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The sulfated and unsulfated forms of cholecystokinin-octapeptide (CCK-8) were compared, with respect to their effect on gastric acid secretion, in the rat. Unsulfated CCK-8 stimulated acid secretion in a dose-dependent manner, while the sulfated form was without stimulatory effect; thus, sulfation of the tyrosine residue in the seventh position from the C terminus completely abolished the gastrin-like action of CCK-8. Compared with pentagastrin and human gastrin II, unsulfated CCK-8 gave lower calculated maximal response. While sulfated CCK-8 given alone had no effect on acid secretion, it caused marked inhibition of the plateau response to submaximal pentagastrin. This inhibition was surmountable with higher doses of pentagastrin, suggesting a competitive type of inhibition. It is, therefore, concluded that lack of sulfation of the tyrosine residue in the seventh position does not exclude CCK-8 from occupying the gastrin receptor; but does prevent the hormone-receptor interaction that leads to the secretory response. These observations in the rat are different from those in the dog where desulfation of tyrosine renders the CCK analog, caerulein, ineffective in its ability to stimulate acid secretion., (Copyright 2000 Academic Press.)

The vagus nerve plays a central role in the regulation of gastric acid secretion and gastrin release. The current understanding of the mechanisms involved in vagal regulation of acid secretion and gastrin release is reviewed. Thyrotropin-releasing hormone from the medullary raphe nuclei appears to be the central excitatory mediator of vagal action in the dorsal motor nucleus. Vagal stimulation of the parietal cell occurs through M3 cholinergic receptors and via the release of histamine and gastrin from enterochromaffin-like cells and G-cells, respectively. Somatostatin exerts a tonic basal inhibition of both the parietal cell and the G-cell. Vagal stimulation suppresses somatostatin release from delta cells, thereby "disinhibiting" these cells.

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.

To determine the relative contributions of neural reflexes and intestinal hormones to the inhibition of gastric acid secretion by intestinal fat, 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 by extragastric titration. When secretion reached a plateau, graded doses of oleic acid or saline were instilled into the jejunal segments. In both groups, acid secretion was inhibited by intrajejunal fat but not saline. At doses of 0.4 and 0.08 mmol oleic acid, there was a 25% and 17% greater maximal inhibition of plateau acid response in the innervated rats than in the transplanted rats, presumably because of the neural contribution. To examine the hormonal mediators, the effects of a somatostatin monoclonal antibody and a cholecystokinin A receptor antagonist (L-364,718) on fat-induced inhibition of gastric acid secretion were studied in transplanted rats. Treatment of the patients with transplants with a somatostatin monoclonal antibody (2.18 mg IV) or L-364,718 (1 mg/kg IV) reduced the fat-induced inhibition of acid secretion by 95% and 28%, respectively. In conclusion, both neural and hormonal mechanisms mediate fat-induced inhibition of gastric acid secretion, with the hormonal mechanism predominating. Somatostatin, and to a lesser extent cholecystokinin, contribute to the hormonal mechanism.

The effects of intracranial pressure on gastric acid secretion were studied in 30 rabbits. Intracranial pressure was increased in a graded and controlled fashion using a barostat connected to a cannula in the lateral cerebral ventricle. Eighteen rabbits were studied under urethane anesthesia with a background subthreshold intravenous infusion of bethanechol. Twelve rabbits were studied in the conscious state. Increases in intracranial pressure led to immediate and significant increases in gastric acid output in a dose-related manner in both conscious and anesthetized animals. Serum gastrin levels did not increase in either group of animals. Vagotomy only partially abolished the increase in acid outputs seen with increased intracranial pressure, whereas atropine completely blocked the response. We conclude that increased intracranial pressure causes stimulation of acid secretion by a gastrin-independent cholinergic mechanism that is only partially mediated by the vagus.

