The overall objective of this proposal is to study the physiological and pathophysiological roles of a non-gastrin acid stimulating peptide (NGASP). This peptide was found during investigation of 44 patients with islet cell tumor with gastric acid hypersecretion and peptic ulceration. Fifteen of them had normal circulating gastrin concentration (less than 150 pg/ml). The extract of their tumors contained NGASP bioactivity that was inactivated by trypsin but not blocked by an anti-gastrin antibody. The bioactivity of the extract potentiated mutually with gastrin to stimulate gastric acid secretion and stimulated histamine release from isolated rat enterochromaffin-like (ECL) cells that was independent of gastrin/CCK-B receptor. Two forms of NGASP have been isolated to homogeneity and one of these, NGASP-3, has been sequenced and shown to potentiate with pentagastrin to stimulate acid secretion. The proposed studies will test the following hypotheses: 1) Circulating NGASP is markedly elevated in patients with ulcerogenic tumor syndrome without hypergastrinemia; 2) NGASP is localized in specific endocrine or nerve cells in the gastrointestinal tract and/or pancreas and is released postprandially into the circulation or gastric mucosa to stimulate secretion of gastric acid and pepsin; 3 plasma level of NGASP may be found elevated (but not as high as that of ulcerogenic tumor syndrome) in duodenal ulcer patients with gastric acid hypersecretion in fasting state; 4) NGASP potentiates the acid stimulating action of circulating gastrin and vice versa, 5) It plays an important role in meal-stimulated acid secretion; 6) It stimulates histamine release from ECL cells of gastric mucosa and may directly stimulate parietal cells to secrete H+. NGASPs will be further purified from the tumors and sequenced. Synthetic NGASPs will be prepared for studying their effects on gastric acid and pepsin secretion in rats and dogs. High titer and specific antibodies for NGASPs will be raised to develop specific radioimmunoassays and used for studying tissue localization and the mechanisms of the release and action of NGASPs. The release of NGASPs in healthy subjects and peptic ulcer patients including those ulcerogenic tumor patients with and without hypergastrinemia will be studied. The results of the proposed studies will lead to a new diagnostic method for screening patients with hypersecretion of NGASP and thus permit early detection of ulcerogenic tumor syndrome without hypergastrinemia and diagnosing a subset of duodenal ulcer patients with high fasting gastric acid secretion. It will undoubtedly open a new frontier in the study of regulation of gastric acid and pepsin secretion.
