Enterogastrone-like effect of peptide YY is vagally mediated in the dog.

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.

Pure human big gastrin. Immunochemical properties, disappearance half time, and acid-stimulating action in dogs.

Biological properties of pure natural human "big gastrin" (designated G-34 because it contains 34 amino acid residues) were compared with those of pure natural heptadecapeptide gastrins (G-17) from human and porcine sources. Radioimmunoassay inhibition curves indicated that G-17 was nearly 1.5 times more potent than G-34 with the antibody used in this study. This difference was confirmed by demonstration of increased immunoreactivity generated when G-34 was converted to G-17 by trypsinization. When infused intravenously into dogs with gastric fistulas and Heidenhain pouches in equimolar doses, G-34 produced slightly higher acid secretory responses than G-17. Responses to sulfated and nonsulfated forms were not significantly different, nor were responses to human and porcine G-17. During infusion of equimolar doses, steady-state serum gastrin concentrations were more than fivefold higher with G-34 than with G-17. The difference in steady-state blood concentrations could be accounted for by a corresponding difference in removal rates. The half times of the G-34 preparations averaged 15.8 min and the half times of the G-17 preparations averaged 3.2 min. The calculated spaces of distribution for G-17 and G-34 were similar, about 25% of body weight. When the increment in serum gastrin was plotted against acid secretory response it was found that nearly five times greater increments in molar concentrations of G-34 than of G-17 were required to produce the same rate of acid secretion. The potency of these two molecular forms of gastrin can be expressed in two different ways. Based on exogenous molar doses, the potencies of G-34 and G-17 were similar. However, based on molar increments in serum gastrin concentration, G-17 was approximately five times more potent than G-34. Hence, fractionation of these gastrin components may be important in estimation of the acid-stimulating action represented by total serum gastrin as measured by radio-immunoassay.

Selective release of somatostatin by calcitonin gene-related peptide and influence on pancreatic secretion.

Calcitonin gene-related peptide is a potent inhibitor of stimulated pancreatic exocrine secretion in vivo. The mechanism of this inhibitory action was studied in dogs and rats. The questions examined were: (1) is the inhibitory action of CGRP on pancreatic secretion mediated by somatostatin? (2) is the inhibition direct, via action on acinar cells, or indirect? and (3) is a neuronal mechanism involved, and, if so, by what pathway? In dogs with chronic pancreatic fistulae, CGRP caused significant inhibition of the outputs of pancreatic protein (63-68%) and of pancreatic bicarbonate (74-89%) and a simultaneous dose-related rise (40-102 fmol/ml) in plasma somatostatin-like immunoreactivity. A similar degree of inhibition was found when exogenous somatostatin was infused to achieve similar levels of plasma somatostatin-like immunoreactivity. More direct evidence of somatostatin mediation of CGRP action was sought in conscious rats with pancreatic fistulae using a potent and specific monoclonal antibody to somatostatin. The latter studies suggest that CGRP has both a somatostatin-dependent and a somatostatin-independent mechanism of action. In isolated rat acini, CGRP did not inhibit CCK-stimulated amylase release, suggesting that its in vivo action is indirect. In the isolated vascularly perfused rat pancreas, CGRP (10(-10)-10(-7) M) inhibited in a dose-dependent manner volume and protein output stimulated by a mixture of CCK-8 and secretin. The inhibitory action of CGRP was blocked by tetrodotoxin (10(-7) M) and by atropine (10(-7) M), but not by hexamethonium (10(-7) M). We conclude that CGRP action: (1) is partly explained by release of somatostatin; (2) is indirect; (3) is neurally mediated; and (4) involves cholinergic muscarinic neurons within the pancreas.

Physiology and pathophysiology of gastrin: a review.

Recent advances in understanding the physiology and pathophysiology of the gastrointestinal hormone, gastrin, are reviewed. Details of gastrin biosynthesis, secretion, and cellular actions may have broad implications for other peptide hormones. Potentially useful antigastrin drugs are described. Areas of future development are suggested.

Opposing central and peripheral actions of brain-gut peptides: a basis for regulation of gastric function.