Intraluminal fat inhibits gastric secretion through as yet undetermined mechanisms which involve release of one or more hormonal enterogastrones. As intraluminal fat releases Peptide YY (PYY) in amounts sufficient to inhibit meal-stimulated acid secretion, this ileo-colonic peptide exhibits the characteristics required of an enterogastrone. The present study seeks to determine the mechanism by which PYY inhibits acid secretion by examining the effects of PYY on gastric acid stimulated by pentagastrin, histamine, and bethanechol. In addition, effects of PYY on the acid response to sham feeding and distention of a denervated gastric pouch were examined. A dose of PYY (400 pmol X kg-1 X h-1) was employed that reproduced blood levels observed after intestinal perfusion with oleic acid and inhibited the acid secretory response to an intragastric meal by 35 +/- 6%. This same dose of PYY maximally inhibited histamine- and pentagastrin-stimulated acid secretion by 28 +/- 7% (P less than 0.05), and 17 +/- 4% (P less than 0.05), respectively. Although PYY had no effect on bethanechol-stimulated secretion it markedly inhibited the secretory response to sham feeding, maximally reducing secretion by 90 +/- 4% (P less than 0.01). We speculate that PYY acts by inhibiting acetylcholine release from vagal nerve fibers rather than by inhibiting acetylcholine's action on the parietal cell. The demonstration that PYY virtually abolishes cephalic phase acid secretion while having little if any effect on the response to exogenous secretogogues gives PYY unique characteristics among the known hormonal inhibitors of gastric secretion.

In dogs provided with Heidenhain pouch and gastric fistula, we studied the effect of near-total excision of the fundic mucosa of the main stomach on acid secretion and gastrin release. Fundic mucosal excision abolished the mean response of the gastric fistula and reduced its maximal response to pentagastrin and to histamine by 85%. The basal Heidenhain pouch acid output increased ninefold, and fasting levels of serum gastrin increased from 36 +/- 3 pg/ml before the 248 +/- 47 pg/ml after fundic mucosa excision. The peak gastrin response to meal rose from 168 +/- 12 before to 392 +/- 49 pg/ml after. This increase could not have been due to changes in pH during the meal as meal pH was held constant at 5.5 by the method of intragastric titration in both pre- and postexcision studies. Following fundic mucosal excision, the acid response of the Heidenhain pouch to meal and to both submaximal and maximal doses of pentagastrin and histamine increased markedly. The maximal response to the meal increased from 41 +/- 9 before to 167 +/- 43 after, expressed as percent of the preexcision maximal histamine output. The corresponding changes in the maximal responses to pentagastrin respectively before to 124 +/ 26 and 230 +/- 31 after, again expressed as percent of the preexcision maximal histamine output. These observations suggest that fundic mucosal excision removes an inhibitory mechanism of both acid secretion and gastrin release.

The effects of cholecystokinin receptor antagonist, dipentyl-3,4-dichloroproglumide (DDP), on stimulated pancreatic and gastric secretion were studied in the rat. DDP dose-dependently inhibited cholecystokinin-stimulated amylase release from dispersed acinar cells. In vivo, DDP inhibited cholecystokinin octapeptide-stimulated amylase and protein secretion. DDP also inhibited pentagastrin-stimulated gastric acid secretion in vivo. Meal-stimulated acid output was decreased by 34% (DDP 400 micrograms/kg/hr) but responsiveness to histamine or parachlorophenyl-gamma-aminobutyric acid was unchanged.

Recently, three new drug types have emerged to treat peptic ulceration. We compared the mechanism of action of omeprazole and somatostatin-14, both inhibitors of gastric acid, with that of tetraprenylacetone, a drug thought to be cytoprotective in the upper gut. Omeprazole and somatostatin-14 caused potent inhibition of meal-stimulated acid secretion in the dog (92% +/- 6% and 97% +/- 1%, respectively). On the other hand, tetraprenylacetone had no significant inhibitory effect on acid secretion (4% +/- 17%). In separate studies, tetraprenylacetone was shown to be a stimulant of gastric bicarbonate secretion in the rabbit, increasing bicarbonate secretion from a basal level of 0 to 86 +/- 28 pmol/2 h. Tetraprenylactone was also found to be a strong stimulant of canine pancreatic bicarbonate secretion. The ability of tetraprenylacetone to stimulate endogenous bicarbonate secretion may explain its ability to heal ulcers both experimentally and clinically.

The colon has been shown to contain an abundance of endocrine cells. Their role is not yet understood. In four dogs prepared with chronic gastric fistula and colonic fistula in the cecum the effects on pentagastrin dose responses of colonic perfusion with the following substance were studied: saline, 15% liver extract pH 7.0; sodium oleate pH 9.4; and 0.08 M HCl. The responses obtained in each of the perfusion studies were compared with those obtained without colonic perfusion. Whereas saline had no effect on these responses, liver extract, sodium oleate, and HCl, each produced significant inhibition. These results suggest that the colon has the capacity for inhibiting gastric acid secretion by some mechanism which may prove to be humoral. Until now the colon has rarely been considered in any assessment of the gut functioning as an endocrine organ. Perhaps a colonic endocrine role should now be given further consideration.

