Hydrogen Sulphide Neurotransmission in the Anal Sphincter

Jonathan Simpson1, Sarah Rayment1, Michael Dashwood2, Yvette Henry3, Hans Gruss3, Austin Acheson1, John Scholefield1, Vince Wilson1. 1Centre for Integrated Systems Biology and Medicine, Department of Surgery & School of Biomedical Sciences, The University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom, 2Clinical Biochemistry, Royal Free and University College Medical School, London, United Kingdom, 3Clinical Development, Norgine Ltd, R&D Division, Harefield, United Kingdom.

Histamine H4 receptors (H4Rs) have been identified in immune/inflammatory cells of different species and have been proposed as a new target for antiinflammatory/ antiallergic drugs (Smits et al., 2009). Immunohistochemistry studies have recently unravelled the presence of H4Rs in the rat gastric mucosa, ghrelin-producing cells being the most abundant cell source (Morini et al., 2008).

In the present study, the effects of selective H4R ligands were tested on different ulcer models from rats and mice (Rainsford, 1978; Tarnawski et al., 1991), in order to unravel a possible functional role of H4Rs in the stomach. The selective H4R antagonist JNJ7777120, when tested at antiinflammatory doses (10-30 mg/kg sc), significantly reduced (approximately 70%) the gastric mucosal damage induced by indomethacin (20 mg/kg sc) in the conscious rat; furthermore, JNJ7777120 (10 mg/kg sc) significantly reduced (approximately 65%) gastrolesive effects of combined administration of indomethacin (30 mg/kg sc) and bethanechol (5 mg/kg ip) in conscious mice. Gastric effects of selective H4R ligands VUF8430 (Lim et al., 2006) and VUF10460 [4-(4-methylpiperazin-1-yl)-6-phenylpyrimidin-2-amine] were different according to the species/model employed.

Both agonists, tested at 10 and 30 mg/kg sc, significantly reduced indomethacin-induced lesions in the rat; the protective effect induced by VUF8430, however, was only evident in the presence of ranitidine (3 mg/kg ip), thus suggesting a histamine H2R-mediated component in the activity of VUF8430. VUF8430 (30 mg/kg sc, co-administered with ranitidine) and VUF10460 (10 mg/kg sc) were ineffective in the mouse against indomethacin/bethanecol-induced lesions.

These data show that H4R antagonists, as opposite to conventional antiinflammatory drugs, may be safe for the stomach, affording gastroprotection in ulcer models from both rats and mice. On the other hand, the effects of H4R agonists do not allow us yet to hypothesize an ulcerogenic role for H4Rs in the gastric mucosa, while focusing on species-dependent pharmacological discrepancies.

Lim HD et al. J Med Chem 49:6650-6651 (2006)
Morini G et al. Inflamm Res 57 (Suppl 1): S57-S58 (2008)
Rainsford KD Biochem Pharmacol 27:877-885 (1978)
Smits RA et al. Drug Disc Today 14:745-753 (2009)
Tarnawski A et al. Aliment Pharm Ther 5 (Suppl 1):79-90 (1991)