The existence of an increasing number of peptides in both the gut and the brain provides the basis for the concept of a brain-gut axis. However, to date, no unifying hypothesis has been put forward to explain the physiologic significance of this remarkable phenomenon. The present study examines the central and peripheral actions on gastric function of cholecystokinin octapeptide (CCK-8), somatostatin, and bombesin, all of which exist in both the gut and brain. Intravenous infusion of CCK-8, in doses of 50, 100, and 200 pmol X kg-1 X hr-1, caused 28%, 38%, and 52% inhibition, respectively, of the rate of gastric emptying of a liquid meal in dogs. By contrast, the injection of 32, 64, and 128 pmol X kg-1 into the lateral cerebral ventricle of these dogs accelerated gastric emptying by 6%, 26%, and 32%, respectively. Bombesin, which stimulated gastric acid secretion in a dose-dependent manner but which had no effect on the submaximal acid response to pentagastrin when administered peripherally, inhibited in a dose-dependent manner the submaximal response to pentagastrin when given centrally, with a maximal inhibition of 66% +/- 5%, at a dose of bombesin of 180 pmol X kg-1. Similarly, somatostatin-14 caused graded inhibition of pentagastrin-stimulated acid secretion when it was administered peripherally but caused dose-dependent augmentation of the acid response when it was given centrally. Maximal inhibition of 51% of the pentagastrin response occurred with a peripheral dose of somatostatin of 800 pmol X kg-1 X hr-1. By contrast, maximal augmentation of the pentagastrin response of 78% occurred when a dose of 400 pmol X kg-1 of the peptide was injected into the lateral ventricle. We conclude that CCK-8, bombesin, and somatostatin have opposing actions on gastric function when administered centrally and peripherally. We propose that this phenomenon may be common to all neuropeptides of the brain-gut axis and may provide a basis for central regulation of gut function.

The use of somatostatin and its analogs in the treatment of surgical disorders.

Somatostatin is a naturally occurring peptide with a wide spectrum of biologic actions, most of which are inhibitory in nature. It has wide distribution, and within the gastrointestinal tract is is found in the pancreas, the stomach, intestinal mucosa, and myenteric neurons. It appears to function as a classic circulating hormone, as well as both a paracrine or locally acting agent and a neurocrine agent. Because of its inhibitory actions on gut endocrine, secretory, and motor functions, it has potential applicability in the treatment of a variety of disorders of interest to the surgeon. Indeed, it has been used successfully in the management of upper gastrointestinal hemorrhage, secretory diarrhea, short bowel syndrome, pancreatitis, gastrointestinal fistulas, and peptide-secreting tumors of the gut (apudomas). This review discusses physiology, pathophysiology, and therapeutic applications of somatostatin that may be important in surgical practice.

Interactions of vasoactive intestinal polypeptide and cholecystokinin octapeptide on the control of gallbladder contraction.

The gallbladder is supplied by three types of vagal fibers: cholinergic, cholecystokinin (CCK)-ergic, and vasoactive intestinal polypeptide (VIP)-ergic. Most previous studies on the interaction of VIP and CCK on gallbladder contraction have been in vitro. In this study we evaluate this interaction more fully in vivo using six dogs with chronic bile fistula. Dose-response curves were constructed to CCK-8 alone and to VIP alone. The effect of graded doses of VIP on maximal response to CCK-8 was also studied. CCK-8 caused the expected dose-related stimulation of gallbladder contraction, while graded doses of VIP had the opposite effect. VIP also caused a dose-related inhibition of the maximal response to CCK-8, decreasing bilirubin output from 39 +/- 8 to 15 +/- 3 mg/hr (p less than 0.05). The corollary to these findings is that gallbladder tone and contraction is regulated by the interplay of stimulatory cholinergic-CCK-ergic and inhibitory VIP-ergic fibers. Further, a plausible explanation for the variable effects of vagotomy on gallbladder contraction is that variable proportions of these opposing fibers are cut.

Evidence for vagus-dependent pancreatic polypeptide-releasing factor in the antrum: studies with the autotransplanted dog pancreas.

Pancreatic polypeptide (PP) response to food is suppressed by truncal vagotomy, antral vagotomy, and antrectomy. The inhibitory effect of antral vagotomy and of antrectomy may be due to inadvertent vagal denervation of the pancreas, disruption of antropyloric neural reflexes, or inhibition of release of a PP-releasing factor from the antrum. In this study we examined the latter hypothesis by achieving total extrinsic pancreatic denervation by orthotopic autotransplantation of the entire pancreas in four dogs. Total extrinsic pancreatic denervation, which abolished the pancreatic juice protein response to insulin, did not significantly alter plasma PP response to a meal (peak 30-minute PP of 696 +/- 192 pg/ml before transplantation versus 961 +/- 80 pg/ml after transplantation). Therefore, postprandial release of PP is, to a large extent, not mediated either by direct vagal innervation of the pancreas or by neural communications between the pancreas and antrum or the pancreas and the small intestine. In two of the dogs with pancreatic transplants, subsequent antral vagotomy resulted in greater than 80% inhibition of postprandial PP response. These findings are consistent with the hypothesis that a PP-releasing factor is present in the antrum and that the release of this factor is dependent on intact antral vagal innervation.

