals. The results of the present study demonstrate that p-MPPI and p-MPPF act as 5-HT_1A receptor antagonists in these measures of postsynaptic 5-HT_1A a receptor activation.     

Intravital microscopy: a new in vivo technique for visualizing and quantifying effects of regulatory peptides on choledochoduodenal junction motility

Using intravital microscopy, we studied the in vivo effects of regulatory peptides on choledochoduodenal junction motility in guinea pigs. During basal and hormone-stimulated periods, intravital microscopy documented rhythmic, asymmetrical, "milking" contractions of the sphincter ductus choledochi (SDC) which occurred independent of sphincter ampullae (SA) contractions or were followed by SA contractions. Cholecystokinin octapeptide (CCK-8) (greater than or equal to 0.01 micrograms/kg) increased the frequency of SDC contractions and at higher doses (greater than or equal to 0.1 microgram/kg) increased the frequency of SA contractions. Pentagastrin (greater than or equal to 1.0 microgram/kg) and secretin (10 micrograms/kg) decreased the contraction frequencies of both sphincters. Biliary manometry demonstrated similar effects of these peptides on the frequency of the SDC and SA contractions, but also showed that CCK-8 (0.1 microgram/kg) increased the amplitude of SDC and SA contractions while pentagastrin (1 microgram/kg) decreased the amplitude of only SDC contractions. Tetrodotoxin and atropine did not affect hormone-induced changes in frequency, but tetrodotoxin reduced the increase in amplitude of contraction caused by CCK-8. We concluded that intravital microscopy provides a sensitive, in vivo technique to visualize and quantify the complex motility of a small structure like the choledochoduodenal junction.     

Action of cholecystokinin on the dog sphincter of Oddi: influence of anti-cholinergic agents.

Effects of cholecystokinin (CCK) on bile flow through the sphincter of Oddi (SO) were studied in anaesthetized dogs. Intravenous injection of CCK (0.25, 0.5, 1 and 2 IDU/Kg) elicited a dose-dependent reduction in flow through the SO in the first minutes after CCK administration. Pirenzepine and atropine decreased significantly (P less than 0.05) by 29% and a 40% respectively the inhibitory effect induced by 1 IDU/Kg of CCK, whereas hexamethonium elicited an increase in the inhibitory effect induced by 0.5 IDU/Kg of CCK (P less than 0.05). Intravenous infusion of cummulative doses of CCK had different effects according to the dose infused. Lower doses (0.025 and 0.05 IDU/Kg/min) increased transphincteric flow, however, high doses (0.1, 0.2 and 0.4 IDU/Kg/min) were inhibitory. These finding indicated that CCK had two effects on the SO : firstly, a contractile effect, probably mediated through a direct myogenic action and neuronal release of ACh, and secondly a relaxant effect, probably mediated by stimulation of inhibitory postganglionic neurons.     

Cholecystokinin-dependent selective inhibitory effect on 'minute rhythm' in the ovine small intestine

Cholecystokinin (CCK) can exert multiple actions on intestinal motility but its effect on the small-intestinal 'minute rhythm' (MR) is virtually unknown. Therefore, the electrical activity from the abomasal antrum, duodenal bulb, duodenum, jejunum and ileum was continuously recorded in six sheep before, during and after slow intravenous administration, of three doses each, of cholecystokinin-octapeptide (CCK-OP) and cerulein. In four of these sheep, two additional electrodes and the strain gauge force transducer were also inserted in the duodenum. Chronic experiments were performed in the fasted and non-fasted animals and saline or CCK peptides were injected during phases 1, 2a or 2b of the duodenal migrating myoelectric complex (MMC). The administration of both CCK peptides in various doses evoked an inhibitory effect mostly in the duodenal bulb, except for the lowest dose of cerulein. The effects of 20 times greater doses of CCK-OP than that of cerulein were more pronounced. The introduction of both CCK peptides during phase 1 of the MMC produced no marked or significant response. In non-fasted animals, the effects of both hormonal peptides, given during phase 2b of the MMC, were often stronger than those given during phase 2a, while in fasted animals the effects of CCK peptides, administered in the course of phases 2a and 2b of the MMC, were similar. Both higher doses of CCK peptides increased the number of spike bursts within the given MR pattern in the duodenum and decreased the incidence of MR mostly in the duodenal bulb. The inhibitory effects of both CCK peptides on the bulbar MR exhibited a dose-response character, though the lowest dose often evoked the slight stimulatory response. It is concluded that CCK principally exerts an inhibitory effect upon the MR in the duodenal bulb and modifies the MR in the duodenum by increasing the spike burst number in a given MR pattern. Both these actions of CCK peptides seem to be physiological. There is a positive relationship between the intensity of the refractory period and the demonstrated effect of CCK in the duodenum.     

The effect of vasoactive intestinal polypeptide (VIP) on the canine gallbladder motility.

1. VIP at doses of 10(-9) to 10(-8) M was ineffective and at doses of 5 x 10(-8) to 10(-7) M exerted a slight inhibitory effect on the tone of the canine gallbladder muscle strip. However, VIP (0.1-1 micrograms/kg) injected intravenously (i.v.) in conscious dogs dose-dependently decreased the gallbladder pressure. 2. VIP did not influence significantly the acetylcholine (ACh)- or carbachol- induced contractions of canine gallbladder under in vitro or in vivo conditions, but it decreased the electrically-induced, atropine-sensitive contractions of gallbladder muscle strips. 3. VIP (5 x 10(-9) to 5 x 10(-8) M) did not influence significantly the dose-response curve for cholecystokinin octapeptide (CCK OP) of canine and guinea-pig gallbladder muscle strips. VIP injected i.v. (0.1-0.5 micrograms/kg) in conscious dogs greatly decreased the CCK OP-induced gallbladder pressure.