Background and purpose:  Hydrogen sulphide is an important mediator of gastric mucosal defence. The use of non‐steroidal anti‐inflammatory drugs continues to be limited by their toxicity, particularly in the upper gastrointestinal tract. We evaluated the gastrointestinal safety and anti‐inflammatory efficacy of a novel hydrogen sulphide‐releasing derivative of naproxen, ATB‐346 [2‐(6‐methoxy‐napthalen‐2‐yl)‐propionic acid 4‐thiocarbamoyl‐phenyl ester].Experimental approach:  The ability of ATB‐346 versus naproxen to cause gastric damage was evaluated in healthy rats and in rats with compromised gastric mucosal defence. Effects on the small intestine and on the healing of ulcers were also assessed. The ability of ATB‐346 to inhibit cyclooxygenase‐1 and 2 and to reduce inflammation in vivo was also evaluated.Key results:  ATB‐346 suppressed gastric prostaglandin E₂ synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. In situations in which the gastric mucosa was rendered significantly more susceptible to naproxen‐induced damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co‐administration with aspirin, antagonism of K_IR6.x channels), ATB‐346 did not cause significant damage. Unlike naproxen and celecoxib, ATB‐346 accelerated healing of pre‐existing gastric ulcers. In a mouse airpouch model, ATB‐346 suppressed cyclooxygenase‐2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB‐346 was as effective as naproxen in adjuvant‐induced arthritis in rats, with a more rapid onset of activity. Unlike naproxen, ATB‐346 did not elevate blood pressure in hypertensive rats.Conclusions and implications:  ATB‐346 exhibits anti‐inflammatory properties similar to naproxen, but with substantially reduced gastrointestinal toxicity.

In fibroblasts, thrombin induces collagen deposition through activation of a G-protein-coupled receptor, proteinase-activated receptor 1 (PAR₁). In the current study, we examined whether PAR₁ antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (BDL). The current results demonstrated that HSCs express PAR₁, as well as proteinase-activated receptors 2 (PAR₂) and 4 (PAR₄), and that all three PARs were up-regulated in response to exposure to growth factor in vitro. Exposure to thrombin and to SFLLRN-(SF)-NH₂, a PAR₁ agonist, and GYPGKF (GY)-NH₂, a PAR₄ agonist, triggered HSC proliferation and contraction, as well as monocyte chemotactic protein-1 (MCP-1) production and collagen I synthesis and release. These effects were inhibited by the PAR₁ antagonist. Administration of this antagonist, 1.5 mg/kg/d, to BDL rats reduced liver type I collagen messenger RNA (mRNA) expression and surface collagen by 63%, as measured by quantitative morphometric analysis. Similarly, hepatic and urinary excretion of hydroxyproline was reduced significantly by the PAR₁ antagonist. In conclusion, PAR_s regulates HSC activity; development of PAR antagonists might be a feasible therapeutic strategy for protecting against fibrosis in patients with chronic liver diseases. (Hepatology 2004;39:365-375.)

H₂S functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study, we have investigated the role of a novel H₂S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4-1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression. In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect. ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K⁺ (K_ATP) channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic cyclooxygenase-2 and interkeukin-1β mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H₂S in both healthy and postcolitic rats. Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K_ATP channel-mediated mechanism. This study provides evidence that H₂S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.