Search

During the past two decades, major advances have been made in our understanding of basic gastric physiology. Appreciation of cellular biology has contributed to rapid progress in gastric pharmacology. Clinicians may choose from a large and rapidly growing list of antiulcer drugs. The proper choice of medical or surgical therapy depends on knowledge of the pathophysiology of peptic ulceration and of the inherent limitations of each approach. Selective drug use, tailoring of medical regimens to individual clinical situations, and the combination of medical and surgical treatments will play prominent roles in the future management of peptic ulceration.

Changes in serum gastrin in response to feeding a meal of beef liver (15 g kg(-1)) were studied in 5 gastric fistula dogs with and without administration of atropine sulfate (0.2 mg kg(-1) intravenously). The studies were repeated after a truncal vagotomy that abolished acid secretion in response to 2-deoxyglucose. Before vagotomy atropine had little effect on the gastrin response to a meal. After vagotomy the gastrin response to feeding was greatly enhanced, but now atropine depressed the gastrin response at all times after the meal. It is concluded that vagotomy enhances the serum gastrin response to feeding and that atropine counteracts this enhancement.

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 advent of the H2-histamine-receptor antagonists has given new life to the old hypothesis that histamine might be the final common chemical mediator of acid secretion. The available evidence, however, does not prove this hypothesis but does confer on histamine a role in the regulation of acid secretion in normal physiology. Evidence is mounting that, in addition to its stimulatory action, the vagus may play an inhibitory role in acid secretion and gastrin release. Our concepts of the gastric phase of acid secretion have been extended by the discovery of cross distension reflexes in the stomach: the pyloro-oxyntic reflex for acid secretion and the oxyntopyloric reflex for gastrin release. In addition, digested protein has been shown to stimulate directly the oxyntic gland mucosa, but the evidence is against a role for this mechanism in the intact stomach. The hormone(s) responsible for the intestinal phase have not been isolated but the physiological characteristics of entero-oxyntin (a nongastrin, enteric substance that acts on the oxyntic cell) have been defined. Gastric inhibitory polypeptide is an excellent candidate for the entero-gastrone released by fat, but whether it is the sole enterogastrone released is yet to be determined.

Peptide YY is an ileocolonic peptide that inhibits meal-stimulated pancreatic secretion when infused in a dose of 400 pmol/kg X h. In this study pancreatic secretion was monitored in response to increasing doses of secretin or cholecystokinin-octapeptide (62.5, 125, 250, and 500 ng/kg X h) during the simultaneous infusion of either saline or peptide YY (400 pmol/kg X h). Peptide YY significantly (p less than 0.05) inhibited the secretory response to the three lowest doses of each pancreatic secretogogue, reducing the bicarbonate response to the 62.5-ng/kg X h dose of secretin by 86% +/- 6% and the protein response to the same dose of cholecystokinin by 57% +/- 16%. In the second limb of the study, the half-life of peptide YY (11.7 +/- 21 min) and the metabolic clearance rate (13.8 +/- 1.6 ml/kg X min) were found to be similar to those of other gastrointestinal hormones. We conclude that inhibition of meal-stimulated pancreatic secretion by peptide YY can be explained by its ability to decrease the responsiveness of the pancreas to endogenous secretogogues.

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.

Peptide YY is a candidate enterogastrone localized to endocrine cells of the ileocolonic mucosa. The purpose of the present study was to determine if blood levels of peptide YY observed after perfusion of the intestine with fatty acids are capable of slowing gastric emptying. Gastric emptying of a 300-ml saline meal was monitored during intravenous infusion of normal saline or graded doses of peptide YY. Gastric emptying was significantly inhibited by infusion of peptide YY in doses of 200 and 400 pmol/kg X h. During the saline control study, 229 +/- 12 ml of the 300-ml saline meal emptied by 10 min. This figure was reduced (p less than 0.01) to 110 +/- 28 ml by the infusion of peptide YY at a dose of 200 pmol/kg X h. This dose of peptide YY produced plasma concentrations (delta PYY = 239 +/- 50 pM) that were lower than those seen in response to intestinal perfusion of oleic acid (delta PYY = 395 +/- 55 pM) in the same animals. We conclude that perfusion of the intestine with oleic acid releases peptide YY in amounts sufficient to slow gastric emptying.

