Glycine‐extended gastrin‐17 stimulates acid secretion only via CCK‐2 receptor‐induced histamine release in the totally isolated vascularly perfused rat stomach

The effects of gastrin precursors have been discussed during recent years. However, the mechanism for their action, whether through a novel receptor on the parietal cell or a cholecystokinin‐2 (CCK‐2) receptor on the enterochromaffin like (ECL) cells, is still not settled. This study examines the effect of glycine‐extended gastrin‐17 (Gly‐G‐17), the main non‐amidated gastrin precursor, on gastric acid secretion and histamine release in the totally isolated vascularly perfused rat stomach. Glycine‐extended gastrin‐17 at the concentrations from 0.52 to 520 nmol L^–1 was administered to the totally isolated vascularly perfused rat stomach. Glycine‐extended gastrin‐17 at 52 or 520 nmol L^–1, and gastrin‐17 at 0.52 nmol L^–1 were co‐administered to examine whether glycine‐extended gastrin augmented maximal gastrin stimulated acid secretion and histamine release. Both Gly‐G‐17 at 52 nmol L^–1 and gastrin‐17 (G‐17) at 0.52 nmol L^–1 were administered together with the histamine‐2 receptor antagonist ranitidine at 10 μmol L^–1. Gastric acid and venous histamine output were measured. Glycine‐extended gastrin‐17 at lower concentrations from 0.52 to 5.2 nmol L^–1 did not stimulate gastric acid output or histamine release, whereas higher concentrations from 52 to 520 nmol L^–1 elicited a concentration‐dependent increase in acid secretion and histamine release. The outputs of acid and histamine at 520 nmol L^–1 Gly‐G‐17 were at the same level as those found for G‐17 at its maximally effective concentration of 0.52 nmol L^–1. Glycine‐extended gastrin‐17 at maximally effective concentration of 520 nmol L^–1 did not augment maximal gastrin stimulated acid secretion or histamine release. Ranitidine inhibited G‐17 and Gly‐G‐17 stimulated acid secretion to a similar degree. This study confirms that the stimulatory effect of Gly‐G‐17 on gastric acid secretion is via a CCK‐2 receptor on the ECL cell.     

ECL cell histamine mobilization and parietal cell stimulation in the rat stomach studied by microdialysis and electron microscopy

Aim: Gastrin stimulates acid secretion by mobilizing histamine from enterochromaffin‐like (ECL) cells that occur predominantly at the base of the gastric glands. The parietal cells occur higher up in the glands nearer to the gastric lumen. The present study was performed to assess whether histamine is transported from the ECL cell via the microcirculation (endocrine route) or local diffusion (paracrine route). Methods: Totally isolated, vascularly perfused, rat stomachs were examined both in basal and gastrin‐stimulated state. Histamine concentrations, determined by radioimmunoassay in venous effluent and microdialysate from an indwelling probe in the submucosa, were monitored over a period of 240 min. Gastrin‐17 was infused through an arterial catheter for 120 min. The parietal cells were examined by electron microscopy, and the percentage of actively secreting parietal cells (displaying secretory canaliculi) in four regions along the glands (basal to surface, zones I–IV) was determined. Results: Gastrin stimulated acid secretion and histamine release as well as parietal cell activation. Upon gastrin stimulation, histamine concentration in the microdialysate was 2.5‐fold higher than in the venous effluent (P = 0.008). The parietal cells in the upper part of the gland (zone III) were found to be activated the most. Conclusion: As the histamine concentrations were higher in the tissue (microdialysate) than in blood, histamine seems to reach the parietal cells via the paracrine route. The fraction of active parietal cells seems to depend more on the age of the parietal cells than on the distance from the ECL cell.     