It is well established that massive small-bowel resection (MSBR) invariably causes hypersecretion of acid in animals with denervated gastric pouches. The effect of MSBR on the secretory responses of both the totally innervated stomach and pancreas have been less well studied. Eighteen adult mongrel dogs were prepared with chronic gastric and pancreatic fistulae. In eight, massive small-bowel resection was performed in addition. Bowel resection did not alter the responses to graded doses of pentagastrin. However, in response to the intragastric titration of a liver extract meal, it had the following effects: (1) profound gastric acid hyposecretion; (2) reduction in pancreatic bicarbonate and protein secretion; and (3) increase in basal and meal-stimulated serum glucagon levels. Hypergastrinemia did not occur after resection. The hyposecretory responses may represent either increased inhibition or decreased secretory stimulation.

Earlier studies of gastric inhibitory polypeptide (GIP) have shown that it is a powerful inhibitor of acid secretion in denervated gastric pouches. Other studies, however, have shown that it is a weak inhibitor in innervated stomach preparations. In this study we evaluated the inhibitory action of GIP in four dogs, each provided with both a vagally denervated (Heidenhain) pouch and a gastric fistula of the innervated stomach. The effect of intravenous infusion of pure porcine GIP (1 microgram X kg-1 X h-1) on pentagastrin dose response was studied with and without background infusion of bethanechol (25 micrograms X kg-1 X h-1). GIP powerfully inhibited pentagastrin-stimulated acid secretion from the Heidenhain pouch but not from the gastric fistula. The maximal inhibition was 76% for the Heidenhain pouch and 29% for the gastric fistula. Despite the attainment of high levels of circulating immunoreactive GIP (greater than 3,000 pg/ml) early after the onset of infusion of the peptide, inhibition occurred relatively late, suggesting that this action of GIP might be mediated by the release of some other substance(s). Background infusion of bethanechol totally abolished the inhibitory action of GIP in both the Heidenhain pouch and gastric fistula.

PCP-GABA, an analogue of the neurotransmitter amino acid, GABA, is as effective a stimulant of vagal centers and acid secretion as sham feeding. Insulin hypoglycemia, a test hitherto widely used for the cephalic phase, is unsafe and nonspecific because it also stimulates catecholamine release which affects gastrin secretion. PCP-GABA, unlike insulin, causes no tachycardia or hypoglycemia; however, the major advantage of PCP-GABA is that it can be used safely intraoperatively to assess completeness of vagotomy. Its muscle relaxant action is an additional advantage in this regard. As an intraoperative test, PCP-GABA is given intravenously shortly after induction of anesthesia to stimulate acid secretion and to reduce gastric mucosal pH, which is measured by an intraluminal combination electrode. The electrode can be moved around through the intact gastric wall to take measurements from multiple sites. When vagotomy is complete, gastric mucosal pH increases to over 6. This test works well in the dog. We hope to assess its clinical use in the near future.

Transmural proximal gastric vagotomy, an experimental procedure designed to denervate the gastric fundus by intramural division of vagal fibers, was evaluated as a means of reducing stimulated gastric acid output. The procedure reduced peak acid output in response to insulin stimulation by 71 percent. Acid production was not further decreased by extramural division of vagal fibers. It also decreased parietal cell sensitivity to pentagastrin stimulation and did not interfere with emptying of a liquid meal. We have concluded that transmural proximal gastric vagotomy is technically straightforward, reliably divides fundic vagal fibers, produces a significant reduction in acid production equivalent to that produced by standard operative techniques, and does not interfere with gastric emptying.

The mucosa of the proximal stomach contains a powerful inhibitor of acid secretion and gastrin release. The release of this inhibitor is dependent on intact vagal innervation of the proximal stomach. Thus, proximal gastric vagotomy interferes with the release of the inhibitor. After proximal gastric vagotomy for peptic ulcer, recurrence rates increase over time. In addition, there is some recovery of acid secretion. Although nerve regeneration or sprouting has been suggested as the possible explanation for these events, we propose that interference with the inhibitory mechanism of the proximal stomach may be another possible explanation for the increasing ulcer recurrence rates after proximal gastric vagotomy. At present, this is only a hypothesis and is suggested only by indirect evidence. Direct testing of the hypothesis will require complete purification of the inhibitor and the development of a specific radioimmunoassay.

