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The present study investigated the role of histamine H3 and H4 receptors in gastric mucosal defense, by the use of selective ligands. Firstly, the affinities of several histaminergic agonists for the rat histamine H3 and H4 receptors were checked in HEK 293 T cells transfected with either receptor subtype. Next, functional activities were determined in conscious rat against the ulcerogenic effect of 0.6 N HCl. Radioligand binding studies showed that immethridine and methimepip were the most selective agonists at rat H3 receptors, whereas VUF10460 displayed approximately a 50-fold selectivity for the rat H4 receptor over the H3 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 H3 receptor antagonist A-331440, but not by the H4 receptor antagonist JNJ7777120. The mixed H3/H4 receptor agonist immepip induced a significant aggravation of HCl damage, which was prevented by JNJ7777120; HCl-induced lesions were also significantly enhanced by the H4 receptor agonists VUF10460 and VUF8430; however, this effect was not modified by JNJ7777120. Overall, this study indicates that, whereas the histamine H3 receptor is involved in the protection of rat stomach against concentrated HCl, the functional role of the H4 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 H3 and H4 receptor functions in vivo.