The contribution of amniotic fluid to fetal growth and gastrointestinal tract development was studied in a rabbit model. In the fetal rabbit, at 23 days gestation, 3 conditions were surgically produced: (1) prevention of swallowing of amniotic fluid by esophageal ligation (n = 8); (2) esophageal ligation but insertion of an esophageal cannula distally to allow continuous infusion into the stomach of bovine amniotic fluid to mimic fetal swallowing (n = 7); and (3) sham operation (n = 7). Fetuses were delivered by Caesarean section at 28 days gestation. Esophageal ligation resulted in significant reductions of birth weight and crown-rump length and a trend to decreased liver weight when compared to sham operated controls. Additionally, marked reductions in gastric and intestinal tissue weight and gastric acidity were found following esophageal ligation. These reductions in both somatic and gastrointestinal tract growth and gastric function were reversed by infusion of amniotic fluid intragastrically. We conclude that amniotic fluid provides 10% to 14% of the nutritional requirements of the normal fetus, and that amniotic fluid contains a potent and as yet undefined gastrointestinal tract trophic factor.

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.

The delay in gastric emptying after a meal is thought to result from nutrient distention-induced release of peptides and neurotransmitters in the gut. The potential contribution of the brain and central neuropeptides to the postprandial regulation of gastric emptying has not been studied adequately. The purpose of this study was twofold: to examine the relative importance and pure central stimulation (sham feeding) or pure peripheral stimulation (duodenal feeding) on gastric emptying, and to determine whether relevant neuropeptides act in the brain to slow gastric emptying of a meal. Six mongrel dogs were prepared with esophageal fistulas, gastric fistulas, duodenal fistulas, and chronic lateral cerebroventricular guides. Gastric emptying of a 300 ml saline solution meal was measured by a phenol red dye dilution technique. Sham feeding of a blenderized meal through the esophageal fistula was used as a central cephalic stimulus. Intraduodenal oleic acid was used as a peripheral stimulus. Both sham feeding and intraduodenal oleic acid inhibited gastric emptying by 59 +/- 12 percent, 73 +/- 5 percent, respectively. In separate studies, we examined the effect on gastric emptying of a bolus injection into the lateral cerebral ventricle of graded doses of corticotropin-releasing factor (110 to 440 pmol/kg), cholecystokinin (16 to 128 pmol/kg), somatostatin-14 (55 pmol/kg), human calcitonin gene-related peptide (230 pmol/kg), and neuropeptide Y (62 to 250 pmol/kg). These peptides are known to affect satiety, gastric emptying, and gastric acid secretion. Of these, only neuropeptide Y and cholecystokinin had an effect on gastric emptying when administered into the lateral cerebral ventricle. Neuropeptide Y inhibited emptying by 28 +/- 8 percent and cholecystokinin accelerated emptying by 32 +/- 12 percent (p less than 0.05). Sham feeding inhibits gastric emptying to a similar degree as intraduodenal feeding, and of the neuropeptides tested, only neuropeptide Y inhibited gastric emptying when given into the brain. The central release of neuropeptides such as neuropeptide Y during a meal may trigger neural pathways that promote postprandial delay in gastric emptying. Central signals may be as important as peripheral signals in the postprandial control of gastric emptying. Further studies are needed to determine the mechanism by which sham feeding inhibits gastric emptying and whether central release of neuropeptide Y is involved.

We studied the effect of graded antral distension on gallbladder contraction both when gastrin release was promoted (alkaline distension) and when gastrin release was blocked (acid distension) in five dogs provided with innervated antral pouch, chronic bile fistula and gastric fistula. Graded distension of the antrum caused graded gallbladder contraction as evidenced by bilirubin output even when gastrin release was completely suppressed. This nongastrin mechanism of gallbladder contraction is abolished by parenteral atropine and by transthoracic truncal vagotomy. These observations provide evidence for a cholinergic, pyloro-cholecystic reflex for gallbladder contraction that is dependent on intact long vagal pathways. Similar reflex mechanisms have been shown to be initiated by antral distension and to cause pancreatic enzyme secretion (pyloro-pancreatic reflex) or acid secretion from the oxyntic gland area of the stomach (pyloro-oxyntic reflex). It would appear, therefore, that the antrum plays a central role in the integration of upper gastrointestinal function not only through the hormone gastrin but also through neural reflex mechanisms.

