Effect of histamine H4 receptor ligands on cholinergic neurotransmission of the rat duodenum

The recently cloned histamine H4 receptor (H4R) was found to play a role in inflammatory and immune responses. Recently, immunohistochemical data have provided evidence that the H4R is also expressed in myenteric neurons of the rodent gastrointestinal tract, suggesting a role for this receptor in the regulation of intestinal peristalsis (1). In the present study we examined whether H4Rs have a role in the regulation of intestinal neurotransmission, by testing selective H4R ligands in the isolated rat duodenum. Twitch responses of longitudinal muscle strips to electrical field stimulation were abolished by atropine (1 µM) and partially reduced by hexamethonium (10 µM), suggesting that pre- and postganglionic cholinergic neurons were activated. Under these experimental conditions, the H4R agonist VUF8430 (2) and histamine, in the presence of H1-, H2- and H3-receptor blockade, did not change electrically-evoked contractions. Similarly ineffective were the selective H4R antagonists VUF10148 and VUF10214 (3), when tested at 10 nM and 100 nM. At higher concentrations (1-10 µM), these compounds evoked a dose-dependent inhibition of electrically evoked contractions, which, however, was mimicked by VUF10181, a chemically related analog, endowed with a 1000-fold lower affinity at H4R (3). In conclusion, functional experiments on isolated rat duodenum did not unravel any role of H4Rs in the control of intestinal neurotransmission. (1) Chazot, PL et al. XXXVI EHRS Meeting, Florence, May 9-12th 2007, p.27 (2) Lim, HD et al J Med Chem 2006;49:6650-6651 (3) Coruzzi, G et al. XXXVI EHRS Meeting, Florence, May 9-12th 2007, p.106