The regulation of sinusoidal resistance is dependent on the contraction of hepatic stellate cells (HSC) around sinusoidal endothelial cell (SEC) through paracrine cross-talk of vasoconstrictor and vasodilator agents. Hydrogen sulfide (H 2 S), a recently discovered gas neurotransmitter, is a putative vasodilator whose role in hepatic vascular regulation and portal hypertension is unexplored. Four-week bile duct-ligated (BDL) rats with cirrhosis and control rats were treated daily with NaHS (56 mol/kg) for 5 days. Isolated livers were perfused first with NaHS for 20 minutes and then with norepinephrine (NE) and the intrahepatic resistance studied. In normal rats and animals with cirrhosis, administration of NE resulted in a dose-dependent increase of portal pressure. This effect was attenuated by H 2 S treatment (P < .05). The H 2 S-induced relaxation of hepatic microcirculation was attenuated by glibenclamide, an adenosine triphosphate (ATP)-sensitive K؉ channel inhibitor. L-Cysteine, a substrate of cystathionine-gamma-lyase (CSE), decreased vasoconstriction in normal rat livers (P < .05) but failed to do so in livers with cirrhosis. BDL resulted in a downregulation of CSE mRNA/protein levels and activity (P < .05). Our in vitro data demonstrate that CSE is expressed in hepatocytes, HSCs, but not in sinusoidal endothelial cells (SEC). HSC activation downregulates CSE mRNA expression, resulting in a defective production of H 2 S and abrogation of relaxation induced by L-cysteine. In conclusion, CSEderived H 2 S is involved in the maintenance of portal venous pressure. The reduction of CSE expression in the liver with cirrhosis contributes to the development of increased intrahepatic resistance and portal hypertension. (HEPATOLOGY 2005;42:539-548.)
Hydrogen sulfide (H 2 S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine -synthase (CBS) and cystathionine-␥-lyase (CSE) mediate enzymatic generation of H 2 S in mammalian cells. Here we have investigated the role of H 2 S in modulating nociception to colorectal distension, a model that mimics some features of the irritable bowel syndrome. Four graded (0.4 -1.6 ml of water) colorectal distensions (CRDs) were produced in conscious rats (healthy and postcolitic), and rectal nociception was assessed by measuring the behavioral response during CRD. Healthy rats were administered with sodium hydrogen sulfide (NaHS) (as a source of H 2 S), L-cysteine, or vehicle. In a second model, we investigated nociception to CRD in rats recovering from a chemically induced acute colitis. We found that CBS and CSE are expressed in the colon and spinal cord.Treating rats with NaHS resulted in a dose-dependent attenuation of CRD-induced nociception with the maximal effect at 60 mol/kg (p Ͻ 0.05). Administration of L-cysteine, a CSE/CBS substrate, reduced rectal sensitivity to CRD (p Ͻ 0.05). NaHSinduced antinociception was reversed by glibenclamide, a ATP-sensitive K ϩ (K ATP ) channel inhibitor, and N -nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric-oxide (NO) synthase inhibitor. The antinociceptive effect of NaHS was maintained during the resolution of colon inflammation induced by intrarectal administration of a chemical irritant. In summary, these data show that H 2 S inhibits nociception induced by CRD in both healthy and postcolitic rats. This effect is mediated by K ATP channels and NO. H 2 S-releasing drugs might be beneficial in treating painful intestinal disorders.
Background and Purpose: Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-tomoderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H 2 Sreleasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. Experimental Approach: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. Key Results: Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by B70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFa, IFNg). Treatment with ADT-OH, the H 2 S-releasing moiety of ATB-429, did not affect severity of colitis. Conclusions and Implications: ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H 2 S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.
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