Peripheral PACAP inhibits gastric acid secretion through somatostatin release in mice

1. Studies in rats suggest that PACAP modulates gastric acid secretion through the release of both histamine and somatostatin. 2. We characterized the effects of exogenous PACAP on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula and in conscious 2-h pylorus ligated mice, and determined the involvement of somatostatin and somatostatin receptor type 2 (SSTR2) by using somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. 3. Urethane-anesthetized wild-type mice had low basal acid secretion (0.10+/-0.01 micromol (10 min)(-1)) compared with SSTR2 knockout mice (0.93+/-0.07 micromol (10 min)(-1)). Somatostatin antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. 4. In wild-type urethane-anesthetized mice, PACAP-38 (3-270 microg kg(-1) h(-1)) did not affect the low basal acid secretion, but inhibited the acid response to pentagastrin, histamine, and bethanechol. 5. In wild-type urethane-anesthetized mice pretreated with somatostatin antibody or PRL-2903 and in SSTR2 knockout mice, peripheral infusion of PACAP-38 or somatostatin-14 did not inhibit the increased basal gastric acid secretion. 6. In conscious wild-type mice, but not in SSTR2 knockout mice, PACAP-38 inhibited gastric acid secretion induced by 2-h pylorus ligation. The antisecretory effect of PACAP-38 was prevented by immunoneutralization of somatostatin. 7. These results indicate that, in mice, peripheral PACAP inhibits gastric acid secretion through the release of somatostatin and the activation of SSTR2 receptors. There is no evidence for stimulatory effects of PACAP on acid secretion in mice.     

Peripheral GABAB agonists stimulate gastric acid secretion in mice

1 We characterized the effects of intravenous GABA and preferential GABAA (muscimol), GABAB (R-baclofen and SKF-97541) and GABAC agonists (imidazole-4-acetic acid) on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula, and determined the role of vagal cholinergic mechanisms, and gastrin and somatostatin by using peptide immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. 2 The selective GABA(B) agonists R-baclofen (0.1-3 mg kg(-1), i.v.) and SKF-97541 (0.01-0.3 mg kg(-1), i.v.) induced a dose-related stimulation of gastric acid secretion. SKF-97541 was about 10 times more potent than R-baclofen stimulating gastric acid secretion. Neither GABA (0.1-100 mg kg(-1), i.v.) nor muscimol (0.1-3 mg kg(-1)) nor imidazole-4-acetic acid (0.1-10 mg kg(-1)) affected basal gastric acid secretion. 3 Stimulatory effects of SKF-97541 (0.1 mg kg(-1), i.v.) were blocked by the selective GABAB antagonist, 2-hydroxysaclofen, cholinergic blockade with atropine, subdiaphragmatic vagotomy or gastrin immunoneutralization. 4 Somatostatin immunoneutralization or SSTR2 blockade with PRL-2903 enhanced the secretory response to SKF-97541 (0.1 mg kg(-1), i.v.) by 78 and 105%, respectively. 5 In SSTR2 knockout mice, SKF-97541 (0.1 mg kg(-1), i.v.) increased basal gastric acid secretion by 48%. Neither GABA nor muscimol nor imidazole-4-acetic acid modified basal gastric acid secretion in SSTR2 knockout mice. 6 These results indicate that, in mice, stimulation of GABAB receptors increases gastric acid secretion through vagal- and gastrin-dependent mechanisms. Somatostatin implication might be secondary to the release of gastrin and the increase in gastric luminal acidity.     

SMS 201-995-induced stimulation of gastric acid secretion via the dorsal vagal complex and inhibition via the hypothalamus in anaesthetized rats.

