Histamine H2 Receptor Antagonism by T-593: Studies on cAMP Generation in Hepa Cells Expressing Histamine H2 Receptor

Abstract

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.