Differential effect of bombesin on intraluminal and intravascular release of gastric gastrin and somatostatin in anaesthetized rats

The aim of the present investigation was to study how bombesin, gastrin-17, cholecystokinin-8 (CCK-8) and electrical vagal stimulation influence the release of gastrin and somatostatin into the gastric lumen. Bombesin (3 and 30 nmol kg-1 h-1), gastrin-17 and CCK-8 (10 nmol kg-1h-1) were infused i.v. and vagal stimulations at 5 V, 2 ms, 5 Hz were performed in anaesthetized rats, in which the stomach was perfused with a dextran solution (pH approximately 6 or approximately 1.5). pH, gastrin and somatostatin levels were measured in the perfusate after having passed the stomach. In addition, blood samples were drawn from the jugular vein in the experiments in which bombesin was infused. Gastrin and somatostatin levels were determined with radioimmunoassay, and gastrin- and somatostatin-like immunoreactivity will be referred to as gastrin and somatostatin below. Infusion of bombesin, 3 and 30 nmol kg-1 h-1, did not influence acid secretion as evidenced by an unchanged intraluminal pH. Nor was the intraluminal secretion of gastrin or somatostatin influenced by bombesin, whereas plasma gastrin and somatostatin levels were significantly increased at the higher dose. In contrast, infusion of CCK-8 and gastrin-17 (10 nmol kg-1 h-1), as well as electrical vagal stimulation, significantly decreased the pH and increased the somatostatin levels in the perfusate. Vagal activation in addition increased the gastrin levels. The present results, demonstrating that bombesin influences plasma and perfusate levels of gastrin and somatostatin differently, indicate that intraluminal and intravascular gastrin and somatostatin release may be separately regulated.     

Small gastrin (G-17) serum levels after stimulation with food during conservative treatment of patients with chronic renal insufficiency

The physiological release mechanism for gastrin is complex, including both mechanical and chemical stimuli. Distention of the antrum is the main mechanical stimulus, and proteins and their degradation products constitute the most potent chemical stimuli. The aim of the present study was to examine the little gastrin (G-17) response to a test meal and to study the relationship between the G-17 concentration and gastric acid secretion in patients with various degrees of chronic renal failure (CRF). In 14 CRF patients under conservative treatment and 12 healthy control subjects, fasting and stimulated G-17 concentrations, as well as basal (BAO), maximal (MAO) and peak acid secretion (PAO) were measured. Mean fasting serum G-17 in CRF patients was 7.8 +/- 0.8 pmol/L, significantly higher (p less than 0.001) than in control subjects (5.9 +/- 1 pmol/L). However, the range of basal G-17 concentrations in both groups of subjects was not different from the normal values (4.2 +/- 11.3 pmol/L). The serum G-17 response to the food stimulation was significantly higher (p less than 0.001) in the control subjects than in the CRF patients. In normal subjects, the increment in the serum G-17 concentration rose to a peak at 30 min, but in the CRF patients the peak increment occurred at 60 min, and the response was more prolonged. There was a little difference in meal-stimulated serum G-17 concentrations in patients with various degrees of renal functional impairment. Basal acid output (BAO) was significantly higher (p less than 0.001) in the control subjects (2.62 +/- 0.51 mmol/h) than in the CRF patients (1.68 +/- 0.4 mmol/h). No significant difference in both the maximal acid output (MAO) and peak acid output (PAO) was found between the groups of CRF patients and control subjects. There was no relationship between G-17 concentrations and the gastric acid output in the CRF patients. From the results of the present study it is concluded that the human kidney is unimportant in the catabolism of G-17 but that the renal failure seems to decrease the rate of the peripheral extraction of gastrin by other tissues. The raised basal and meal-stimulated G-17 concentrations sometimes seen in CRF patients are associated with decreased rather than increased gastric acid secretions.     

The regulation of gastric acid secretion – clinical perspectives

The purpose of this review, based upon 40 years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug‐induced hypo‐acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long‐term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet‐ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.     