1. SMS 201-995, a somatostatin analogue which interacts with highest affinities at somatostatin receptor subtypes 5 > 2 > or = 3, was microinjected into selective brain sites and its influence on pentagastrin (10 micrograms kg-1 h-1, i.v.)-stimulated gastric acid secretion was investigated in rats anaesthetized with urethane. Gastric acid secretion was measured by flushing the stomach with saline through a gastric cannula every 10 min. 2. SMS 201-995 microinjected into the dorsal vagal complex (DVC, 7, 15, 30 and 60 ng) dose-dependently increased pentagastrin-stimulated gastric acid secretion. The peak acid response was reached within 20 min and returned to basal level 50 min post-injection. SMA 201-995 (30 ng) microinjected into the surrounding area or the central amygdala did not modify pentagastrin-stimulated acid secretion. 3. SMS 201-995 injected into the lateral ventricle (i.c.v., 100, 200, or 300 ng), paraventricular nucleus (PVN) or lateral hypothalamus (LH) (7.5, 15, or 30 ng) dose-dependently inhibited pentagastrin-stimulated gastric acid secretion. SMS 201-995 (30 ng) microinjected into the area surrounding the PVN or LH did not modify the acid secretion response to pentagastrin. 4. Vagotomy prevented the effects of SMS 201-995 (30 ng) microinjected into the DVC and LH. 5. Spinal cord transection abolished the inhibitory action of SMS 201-995 (30 ng) microinjected into the PVN but not the LH. 6. These results demonstrate that SMS 201-995 acts in the DVC to enhance and in the LH and PVN to inhibit pentagastrin-stimulated gastric acid secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of a long-acting somatostatin analogue (SMS 201–995) on intermediary metabolism and gut hormones after a test meal in normal subjects

SMS 201-995 is an octapeptide analogue of somatostatin. The effect of a single subcutaneous (s.c.) injection of 50 micrograms SMS 201-995 on post-prandial intermediary metabolism was investigated in normal subjects. In spite of a long-lasting post-prandial suppression of insulin secretion, there were no significant changes in the plasma concentration of alanine, glycerol, 3-OH-butyrate or lactate. However, SMS 201-995 impairs carbohydrate tolerance, probably due to inhibition of insulin secretion. Basal and post-prandial plasma concentrations of the gut regulatory peptides pancreatic glucagon, motilin, pancreatic polypeptide, gastric inhibitory polypeptide, enteroglucagon, gastrin and peptide YY were suppressed up to 5 hours after subcutaneous administration of a single dose of SMS 201-995.     

Prolonged inhibition of meal-stimulated acid secretion and gastrin release following single subcutaneous administration of octreotide (SMS 201–995) in man

Single subcutaneous doses of the somatostatin analogue, SMS 201-995, were evaluated for the degree and duration of effects on acid secretion, serum gastrin levels, and gastric emptying in eight human male subjects (mean age 44 years) over an 8-h period. All the subjects received subcutaneous 50-micrograms and 100-micrograms doses of SMS 201-995 and placebo on three separate days in a double-blind random order. Drug or placebo was administered at time 0 followed by peptone meals at time 0, 2, 4, and 6-h. Peptone meals were evacuated at time 1, 3, 5 and 7-h to create 'basal' conditions between alternate hours. Gastric acid secretion was determined hourly beginning at time--1. Both the 50-micrograms and 100-micrograms doses of SMS 201-995 significantly inhibited 'basal' and peptone meal-stimulated gastric acid secretion throughout the 8-h measurement period. The minimum effective plasma concentration of SMS 201-995 for inhibition of peptone meal-stimulated gastric acid secretion was approximately 1000 pg/ml. Peptone meal-stimulated plasma gastrin concentrations were inhibited for 5 and 7 h after 50-micrograms and 100-micrograms doses of SMS 201-995, respectively, whereas 'basal' plasma gastrins were inhibited for 4 and 6 h, respectively. Gastric emptying determined by marker dilution was not significantly enhanced compared to placebo. These results indicate prolonged and potent effects of single subcutaneous doses of SMS 201-995 on peptone-meal stimulated acid secretion and gastrin release.     

Gastric functions in gastrin gene knock-out mice

The gastric hormone gastrin was the 2nd hormone to be identified and was initially recognized for its ability to induce acid secretion. Following the purification and subsequent development of specific radioimmunoassays for gastrin, it was also shown to be a regulator of oxyntic mucosal growth. To explore the importance of gastrin or its receptors for gastric development and gastric physiology both have been knocked out. The knock-out mice are viable, develop with any gross abnormalities, and are fertile. Even though gastrin acts as a growth factor during hypergastrinaemia there was no general atrophy of the gastrin mucosa in the knock-out mice. But the maturation of both parietal and ECL cells were disturbed and the number of parietal cells reduced. Furthermore, lack of gastrin impaired basal acid secretion and rendered the parietal cells unresponsive to histamine and acetylcholine, the other two major stimulators of gastric acid secretion. Despite the major changes in gastric physiology, the number of genes down-regulated in the gastrin knock-out mice is modest. The achlorhydria due to lack of gastrin also leads to bacterial overgrowth of the stomachs of the gastrin knockout mice, which could facilitate the development of gastric ulcer disease and cancer.     

