Neuroendocrine cell hyperplasia and neuroendocrine carcinoma of the rodent fundic stomach.

Certain substances when given orally to rats have effects on the neuroendocrine cells of the fundic stomach. Such compounds also have effects on acid or its secretion, which is to a greater or lesser extent suppressed, with a consequent rise in serum gastrin, followed by an increase in the number of histamine-secreting ECL cells. These changes are seen with the histamine H2 receptor antagonists loxtidine, SKF 93479, ICI 162,846 and ranitidine; with the hypolipidaemic agents clofibrate, ciprofibrate and benzofibrate; with sodium bicarbonate and pentagastrin; and with omeprazole, a potent inhibitor of the parietal cell proton pump mechanism. Changes in the pH of the rat stomach stimulate the neuroendocrine G cells of the pylorus to secrete gastrin, which acts on the ECL cells of the fundus causing the production of histamine, which in turn stimulates the parietal cell. This sequence leads to an excess of circulating gastrin, which is detectable within 5 days. Subsequently increases in the number of ECL cells occur, the hyperplasia being related to hypergastrinaemia and the degree of acid suppression. The hyperplastic response is rapid, being so obvious with loxtidine at 39 days that there is good reason to suppose it could well be detected earlier. Using omeprazole, hyperplasia was found at 28 days after oral doses of 140 mg/kg/day. In order to get an equivalent degree of acid suppression with ranitidine it was necessary to deliver 420 mg/kg/day by subcutaneous infusion using an osmotic minipump, when hyperplasia occurred. Interestingly, only omeprazole produced a hyperplastic response of G cells. Such results reflect the covalent binding of omeprazole to the proton pump as opposed to the competitive binding of ranitidine to the histamine H2 receptor site. In addition to ECL cell hyperplasia there is ample evidence from lifetime studies in rats and mice that neoplasia may result. Neuroendocrine carcinomas (carcinoids) of the rat fundic stomach have been observed with loxtidine, omeprazole, SKF 93479 and ICI 162,846. They are seen late in the 2-year rat studies and are most unlikely to have arisen purely as an extension of the hyperplastic response. It is possible that the prolonged disturbance of gastric homoestasis resulting from achlorhydria result in the production of a carcinogen or carcinogens, in which event it is not too surprising, in view of the neuroendocrine hyperplasia, that the tumours seen are neuroendocrine carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Desmosomal glycoprotein DGI, a component of intercellular desmosome junctions, is related to the cadherin family of cell adhesion molecules.

Among the variety of specialized intercellular junctions, those of the adherens type have the most obvious association with cytoskeletal elements. This may be with the actin microfilament system as in the zonula adherens or with intermediate filaments as in the macula adherens, or desmosome. In the former case, it is clear that transmembrane glycoproteins of the cadherin family are important adhesive components of the molecular assembly. We now show for desmosomes that a major glycoprotein component (desmosomal glycoprotein DGI) has extensive homology with the cadherins, defining an extended family, but also has unique features in its cytoplasmic domain that are likely to be relevant to the association with intermediate rather than actin filaments. A novel 282-residue extension contains repeats of approximately 29 amino acid residues predicted to have an antiparallel beta-sheet structure, followed by a glycine-rich sequence. As in the cadherins, the extracellular domain contains possible Ca2(+)-binding sequences and a potential protease processing site. The cell adhesion recognition region (His-Ala-Val) of the cadherins is modified to Arg-Ala-Leu.

An evaluation of the safety of ranitidine during seven years daily oral administration to beagle dogs.

1. Ranitidine hydrochloride was administered orally to Beagles at doses equivalent to 50 mg once daily, or 5 mg twice daily, of ranitidine base/kg for more than 7 years. 2. Apart from looseness of faeces, seen mainly after doses of 50 mg/kg and only rarely after the first year of such treatment, there were no adverse clinical effects. There were no deaths related to treatment. 3. Periodic gastroscopy revealed nothing abnormal. 4. Peak plasma levels of ranitidine occurred within 2 h of dosing; levels were proportional to the doses administered. 5. There were no major differences in fasting plasma gastrin levels between treated and untreated dogs; the expected increase occurred in response to the provision of food and, predictably, this was greater following a dose of ranitidine. 6. A normal histamine-induced gastric secretory response was demonstrated. 7. Necropsy revealed no lesions of toxicological significance. Macroscopically the stomachs appeared normal but microscopic examination showed some gastritis in both treated and control dogs. No changes in enterochromaffin-like (ECL) cells were detected. Electron microscopy showed unimpaired secretory activity of parietal cells. 8. Thus, after more than 7 years administration to beagle dogs of doses in excess of the normal daily therapeutic dose, the stomachs showed no changes attributable to treatment and their secretory capacity was unimpaired.

