Histamine H2-Receptor Antagonism of T-593: Studies on Positive Chronotropic Responses in Guinea Pig Atria.
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概要
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Histamine H<SUB>2</SUB>-antagonistic properties of the novel H<SUB>2</SUB>-antagonist T-593, (±)-<I>N</I>-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-<I>N''</I>-[2-[[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-<I>N"</I>-(methylsulfonyl) guanidine were investigated on the histamine-induced positive chronotropic responses in isolated guinea pig right atria. T-593 at 3 × 10<SUP>-1</SUP>-3 × 10<SUP>-6</SUP> M suppressed the maximal responses of the histamine concentration-response curves in a concentration-dependent fashion, indicating that T-593 is an unsurmountable antagonist. The pD''2 values were 5.50 for T-593 and 5.61 for famotidine; and the IC<SUB>50</SUB> values at 1 × 10<SUP>-5</SUP> M histamine were 1.05 × 10<SUP>-6</SUP> M for T-593, 1.59 × 10<SUP>-6</SUP> M for ranitidine and 1.67 × 10<SUP>-7</SUP> M for famotidine. T-593 is a racemic compound composed of two enantiomers, (-)-T-593 and (+)-T-593. The histamine H<SUB>2</SUB>-antagonistic activity of (-)-T-593 was 1.5-fold more potent than that of racemic T-593, but (+)-T-593 scarcely inhibited the histamine-induced positive chronotropic response. Histamine H2-antagonism by racemic T-593 was mainly attributed to (-)-T-593. Isoproterenol-induced positive chronotropic responses were not affected by T-593 even at 3 × 10<SUP>-5</SUP> M. Pretreatment of ranitidine for 10 min prior to application of T-593 protected H<SUB>2</SUB>-receptors from unsurmountable antagonism by T-593. Reversibility of H<SUB>2</SUB>-antagonism was determined every 1 hr after a 30-min treatment of H</SUB>2</SUB>-antagonists. T-593 inhibited the positive chronotropic responses for over 6 hr in contrast to fast recovery from inhibition by ranitidine or famotidine. This result showed that T-593 is a slowly dissociable, long-acting histamine H<SUB>2</SUB>-antagonist.
- 公益社団法人 日本薬理学会の論文
著者
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Arai Hirotoshi
Research Laboratories, Toyama Chemical Co., Ltd.
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Nakagawa Masaya
Research Laboratories, Toyama Chemical Co., Ltd.
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Tanada Kikuko
Research Laboratories, Toyama Chemical Co., Ltd.
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Yamaguchi Hidetoshi
Research Laboratories, Toyama Chemical Co., Ltd.
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Hirai Shiro
Research Laboratories, Toyama Chemical Co., Ltd.
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