Vagal control of gastrin release in the dog: pathways for stimulation and inhibition.

The vagus has a dual effect on gastrin: it both stimulates and inhibits its release. To determine the gastric vagal pathways for these opposing effects, plasma gastrin and acid responses to meal (intragastric titration of 15% liver extract, pH 5.5) and to insulin (0.5 U regular insulin intravenously) were studied in seven dogs in three consecutive stages: a control stage, after antral vagotomy (AV), and after subsequent proximal gastric vagotomy (PGV). AV abolished the plasma gastrin response to insulin but had no effect on either basal or meal-stimulated gastrin release. Subsequent PGV caused significant elevation in basal plasma gastrin concentration, no further change in the gastrin response to insulin, but a significant increase in meal-stimulated gastrin release. AV decreased acid response to insulin nonsignificantly and had no effect on meal-stimulated acid secretion. Subsequent PGV reduced by 90% the acid response to insulin, had negligible effect on the gastric fistula acid response to meal, but increased Heidenhain pouch response sixfold. These studies show that vagal stimulation of gastrin release is mediated along direct antral vagal pathways, while vagal inhibition requires intact vagal fibers to the proximal stomach. The mechanism by which the fundic vagal pathways exert an inhibitory influence on the G cell in the antrum is yet to be elucidated.

Somatostatin inhibits pancreatic exocrine secretion via a neural mechanism.

The mechanism of inhibition of pancreatic exocrine secretion by somatostatin is unknown. We hypothesized that somatostatin acts indirectly, via intrinsic pancreatic neurons, to inhibit pancreatic exocrine secretion. To test this hypothesis, amylase and volume outputs in response to secretin (10(-8) mol/L) and cholecystokinin octapeptide (CCK) (10(-8) mol/L) were studied in the rat isolated, perfused, pancreas model. Somatostatin (10(-7) mol/L) significantly inhibited amylase output by 48% compared with control (352 +/- 57 v 676 +/- 85 U/30 min, P less than .05 by ANOVA). Blockade of axonal neuronal transmission by tetrodotoxin (10(-7) mol/L) completely abolished the inhibitory effect of somatostatin (992 +/- 53 U/30 min). Similar effects were seen on volume output. The inhibitory effect of somatostatin on amylase output was not affected by cholinergic receptor blockade with atropine (328 +/- 65 U/30 min) or by sympathetic ganglionic blockade with hexamethonium (360 +/- 68 U/30 min). This suggests that the intrinsic pancreatic neurons responsible for the inhibitory effect of somatostatin are peptidergic. The possibility that somatostatin acts directly on the acinar cell to inhibit exocrine secretion was tested by incubating varying doses of somatostatin (10(-12) to 10(-7) mol/L) with isolated pancreatic acini in the presence of graded concentrations of CCK (10(-12) to 10(-10) mol/L). In this model, CCK alone is a potent stimulant of amylase release, with a Km of 6 X 10(-12) mol/L and a Vmax of 22 +/- 3% total amylase. In this model, somatostatin had no inhibitory effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine gut neoplasms. Important lessons from uncommon tumors.

OBJECTIVE: To review our experiences in order to high-light some important lessons learned in the treatment of patients with neuroendocrine gut neoplasms. DESIGN: Retrospective analysis of case series of 70 patients with neuroendocrine gut neoplasms treated between 1983 and 1993. The clinical features of individual patients illustrate lessons in surgical treatment. SETTING: University hospitals with tertiary care referral practice. INTERVENTIONS: The main intervention was abdominal exploration in 43 patients, with resection of the primary tumor in 39 and of hepatic metastases in four. MAIN OUTCOME MEASURES: To describe the tumors seen and to identify major lessons learned. RESULTS: Of 70 patients with neuroendocrine tumors treated, 31 had carcinoid tumors, 10 each had insulinomas and gastrinomas, five had vipomas, nine had non-functioning islet cell tumors, three had glucagonomas, and one each had somatostatinoma and a possible cholecystokinin-secreting tumor (or CCKoma). Important lessons learned include: (1) the importance of preoperative tumor localization; (2) in multiple endocrine neoplasia, type I syndrome, the tumor found may not be the one responsible for the patient's symptoms; (3) solitary sporadic tumors secreting multiple peptides may mimic multiple tumors in multiple endocrine neoplasia, type I syndrome; (4) one needs to be prepared for the unexpected, such as the carcinoid crisis; (5) resection may sometimes be necessary even with advanced local disease; and (6) selected patients may benefit from pancreaticoduodenectomy. CONCLUSIONS: These rare tumors are interesting in their clinical presentation and can be challenging in their treatment.