Even though rabbit gastric glands are a commonly used model for the study of gastric physiology, little is known about the secretion of gastric acid in the rabbit in vivo. Gastric acid secretion in response to pentagastrin, histamine, and bethanechol stimulation, and the effect of specific cholinergic and histamine H2-receptor blockers was studied in 62 urethane-anesthetized rabbits. Additionally, the responses of eight conscious rabbits prepared with chronic gastric fistula were compared with similarly prepared conscious dogs (n = 10) and conscious rats (n = 18). In anesthetized rabbits, maximal pentagastrin stimulation resulted in acid outputs only 22% that of maximal histamine stimulation, but this was enhanced by restoring cholinergic tone with a subthreshold infusion of bethanechol. In conscious rabbits, pentagastrin was an effective stimulant, resulting in maximal acid output 70% that of maximal histamine stimulation. This is in contrast to the in vitro findings reported reported by others utilizing isolated gastric glands and cells. Histamine was a potent stimulant of acid secretion in both the anesthetized and conscious rabbit, an observation that parallels the in vitro findings. Unlike the dog and rat, atropine was ineffective as an inhibitor of histamine-stimulated acid secretion in the conscious rabbit, although it was marginally effective against histamine in anesthetized rabbits and against pentagastrin in conscious rabbits. It is concluded that cholinergic tone plays a crucial role in pentagastrin-stimulated acid secretion in the rabbit. This may be an explanation for the poor response to pentagastrin described in isolated rabbit gastric gland preparations.

The synthetic mammalian bombesin-like peptides, canine gastrin releasing peptide 27, 23 and 10, and porcine gastrin releasing peptide 27 were compared with amphibian bombesin 14 and 10 during intravenous infusions into six conscious dogs with chronic gastric cannulae. Gastrin and gastrin releasing peptide were measured in peripherally sampled venous blood by radioimmunoassay and gastric acid secretions were collected. All forms of gastrin releasing peptide stimulated gastrin release and gastric acid secretion in a dose-dependent manner. The larger canine and porcine peptides were more potent than the decapeptide. Bombesin 14 was more potent than bombesin 10. A rise in the venous concentration of immunoreactive gastrin releasing peptide of only 20 fmol ml-1 stimulated gastrin release to about 50% of maximal. Gastrin releasing peptide 10 was cleared from the circulation three times faster than the larger forms and this may account for the apparent differences in potency.

Calcitonin gene-related peptide (CGRP) is a 37-residue peptide recently characterized in the brain and found in high concentrations in the gut, particularly in the stomach and pancreas. The effects of intravenous infusion of human and rat CGRP (260 pmol . kg-1 . h-1) on gastric secretion and emptying and pancreatic exocrine secretion were studied in conscious dogs. CGRP inhibited by 60-75% gastric acid secretion stimulated by a meal, sham feeding, or step doses of bombesin but did not modify acid response to step doses of histamine or bethanechol. The inhibitory effect of CGRP is not due to blockage of postprandial or bombesin-stimulated gastrin release. CGRP did not influence basal or meal-stimulated pancreatic exocrine secretion or the rate of gastric emptying of a saline meal. These results indicate that CGRP is a potent and selective inhibitor of gastrin-mediated acid secretion in dogs and, under these conditions, did not alter other gastrointestinal functions such as gastric emptying or pancreatic exocrine secretion.

The ability of intracisternal insulin-like growth factor II (IGF II) to inhibit gastric acid secretion was studied in rats. Centrally-administered IGF II dose-dependently inhibited acid secretion stimulated by pentagastrin. The effect was abolished by vagotomy. IGF II did not inhibit acid secretion stimulated by histamine or PCP-GABA.

A novel stimulant of gastric acid secretion was extracted and purified from the non-antral gastric mucosa of the canine stomach and some of its biological properties were examined. Tissue was boiled in water and extracted in 2% trifluoroacetic acid. The stimulatory activity was purified by a combination of reverse-phase high pressure liquid chromatography (HPLC) and gel filtration. Fractions were assayed for a stimulation of basal, pentagastrin- and histamine-stimulated gastric acid secretion in the anaesthetized rat. Stimulatory activity was eluted from reverse-phase HPLC columns with acetonitrile and its elution from Sephadex G-10 and G-50 columns suggested a molecular weight of 1,000 to 3,000. The highly purified extracts enhanced basal, pentagastrin- and histamine-stimulated acid secretion in the rat. A stimulatory fraction was purified which was devoid of immunoreactive gastrin and gastrin-releasing peptide and contained only small amounts of histamine. Its chromatographic properties differed from those of histamine and acetylcholine. On two occasions the stimulant was purified to homogeneity and found to contain amino acids. Insufficient pure material was obtained for full characterization. The stimulant has been tentatively called oxyntin.