The fade of gastrin-stimulated gastric acid secretion in the rat is due to depletion of releasable mucosal histamine

The present study examines the applicability of the isolated, acid-secreting vascularly perfused rat stomach for long-term physiological and pharmacological studies. The model was used to study the fade of acid secretion during gastrin stimulation. The stomachs were stimulated by exogenous gastrin or histamine alone or in succession. Acid secretion and venous histamine concentrations were measured. Gastrin and histamine potently stimulated acid output, histamine-stimulated acid secretion was sustained for 300 min while gastrin-stimulated secretion peaked at 120 min and declined towards basal output at 300 min. Stomachs rendered tachyphylactic to gastrin could be re-stimulated by exogenous histamine. Venous histamine output during gastrin stimulation decreased in parallel to acid secretion. Thus, the acid-secreting, isolated vascularly perfused rat stomach can be used for physiological and pharmacological studies with histamine as stimulant for at least 300 min. The present results strongly indicate that the effect of gastrin on acid secretion is mediated by histamine, and that fade of acid secretion during stimulation with gastrin is due to depletion of releasable mucosal histamine.     

The vagus regulates histamine mobilization from rat stomach ECL cells by controlling their sensitivity to gastrin

The ECL cells in the oxyntic mucosa secrete histamine in response to gastrin, stimulating parietal cells to produce acid. Do they also operate under nervous control? The present study examines histamine mobilization from rat stomach ECL cells in situ in response to acute vagal excitation and to food or gastrin following vagal or sympathetic denervation. Applying the technique of microdialysis, we monitored the release of histamine by radioimmunoassay. Microdialysis probes were placed in the submucosa on either side of the stomach, 3 days before experiments. The rats were awake during microdialysis except when subjected to electrical vagal stimulation. One-sided electrical vagal stimulation raised serum gastrin and mobilized gastric histamine. However, gastrin receptor blockade prevented the histamine mobilization, indicating that circulating gastrin accounts for the response. Vagal excitation by hypoglycaemia (insulin) or pylorus ligation did not mobilize either gastrin or histamine. The histamine response to food was almost abolished by gastrin receptor blockade, and it was halved on the denervated side after unilateral subdiaphragmatic vagotomy. While the histamine response to a near-maximally effective dose of gastrin was unaffected by vagotomy, the response to low gastrin doses was reduced significantly. Abdominal ganglionic sympathectomy failed to affect the histamine response to either food or gastrin. In conclusion, gastrin is responsible for most of the food-evoked mobilization of ECL-cell histamine. The histamine response to electrical vagal stimulation reflects the effect of circulating gastrin rather than a direct action of the vagus on the ECL cells. Vagal denervation was accompanied by an impaired histamine response to food intake, probably reflecting the right-ward shift of the serum gastrin concentration–histamine response curve. The results suggest that the vagus controls the sensitivity of the ECL cells to gastrin.     

Topical Review

Transepithelial transducing cells, particularly the gastrin (G) cell, co-ordinate gastric acid secretion with the arrival of food in the stomach. Recent work suggests that multiple active products are generated from the gastrin precursor, and that there are multiple control points in gastrin biosynthesis. Biosynthetic precursors and intermediates (progastrin and Gly-gastrins) are putative growth factors; their products, the amidated gastrins, regulate epithelial cell proliferation, the differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and the expression of genes associated with histamine synthesis and storage in ECL cells, as well as acutely stimulating acid secretion. Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which in turn inhibit parietal cell function but stimulate the growth of surface epithelial cells. Plasma gastrin concentrations are elevated in subjects with Helicobacter pylori , who are known to have increased risk of duodenal ulcer disease and gastric cancer. Studies of the physiology of gastrin may therefore contribute to an understanding of the mechanisms relevant to major upper gastrointestinal tract disease.     

