Hirotoshi Arai

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

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.

[Characteristics of T-593, a novel antiulcer agent, and each of its enantiomers on pharmacodynamics].

T-593 consists of two optical isomers, (-)-S and (+)-R. Our previous report showed that T-593 has biphasic effects, that is a long-lasting antisecretory action and an improving effect on gastric mucosal blood flow (GMBF). In this study, we compared the sole potency of each isomer on these bi-phasic effects. On the anti-secretory action investigated by the pylorus-ligation method, the (-)-S-isomer showed strong inhibition, while the (+)-R-isomer showed no effect, whereas the GMBF improvement was provided by the (+)-R-isomer. These results show the bi-phasic effects of racemic T-593 are separately derived from each isomer. The (-)-S-isomer strongly inhibited acute gastric mucosal lesion formation, with a potency comparable to T-593 itself, while the (+)-R-isomer showed less effect. Chronic gastric ulcer induced by acetic acid was, however, not healed by the sole treatment of each optical isomer, while racemic T-593 showed a significant effect. This result shows not only anti-secretion but also GMBF improvement is necessary to heal the chronic ulcer. This interesting property of T-593 is expected to raise the quality of ulcer healing (QOUH) and also may prevent ulcer recurrence.