The lack of effects of somatostatin on gastric responses induced by electrical vagal stimulation

The effects of somatostatin on ulcer formation, gastric acid secretion and histamine release were assessed during vagus nerve stimulation in rats. Direct electrical vagal stimulation significantly increased histamine release and acid output in gastric secretion but decreased mast cell counts in gastric glandular mucosa. Hemorrhagic ulceration on the gastric glandular mucosa was also observed. Somatostatin pretreatment (10 micrograms/kg) did not inhibit gastric ulcer formation, gastric acid secretion or histamine release induced by vagal stimulation. Cimetidine (an H2 blocker) pretreatment, however, significantly decreased gastric acid secretion as well as ulcer formation. The present study indicates the direct vagal stimulation increases gastric acid secretion and ulcer formation. These effects are partially histamine dependent. Somatostatin did not inhibit histamine release induced by vagal stimulation and reflects the inability of the drug to prevent ulcer formation and gastric output under these conditions in rats. However, the inhibition of basal gastric acid secretion produced by somatostatin might be useful clinically in humans.     

Excessive grooming induced by somatostatin or its analog SMS 201-995

Intracerebroventricular (i.c.v.) administration of somatostatin or SMS 201-995 induces excessive grooming behavior in rats. The grooming inducing effect of somatostatin is rather weak, as doses of 300 ng or less did not result in increased total grooming scores. In contrast a dose of 10 ng SMS 201-995 already significantly increased the total grooming scores. However, doses of 100 ng and more did not further increase the total grooming scores reached with a 50 ng dose of this peptide. Systemic administration of SMS 201-995 in doses up to 900 micrograms did not result in excessive grooming behavior. The patterns of excessive grooming induced by i.c.v. SMS 201-995 and somatostatin were characterized by a predominant display of scratching. Since peptide-induced scratching is mainly due to activation of opiate receptor systems it is suggested that opiate receptors are involved in the behavioral response to SMS 201-995 and somatostatin administration. This suggestion is further supported by the suppressive effect of naloxone on excessive grooming induced by these peptides. Haloperidol and neurotensin also suppress the excessive grooming induced by somatostatin but not that induced by SMS 201-995. Finally, tolerance developed to the grooming-inducing effect of SMS 201-995 and somatostatin. In addition there was cross tolerance between somatostatin and SMS 201-995.     

Regulatory mechanism of gastric acid secretion and mucosal integrity--an analysis with various gene deficient mice

Mechanisms for gastric acid secretion have been elucidated through invention of new methods and new drugs. Current genetic technology have generated knockout (KO) mice lacking receptors such as CCK2, histamine H2, muscarinic M3 and M1, or enzymes such as histidine decarboxylase (HDC) and H+,K(+)-ATPase. Here, we review the functional and morphological changes in the gastric mucosa of such KO mice. In M3R-KO mice (intragastric pH 5.9), carbachol, histamine and gastrin stimulated acid secretion like they did in wild-type mice. Carbachol-stimulated acid secretion was significantly inhibited by famotidine and pirenzepine. The serum gastrin level in M3R-KO mice was increased, yet the stomach weight and the gastric mucosa remained unchanged. In H2R-KO mice (intragastric pH 3.0), serum gastrin and mucosal histamine levels significantly increased. Carbachol significantly stimulated acid secretion, yet histamine and gastrin had little or no effect on acid secretion. The stomach wet weight increased with time after birth and the serum albumin level was decreased. In the gastric mucosa with hyperplasia, numerous enlarged cysts and a marked expression of TGF-alpha were observed, indicating the occurrence of Menetrier's disease like mucosal changes. G/D cell ratio was greatly increased, providing evidence of the increased serum gastrin level. In HDC-KO mice (intragastric pH 4.5), the stomach weight was also increased 6 mo after birth, with no enlarged cysts in the gastric mucosa. CONCLUSION: The above results indicate that KO mice can be used to yield many important findings that selective antagonists cannot reveal.     

