title: Selective histamine H₃ and H₄ receptor agonists exert opposite effects against the gastric lesions induced by HCl in the rat stomach.
abstract: The present study investigated the role of histamine H(3) and H(4) receptors in gastric mucosal defense, by the use of selective ligands. Firstly, the affinities of several histaminergic agonists for the rat histamine H(3) and H(4) receptors were checked in HEK 293T cells transfected with either receptor subtype. Next, functional activities were determined in conscious rat against the ulcerogenic effect of 0.6N HCl. Radioligand binding studies showed that immethridine and methimepip were the most selective agonists at rat H(3) receptors, whereas VUF10460 displayed approximately a 50-fold selectivity for the rat H(4) receptor over the H(3) receptor. In conscious rats, immethridine and methimepip significantly reduced (66% and 48% inhibition, respectively) the gastric lesions induced by HCl; the effect of immethridine was antagonized by the H(3) receptor antagonist A-331440, but not by the H(4) receptor antagonist JNJ7777120. The mixed H(3)/H(4) receptor agonist immepip induced a significant aggravation of HCl damage, which was prevented by JNJ7777120; HCl-induced lesions were also significantly enhanced by the H(4) receptor agonists VUF10460 and VUF8430; however, this effect was not modified by JNJ7777120. Overall, this study indicates that, whereas the histamine H(3) receptor is involved in the protection of rat stomach against concentrated HCl, the functional role of the H(4) receptor is still to be defined, although selective agonists induce proulcerogenic effects under HCl challenge. Finally, the species-dependent variations in affinity and receptor selectivity observed for most ligands need to be carefully addressed in the pharmacological characterization of histamine H(3) and H(4) receptor functions in vivo.
authors.affiliation: Department of Human Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology, University of Parma, 43100 Parma, Italy. gabriella.coruzzi@unipr.it
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coruzzi
authors.forename: Maristella
authors.initials: M
authors.lastname: Adami
authors.forename: Cristina
authors.initials: C
authors.lastname: Pozzoli
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rogier
authors.initials: R
authors.lastname: Smits
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D006851:Hydrochloric Acid; D008297:Male; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D014162:Transfection
chemical_list: D017442:Histamine Agonists; D006633:Histamine Antagonists; C498828:Hrh4 protein, rat; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D006851:Hydrochloric Acid