Renal tubular transport and metabolism of carboxyamidated and glycine-extended gastrins in pigs

Renal handling of postprandial and intravenously administered gastrin was investigated in anaesthetised pigs. The fractional extraction of postprandial carboxyamidated and glycine-extended gastrin in the kidneys was 0.21 ± 0.01 and 0.16 ± 0.02, but the respective urinary clearance comprised only 0.57 ± 0.03 and 0.44 ± 0.05% of the GFR (P < 0.02). The respective total body clearance of carboxyamidated and glycine-extended gastrin-17 (gastrin-17 and gastrin-17Gly) during continuous infusion was 22.9 ± 1.5 and 19.6 ± 1.4 mL kg^?1 min^?1 (NS), and the renal fractional extraction of the peptides was 0.31 ± 0.03 and 0.29 ± 0.05, respectively. The kidneys accounted for 8% of total body clearance of gastrin-17. Renal filtration rate of gastrin-17 exceeded renal extraction rate (9.739 ± 0.487 vs. 6.407 ± 0.321 pmol min^?1). Urinary clearance of gastrin-17 and gastrin-17Gly amounted only 0.91 ± 0.16 and 0.13 ± 0.03%, respectively, of the GFR (P < 0.01), but urinary excretion rate correlated with the filtered amount of the peptides (r = 0.93, P < 0.01). Neither was a renal plasma threshold recorded nor was a T_m value for tubular uptake or degradation of gastrin achieved in spite of supraphysiological plasma levels of the peptides. The results indicate that filtered gastrin is almost completely removed in the renal tubules, primary by metabolism although part of the absorbed peptides may be returned to the circulation in intact form. The process for uptake or metabolism has a high capacity but varies with the molecular form of gastrin.     

Inhibitory action of somatostatin on isolated gastric glands and parietal cells

The action of somatostatin in vitro was characterized using glands and parietal cells isolated from rabbit gastric mucosa. In the presence of the reducing agent dithiothreitol, somatostatin was found to inhibit gastrin- and histamine-stimulated acid formation in glands as measured by [14C]aminopyrine (AP) accumulation and oxygen consumption, both measurements that appear to be reliable indexes of parietal cell acid formation. In glands the inhibition of the secretory response to gastrin was more potent (60-80%) than that to histamine (15-25%). The kinetics of somatostatin inhibition of responses to both agents were noncompetitive. The apparent IC50 for the partial somatostatin inhibition of histamine-stimulated AP accumulation was similar to that for gastrin (approx 3 X 10(-9) M) when maximum concentrations of histamine (10(-4) M) or gastrin (10(-7) M) were used. The inhibitory action of somatostatin appeared to be specific, inasmuch as this peptide had no significant effect on basal secretion or secretion stimulated by carbachol, dibutyryl cAMP, cholera toxin, or elevated extracellular K+. In purified parietal cell preparations, somatostatin inhibited histamine- but not gastrin-stimulated AP accumulation. Moreover, the inhibition of histamine-stimulated AP accumulation in parietal cells was more pronounced than in glands. These results suggest that somatostatin acts directly on parietal cells to inhibit histamine activation of H+ secretion. Somatostatin also acts indirectly to inhibit gastrin, perhaps by blocking the release of histamine from paracrine- or endocrinelike cells present in the glands.     

Molecular Forms of Gastrin in Antral Mucosa,Plasma and Gastric Juice during Vagal Stimulation of Anesthetized Cats

Gastrin was released by electrical vagal stimulation in anesthetized cats. Antral mucosa, blood and gastric juice samples collected during vagal stimulation were subjected to gel filtration in order to characterize the different molecular forms of gastrin. In antral mucosa component III (gastrin-17) predominated. Besides, the antrum contained 5 per cent component II (gastrin-34, “big” gasirin), I per cent component I and trace amounts of component IV (gastrin-14 or “mini” gastrin). Immediately after vagal stimulation, component III (gastrin-17) appeared in the gastric venous effluent followed within a few minutes by component IV (gastrin-14). Component I and II (gastrin-34) were not detectable in any of the plasma samples. We suggest that component III (gastrin-17) is released from the antral mucosa and is then rapidly metabolized to component IV (gastrin-14) possibly to a significant extent in the fundic region of the stomach. Large amounts of component III (gastrin-17) were found in the vagally-induced gastric juice. Only very small amounts of degradation products were present, indicating that cat gastrin is relatively resistant to peptic degradation and acid hydrolysis.     

