title: 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 x 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 x 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 insurmountable antagonistic action against histamine H2 receptor. T-593 may interact with the histamine H2 receptor molecule in a slowly associable and dissociable manner.
authors.affiliation: First Department of Internal Medicine, University of Tokyo Hospital, Tokyo, Japan. tashiro-1im@h.u-tokyo.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Tashiro
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Inoie
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D004285:Dogs; D006146:Guanidines / Q000494:pharmacology*; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D006146:Guanidines; D006635:Histamine H2 Antagonists; D013450:Sulfones; C088837:T 593; D006632:Histamine; D011899:Ranitidine; D000242:Cyclic AMP