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PubMed1989

Neural mechanisms of pancreatic polypeptide release in conscious dogs.

L364,718, a potent and specific antagonist for peripheral cholecystokinin (CCK) receptors, was used to determine its effect on plasma levels of pancreatic polypeptide (PP) after administration of 2-deoxy-D-glucose (2-DG, a central vagal activator) and of bethanechol (a cholinergic receptor agonist). Six conscious dogs were used in this study. Intravenous injection of 2-DG (75 mg/kg) caused significant increases in plasma levels of PP and gastrin, but there was no significant rise in plasma levels of immunoreactive and bioactive CCK. Intravenous injection of L364,718 (20 nmol/kg) significantly inhibited the PP response stimulated by 2-DG injection by approximately 60% but did not affect gastrin. Plasma levels of PP were increased dose dependently by bethanechol infusion and were not altered significantly by injections of L364,718. The results indicate that L364,718 inhibits PP response stimulated by a central vagal activator (2-DG) but not by cholinergic receptor agonist (bethanechol). This study suggests that CCK might be involved in the neural control of PP release as a neurotransmitter but probably not as a final activator of PP cells in dogs.

Animals↗
PubMed1989

Benzodiazepine analogues L365,260 and L364,718 as gastrin and pancreatic CCK receptor antagonists.

We examined the ability of the recently described 3-(benzoylamino)benzodiazepine analogue L365,260 and the 3-(acylamino)benzodiazepine analogue L364,718 to distinguish gastrin from pancreatic cholecystokinin (CCK) receptors. Neither L365,260 nor L364,718 when present alone (1 microM) caused stimulation of amylase release from guinea pig pancreatic acini or caused contraction of smooth muscle cells from guinea pig stomach. Each analogue inhibited CCK-stimulated amylase release, gastrin-17-I-stimulated smooth muscle contraction, binding of 125I-Bolton-Hunter-cholecystokinin octapeptide (125I-BH-CCK-8) to pancreatic CCK receptors, and binding of 125I-gastrin-17-I to gastrin receptors on pancreatic acini. L365,260, (Ki, 7.3 +/- 0.8 nM) was 50-70 times more potent than L364,718 at inhibiting binding of 125I-gastrin to pancreatic acini or gastrin-stimulated smooth muscle contraction. In contrast, L364,718 (Ki, 4 +/- 1 nM) was 145-200 times more potent than L365,260 at inhibiting binding of 125I-BH-CCK-8 to pancreatic acini or CCK-stimulated amylase release. Neither L364,718 nor L365,260 distinguished between high- and low-affinity CCK binding sites. L365,260 and L364,718 did not inhibit binding of radiolabeled vasoactive intestinal peptide, secretin, bombesin, substance P, or N-methylscopolamine to pancreatic acini. These results demonstrate that, in contrast to other gastrin-CCK receptor antagonists described, L365,260 is a selective gastrin receptor antagonist having an 80-fold higher affinity for gastrin than pancreatic CCK receptor, whereas L364,718 has a 125-fold higher affinity for pancreatic CCK receptors. Because of the selectivity of these two antagonists the involvement of CCK and gastrin in various physiological processes can be differentiated even when both receptors occur on the same cell.

Amylases↗
PubMed1989

Properties of receptors for gastrin and CCK on gastric smooth muscle cells.