Effect of somatostatin analogs on gastric acid secretion in dogs and rats

The effects of several superactive analogs of somatostatin on gastric acid response to various exogenous and endogenous stimulants were investigated in conscious dogs and rats with gastric fistulae (GF). The inhibition was compared to that induced by somatostatin-14 (S-S-14) at two dose levels. Several octapeptide analogs of somatostatin including (RC-160) and (RC-121), which were superactive in tests on suppression of GH levels, were 4-5 times more potent than S-S-14 in inhibiting desglugastrin-stimulated gastric acid secretion in GF dogs. The analog RC-160 also reduced the rise in serum gastrin levels and gastric acid secretion induced by sham feeding (SF) in dogs with gastric and esophageal fistulae (EF), but did not decrease food consumption. Gastric acid secretion induced by histamine (80μg/kg/h) in dogs was not affected by 1-5μg/kg/h of analog RC-121 or by 5μg/kg/h of S-S-14. Analogs RC-160, RC-121, and RC-98-I and others also powerfully inhibited desglugastrin-induced gastric acid secretion in GF rats. Hexapeptide cyclo(-Pro-Phe-D-Trp-Lys-Thr-Phe) was only about half as potent as S-S-14 in dogs but its activity was higher in rats. The results indicate that octapeptide analogs which are superactive in GH-inhibition tests are also more potent than S-S-14 in suppressing gastric acid secretion. These findings may be of clinical value.     

Antisecretory effect of somatostatin on gastric acid via inhibition of histamine release in isolated mouse stomach

Somatostatin is known to inhibit gastric acid secretion via both inhibition of histamine release from gastric enterochromaffin-like cells and direct inhibition of parietal cell function. We tried to clarify which of these two mechanisms plays a more important role in the inhibition of gastric acid section by somatostatin using isolated mouse stomach preparations. The gastric acid secretion stimulated by histamine was not inhibited by pretreatment with somatostatin (1 micro M), but somatostatin abolished acid secretion induced by 4-[[[(3-chlorophenyl)amino]carbonyl]oxy]-N,N,N,-trimethyl-2-butynyl-1-aminium chloride (McN-A-343), a muscarinic M(1) receptor agonist. In addition, the histamine-H(2) receptor antagonist famotidine also completely inhibited the secretion stimulated by McN-A-343. Similarly, pretreatment with both somatostatin and famotidine completely abolished pentagastrin-induced acid secretion. Somatostatin partially inhibited the acid secretion stimulated by bethanechol. The late sustained acid secretion induced by bethanechol was reduced more strongly by somatostatin than the initial peak secretion. In addition, somatostatin had no effect on the transient increase in bethanechol-induced acid secretion in famotidine-pretreated preparations. Somatostatin had no effect on basal histamine secretion in isolated mouse stomach preparations, but markedly reduced histamine release induced by McN-A-343 and bethanechol. The present study showed that the acid secretory response via the endogenous histamine-mediated pathway was inhibited by somatostatin, but the response to a direct activation of gastric parietal cells was not. These results suggest that the inhibition of histamine release from enterochromaffin-like cells plays a more important role in the inhibition of gastric acid secretion by somatostatin than the direct inhibition of parietal cells. In addition, somatostatin inhibited the sustained acid secretion more strongly than the initial peak secretion after the cholinergic stimulation.     

Effects of somatostatin and loxiglumide on gallbladder motility

Cholecystokinin (CCK) is the major hormonal stimulus of gallbladder contraction. Both somatostatin and CCK-A receptor antagonists inhibit stimulation of the gallbladder by CCK. The aim of this study was to compare the effect of somatostatin and the CCK-A receptor antagonist loxiglumide (CR 1505) on gallbladder volume at baseline and after feeding.In random order nine healthy subjects received somatostatin (IV loading dose 125 g, followed by IV infusion of 125 g · h^–1), loxiglumide (10 mg · kg^–1 · h^–1) and control saline. Gallbladder volumes and plasma CCK levels were measured basally and during stimulation by an intraduodenal infusion of fat using, respectively, ultrasound and a sensitive and specific radioimmunoassay.Mean basal gallbladder volume was similar prior to the saline control (28.5 ml), loxiglumide (28.7 ml) and somatostatin (23.4 ml) experiments. In the control experiment, intraduodenal fat led to a significant increase in plasma CCK from 2.6 to 4.8 pmol · l^–1, accompanied by contraction of the gallbladder to 2.0 ml. Loxiglumide induced dilatation of the gallbladder to 40 ml and prevented the any contraction in response to intraduodenal fat. During the somatostatin infusion, gallbladder volume remained the same both basally and during fat stimulation. The plasma CCK response to intraduodenal fat was exaggerated by loxiglumide and was abolished by somatostatin.We conclude that there are major differences between the effects of loxiglumide and somatostatin on gallbladder motility. Loxiglumide dilates the gallbladder, while somatostatin prevents its contraction during fat stimulation.     

Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice

To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.     

The mechanism whereby growth hormone-release inhibiting hormone (somatostatin) inhibits food stimulated gastric acid secretion in the cat.

