pd-136450 and Achlorhydria

Gastrin stimulates histidine decarboxylase (HDC) activity and proliferation of enterochromaffin-like (ECL) cells. Furthermore, it has been suggested that gastrin controls HDC gene expression. We therefore analysed the effect of gastrin receptor blockade by PD 136 450 (CAM 1189) on HDC gene expression. The influence of PD 136 450 on gastrin, somatostatin, and chromogranin A was also evaluated.. Gene expression of HDC, gastrin, somatostatin, and chromogranin A (CgA) was analysed by Northern blot analyses after 14 days' application of the proton pump inhibitor BY 308 and/or the gastrin/cholecystokinin B receptor antagonist PD 136 450.. PD 136 450 had no significant effect on gastrin mRNA or somatostatin mRNA in controls and during proton pump inhibition. BY 308 treatment resulted in a marked induction of HDC and CgA mRNA, whereas concomitant PD 136 450 in a concentration previously shown to suppress maximal pentagastrin-induced gastric acid secretion and to prevent BY 308-induced ECL cell proliferation did not result in significant alteration. PD 136 450 increased HDC significantly and CgA mRNA to a lesser extent in normogastrinaemic rats, whereas previous work showed a decreased ECL cell labelling index.. These data suggest that there are independent regulatory pathways for ECL cell proliferation and gene expression. Other factors besides gastrin may act through PD 136 450-insensitive pathways to control HDC and CgA gene expression.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Achlorhydria; Animals; Blotting, Northern; Chromogranin A; Chromogranins; Enzyme Inhibitors; Female; Gastrins; Gene Expression; Histidine Decarboxylase; Indoles; Omeprazole; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; RNA, Messenger; Somatostatin

Hyperplasia of the oxyntic enterochromaffinlike cells in response to long-lasting blockade of acid secretion is closely related to hypergastrinemia. In the present study, the effect of a specific gastrin receptor antagonist on proton pump inhibitor-induced changes on serum gastrin levels, mucosal height, as well as gastrin- and enterochromaffin-like cells was investigated in rats. The proton pump inhibitor BY 308 or the vehicle methylcellulose [Methocel (controls)] was administered for 2 weeks in the presence and absence of the gastrin receptor antagonist PD 136450 (CAM 1189). BY 308 significantly increased serum gastrin levels, gastrin cell density, and antral gastrin concentration. Concomitant application of PD 136450 did not alter this response. In the oxyntic stomach, mucosal height, enterochromaffinlike cell density, labeling index of enterochromaffinlike cells, and histamine concentration were elevated after treatment with BY 308. These increases were almost completely abolished by PD 136450. Even in normogastrinemic control rats, PD 136450 significantly decreased mucosal height of the oxyntic part of the stomach and the labeling index of enterochromaffinlike cells. The results show that (a) trophic effects of drug-induced achlorhydria are mediated by gastrin; (b) even in control rats (normogastrinemic), gastrin is a trophic factor for the oxyntic mucosa; and (c) antral gastrin cell hyperplasia in states of chronic achlorhydria is not mediated by gastrin itself.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Achlorhydria; Animals; Enterochromaffin Cells; Gastrins; Histamine; Indoles; Male; Omeprazole; Phenethylamines; Proton Pumps; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Stomach; Time Factors