Previous studies have demonstrated that cholecystokinin (CCK), gastrin, and structurally related peptides can interact with various types of receptors that can be distinguished by their relative affinities for agonists and antagonists. In the present study we examined the effect of gastrin, the COOH-terminal octapeptide of CCK (CCK-8), and the tetrapeptide of CCK (CG-4) on contraction of dispersed gastric smooth muscle cells from guinea pig and tested the ability of various CCK receptor antagonists to affect agonist-induced muscle cell contraction. For purposes of comparison we tested the effect of each antagonist on CCK-stimulated amylase secretion by pancreatic acini from guinea pig. On gastric smooth muscle cells, CCK-8, gastrin, and CG-4 were all full agonists. CCK-8 and gastrin were equipotent and CG-4 was 6,000-fold less potent. Each antagonist caused inhibition of CCK-stimulated contraction with relative potencies (IC50): L364,718 (4 microM) = CBZ-CCK-(27-32)-NH2 (3 microM) greater than proglumide analogue 10 (90 microM). Inhibition by each of the antagonists was competitive in nature, specific for CCK peptides, and each had the same IC50 whether contraction was stimulated by CCK-8, gastrin, or CG-4. Relative potencies (IC50) of the three antagonists for inhibiting CCK-stimulated amylase release from pancreatic acini were L364,718 (3 nM) greater than proglumide analogue 10 (200 nM) greater than CBZ-CCK-(27-32)-NH2 (3 microM). These results demonstrate that gastric smooth muscle cells possess receptors that differ from CCK receptors on pancreatic acini in terms of affinities for both agonists and certain antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1989

Effects of the CCK receptor antagonist L364,718 on pancreatic growth in adult and developing animals.

Although exogenous administration of cholecystokinin (CCK) or dietary manipulation to increase circulating CCK have previously been shown to promote pancreatic growth, the role of CCK in controlling normal pancreatic development remains unclear. A potent CCK receptor antagonist, L364,718, was administered to rats, guinea pigs, and hamsters to block the effect of endogenous CCK. Animals were given continuous infusions of L364,718 (25 nmol.kg-1.h-1), CCK octapeptide [(CCK-8) 200 pmol.kg-1.h-1], or both CCK-8 and L364,718 for 14 and 28 days. Adult (4-mo-old) and young (4-wk-old) animals were used. CCK-8 and L364,718 were administered via separate, subcutaneously implanted mini-osmotic pumps. Infusions of CCK-8 alone for 28 days resulted in a 21.7% increase in wet pancreatic weight in 4-wk-old rats and a 22.7% increase in 4-wk-old guinea pigs (both P less than 0.001 compared with controls). Similar increases were found in DNA, RNA, and total protein contents. Coadministration of L364,718 totally blocked the trophic effects of exogenously infused CCK-8 in rats and guinea pigs. Administration of L364,718 alone in hamsters, guinea pigs, and rats for 14 and 28 days failed to alter the normal growth of the pancreas gland as measured by these parameters. Although elevated levels of CCK appear to promote a potent trophic response in the growing pancreas, this regulatory peptide does not appear to be an essential trophic factor for the normal growth of the exocrine pancreas in these animals.

Aging↗
PubMed1989

Role of endogenous cholecystokinin on vagally stimulated pancreatic secretion in dogs.

Pancreatic exocrine secretion was evoked by electrical stimulation of the vagus nerves (EVS) in dogs to determine whether a gut hormone was responsible for the pancreatic stimulatory activity. In 39 dogs, pancreatic juice was continuously collected to measure volume, bicarbonate, and amylase output, while portal and femoral venous plasma concentrations of gastrin, cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), and pancreatic polypeptide (PP) were determined by radioimmunoassay. EVS produced a significant increase in the pancreatic secretion. Although concentrations of all four peptides significantly increased in plasma, only CCK at the concentration in venous circulation was bioactive in dispersed rat pancreatic acini preparations. This bioactivity of CCK was completely blocked by CR 1409, a CCK-receptor antagonist. The pancreatic secretion by EVS was reduced significantly by intravenous MK-329 (formerly L364,718) to as low as 22% of control values and was completely suppressed by intravenous atropine. The increment in plasma CCK by EVS was also significantly suppressed by atropine. The present study indicates that increased pancreatic secretion by EVS is in part mediated by endogenous CCK.

Amylases↗
PubMed1990

Effect of CCK antagonist L 364718 on meal-induced pancreatic secretion in rats.

