CCK2 receptor antagonists: pharmacological tools to study the gastrin–ECL cell-parietal cell axis

Håkanson, R.; Ding, Xi‐Qin; Norlén, Per; Lindström, Erik

doi:10.1016/s0167-0115(99)00008-7

Cited by 33 publications

(20 citation statements)

References 90 publications

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“…Histamine production is diminished by ϳ10% in the presence of the CCK2 blocker proglumide, suggesting that gastrin is active along this pathway. This finding is different than other studies, where in various species histamine is believed to be predominately mediated by gastrin to elevate acid secretion (11,15,19,20). Although we show that this pathway is active in the guinea pig, no other studies have monitored both the direct and indirect gastrin pathways leading to the activation of the parietal cell in one experiment on any species.…”

Section: Discussioncontrasting

confidence: 99%

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Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach

Bitziou

Patel

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Gastric acid secretion is regulated by three primary components that activate the parietal cell: histamine, gastrin, and acetylcholine (ACh). Although much is known about these regulatory components individually, little is known on the interplay of these multiple activators and the degree of regulation they pose on the gastric acid secretion mechanism. We utilized a novel dual-sensing approach, where an iridium oxide sensor was used to monitor pH and a boron-doped diamond electrode was used for the detection of histamine from in vitro guinea pig stomach mucosal sections. Under basal conditions, gastrin was shown to be the main regulatory component of the total acid secretion and directly activated the parietal cell rather than by mediating gastric acid secretion through the release of histamine from the enterochromaffin-like cell, although both pathways were active. Under stimulated conditions with ACh, the gastrin and histamine components of the total acid secretion were not altered compared with levels observed under basal conditions, suggestive that ACh had no direct effect on the enterochromaffin-like cell and G cell. These data identify a new unique approach to investigate the regulation pathways active during acid secretion and the degree that they are utilized to drive total gastric acid secretion. The findings of this study will enhance our understanding on how these signaling mechanisms vary under pathophysiology or therapeutic management.

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Section: Discussioncontrasting

confidence: 99%

“…shown that gastrin stimulation induces histidine decarboxylase to synthesize histamine (11,15,30). ACh is released from postganglionic neurons and stimulates the parietal cells directly via M3 receptors and indirectly via M2 and M4 inhibition of somatostatin secretion (34,35).…”

Section: Studies Utilizing Isolated Ecl Cells and In Vitro Assays Havementioning

confidence: 99%

Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach

Bitziou

Patel

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…AG-041R, a potent and specific gastrin receptor antagonist (Ding et al, 1997;Chiba et al, 1998;Fukui et al, 1998;Hakanson et al, 1999), was a gift from Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). NS-398, a specific inhibitor of COX-2 (Futaki et al, 1993a,b;Masferrer et al, 1994;Tsuji et al, 1996), was purchased from Cayman Chemicals (Ann Arbor, MI).…”

Section: Methodsmentioning

confidence: 99%

“…The functionally defined receptors for gastrin include cholecystokinin A receptor, which is discriminating for sulfated CCK 8 ; gastrin/cholecystokinin B (CCKB) receptor, which binds gastrin 17 sulfated and nonsulfated CCK 8 with nearly equal affinities; cholecystokinin C, which is a low-affinity gastrin binding protein; and novel, high-affinity receptors selective for amidated gastrin, processing intermediates of gastrin, or both (Yassin, 1999). We also examined the influences of a gastrin/CCKb receptor antagonist (Ding et al, 1997;Chiba et al, 1998;Fukui et al, 1998;Hakanson et al, 1999) on gastric mucosal expression of cyclooxygenase and gastric mucosal protection.…”

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confidence: 99%

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

Tsuji

Sun

Tsujii

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2-one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E 2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE 2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE 2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE 2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE 2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

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“…In several rat studies, treatment with CCK2R antagonists caused changes in ECL cell activity, indicating the presence of the receptor on these cells (131,195). Binding and functional studies demonstrated that both CCK1R and CCK2R are present on guinea pig chief cells (91, 389).…”

Section: Stomachmentioning

confidence: 99%

Cholecystokinin and Gastrin Receptors

Dufresne

Seva²,

Fourmy³

2006

Physiological Reviews

422

418

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Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.

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CCK2 receptor antagonists: pharmacological tools to study the gastrin–ECL cell-parietal cell axis

Cited by 33 publications

References 90 publications

Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach

Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

Cholecystokinin and Gastrin Receptors

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