Advances in drug therapy for peptic ulcer disease.

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.

Control of dumping symptoms by somatostatin analogue in patients after gastric surgery.

Octreotide acetate is a long-acting analogue of the naturally occurring inhibitory gastrointestinal peptide, somatostatin. We tested the efficacy of octreotide in controlling the symptoms of dumping syndrome in response to a provocative meal in a randomized, double-blinded, crossover trial in nine severely affected patients. Pretreatment with octreotide acetate (100 micrograms injected subcutaneously) reduced postprandial dumping symptoms from a mean +/- SEM score of 15.7 +/- 1.6 (placebo treatment day) to 4.6 +/- 1.7. With placebo treatment, all nine patients became symptomatic in response to the meal, whereas with octreotide treatment, symptoms occurred in only two of nine patients. Similarly, all placebo-treated patients showed a postprandial increase in pulse rate to a mean +/- SEM of 105 +/- 6 beats per minute, whereas only one of nine octreotide-treated patients showed an increase in pulse rate (mean +/- SEM, 80 +/- 3 beats per minute). These differences were also statistically significant. While no significant changes were observed in postprandial hematocrit values or osmolality between placebo and octreotide treatments, octreotide prevented hypoglycemia in four affected patients and significantly inhibited insulin release. We conclude that octreotide is a useful tool in the treatment of patients with severe, refractory dumping syndrome.

Reduced mortality from bleeding pseudocysts and pseudoaneurysms caused by pancreatitis.

Exigent hemorrhage from pseudocysts and pseudoaneurysms is the most rapidly lethal complication of pancreatitis. Of eight patients with this unusual entity seen by us, all had acute gastrointestinal hemorrhage; two patients had intraperitoneal bleeding as well. Preoperative visceral arteriograms accurately defined the bleeding lesion and greatly aided in planning operative strategy in six patients. Emergency celiotomy and arterial ligation were accomplished in seven patient, and one patient underwent successful transcatheter arterial embolization. Pancreatic resection was not required in any patient for control of hemorrhage, although gastrectomy was necessary in three cases. One elderly patient died of sepsis five weeks after operation. Our mortality of 12.5% compares favorably with the 37% overall mortality from 123 cases reported in the literature.

Corticotropin-releasing factor inhibits gastric emptying in dogs: studies on its mechanism of action.

The effects of corticotropin-releasing factor (CRF) on gastric emptying of a saline solution was further investigated in six dogs prepared with gastric fistulas and chronic cerebroventricular guides and in four other dogs with chronic gastric fistulas and pancreatic (Herrera) cannulas. Intravenous infusion of CRF significantly inhibited gastric emptying whereas intracerebroventricular injection of CRF had no effect. Pharmacologic blockade of beta-adrenergic system by propranolol did not modify intravenous CRF induced delay in gastric emptying. Intravenous CRF did not influence basal pancreatic secretion whereas secretin infused stimulated bicarbonate secretion. These results indicate that intravenous but not intracerebroventricular administration of CRF inhibited gastric emptying of a saline solution in dogs. The inhibitory effect of intravenous CRF on gastric emptying is not mediated by the beta-adrenergic nervous system, and not secondary to the release of other peptides that affect both pancreatic secretion and gastric emptying such as cholecystokinin and peptide YY.

Effects of cholecystokinin and gastrin antagonists on pancreatic exocrine secretion stimulated by gastrin-releasing peptide.

