Functional characterisation of the novel histamine H(3) receptor agonist, VUF 5810, on the guinea-pig isolated ileum

It is known that the activation of prejunctionally-located histamine H3 receptors down-regulates the exocytotic acetylcholine release from the myenteric plexus and thus produces a negative control on the intestinal motility [1]. Most studies were performed by using the H3 receptor agonist (R) alpha-methylhistamine, which interferes also with the histamine H4 receptor, and the non-selective ligand histamine. Therefore, more selective compounds are requested for further characterisation of the different histamine receptor subtypes. We studied the effects of the immepip analog VUF 5810, a highly selective H3 receptor agonist previously characterised in SK-NM-C cells expressing the human H3 receptor protein, on the isolated guinea pig ileum. The agonistic effect was measured in terms of inhibition of electrical stimulation (0.1 Hz, 0.5 msec, 200-250 mA)-evoked muscle contractions, which are induced by endogenous acetylcholine. The compound VUF 5810, as well as the H3/H4 agonists, immepip and (R) alpha-methylhistamine, induced a concentration-dependent reduction of the amplitude of the neurogenic response. All these agonists gave ~60% of maximum reduction of contractions, without affecting the contractile effect elicited by exogenous acetylcholine. The calculated pD2 value of VUF 5810 (8.22) was close to that of immepip (8.53) and ~10 times higher than that of MHA (7.61). The putative H3 receptor antagonist, FUB 649, as well as the H3/H4 receptor antagonist, thioperamide, caused a rightward shift of the concentration-response curves of VUF 5810 (pA2 FUB 649: 8.55; thioperamide: 8.94), showing a sourmountable antagonism. VUF 5810 did not cause any change in the basal tone of the preparations, even at 100 micromol, thus excluding any effect at H1 and H2 receptors. These results suggest that VUF 5810 behaves as a full and potent agonist at prejunctional histamine receptors controlling the acetylcholine release from the myenteric plexus. The antagonistic effect of thioperamide and FUB 649 is consistent with the involvement of H3 receptors. [1] Bertaccini et al., in: Leurs R., Timmerman H. (eds.), The histamine H3 receptor, Elsevier Science B.V., Amsterdam, 1998, pp 59-111.