The specific cholecystokinin (CCK)-receptor antagonist L 364718 was used to examine the role of CCK in meal-induced pancreatic secretion. Unanesthetized rats with gastric, jugular vein, bilepancreatic, and duodenal cannulas were used; bile-pancreatic juice was recirculated. Basal amylase secretion (30% of maximal) was not inhibited by L 364718 doses of 0.5 or 2 mg/kg intravenously. L 364718 (0.02 to 2 mg/kg) caused dose-related inhibition of the maximal amylase response to CCK-8 (200 pmol.kg-1.h-1), with greater than 80% inhibition at doses greater than or equal to 0.5 mg/kg. L 364718 (0.5 mg/kg) shifted the dose-response curve to CCK-8 (25-3,200 pmol.kg-1.h-1) to the right (ED50 increased 10-fold) but did not alter maximal amylase output consistent with competitive inhibition of CCK in vivo. Ingestion of liquid food significantly increased amylase output threefold above basal. L 364718 (0.5 mg/kg) completely blocked this response. These results suggest that although CCK does not regulate basal pancreatic enzyme secretion, it is the primary mediator of pancreatic enzyme secretion in response to a liquid meal.

Amylases↗
PubMed1990

Reduced cholecystokinin mediates the inhibition of pancreatic growth induced by bile salts.

The effects of luminal bile salts on plasma levels of cholecystokinin (CCK) and growth of the pancreas in mice were studied. Nonfasting levels of plasma CCK in control mice were 8.1 +/- 1.5 pM. Feeding mice a 0.5% (wt/wt) sodium taurocholate-supplemented diet for 1 wk significantly lowered nonfasting levels of plasma CCK to 4.1 +/- 0.5 pM and decreased the total contents of pancreatic DNA by 22%, RNA by 25%, and protein by 24%. All of the inhibitory effects of taurocholate on pancreatic growth were completely reversed by the simultaneous administration of CCK-8 (3 micrograms/kg, 3 times daily). In contrast, intraluminal neutralization of endogenous bile salts by feeding a 4% (wt/wt) cholestyramine-supplemented diet for 1 wk significantly elevated nonfasting levels of plasma CCK to 14.7 +/- 1.5 pM and increased the total contents of pancreatic DNA by 34%, RNA by 40%, and protein by 35%. All of the stimulatory actions of cholestyramine on pancreatic growth were completely abolished by the administration of the highly potent and specific CCK-receptor antagonist L364,718 (1 mg/kg, twice daily). These findings, therefore, indicate that bile salts appear to play a physiological role in pancreatic growth by regulation of plasma levels of CCK.

Animals↗
PubMed1990

Distinct receptors for cholecystokinin and gastrin on muscle cells of stomach and gallbladder.

A technique of receptor protection that enables selective preservation of one receptor type was used in conjunction with preferential antagonists of cholecystokinin (L364,718) and gastrin (L365,260) to characterize cholecystokinin (CCK) and gastrin receptors on isolated single muscle cells of the guinea pig stomach and gallbladder. In gastric muscle cells, CCK-8 and gastrin-17 were equipotent and the concentration causing 50% inhibition of response (IC50) values of both antagonists were independent of the agonist, whereas in gallbladder muscle cells, CCK-8 was more potent than gastrin-17 and the IC50 values of the antagonists were dependent on the agonist. In gastric muscle cells, CCK-8, gastrin-17, and L364,718 protected completely the response to CCK-8 or gastrin-17, and L365,260 protected partially but equally the response to both agonists. In gallbladder muscle cells, CCK-8 and L364,718 protected completely and gastrin-17 and L365,260 protected partially the response to CCK-8; conversely, gastrin-17 and L365,260 protected completely and CCK-8 and L364,718 protected partially the response to gastrin-17. The patterns of response in muscle cells from the two regions indicate the presence of one receptor type in gastric muscle cells that interacts equally with gastrin and CCK, and of two receptor types in gallbladder muscle cells, one of which interacts preferentially with CCK and the other preferentially with gastrin.

