Background/Aim: Based on animal models, lafutidine, a novel histamine H2 receptor (H2R) antagonist, is reported to show potent and long-lasting antagonisms of histamine H2R-mediated effects. However, no reports have been published concerning its direct interaction with the human H2R. This study aims at characterizing its interaction with human H2R. Methods: Chinese hamster ovary cell lines stably expressing human H2Rs were obtained. The dose-dependent effects of lafutidine and famotidine on [3H]tiotidine binding and histamine-stimulated cAMP production were analyzed. The effects of preincubation with 2.78 × 10–7M of lafutidine or famotidine for 30 min on histamine-dependent cAMP production and [3H]tiotidine binding were also examined after 0, 1, 2, 4, and 12 h. This concentration is below the Cmax of lafutidine (10 mg p.o.) and above the Cmax of famotidine (20 mg p.o.). Results: Lafutidine inhibited [3H]tiotidine binding and histamine-stimulated cAMP production as or more potently than famotidine. At higher concentrations lafutidine was more potent than famotidine. In addition, preincubation with 2.78 × 10–7M lafutidine, but not with 10–5M famotidine, had marked inhibitory effects which persisted as long as after extensive washing. Conclusion: Lafutidine shows a potent and long-lasting antagonism on the human H2R.

Journal Section:
Original Paper: Gastric Disorders
Keywords:
Cyclic adenosine monophosphate production, Famotidine, Histamine H2 receptor, [3H]tiotidine, Lafutidine
1.
Diaz J, Vizuete ML, Traiffort E, Arrang JM, Ruat M, Schwartz JC: Localization of the histamine H2 receptor and gene transcripts in rat stomach: Back to parietal cells. Biochem Biophys Res Commun 1994;198:1195–1202.
[PubMed]
https://doi.org/10.1006/bbrc.1994.1169
2.
Fukushima Y, Ohmachi Y, Asano T, Nawano M, Funaki M, Anai M, Ogihara T, Inukai K, Onishi Y, Sakoda H, Saitoh T, Matsuhashi N, Yazaki Y, Sugano K: Localization of the histamine H2 receptor, a target for antiulcer drugs, in gastric parietal cells. Digestion 1999;60:522–527.
[PubMed]
https://doi.org/10.1159/000007701
3.
Soll AH, Wollin A: Histamine and cyclic AMP in isolated canine parietal cells. Am J Physiol 1979;237:E444–E450.
[PubMed]
4.
Soll AH: Secretagogue stimulation of [14C]aminopyrine accumulation by isolated canine parietal cells. Am J Physiol 1980;238:G366–G375.
[PubMed]
5.
Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM: Definition and antagonism of histamine H2-receptors. Nature 1972;236:385–390.
[PubMed]
6.
Pounder R: Histamine H2-receptor antagonists. Baillières Clin Gastroenterol 1988;2:593–608.
[PubMed]
7.
Shibata M, Yamaura T, Inaba N, Onodera S, Chida Y, Ohnishi H: Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs. Eur J Pharmacol 1993;235:245–253.
[PubMed]
https://doi.org/10.1016/0014-2999(93)90143-6
8.
Onodera S, Shibata M, Tanaka M, Inaba N, Arai Y, Aoyama M, Lee B, Yamaura T: Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity. Arzneimittelforschung 1999;49:519–526.
[PubMed]
9.
Onodera S, Shibata M, Tanaka M, Inaba N, Yamaura T, Ohnishi H: Gastroprotective activity of FRG-8813, a novel histamine H2-receptor antagonist, in rats. Jpn J Pharmacol 1995;68:161–173.
[PubMed]
10.
Ichikawa T, Ishihara K, Komuro Y, Kojima Y, Saigenji K, Hotta K: Effects of the new histamine H2 receptor antagonist, FRG-8813, on gastric mucin in rats with or without acidified ethanol-induced gastric damage. Life Sci 1994;54:PL159–PL164.
11.
Ichikawa T, Ishihara K, Saigenji K, Hotta K: Lafutidine-induced stimulation of mucin biosynthesis mediated by nitric oxide is limited to the surface mucous cells of rat gastric oxyntic mucosa. Life Sci 1998;62:PL259–PL264.
12.
Gantz I, Munzert G, Tashiro T, Schäffer M, Wang L, Del Valle J, Yamada T: Molecular cloning of the human histamine H2 receptor. Biochem Biophys Res Commun 1991;178:1386–1392.
[PubMed]
13.
Fukushima Y, Oka Y, Katagiri H, Saitoh T, Asano T, Ishihara H, Matsuhashi N, Kodama T, Yazaki Y, Sugano K: Desensitization of canine histamine H2 receptor expressed in Chinese hamster ovary cells. Biochem Biophys Res Commun 1993;190:1149–1155.
[PubMed]
https://doi.org/10.1006/bbrc.1993.1170
14.
Fukushima Y, Asano T, Takata K, Funaki M, Ogihara T, Anai M, Tsukuda K, Saitoh T, Katagiri H, Aihara M, Matsuhashi N, Oka Y, Yazaki Y, Sugano K: Role of the C-terminus in histamine H2 receptor signaling, desensitization and agonist-induced internalization. J Biol Chem 1997;272:19464–19470.
[PubMed]
https://doi.org/10.1074/jbc.272.31.19464
15.
Fukushima Y, Asano T, Katagiri H, Aihara M, Saitoh T, Anai M, Funaki M, Ogihara T, Inukai K, Matsuhashi N, Oka Y, Yazaki Y, Sugano K: Interaction between the two signal transduction systems of the histamine H2 receptor: Desensitizing and sensitizing effects of histamine stimulation on histamine-dependent cAMP production in Chinese hamster ovary cells. Biochem J 1996;320:27–32.
[PubMed]
16.
Fukushima Y, Oka Y, Saitoh T, Katagiri H, Asano T, Matsuhashi N, Takata K, van Breda E, Yazaki Y, Sugano K: Structural and functional analysis of the canine histamine H2 receptor by site-directed mutagenesis: N-glycosylation is not vital for its action. Biochem J 1995;310:553–558.
[PubMed]
17.
Ichikawa T, Ishihara K, Shibata M, Yamaura T, Saigenji K, Hotta K: Stimulation of mucin biosynthesis in rat gastric mucosa by FRG-8813 and its structural analogs. Eur J Pharmacol 1996;297:87–92.
[PubMed]
18.
Onodera S, Tanaka M, Aoyama M, Arai Y, Inaba N, Suzuki T, Nishizawa A, Shibata M, Sekine Y: Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats. Jpn J Pharmacol 1999;80:229–235.
[PubMed]
https://doi.org/10.1254/jjp.80.229
19.
Otsuka H, Fukushima Y, Tamai M, Takahashi H, Mori H, Asano T, Katsube T, Ogawa K, Kajiwara T, Ohkawa S, Saitoh T: Long-lasting binding of IT-066 to the human histamine H2 receptor. Dig Dis Sci 2000;45:796–801.
[PubMed]
© 2001 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2001
You do not currently have access to this content.