Bombesin, acetylcholine, prostaglandins and somatostatin are all thought to be involved in the regulation of gastrin release and gastric secretion. We have studied the effects of low doses of atropine, 16-16(Me)2-prostaglandin E2 (PGE2) and somatostatin-14 on bombesin-stimulated gastrin release and gastric acid and pepsin secretion in conscious fistula dogs. For reference, synthetic gastrin G-17 was studied with and without somatostatin. Bombesin, in a dose-related manner, increased serum gastrin, which in turn stimulated gastric acid and pepsin secretion in a serum gastrin, concentration-dependent manner. Somatostatin inhibited gastrin release by bombesin as well as the secretory stimulation by G-17; the combination of sequential effects resulted in a marked inhibition of bombesin-stimulated gastric acid and pepsin secretion. PGE2 also strongly inhibited gastrin release and acid and pepsin secretion. Atropine had no significant effect on gastrin release, but greatly inhibited gastric secretion. Thus somatostatin and PGE2 inhibited at two sites, gastrin release and gastrin effects, while atropine affected only the latter.

Animals↗

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Analysis of food stimulation of gastrin release in dogs by a panel of inhibitors.

The release of gastrin into the serum of five conscious gastric fistula dogs after a meat meal was monitored for 2 hours. Neither the rate of increase in serum gastrin nor the 2 hour cumulative integrated gastrin response was changed by administration of small doses of somatostatin tetradecapeptide (0.5 microgram/kg.hr IV for 2 hr), 16-16 dimethyl prostaglandin E2 (0.25 microgram/kg.hr IV for 2 hr or 1 microgram/kg intragastrically), or bethanechol (20 micrograms/kg.hr IV for 2 hr). Acidification of the food in the antrum to pH 1.2 to 1.4 eliminated serum gastrin release in response to food. In control studies, serum gastrin levels were not altered by IV administration of saline for 2 hr with no food or when a plate of food was held just out of the dogs' reach (teasing). Food-stimulated gastrin release was contrasted with that stimulated by bombesin under identical laboratory conditions [17]. In each case, antral acidification, somatostatin, prostaglandin E2 and bethanechol affected bombesin-stimulated gastrin release differently from that stimulated by food. We conclude that food and bombesin release gastrin by different pathways.

Animals↗

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Frog gastric mucosal ATPase.

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Adenosine Triphosphatases↗

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Clinical aspects of ECL-cell abnormalities.

ECL cell hyperplasia results from hypergastrinemia, and in man this occurs due to achlorhydria in atrophic gastritis (pernicious anemia [PA]) and gastrinoma (Zollinger-Ellison syndrome [ZES]). Progression to neoplasia, i.e., ECL cell carcinoids (usually small, multicentric and non-functional), occurs in some five to 10 percent of patients with PA where they remain gastrin-dependent and reversible by normalization of serum gastrin by antrectomy. Even if untreated, the carcinoids are almost invariably benign and do not cause death. In ZES, ECL cell hyperplasia is progressive due to hypergastrinemia. However, carcinoids develop only in the MEN-I subtype but pose no additional threat of malignancy. A conservative approach is recommended for small multicentric carcinoids, and the tumors do not need removal. By contrast, single, large, non-gastrin-dependent carcinoids represent a different biological and clinical problem and are frequently malignant.

Carcinoid Tumor↗

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Pepsin and the esophagus.

Esophagitis results from excessive exposure of the esophagus to gastric juice through an ineffective or dysfunctional lower esophageal sphincter mechanism. A possible role of pepsin in damaging the esophageal mucosa with consequent esophagitis may be examined directly by testing pepsin under various conditions in experimental models of esophagitis. Since gastric juice contains both acid and pepsin, all experiments examine separately effects of perfusion of the esophagus by acid without and with pepsin in various combinations. Acid perfusion alone at concentrations represented by pH 1.3 or above does not produce esophagitis. The addition of pepsin to acid between pH 1 and 3.5 causes considerable acute esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5, pepsin does not damage the esophagus. The damage caused by acidified pepsin may be made much worse by the further addition of aspirin or other NSAIDs, presumably by further breaking down mucosal barriers.

Animals↗

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Pathobiology and management of hypergastrinemia and the Zollinger-Ellison syndrome.

Gastrin is both stimulatory and trophic to the cells of the gastric fundus--parietal and peptic cells, and enterochromaffin-like (ECL) cells which are major intermediaries of the gastrin effect. Gastrin (from the antrum) and acid (from the fundus) represent the interactive positive and negative limbs of a feedback loop. The nature and extent of sub-loops, perhaps involving the vagus, acetylcholine, histamine, and other peptides and cell products are at present unclear or unknown. Loss of either gastrin or acid has predictable consequences. Absent acid, as in pernicious anemia or as a result of omeprazole, leads to hypergastrinemia. In rats, such hypergastrinemia (gastrin > 1,000 pg/ml) causes fundic ECL hyperplasia and, eventually, carcinoids; in humans with pernicious anemia, hypergastrinemia causes ECL-cell hyperplasia, which may progress to carcinoids that are reversible upon withdrawal of gastrin, illustrated by three cases described here. Loss of gastrin by antrectomy for duodenal ulcer leads to fundic involution and marked reduction in basal acid output, maximal acid output, and fundic histamine. An uncontrolled excess of gastrin, as from a gastrinoma outside the negative feedback loop, causes acid and pepsin hypersecretion with upper GI mucosal damage, the Zollinger-Ellison syndrome. This paper summarizes the abnormal regulation of gastrin and the biology, natural history, diagnosis, and management of ZE syndrome by medical and surgical means.

Gastrins↗

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Gastrin I, pentagastrin and histamine in the fistula dog.

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Animals↗

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Medical management of esophageal reflux.

Gastroesophageal reflux of varying severity is a common disorder for which medical attention is sought at all levels, from pharmacists to specialist physicians and surgeons. This brief overview represents my current understanding of reflux, its effects on the esophagus and my personal approach to treatment of these disorders. Of necessity, because the literature is so extensive (a Medline search on reflux from 1966 to 1993 yielded over 1500 papers.), I have relied in places on the extensive review by Marks and Richter [1]. My paper emphasizes the evaluation and treatment of patients with symptomatic reflux, esophagitis and its complications. It describes why it is important to grade the disorders so that the treatment used is appropriate to the severity of the disease. The more severe the disease, the more specific the diagnostic information needed and the more exacting the treatment. Various treatments and outcomes of therapy are discussed, and a role for surgery is defined. The essence of effective medical treatment of esophagitis is to reduce acidity of the refluxate to a level outside the optimum proteolytic pH range of pepsin, i.e. greater than pH 3.5.

Anti-Ulcer Agents↗

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Management of refractory and complicated reflux esophagitis.

Simple intermittent heartburn with minor or no esophagitis can be treated with simple measures including lifestyle changes and antacids as needed, or H2 receptor antagonists (H2RA), and has a good outcome. Problematic reflux includes resistance to therapy, stricture, Barrett's esophagus and aspiration. Severe reflux esophagitis, often resistant to H2RA therapy, requires more potent treatment with potent acid suppression using proton pump inhibitors, often indefinitely. When complicated by stricture, dilatations with potent acid suppression are needed. Barrett's esophagus is subject to esophagitis, which is no more difficult to treat than other cases of esophagitis. Reflux in Barrett's esophagus should be treated on its own merits without regard to the presence of Barrett's epithelium. Dysplasia leading to adenocarcinoma is a different problem, apparently not influenced by reduced exposure to acid. Indications for antireflux surgery are quite limited and should be carefully analyzed as a cost/risk/benefit problem.

Barrett Esophagus↗