Animals↗
PubMed1990

Control of interdigestive and intraduodenal meal-stimulated pancreatic secretion in rats.

Mechanisms of neural (vagal and cholinergic) and hormonal [cholecystokinin (CCK)] control of pancreatic exocrine secretion were studied in basal interdigestive conditions and after stimulation by an intraduodenal meal in rats equipped with a semichronic pancreatic fistula. Bile was recirculated into the duodenum, and a solution of trypsin and electrolytes was continuously infused. Pancreatic secretion was compared in control experiments, after vagotomy, and after venous infusion of cholinergic and CCK antagonists. Basal pancreatic secretion was decreased by atropine, pirenzepine, and hexamethonium and to a lesser extent by vagotomy (protein output decreased more than fluid and HCO3- outputs). The CCK antagonists L364,718 and lorglumide had no effect on basal interdigestive pancreatic secretion. Small doses of atropine (8 and 25 micrograms.kg-1.h-1) did not modify the cumulated pancreatic response to the meal, whereas larger doses (75 and 225 micrograms.kg-1.h-1) increased it by 40-85%, according to the variables. Pirenzepine and hexamethonium did not modify the pancreatic response. Vagotomy had no effect on fluid and HCO3- responses and tended to increase protein response. L364,718 and lorglumide completely inhibited the protein response and decreased the fluid and HCO3- responses by 75 and 40%, respectively. L364,718 also suppressed the increased pancreatic response induced by atropine. This work confirms the prominent role of neural cholinergic mechanisms in the control of basal interdigestive pancreatic secretion in rats. In contrast, the pancreatic protein response to an intraduodenal meal depends on CCK, whereas fluid and HCO3- responses also depend on other hormonal factors. Our results suggest that a muscarinic (probably M3) mechanism can decrease the postprandial CCK release independently of the pancreatic feedback control by trypsin.

Animals↗
PubMed1991

Characterization of a gastrin-type receptor on rabbit gastric parietal cells using L365,260 and L364,718.

Previous studies have demonstrated that gastrin and the COOH-terminal octapeptide of cholecystokinin (CCK-8) stimulated in vitro acid secretion from isolated rabbit gastric parietal cells. Both peptides bind to receptor sites located on these cells and induce an increase in phosphoinositide turnover and an uptake of [14C]aminopyrine ([14C]AP) with the same efficacy and potency. In the present study, we used the 3-(benzoylamino)-benzodiazepine analogue L365,260 and the 3-(acylamino)-benzodiazepine analogue L364,718 to investigate what type of receptor (gastrin type or CCK-A type) is involved in the regulation of the H+ secretory activity of the rabbit parietal cell. Neither L365,260 nor L364,718 alone caused stimulation of [3H]inositol phosphates ([3H]InsP) production. Each analogue inhibited 125I-labeled gastrin or 125I-CCK-8 binding to parietal cells and gastrin- or CCK-8-induced [3H]InsP production and [14C]AP accumulation. In all cases, L365,260 was approximately 70-100 times more potent than L364,718 (IC50 approximately 2-4 nM for L365,260 and approximately 0.2-0.4 microM for L364,718). Nevertheless, each antagonist displayed the same potency to inhibit the effects of gastrin or CCK-8. These results demonstrate that gastrin and CCK-8 interact with the same "gastrin-type" receptor on parietal cells. Moreover, L365,260 behaves as a competitive antagonist of the action of gastrin on parietal cells. Gastrin induces a rise in the levels of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] within the first seconds after parietal cell stimulation. The fact that L365,260 (10 nM) totally suppressed the gastrin-induced formation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 suggests the involvement of these isomers in the mediation of acid secretion through gastrin receptor activation.

Aminopyrine↗
PubMed1991

Effect of two new cholecystokinin antagonists on gallbladder emptying in opossums.

