Selective histamine H3 and H4 receptor agonists exert opposite effects against the gastric lesions induced by HCl in the rat stomach

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 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 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. (C) 2011 Elsevier B.V. All rights reserved.