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Histamine H2-receptor antagonistic properties of the anti-ulcer agent T-593, (±)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyI)ethyl]-3-[2[[[5-(methylamino)methyl-2-furyllmethyl]thio]ethyl]-2-(methylsulfonyl)guanidine, were investigated on [14C]aminopyrine accumulation in isolatea canine gastric mucosai cells and compared with those of ranitidine and famotidine. The potency of T-593-inhibition of [14C-aminopyrine accumulation stimulated by 10−4 M histamine, with an IC50 value of 1.85 × 10−6 M, was approximately 5 times greater than that of ranitidine, but half that of famotidine. T-593 did not affect [14C-aminopyrine accumulation stimulated by carbachol or dibutyryl-cAMP. T-593 depressed the maximal response of the histamine concentration-response curve with a dose-related displacement to the right, indicating that the nature of the H2-receptor antagonism of T-593 was insurmountable and included noncompetitive inhibition. The inhibitory efficacy of T-593 was time-dependent and was retained after the cells were washed. The inhibitory potency of (—)-S-T-593, one of the enantiomers, on the [14C]aminopyrine accumulation stimulated by histamine was approximately twice that of racemic T-593 and it also behaved as an insurmountable H2-receptor antagonist. However, the potency of (+)-R-T-593 was markedly weak. These results suggest that T-593 has H2-receptor antagonism that is insurmountable and this agent slowly associates and dissociates with the receptor in isolated canine gastric mucosal cells and that the specific substance causing H2-receptor antagonism is (—)-S-T-593.