Interaction between gastrin-17 and oxytocin on plasma levels of insulin, glucagon and glucose in conscious dogs

The aim of the present study was to investigate how infusion of gastrin-17 and oxytocin affects plasma levels of insulin, glucagon and glucose in order to elucidate how the two hormones contribute to metabolic changes seen in situations where they are released, e.g. feeding and suckling during lactation. Thus, gastrin-17 (0.5 and 2.0 nmol kg-1 h-1) and oxytocin (0.11 and 1.1 nmol kg-1 h-1) were infused separately or simultaneously into conscious dogs. Both gastrin-17 and oxytocin induced significant, dose-dependent increases in insulin levels. An additive effect on insulin levels was obtained when gastrin-17 and oxytocin were infused simultaneously. Glucagon levels were not affected by gastrin-17 whereas infusion of 1.1 nmol kg-1 h-1 of oxytocin was followed by a significant increase. In contrast to a slight transient increase in the glucose level induced by oxytocin, infusion of gastrin-17 caused a sustained period of hypoglycaemia. Thus, infusion of gastrin-17 and oxytocin, respectively, gave rise to different ratios between circulating concentrations of insulin and glucagon reflected in different effects on the glucose level. The gastrin-induced hypoglycaemia could reflect that gastrin, via a release of insulin, promotes storing of glucose, e.g. in connection with feeding. That infusion of oxytocin caused a parallel increase in insulin and glucagon levels together with a slight increase in the glucose level could imply that oxytocin favours mobilization of glucose, e.g. during lactation.     

Gastrin-induced apoptosis contributes to carcinogenesis in the stomach

Hypergastrinemia in INS-GAS mice leads to accelerated carcinogenesis of the stomach, but the mechanisms have not been well defined. We investigated the possible role of gastrin-induced gastric cell apoptosis in the development of gastric cancer. We examined apoptosis and the expression of Bcl-2 family proteins in INS-GAS mice of different ages, as well as in gastrin-deficient (GAS-KO) mice after gastrin-17 (G-17) infusion. In addition, we studied the effects of the gastrin/cholecystokinin-2 (CCK-2) receptor antagonist YF476 and/or histamine H2 (H-2) receptor antagonist loxtidine on apoptosis and atrophy in INS-GAS mice with or without Helicobacter felis (H. felis) infection. INS-GAS mice had age-associated increases in Bax protein expression and decreases in Bcl-2 protein expression, along with increased glandular and epithelial cell apoptosis. At 8-week gastrin infusions in GAS-KO mice resulted in a similar pattern of altered Bax and Bcl-2 expression, followed by gastric cell apoptosis. H. felis infection of INS-GAS mice led to increased apoptosis and the development of atrophy, whereas treatment with either YF476 and/or loxtidine strongly inhibited both apoptosis and atrophy. In vitro studies with Fas-expressing RGM1 cells showed that gastrin stimulation alone directly induced apoptosis via gastrin/CCK-2 receptor and synergized with FasL stimulation. These results indicate that gastrin can induce apoptosis in gastric epithelial cells and contribute to the development of gastric carcinogenesis.     

Ionized calcium influences gastrin stimulated histamine release and acid secretion, but not histamine stimulated acid output in the totally isolated vascularly perfused rat stomach

When changing from bovine serum albumin to dextran T70 as colloid without adjusting the total calcium concentration in the vascular perfusate of the totally isolated vascularly perfused rat stomach, we noticed a drastic fall in gastrin-stimulated acid secretion. In the present study the effect of the two colloids on ionized calcium in the vascular perfusate as well as the effect on acid secretion and vascular histamine release were studied. There was no difference in gastrin-stimulated acid secretion or vascular histamine release between the two colloids after adjusting the total calcium concentrations so that ionized calcium was similar. Whereas baseline acid secretion showed no marked dependency of ionized calcium within the range tested (0.73-1.54 mmol l-1, gastrin-stimulated acid secretion was highly dependent on ionized calcium being reduced at the higher concentration of Ca2+. Histamine stimulated acid secretion, on the other hand, was virtually unaffected by the concentration of ionized calcium in the same range. Like gastrin-stimulated acid secretion, gastrin-stimulated histamine release was inhibited at higher Ca2+ concentrations. Thus, elevated Ca2+ concentrations seemed to reduce gastrin-stimulated acid secretion by inhibiting vascular histamine release.     

