Histamine H2-Receptor Antagonists in Peptic Ulcer Disease

Deakin, Mark; Williams, John G.

doi:10.2165/00003495-199244050-00003

Cited by 45 publications

(42 citation statements)

References 80 publications

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“…In vivo modulation of H2 receptor function after treatment of H2 antagonists has been reported (2,(19)(20)(21)(22). Prolonged H2 receptor blockade was found to result in increased parietal cell sensitivity to H2 agonists (22), increased intragastric hyperacidity after abrupt withdrawal (21), and the development of tolerance (2,5,19,23,24). Coruzzi and Bertaccini (22) and Nwokolo et al (21) hypothesized that these observations could be explained by an upregulation of H2 receptors.…”

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confidence: 97%

“…The actual target of these drugs have recently been questioned (3,4), but is generally considered to be the H2 receptor on the gastric parietal cell (4). As such, the H2 antagonists constitute currently one of the prominent therapies for duodenal and gastric ulcers (5). These drugs have been widely prescribed and are currently also clinically evaluated as immunosuppressants (6) and for the treatment of central nervous system disorders (7)(8)(9)(10).…”

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confidence: 99%

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Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Smit

Leurs

Alewijnse

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

212

148

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Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time-and dosedependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leut24Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonistindependent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.Following the discovery of burimamide as a selective histamine H2 receptor antagonist (1) various related drugs (cimetidine, ranitidine, famotidine, nizatidine) have proven to be of great importance in the regulation of gastric acid secretion (2). The actual target of these drugs have recently been questioned (3, 4), but is generally considered to be the H2 receptor on the gastric parietal cell (4). As such, the H2 antagonists constitute currently one of the prominent therapies for duodenal and gastric ulcers (5). These drugs have been widely prescribed and are currently also clinically evaluated as immunosuppressants (6) and for the treatment of central nervous system disorders (7-10).The histamine H2 receptor is a member of the large multigene family of G-protein coupled receptors (GPCR) (11). Functionality and expression of members of the GPCR family are generally dynamically regulated after agonist or antagonist exposure (12,13 Studies examining the molecular mechanism underlying H2 receptor function have been greatly facilitated by the cloning of the genes encoding the histamine H2 receptor (25-28). Model systems, expressing a homogeneous population of (mutant) H2 receptors, are currently available for studies regarding H2 receptor function and regulation (18,29,30). In the present study we describe upregulation of H2 receptors after prolonged treatment of transfected Chinese hamster ovary (CHO) cells with some H2 antagonists. In our study, we observed that the histamine H2 receptor shows a spontaneous, histamine-independent activity. For some GPCRs, increased basal agonist-independent receptor activity can be inhibited by certain antagonists referred to as...

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confidence: 97%

mentioning

confidence: 99%

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Smit

Leurs

Alewijnse

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

212

148

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“…For example, the selective affinity of the inverse agonists cimetidine and metiamide for histamine H2 receptors has been linked to tolerance to H2 receptor blockade (Nwolko et al, 1990;Wilder-Smith et al, 1990;Deakin and Williams, 1992). This tolerance is believed to occur through the elevation of histamine receptor levels (Nwolko et al, 1991).…”

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confidence: 99%

Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism

Kenakin¹

2004

Mol Pharmacol

201

149

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This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of negative efficacy demonstrate inverse agonism in constitutively active receptor systems. This is a phenotypic behavior that can only be observed in the appropriate assay; a lack of observed inverse agonism is evidence that the ligand does not possess negative efficacy only if it can be shown that constitutive receptor activity is present. In the absence of constitutive activity, inverse agonists behave as simple competitive antagonists. A survey of 105 articles on the activity of 380 antagonists on 73 biological G-protein-coupled receptor targets indicates that, in this sample dataset, 322 are inverse agonists and 58 (15%) are neutral antagonists. The predominance of inverse agonism agrees with theoretical predictions which indicate that neutral antagonists are the minority species in pharmacological space.

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“…Because proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ have been shown to activate neutrophils (Klebanoff et al, 1986), inhibition of either neutrophil activation or proinflammatory cytokine production may contribute to prevent ischemia/reperfusion-induced liver injury. Ranitidine, a well known H 2 receptor antagonist, has proved effective in patients with gastric ulcers (Deakin and Williams, 1992). We have demonstrated previously that ranitidine prevents the release of neutrophil elastase and reactive oxygen species, the cell surface expression of CD11b and CD18, and the increase in intracellular calcium concentration in neutrophils stimulated with formyl-methionylleucyl-phenylalanine (fMLP) .…”

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confidence: 99%

Ranitidine Reduces Ischemia/Reperfusion-Induced Liver Injury in Rats by Inhibiting Neutrophil Activation

Okajima¹,

Harada²,

Uchiba³

2002

J Pharmacol Exp Ther

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We previously reported that ranitidine, an H 2 receptor antagonist, inhibited neutrophil activation in vitro and in vivo, contributing to reduce stress-induced gastric mucosal injury in rats. In this study, we examined whether ranitidine would reduce ischemia/reperfusion-induced liver injury, in which activated neutrophils are critically involved, in rats. We also examined the effect of famotidine, another H 2 receptor antagonist, on leukocyte activation in vitro and after ischemia/reperfusion-induced liver injury in rats to know whether inhibition of neutrophil activation by ranitidine might be dependent on its blockade of H 2 receptors. Ranitidine inhibited the activation of neutrophils in vitro as reported previously, whereas famotidine significantly enhanced it. Ranitidine inhibited the production of tumor necrosis factor-␣ (TNF-␣) in monocytes stimulated with lipopolysaccharide in vitro, whereas famotidine did not. Although hepatic ischemia/reperfusion-induced increases in hepatic tissue levels of TNF-␣, cytokine-induced neutrophil chemoattractant, and hepatic accumulation of neutrophils were inhibited by intravenously administered 30 mg/kg ranitidine, these increases were significantly enhanced by 5 mg/kg i.v. famotidine. The decreases in both hepatic tissue blood flow and bile secretion and the increases in serum levels of transaminases seen after reperfusion were significantly inhibited by ranitidine, whereas these changes were more marked in animals given famotidine than in controls. These observations strongly suggested that ranitidine could reduce ischemia/reperfusion-induced liver injury by inhibiting neutrophil activation directly, or indirectly by inhibiting the production of TNF-␣, which is a potent activator of neutrophils. Furthermore, the therapeutic efficacy of ranitidine might not be explained solely by its blockade of H 2 receptor.

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Histamine H2-Receptor Antagonists in Peptic Ulcer Disease

Cited by 45 publications

References 80 publications

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism

Ranitidine Reduces Ischemia/Reperfusion-Induced Liver Injury in Rats by Inhibiting Neutrophil Activation

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