Changes in the gastric mucosa of the mouse associated with long lasting unsurmountable histamine H2 blockade.

The oral administration of loxtidine to mice at doses of 600, 250, and 50 mg/kg/day for 746 days produced carcinoid tumours of the gastric fundus. The fundic mucosa also showed marked atypical hyperplasia with changes in foveolar cells similar to those seen in early incomplete metaplasia. These effects may be related to the prolonged achlorhydria produced by this potent unsurmountable histamine H2 receptor antagonist.

Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat.

The oral administration of loxtidine, a potent histamine H2-antagonist, to a total of 378 rats at doses of 50, 185, or 685 mg/kg/day for 116 weeks resulted in the late formation of carcinoid tumours of the gastric fundus. The first such tumour was detected after 712 days of treatment. There was no dose related response; 11 rats at the low level of treatment were affected, 12 at the intermediate and 11 at the high. Twenty seven females but only seven males were affected. No gastric tumours were found in the 228 controls. There is no evidence that loxtidine acts as a direct carcinogen and it is suggested that the tumours were the result of prolonged achlorhydria produced by a potent unsurmountable histamine H2 receptor antagonist.

Polypeptide components of bovine heart cytochrome c oxidase. Cross-identifications in two high-resolution polyacrylamide-gel electrophoresis systems.

Two-dimensional polyacrylamide-gel electrophoresis has been used to correlate polypeptide components of bovine heart cytochrome c oxidase that are resolved by two high resolution systems. The systems utilise chloral hydrate (2,2,2-trichloroethane-1,1-diol), which resolves fifteen components, and sodium dodecyl sulphate and urea, which resolves thirteen components. Seven components have been isolated and identified from their amino acid compositions in terms of polypeptides for which the amino acid sequence is known. Full resolution of all components present in this enzyme cannot be accomplished using any single-dimension system currently available.

Beta-adrenoceptor stimulants and mesovarian leiomyomas in the rat.

The experiment reported here shows that mesovarian leiomyomas may be induced in rats by the administration of 2 chemically distinct adrenergic stimulants, salbutamol or terbutaline. That the induction of these benign tumours is a function of adrenergic stimulation is shown by the fact that the concurrent administration of the adrenergic blocker propranolol prevented their development.

Beclomethasone dipropionate aerosol and nasal mucosa.

1. Biopsies taken from the inferior turbinates of patients undergoing treatment with beclomethasone dipropionate aerosol for allergic rhinitis showed no changes attributable to this treatment. 2. A reduction in oedema and eosinophilia was noted but there was no effect on the thickening of the basement membrane.

Affinity of labetalol for ocular melanin.

1 The toxicity of labetalol has been studied in mice, rats, rabbits, and dogs, and reproductive studies have been carried out in rats and rabbits. Nothing was observed in any of these species to suggest that patients taking labetalol might be exposed to any toxic hazard. 2 During the reproductive studies 14C-labetalol was used to study placental transfer. Radioactivity was present in the uveal tract of the foetal eye. 3 Radioactive labetalol but not its metabolites was bound to the melanin pigment of the eye. This binding was reversible. It was not possible to saturate the melanin of the cat and dog eye even with prolonged dosing with labetalol. 4 Chloroquine, given orally at doses of 1.5-6 mg/kg/d for 4-7 weeks, produced changes in the cat retina. When oral doses of 20 mg labetalol/d were given to cats for 7 months, no oculotoxic effects were observed. 5 Detailed ophthalmological and histological examinations were carried out on the rats, rabbits, cats and dogs used in these studies. No changes indicative of oculotoxicity were observed. In the reproductive studies no effects were observed in the developing rat or rabbit eye, which could be consequent on the placental transfer of labetalol or its metabolites.