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

摘要

References(27) Cited-By(11) 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 × 10-1-3 × 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 × 10-5 M histamine were 1.05 × 10-6 M for T-593, 1.59 × 10-6 M for ranitidine and 1.67 × 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 × 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.