The effects of somatostatin and metiamide on tachyphylaxis of pentagastrin stimulated gastric acid and pepsin secretion in the conscious cat.

1. Pentagastrin stimulated gastric acid and pepsin secretions show parallel rates of tachyphylaxis in the conscious cat. The responses to histamine show only slight tachyphylaxis. 2. Somatostatin 10 microng.kg(-1).hr(-1) inhibits pentagastrin but not histamine stimulated acid secretion and inhibits pentagastrin stimulated pepsin secretion. 3. The inhibition of pentagastrin stimulated acid and pepsin secretion by Somatostatin delays the tachyphylaxis of these responses, but the rates of tachyphylaxis when they do subsequently occur are identical. 4. Metiamide 10 mg-kg(-1)-hr(-1) equally inhibits histamine and pentagastrin stimulated acid secretion but does not inhibit pentagastrin stimulated pepsin secretion. 5. Inhibiton of acid secretion during metiamide infusion neither prevents nor delays acid nor pepsin tachyphylaxis. 6. It is suggested that tachyphylaxis of acid and pepsin secretion is a gastrin receptor phenomenon and that Somatostatin occupies or modifies the behaviour of these receptors, preventing tachyphylaxis. Metiamide, however, exerts its action only on the histmine H2-receptor and not the gastrin receptor mechanism, and this apparently does not prevent or delay acid tachyphylaxis.     

Stimulation of gastrin and somatostatin secretion from the isolated rat stomach by bombesin

The role of bombesin in the regulation of gastrin and somatostatin secretion was examined using an isolated vascularly perfused rat stomach preparation. Bombesin caused a biphasic, dose-dependent increase in gastrin and bombesin secretion. Neither somatostatin nor gastrin secretion was inhibited by atropine. The maximal gastrin response to bombesin (198 +/- 75% above basal levels) was less than one-half the maximal response to methacholine (462 +/- 94%). It was postulated that the concomitant release of somatostatin, in part from antral mucosa, attenuated the gastrin response to bombesin; the notion was tested with somatostatin antiserum. A 50- to 100-fold excess of sheep somatostatin antiserum augmented significantly the maximal gastrin response to bombesin by 966% in the initial peak period and by 532% in the plateau period; the response in the plateau period was not significantly different from the maximal response to methacholine. Methacholine stimulated the release of gastric bombesin also, but the exact cellular origin of the peptide could not be ascertained. On the basis of these results and of the topography of antral bombesin neurons and somatostatin D cells, a model for the neural (via bombesin) and paracrine (via somatostatin) control of gastrin secretion within the antrum is proposed.     

Inhibition of gastric acid secretion inthe Atlantic cod, Gadus morhua, by sulphated and desulphated gastrin, caerulein, and CCK-octapeptide

Gastric acid secretory effects of gastrin/CCK-like peptides have been assayed in cods rendered "spontaneously" secreting by a continuous intestinal perfusion with diluted (33%) seawater. A high dose of pentagastrin induced a weak stimulation (31%) of acid output, while gastrin 17-II, caerulein and CCK8 were inhibitory. Caerulein was the most potent peptide, with an estimated D50 for inhibition of 0.013 nmol/kg.h. Although displaying lower potencies, also the desulphated forms of gastrin-17, caerulein and CCK8 were inhibitory. The results may be explained by release of an endogenous inhibitor, or by interaction with endogenous "codfish gastrin". In the latter case two alternatives are considered: Either gastrin 17, CCK8, and caerulein possess lower efficacies than "codfish gastrin" and therefore act as partial agonists. Alternatively, "codfish gastrin" is itself an inhibitory principle (gastron), the effect of which is mimicked by gastrin 17, caerulein and CCK8. The actions of gastrin and the gastrin-like peptides in the cod indicate a structure-activity relationship different from previously described systems, both mammalian and submammalian.     