Growth hormone-release inhibiting hormone (somatostatin) inhibits the gastric acid response to food in concious cats. We have confirmed that this tetradecapeptide blocks the food stimulated gastrin release. However, the inhibition of gastrin release is delayed relative to that of acid secretion, &howing that the inhibition of food stimulated acid secretion is by primary effect on the acid secretory mechanism. No evidence was found of potentiation of either the gastric acid output or serum concentration of gastric in response to food.     

Involvement of somatostatin receptor subtypes in membrane ion channel modification by somatostatin in pituitary somatotropes

1. Growth hormone (GH) secretion from pituitary somatotropes is mainly regulated by two hypothalamic hormones, GH-releasing hormone (GHRH) and somatotrophin releasing inhibitory factor (SRIF). 2. Somatotrophin releasing inhibitory factor inhibits GH secretion via activation of specific membrane receptors, somatostatin receptors (SSTRs) and signalling transduction systems in somatotropes. 3. Five subtypes of SSTRs, namely SSTR1, 2, 3, 4 and 5, have been identified, with the SSTR2 subtype divided into SSTR2A and SSTR2B. All SSTRs are G-protein-coupled receptors. 4. Voltage-gated Ca(2+) and K(+) channels on the somatotrope membrane play an important role in regulating GH secretion and SRIF modifies both channels to reduce intracellular free Ca(2+) concentration and GH secretion. 5. Using specific SSTR subtype-specific agonists, it has been found that reduction in Ca(2+) currents by SRIF is mediated by SSTR2 and an increase in K(+) currents is mediated by both SSTR2 and SSTR4 in rat somatotropes.     

Examination of somatostatin involvement in the inhibitory action of GIP,GLP-1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue

1. The effect of a new type 2 selective somatostatin (SRIF) receptor antagonist (DC-41-33) on somatostatin-induced inhibition of pentagastrin-stimulated gastric acid secretion in conscious, chronic gastric fistula equipped rats was studied.
2. Infused intravenously, DC-41-33 dose-dependently inhibits SRIF-induced inhibition of pentagastrin-stimulated gastric acid secretion with an IC₅₀ of 31.6±1.2 nmol kg⁻¹ versus 10 nmol kg⁻¹ SRIF and blocks the inhibitory effects of SRIF when simultaneously co-infused. Its effectiveness provides additional evidence that SRIF-inhibition of gastric acid release is a SRIF type 2 receptor-mediated process.
3. DC-41-33 is able to completely reverse the inhibitory effect of glucose-dependent insulinotropic polypeptides, GIP and GIP-(1–30)NH₂, and glucagon-like polypeptide, GLP-1(7-36)NH₂, on pentagastrin-stimulated gastric acid secretion thus confirming that they exert these effects through stimulation of endogenous SRIF release.
4. DC-41-33 only partially blocks potent amylin and adrenomedullin-induced inhibition of gastric acid secretion, therefore suggesting that somatostatin may not function as a primary mediator in the action of these peptides.
5. Our results indicate that DC-41-33, is a potent in vivo inhibitor of exogenous and endogenous SRIF in rats. It represents a new class of SRIF analogues which should eventually provide excellent tools for further evaluating the many physiological roles of SRIF and its five receptor subtypes.

     

Effect of sulpiride isomers on gastric acid and gastrin secretion in healthy man

The effects of the antidopaminergic drug sulpiride on gastric acid secretion and gastrin release have been evaluated in 42 healthy individuals. Basal and submaximal pentagastrin (0.5 micrograms/kg-h)-stimulated gastric acid secretion, as well as basal and meal-induced gastrin secretion, were studied after acute intramuscular administration of racemic sulpiride (100 mg) and its L-(50 mg) D-(50 mg) isomers. Racemic and L-sulpiride significantly decreased stimulated serum gastrin concentration, but they did not affect fasting serum gastrin or basal and stimulated gastric acidity. D-sulpiride significantly decreased gastric acid secretion, without affecting serum gastrin levels. While the effects of racemic and L-sulpiride are analogous to those of other antidopaminergic drugs, D-sulpiride mimics the action of dopamine, at least at gastric level. These data support the hypothesis that the D-isomer may possess agonist-antagonist activity at dopamine receptors. Since racemic sulpiride has been used with conflicting results in the therapy of patients with peptic ulcer, in the light of the present results it would be of interest to study separately the efficiency of the D- and L-isomers of the drug in healing peptic ulcer.     