In this investigation we evaluated the effect of two new cholecystokinin (CCK) antagonists, CR 1409 and L364,718, on gallbladder emptying in the opossum. Gallbladder emptying was elicited by both exogenous and endogenous CCK. The three test challenges were 1) intravenous infusion of CCK octapeptide (OP) (10 ng.kg-1.min-1), 2) feeding, and 3) intraduodenal infusion of Isocal (0.4 ml/min), a fat-containing nutrient. During control conditions each test challenge elicited approximately 60% gallbladder emptying within 30 min and 70% emptying by 60 min. At given doses both CR 1409 and L364,718 substantially antagonized or abolished the gallbladder emptying elicited by each of the test challenges. The antagonism for postprandial gallbladder emptying was diminished between 30 and 50 min compared with that for CCK-OP infusion and intraduodenal infusion of Isocal. Unexpectedly, the gallbladder emptying induced by infusion of motilin (5 micrograms.kg-1.h-1) was antagonized by either CR 1409 or L364,718. In anesthetized animals, gallbladder contraction was induced by a variety of agonists, such as bethanechol, histamine phosphate, 5-hydroxytryptamine, and phenylephrine. In this later model CR 1409 and L364,718 functioned solely as selective antagonists. We conclude that for the opossum gallbladder 1) the CCK antagonists CR 1409 and L364,718 antagonize or abolish gallbladder emptying induced by exogenous or endogenous CCK; 2) the pattern of CCK antagonism after feeding suggests that the early phase of postprandial gallbladder emptying is mediated by a mechanism other than endogenous CCK, whereas late postprandial emptying is mediated by release of endogenous CCK; and 3) CR 1409 and L364,718 are not totally specific antagonists for gallbladder CCK receptors alone but also antagonize gallbladder contraction induced by motilin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

CCK-B (gastrin) receptor regulates gastric histamine release and acid secretion.

To study the interdependence between gastric histamine release and acid secretion, we examined the effects of gastrin-(1-17) [G-(1-17)] or cholecystokinin-(1-33) [CCK-(1-33)] alone or combined with the gastrin (CCK-B) antagonist L365,260 or the CCK-A antagonist L364,718 in the isolated vascularly perfused rat stomach. G-(1-17) and CCK-(1-33) gave concentration-dependent increases in acid secretion and histamine release. Gastrin or CCK-A antagonist alone did not stimulate histamine release or acid secretion. Maximally G-(1-17) or CCK-(1-33) stimulated histamine release and acid secretion was unchanged by the CCK-A antagonist, while the gastrin antagonist induced a parallel and concentration-dependent decrease in stimulated histamine and acid secretion. We conclude that G-(1-17) and CCK-(1-33) stimulate histamine and acid secretion by a CCK-B (gastrin) receptor. The present results indicate that gastrin, at least in this species, stimulates acid secretion by releasing histamine.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Hormonal control of avian pancreas by gastrin-releasing peptide from the proventriculus.

Endocrine cells in the acid-secreting part of the avian stomach, the proventriculus, contain two forms of gastrin-releasing peptide (GRP) of 27 and 6 residues, respectively. We have examined the actions of exogenous GRP-27 and GRP-6 and endogenously released GRP in the control of pancreatic secretion in urethan-anesthetized turkeys. Chicken GRP-27 and the structurally related amphibian peptide bombesin were potent stimulants of fluid and protein output from the pancreas (at 6-100 pmol/kg, iv). GRP-6 had no significant effect at doses up to 1,000 times higher. A bombesin antagonist, (CH3)2-CHCO-[D-Ala24]GRP-20--26-NHCH3, inhibited the action of exogenous chicken GRP-27 but did not inhibit intravenous cholecystokinin octapeptide (CCK-8). Distension of the proventriculus with a solution of peptone produced an increase in the flow of pancreatic juice and an increase in protein output, which was not reduced by atropine. The bombesin antagonist produced a reversible inhibition of this response. A CCK-gastrin antagonist, BOC-beta-Ala-Trp-Leu-Asp-O(CH2)2- phenyl(4F), which inhibited the action of exogenous CCK, had no effect on the pancreatic response to exogenous GRP-27 or to distension of the proventriculus with peptone. We suggest that protein-rich solutions in the proventriculus release GRP, which in turn acts directly on the pancreas to stimulate enzyme secretion.

