title: Histamine H2-receptor antagonism of T-593: studies on positive chronotropic responses in guinea pig atria.
abstract: Histamine H2-antagonistic properties of the novel H2-antagonist T-593, (+-)-N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-[2- [[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-N"- (methylsulfonyl) guanidine were investigated on the histamine-induced positive chronotropic responses in isolated guinea pig right atria. T-593 at 3 x 10(-7)-3 x 10(-6) 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 IC50 values at 1 x 10(-5) M histamine were 1.05 x 10(-6) M for T-593, 1.59 x 10(-6) M for ranitidine and 1.67 x 10(-7) M for famotidine. T-593 is a racemic compound composed of two enantiomers, (-)-T-593 and (+)-T-593. The histamine H2-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 x 10(-5) M. Pretreatment of ranitidine for 10 min prior to application of T-593 protected H2-receptors from unsurmountable antagonism by T-593. Reversibility of H2-antagonism was determined every 1 hr after a 30-min treatment of H2-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 H2-antagonist.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd., Japan.
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.forename: K
authors.initials: K
authors.lastname: Tanada
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Hirai
mesh_terms: D000818:Animals; D001665:Binding Sites; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria; D006339:Heart Rate / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D013268:Stimulation, Chemical; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D006146:Guanidines; D006635:Histamine H2 Antagonists; D013450:Sulfones; C088837:T 593; D006632:Histamine