Sustained Cholecystokinin–B/Gastrin Receptor Blockade Does Not Impair Basal or Histamine–Stimulated Acid Secretion in Chronic Gastric Fistula Rats

Abstract: Gastrin is a physiologically important secrelagogue. It is thought to stimulate parietal cells indirectly by mobilizing histamine from enterochromaffin–like (ECL) cells in the oxyntic mucosa. Gastrin stimulates the secretory activity and growth of the ECL cells via an action on cholecystokinin–B/gastrin receptors. Acute cholecystokinin–B/gastrin receptor blockade is known to inhibit gastrin–stimulated acid secretion but whether sustained cholecystokinin–B/gastrin receptor blockade will impair basal, gastrin– and histamine–stimulated acid secretion remains uncertain. The present study was designed to study the effect of long–term (4 weeks) cholecystokinin–B/gastrin receptor blockade on basal and stimulated acid secretion in conscious rats. The selective cholecystokinin–B/gastrin receptor antagonist YM022 (3 μmol kg^–1 hr^–l) was given to gastric fistula rats by continuous subcutaneous infusion via osmotic minipumps for various times from 2 hr to 4 weeks. Basal, gastrin– and histamine– stimulated acid secretion were examined during and after cessation of treatment. Basal and histamine–stimulated acid secretion was not affected by YM022 during the 4 week period of administration, whereas gastrin–induced acid secretion was inhibited. YM022 induced hypergastrinaemia in freely fed rats but did not affect the serum gastrin level in fasted rats. The serum gastrin concentration and gastrin–induced acid secretion returned to control levels 3–7 days after termination of YM022 administration.     

Effect of 40749 RP on basal and sham feeding stimulated gastric secretion in man

Summary 40749 RP, a pyridyl-2-tetrahydrothiophene derivative, is known to be a potent inhibitor of the gastric acid response to pentagastrin, betazole and a meal.In 6 healthy young volunteers, a single oral dose of 2 mg · kg^–1 greatly reduced the gastric acid secretory response to sham-feeding. By contrast, neither gastric pepsin nor the plasma PP response were altered by the drug. No change was observed in plasma gastrin, motilin, VIP or somatostatin concentrations.The results show that 40749 RP is also active on the pure vagus-stimulated gastric acid secretion. The lack of effect upon gastric pepsin and plasma PP suggests that 40749 RP is not likely to act on the basolateral cholinergic receptor and that it affects further cellular steps involved in hydrogen ion secretion.     

Somatostatin sst2 receptor-mediated inhibition of parietal cell function in rat isolated gastric mucosa.

1. The aim of this study was to determine the location and functional characteristics of the somatostatin (SRIF) receptor type(s) which mediate inhibition of acid secretion in rat isolated gastric mucosa. 2. Gastrin (1 nM-1 microM), dimaprit (10 microM-300 microM) and isobutyl methylxanthine (IBMX, 1 microM-100 microM) all caused concentration-dependent increases in acid output. Responses to gastrin were almost completely inhibited by ranitidine (10 microM) at a concentration which abolished the secretory response to dimaprit. In contrast, responses to IBMX were not changed by ranitidine suggesting that IBMX acts directly on the parietal cell and not indirectly by releasing histamine from enterochromaffin-like (ECL) cells. 3. SRIF-14 (1 nM-1 microM) had no effect on basal acid output, but inhibited acid output produced by gastrin, dimaprit and IBMX in a concentration-dependent manner with respective EC50 values of 46, 54 and 167 nM. The peptidase inhibitors, amastatin (10 microM) and phosphoramidon (1 microM), had no effect on SRIF-induced inhibition of dimaprit stimulated gastric acid secretion. 4. The inhibitory effect of a range of SRIF analogues on gastrin-, dimaprit- and IBMX-induced acid secretion was also studied. Irrespective of the secretagogue used to increase acid output, the rank order of potencies was similar (BIM-23027 = seglitide = octreotide > SRIF-14 = SRIF-28 > L-362,855). The linear peptide BIM-23056 was devoid of agonist or antagonist activity in concentrations up to 1 microM. 5. The sst2 receptor selective peptides, BIM-23027, seglitide and octreotide were the most potent inhibitors of gastrin-, dimaprit- and IBMX-induced acid secretion suggesting that SRIF receptors resembling the recombinant sst2 receptors are involved. Furthermore, since dimaprit and IBMX stimulate gastric acid secretion independently of histamine release, sst2 receptor-mediated inhibition must occur at the level of the parietal cell itself.