Histamine H2-Receptor Antagonism of T-593: Studies on Positive Chronotropic Responses in Guinea Pig Atria

Arai, Hirotoshi; Nakagawa, Masaya; Tanada, K; Yamaguchi, Hidetoshi; Hirai, Shiro

doi:10.1254/jjp.64.251

Cited by 12 publications

(6 citation statements)

References 13 publications

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“…This is the basis of insurmountable antagonism, which is frequently observed for different cellular responses. For example in the context of contraction of the guinea pig ileum (H 1 R), cellular calcium response (H 1 R), positive chronotropic response (H 2 R), and stomach acid secretion (H 2 R) insurmountable antagonism is observed for several histamine receptor antagonists [29,31,78,79]. Fundamental for this effect is that receptor is preoccupied by the antagonist (t = 0 in Fig.…”

Section: Surface Plasmon Resonance (Spr)mentioning

confidence: 99%

Ligand-Binding Kinetics on Histamine Receptors

Bosma

Mocking

Leurs

et al. 2017

Methods in Pharmacology and Toxicology

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Section: Surface Plasmon Resonance (Spr)mentioning

confidence: 99%

Ligand-Binding Kinetics on Histamine Receptors

Bosma

Mocking

Leurs

et al. 2017

Methods in Pharmacology and Toxicology

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“…Arai et al [12] showed that pretreatment with ranitidine for 10 min prior to the application of T-593 protected H 2 receptors from the unsurmountable antagonism by T-593 on positive chronotropic response in guinea pig isolated atria. 9 The molecular mechanism for the interaction between the T-593 molecule and the histamine H 2 receptor protein that determines competitive, irreversible or slow onset binding to the receptor is still unknown.…”

Section: In This Study (S)-(-)-t-593mentioning

confidence: 99%

“…T-593 has a chemical structure including a ß-hydroxyphenethylamine moiety combined with an amino methyl furan by a flexible chemical chain. We have previously demonstrated that T-593 shows a time-dependent and unsurmountable [11] antagonism against histamine H 2 receptor in a positive chronotropic response in isolated guinea pig right atria [12].…”

Section: Introductionmentioning

confidence: 96%

Histamine H<sub>2</sub> Receptor Antagonism by T-593: Studies on cAMP Generation in Hepa Cells Expressing Histamine H<sub>2</sub> Receptor

Tashiro

Ono²,

Watanabe³

et al. 1999

Pharmacology

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Histamine H₂ receptor antagonism by T-593 was investigated in Hepa cells expressing canine histamine H₂ receptors. T-593 inhibited generation of cAMP in Hepa cells stimulated by 10^–5 mol/l histamine with an IC₅₀ value of 2.3 × 10^–6 mol/l, (S)-(–)-T-593, one of the enantiomers comprising racemic T-593, inhibited cAMP generation with an IC₅₀ value of 6.1 × 10^–7 mol/l. On the other hand, the other enantiomer (R)-(+)-T-593 exhibited only a negligible effect. Incubation of the cell with (S)-(–)-T-593 for 60 min depressed the maximal response of the concentration-response curve of histamine with a nonparallel rightward shift. The slope of a Schild plot was 1.27. In contrast, (S)-(–)-T-593 caused a parallel rightward shift of the curve, with a Schild plot slope that did not significantly differ from unity, by treating the cells for 15 min. The H₂ receptor-blocking action of (S)-(–)-T-593 remained almost unaffected after washing out the drug, whereas the effect of ranitidine was reversible after washing. These results suggest that T-593 possesses a time-dependent unsurmountable antagonistic action against histamine H₂ receptor. T-593 may interact with the histamine H₂ receptor molecule in a slowly associable and dissociable manner.

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“…is a novel anti-ulcer agent (see structural formula) that has a secondary amine group and a β-hydroxyphenethyl group [2]. Amagase et al [1] recently reported that T-593 has potent inhibitory effects on gastric acid secretion and pepsin secretion.…”

Section: Introductionmentioning

confidence: 99%

“…Amagase et al [1] recently reported that T-593 has potent inhibitory effects on gastric acid secretion and pepsin secretion. only the latter of which is responsible for antagonism against histamine H 2 -receptors [2]. However, the effects of these enantiomers on gastric mucosal protection have not been clarified.…”

Section: Introductionmentioning

confidence: 99%

Effects of Osutidine (T-593) and its Enantiomers on Gastric Mucosal Hemodynamics and Mucosal Integrity in Anesthetized Rats

Tsuji

Tsujii

Kawai

et al. 2011

Arzneimittelforschung

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T-593 (osutidine, CAS 140695-21-2) is a new anti-ulcer agent that consists of two enantiomers, (+)-(R)-T-593 and (-)-(S)-T-593. The present study was designed to investigate the effects of T-593, (+)-(R)-T-593 and (-)-(S)-T-593 on ethanol-induced gastric damage in rats. Rats were given intraperitoneal administration of vehicle, racemic T-593, (+)-(R)-T-593 or (-)-(S)-T-593. 30 min later, the rats intragastrically received a 1-ml solution of 40% ethanol, and 30 min thereafter, they were sacrificed for assessment of gastric damage. Gastric hemodynamics were assessed by reflectance spectrophotometry and laser Doppler flowmetry during the experiment. Gastric damage was significantly suppressed by racemic T-593 in a dose-dependent manner. While 60 mg/kg of (+)-(R)-T-593 and (-)-(S)-T-593 also suppressed ethanol-induced gastric injury, the same dose of racemic T-593 exerted the most potent anti-ulcerative activity. Both (+)-(R)-T-593 and racemic T-593 increased gastric mucosal blood flow and abolished gastric mucosal blood flow stasis induced by 40% ethanol. Although (-)-(S)-T-593, which antagonizes histamine H2-receptors, exerts an antiulcerative effect, (+)-(R)-T-593 also protects the gastric mucosa from ethanol-induced injury, possibly by influencing gastric mucosal hemodynamics. Thus racemic T-593 may protect the gastric mucosa by antagonizing H2-receptors and by enhancing gastric circulation in rats.

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Histamine H2-Receptor Antagonism of T-593: Studies on Positive Chronotropic Responses in Guinea Pig Atria

Cited by 12 publications

References 13 publications

Ligand-Binding Kinetics on Histamine Receptors

Ligand-Binding Kinetics on Histamine Receptors

Histamine H<sub>2</sub> Receptor Antagonism by T-593: Studies on cAMP Generation in Hepa Cells Expressing Histamine H<sub>2</sub> Receptor

Effects of Osutidine (T-593) and its Enantiomers on Gastric Mucosal Hemodynamics and Mucosal Integrity in Anesthetized Rats

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