Amino Acid Sequence↗
PubMed1992

Intestinal acid inhibits gastric acid secretion by neural and hormonal mechanisms in rats.

To determine the relative contributions of neural reflexes and intestinal hormones to the inhibition of gastric acid secretion by intestinal acidification, rats with an extrinsically denervated, transplanted segment of jejunum, and those with an innervated segment of jejunum, were studied. Postoperatively, meal-stimulated gastric acid secretion was measured. When the acid secretory response to intragastric liver extract reached a plateau, graded concentrations of hydrochloric acid or saline were instilled into the jejunal segments. Gastric acid secretion was inhibited by intrajejunal acid (pH 2.5) by 79% in the innervated rats and by 64% in the transplanted group. Thus at a pH of 2.5 there was a 15% greater maximum inhibition of plateau acid response in the innervated rats than in the transplanted rats, presumably because of the extrinsic neural contribution. To examine the hormonal mediators, the effects of a somatostatin monoclonal antibody and a CCK-A receptor antagonist (L 364718) on acid-induced inhibition of gastric acid secretion were studied in transplanted rats. Treatment with a somatostatin monoclonal antibody or with L 364718 reduced the acid-induced (pH 2.5) inhibition of gastric acid secretion by 93 and 27%, respectively. Jejunal acidification inhibits gastric acid secretion in the rat by both neural and hormonal mechanisms. The hormonal mechanism is mediated by somatostatin and CCK.

Acids↗
PubMed1992

Both CCK-A and CCK-B/gastrin receptors mediate pepsinogen release in guinea pig gastric glands.

We evaluated the affinity of cholecystokinin octapeptide (CCK-8), gastrin, and subtype-selective CCK agonists for CCK/gastrin receptors and compared it with the ability of these peptides to stimulate phosphoinositide (PI) hydrolysis and pepsinogen release in guinea pig gastric glands. Competitive binding studies using 125I-labeled Bolton-Hunter-CCK-8 and 125I-gastrin showed the presence of CCK-B/gastrin receptors in gastric glands and dispersed chief cells. In contrast, the potency of peptides in stimulating PI hydrolysis in both gastric glands and dispersed chief cells displayed a profile similar to CCK-A receptors found in pancreatic acini, i.e., CCK-8 = A 71378 greater than A 71623 greater than A 70874 much greater than A 72962 = CCK-8 (desulfated) greater than gastrin II greater than gastrin I. In general, the rank order of potency of peptides for stimulation of PI hydrolysis correlated well with their ability to stimulate pepsinogen release. At concentrations greater than 10 microM, efficacies of gastrin I and II in stimulating pepsinogen release from gastric glands were near 90% of the maximal activity of CCK-8. The inhibitory potency of MK-329, a selective CCK-A receptor antagonist, was similar against either CCK-8 (10 nM) or gastrin I (10 microM), except that a minor portion (approximately 30-40%) of gastrin I-induced pepsinogen release was insensitive to MK-329. The MK-329-insensitive component was inhibited by CI-988, a potent and selective CCK-B/gastrin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Innervation of pylorus in control of motility and gastric emptying.

The motility index (MI) and contractile frequency were determined for the gastric antrum, pylorus, and duodenum during digestive and interdigestive states in eight dogs before and after resection of the ramus pyloricus nervi vagi (NR) and after selective proximal vagotomy (SPV) subsequent to NR. Neither NR nor subsequent SPV altered the migrating motor complex in the interdigestive state. In the digestive state, NR decreased the MI in the antrum, pylorus, and duodenum. The MI did not further change after SPV subsequent to NR. The cholecystokinin antagonist L364,718 decreased MI in the antrum, pylorus, and duodenum. After NR, L364,718 caused a further reduction in the MI during administration. Gastric emptying was accelerated after NR. SPV subsequent to NR increased gastric emptying further. L364,718, in the absence of NR, accelerated gastric emptying but only during the initial period of emptying. After NR, L364,718 also decreased the time required for emptying of 50 and 100% of the meal. After SPV subsequent to NR, no additional acceleration of emptying occurred.