The doses of cholecystokinin (CCK) that have been shown to cause satiety after peripheral administration are pharmacological and whether "physiological" doses of exogenous CCK or endogenously released CCK have a satiety effect is not known. The purpose of the present study is threefold: to compare the potency of endogenous and exogenous CCK for their satiety, cholecystokinetic, and pancreozyminic actions; to determine whether small doses of CCK in the presence of gastric distension cause satiety; and to test the satiety effect of CCK administered centrally into the lateral cerebral ventricle. Dogs were prepared with cerebroventricular guides and esophageal and duodenal fistulas (n = 4), with chronic bile fistulas (n = 8), and chronic pancreatic fistulas (n = 7). Satiety effect was quantified in the esophageal fistula dog by the amount of blenderized food sham fed within 7.5 min. Duodenal perfusion of fat, used as a releaser of endogenous CCK, stimulated pancreatic protein, and gallbladder contraction with D50 values of 1.5 and 0.3 mmol/h, respectively, but had no effect on the volume sham fed (316 +/- 82 ml/min without and 371 +/- 41 ml/min with the maximal dose of sodium oleate infused). The D50 values of CCK-8 (pmol X kg-1 X h-1) for satiety and for stimulation of pancreatic enzyme secretion and gallbladder contraction were 440, 120, and 22, respectively. Injection of CCK-8 into the lateral cerebral ventricle inhibited sham feeding in a dose-dependent manner. We conclude that duodenal fat in doses producing maximal gallbladder and pancreatic stimulation has no satiety effect in the dog.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of somatostatin (SS-14) was tested in an anesthetized rabbit model of closed-loop ileal obstruction. Experimental groups included (1) immediate treatment (N = 6) receiving SS-14 2,000 pmol X kg-1 X h-1 intravenously (I.V.) beginning at the time of ileal obstruction, (2) delayed treatment (N = 5) receiving SS-14 beginning 6 hours following ileal obstruction, and (3) control (N = 6) receiving only hydration. After 24 hours, all rabbits were killed. Significantly decreased intestinal luminal volume and sodium and potassium output was observed with both immediate and delayed SS-14 treatment when compared to control. Additionally, the gross and microscopic pathologic features of intestinal distension, inflammation, and necrosis seen in control rabbits were absent in rabbits treated with SS-14. The known broad spectrum of physiologic activity of SS-14 on the gastrointestinal tract appeared beneficial in this rabbit model of intestinal obstruction.

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.

Of a series of 130 patients undergoing operation for peptic ulcer disease at the Vancouver General Hospital, seven patients with personality defects had a disastrous outcome after operation.THE MAIN FEATURES OF THIS POSTGASTRECTOMY SYNDROME WERE REMARKABLY SIMILAR: persistent abdominal pain without demonstrable cause, intermittent and inexplicable nausea and vomiting, continued analgesic drug dependence and marked nutritional deficiencies. The high incidence was surprising and was not confined to any particular socioeconomic group. Such patients fall into three groups: those with true ulcer disease, those with salicylate addiction, and those without positive signs of ulcer but with chronic complaints. A history of a personality defect should warn the surgeon, and operation should be performed only for the complications of true ulcer disease. Though operation may cure the ulcer, the patient is worse off because the resulting physiologic derangements cannot be accepted or handled by him. These patients continue to haunt the surgeon, and the syndrome has been named the "albatross" syndrome.

The effect of smoking three cigarettes over a one-hour period on the pentagastrinstimulated submaximal plateau of acid and pepsin secretion was observed in 12 healthy human volunteers comprising men and women and smokers and non-smokers. No significant overall change in secretion was observed. In one subject, however, acid secretion was significantly inhibited (p < 0.01) and in one individual significant late stimulation (p < 0.01) of both acid and pepsin was observed.

In dogs with chronic pancreatic fistulas, pure cholecystokinin (CCK), CCK-variant, 20% pure CCK, octapeptide of CCK, and caerulein all gave the same high maximal protein outputs and low maximal bicarbonate outputs. 10% pure CCK gave higher bicarbonate output that can be achieved with pure CCK. By intestinal perfusion, HCI gave greater protein output than can be achieved with secretine alone, sodium oleate gave greater bicarbonate output than can be achieved with pure CCK alone, and tryptophan gave maximal bicarbonate output less than that of pure CCK. On the hypothesis that intestinally perfused stimulants act solely by release of secretin and CCK, the effects of tryptophan can be accounted for by release of CCK alone, of HCI by release mainly of secretin plus small amounts of CCK, and of oleate by release mainly of CCK plus small amounts of secretin.

Both secretin, and the single substance which possesses both cholecystokinin and pancreozymin activity, have been shown to inhibit gastric acid secretory responses. Since potentiation may occur between pairs of stimulants of gastric secretion, the effects of combining secretin and cholecystokinin/pancreozymin have been studied in Heidenhain pouches stimulated by continuous intravenous pentagastrin. Evidence suggesting potentiation between these two inhibitor agents is presented.