Inhibition of gastric acid secretion in the Atlantic cod,Gadus morhua,by sulphated and desulphated gastrin,caerulein, and CCK-octapeptide

Gastric acid secretory effects of gastrin/CCK-like peptides have been assayed in cods rendered “spontaneously” secreting by a continuous intestinal perfusion with diluted (33%) seawater. A high dose of pentagastrin induced a weak stimulation (31 %) of acid output, while gastrin 17–11, caerulein and CCK8 were inhibitory. Caerulein was the most potent peptide, with an estimated D₅₀for inhibition of 0.013 nmol/kg h. Although displaying lower potencies, also the desulphated forms of gastrin-17, caerulein and CCK8 were inhibitory. The results may be explained by release of an endogenous inhibitor, or by interaction with endogenous “codfish gastrin”. In the latter case two alternatives are considered: Either gastrin 17. CCK8, and caerulein possess lower efficacies than “codfish gastrin” and therefore act as partial agonists. Alternatively, “codfish gastrin” is itself an inhibitory principle (gastrin). the effect of which is mimicked by gastrin 17. caerulein and CCK8. The actions of gastrin and the gastrin-like peptides in the cod indicate a structure-activity relationship different from previously described systems, bot mammalian and submam-malian.     

Effect of 13-NLE-motilin on gastric secretion, serum gastrin level and mucosal blood flow in dogs.

1. In dogs with gastric fistulas and vagally innervated fundic and antral pouches, 13-norleucine-motilin (13-nle-motilin), a synthetic analogue of motilin, infused intravenously in graded doses produced a dose-dependent increase in gastric acid and pepsin outputs. 2. The motilin-induced stimulation of gastric secretion occurred independently of antral pH and was not accompanied by any alteration in the serum gastrin level suggesting that motilin did not affect the release of gastrin. 3. When infused intravenously in a constant dose against a constant background stimulation with pentagastrin or histamine 13-nle-motilin inhibited both acid and pepsin secretion from the main stomach and fundic pouch. 4. The inhibitory effect of 13-nle-motilin was always associated with a marked reduction in mucosal blood flow but without any change in the ratio of aminopyrine concentration in the gastric juice and blood plasma indicating that this peptide primarily affected gastric secretion but did not limit the gastric mucosal microcirculation.     

Effects of gastrin on the histamine-secretory and proliferative activity of cultured carcinoid cells derived from the stomach of the rodent Mastomys natalensis

The effects of gastrin on the synthesis and release of hista-mine and on cellular prollferatlon were Investigated in a homotransplantable carcinold tumor implanted in the rodent Mastomys natalensis and in cultured cells derived from the tumor. The homotransplanted tumor was immunopositive for histamine, synaptophysin and protein gene product 9.5, and its cells contained numerous secretory granules that were vlsualized by electron microscopy. When carcinold cells were cultured in a medlum with a high concentration of gastrin-1 (10⁴ pg/mL) for 7 days, large electron-dense secretory granules were characteristically observed in the cytoplasm. By contrast, only a few such granules and numerous seaondary lysosomes were seen in cells that had been cultured in the same medium without gastrin-1. A high concentration of gastrin-1 (10⁴ pg/mL) slgniflcantly Increased the release of histamine Into the culture medium from the carcinoid cells compared wlth the control (P<0.05). Cellular proIiferation, as determlned by monitoring the incorporatlon of [methyl-³H]-thymidine into the carcinold cells Increased sig nfficantly at lower concentrations of gastrin-1 (10² and 10³ pg/ mL), (P<0.05). At higher concentratlons (10⁴ pg/mL or more), gastrin-1 had no effect on proliferatlon. These findings Indicate that gastrin stimulates the synthesis and release of histamlne by carclnoid cells, as well as their proliferation.