Animals↗
PubMed1992

Cholecystokinin inhibits gastric acid secretion through type "A" cholecystokinin receptors and somatostatin in rats.

The purpose of this study was to determine whether selective antagonism of type "A" cholecystokinin (CCK) receptors blocks inhibition of gastric acid secretion produced by CCK and whether this inhibition is mediated through either a somatostatin-dependent pathway or a vago-vagal reflex. Intravenous infusion of CCK (0.04-10 nmol.kg-1.h-1) dose dependently inhibited pentagastrin-stimulated gastric acid secretion in urethan-anesthetized rats, with a 50% inhibitory dose of 0.9 nmol.kg-1.h-1 and a maximum inhibition of approximately 50%. Blockade of type A CCK receptors using the selective type A receptor antagonist MK-329 completely reversed the inhibitory effect produced by a maximal dose (4 nmol.kg-1.h-1) of CCK. Immunoneutralization of endogenous somatostatin by administration of somatostatin monoclonal antibody abolished the inhibition produced by CCK. Concentrations of somatostatin in portal venous plasma were significantly increased after CCK administration; the increase in somatostatin was blocked by pretreatment with MK-329. In contrast, CCK-induced inhibition of gastric acid secretion was unaltered after perivagal capsaicin treatment. These results indicate that CCK inhibits gastric acid secretion in rats by activation of type A CCK receptors and through release of endogenous somatostatin.

Animals↗
PubMed1993

Gastrin and CCK activate phospholipase C and stimulate pepsinogen release by interacting with two distinct receptors.

Both gastrin and cholecystokinin (CCK) can stimulate pepsinogen release from chief cells, but controversy exists about the receptors or intracellular mediators involved. In the present study, we prepared isolated chief cells from guinea pig stomach (> 90% pure) to investigate the ability of gastrin and CCK to alter cell function. The COOH-terminal octapeptide of CCK (CCK-8) caused an eightfold increase in pepsinogen release (EC50, 54 nM). Both CCK-8 and gastrin increased inositol phosphates, with CCK-8 (1 microM) and gastrin (3 microM) causing a 40- and 14-fold increase in [3H]IP1, 10- and 6-fold for [3H]IP2, and 8- and 4-fold for [3H]IP3. CCK-8 caused a half-maximal increase in [3H]IP3 at 2 nM, and the dose-response curve was monophasic, whereas with gastrin the curve was biphasic, with an EC50 of the initial component (20% maximal) at 38 nM and the second component at 10 microM. L-364,718 (0.1 microM) inhibited the secondary increase seen with gastrin concentrations > 10 nM. The CCK-A-selective agonist A-71378 was 85-90% as efficacious as CCK-8 and was equally potent. With 0.1 microM L-364,718, A-71378 caused no increase in [3H]inositol phosphates until > 10 nM, whereas CCK-8 caused 15% of maximal increase at concentrations > 0.3 nM. Similar results were obtained with cytosolic calcium measured using fura-2 or on CCK-8- or gastrin-stimulated pepsinogen release. These results demonstrate that gastrin and CCK-8 can alter chief cell function by interacting with either a CCK-A or CCK-B/gastrin receptor. Both receptors are coupled to phospholipase C and cause changes in inositol phosphates, cytosolic calcium, and pepsinogen release; however, the intracellular amplification differs between the two receptor subtypes. Activation by CCK-related peptides of the CCK-A receptor subtype accounts for 85-90% of the maximal changes in cellular function, and activation of the CCK-B/gastrin receptor accounts for 10-20% of maximal changes.

Animals↗