The effects of a specific cholecystokinin (CCK) receptor antagonist (L364,718) and a gastrin receptor antagonist (L365,260) on gastrin-releasing peptide-10 (GRP-10)-stimulated pancreatic secretion were investigated in the anesthetized rat. GRP-10 stimulated pancreatic exocrine secretion in a dose-dependent manner. A dose of 1.0 nmol/kg/h elicited a significant increase in pancreatic protein output. L364,718 (2.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous CCK-8 (3.0 nmol/kg/h) on pancreatic secretion, did not suppress the excitatory effect of GRP-10. L365,260 (5.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous gastrin (20 micrograms/kg/h) on gastric acid secretion, did not suppress the excitatory effect of GRP-10 either. We concluded that CCK or gastrin do not mediate the excitatory mechanism of bombesin/GRP on pancreatic secretion. Since CCK and gastrin are the most probable candidates for excitatory mediator of bombesin/GRP, these results support the hypothesis that bombesin/GRP directly stimulates the exocrine pancreas in the rat.

Geranyl-geranyl acetone: a novel stimulant of secretin release in the dog.

Geranyl-geranyl acetone (GGA), a new acyclic polyisoprenoid, anti-ulcer drug appears to exert its beneficial effect by stimulating bicarbonate secretion from the stomach and pancreas. Its efficacy in stimulating pancreatic bicarbonate is particularly striking, and this study was designed to examine the mechanism for this action. Since it is structurally similar to the side chain of the prostaglandin molecule, its ability to stimulate bicarbonate secretion could be a direct one. On the other hand, the magnitude of pancreatic bicarbonate response (about 50% of maximal response to secretin) suggests it might act by releasing secretin. Two types of experiments were performed in dogs with pancreatic fistulas: first, secretagogue interactions were examined by studying the effect of intraduodenal GGA (8 mg/kg) or its carrier (control) on the dose-response curves to exogenous secretin and cholecystokinin octapeptide (CCK-8); second, the effect of graded doses of intraduodenal GGA on pancreatic bicarbonate and plasma secretin-like immunoreactivity (SLI) responses was tested directly. Pancreatic bicarbonate responses (micromoles per 30 min) were to secretin doses of 32, 125, and 500 ng/kg/h. Without and with GGA, responses were 74 +/- 27, 952 +/- 215, and 2,000 +/- 425 and 599 +/- 110, 1,624 +/- 472, and 2,129 +/- 398 ng/kg/h, respectively. Similarly, the bicarbonate responses to CCK-8 were augmented. Basal plasma SLI was 1.5 +/- 0.6 pM/ml. Peak plasma SLI in response to 2, 4, and 8 mg of GGA intraduodenally were 6.8 +/- 0.7, 8.9 +/- 3.1, and 19.6 +/- 2.7 pM/ml, respectively. It is concluded that GGA is a potent stimulant of pancreatic bicarbonate secretion, and this action appears to be mediated by the release of duodenal secretin.

Tachykinins mediate contraction of the human lower esophageal sphincter in vitro via activation of NK2 receptors.

The contractile response to natural tachykinins and selective peptide agonists for tachykinin receptors was studied in strips of circular smooth muscle of human lower esophageal sphincter in vitro. The effects of phosphoramidon, which inhibits neutral endopeptidase (EC.3.4.24.11) and of the non-peptide compounds, SR 48968 and CP-96,345, which selectively block NK1 and NK2 receptors, respectively, were also investigated. Substance P, neurokinin A and neurokinin B produced a concentration-dependent contractile response. The rank order of potency was neurokinin A > neurokinin B > substance P. Phosphoramidon (1 microM) potentiated the response to substance P without changing the order of potency of natural tachykinins. The NK2-selective agonist, ([ beta Ala8]neurokinin A-(4-10)), produced a concentration-dependent contraction. The NK1 ([Sar9,Met(O2)11]substance P, 1 microM) and NK3 ([MePhe7]neurokinin B, 1 microM) selective agonists, however, did not exert any contractile effect. The selective NK2 antagonist, SR 48968, potently inhibited in a concentration-dependent (10 nM-1 microM) manner the response to neurokinin A, without affecting the response to carbachol. The selective NK1 antagonist, CP-96,345 (1 microM), did not affect the response to neurokinin A. These results indicate that tachykinins contract the circular muscle of human lower esophageal sphincter, and that this effect is mediated by NK2 receptor stimulation. Moreover, a phosphoramidon-sensitive mechanism plays a role in the regulation of the response to substance P.

Central nervous system inhibition of pentagastrin-stimulated acid secretion by insulin-like growth factor II.

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.

Partial purification of a novel stimulant of gastric acid secretion from canine non-antral mucosa.

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.