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Pentagastrin gastroprotection against acid is related to H2 receptor activation but not acid secretion.

ABSTRACT: BACKGROUND: Pentagastrin enhances gastric mucosal defense mechanisms against acid and protects the gastric mucosa from experimental injury. AIMS: To investigate whether this gastroprotection is mediated by histamine receptors or occurs as a secondary effect of acid secretion stimulation. METHODS: The effects of omeprazole (100 mumol/kg), ranitidine (20 mg/kg), and pyrilamine (10 mg/kg) on pentagastrin (80 micrograms/kg/h) induced gastroprotection against acidified aspirin injury were examined in a luminal pH controlled model. The effects of these compounds on pentagastrin enhanced gastroprotective mechanisms were investigated using intravital microscopy, in which intracellular pH of gastric surface cells (pH1), mucus gel thickness, gastric mucosal blood flow, and acid output were measured simultaneously. RESULTS: Pentagastrin protected rat gastric mucosa from acidified aspirin injury. This gastroprotection was abolished by ranitidine, but not omeprazole or pyrilamine. Pentagastrin induced a hyperaemic response to luminal acid challenge, increased mucus gel thickness, and elevated pHi during acid challenge. Ranitidine reversed these enhanced defence mechanisms, whereas omeprazole and pyrilamine preserved these effects. CONCLUSIONS: These data indicate that pentagastrin associated gastroprotection and enhanced defence mechanisms against acid result mainly from activation of histamine H2 receptors, and not as an effect of the stimulation of acid secretion.

SUBMITTER: Tanaka S

PROVIDER: S-EPMC1727250 | biostudies-other | 1998 Sep

REPOSITORIES: biostudies-other

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Project description:OBJECTIVES:Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS:KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS:We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS:Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.

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Pentagastrin gastroprotection against acid is related to H2 receptor activation but not acid secretion.

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