INHIBITION OF H2S PRODUCTION REDUCES PORTAL PRESSURE BY DECREASING INTRAHEPATIC RESISTANCE IN RATS WITH CIRRHOSIS

Background: Hydrogen sulfide (H2S) is a gaseous signaling molecule with vasodilatatory properties and a recognized role in the regulation of oxidative stress, inflammation and fibrosis in the liver. However, its contribution to the development of portal hypertension and complications of cirrhosis is not clear. Methods: We evaluated the hemodynamic effects of in vivo inhibition of H2S synthesis in a rat model of experimental cirrhosis. Eight control rats and sixteen rats with bile duct ligation-induced cirrhosis were studied. Eight cirrhotic rats were treated with propargylglycine (PAG; 30 mg/kg via intragastric gavage), a selective inhibitor of cystathionine γ-lyase, the main source of H2S in the cardiovascular system and liver. Portal and systemic pressures were measured using polyethylene-50 catheters. Small resistance mesenteric arteries were mounted on a wire myograph to assess dose-response curves to acetylcholine (ACh) and sodium hydrosulphide (NaHS), an H2S donor. Liver samples were collected for histological analysis and evaluation of mRNA expression of IL-6, TNF-α, TGF-β, and collagen I by real-time PCR. Plasma levels of ALT, creatinine and bilirubin were also measured. Results: In cirrhotic rats, PAG treatment significantly reduced portal pressure (10.4 ± 2.7 mmHg versus 16.0 ± 3.9 mmHg, P < 0.05) without affecting systemic pressure. No differences were observed in mesenteric artery responses to ACh or NaHS between treated and untreated cirrhotic rats. In the liver, PAG treatment significantly reduced the expression of IL-6 (P= 0.008), TGFβ (P= 0.008), and collagen I (P= 0.008), and markedly attenuated hepatic fibrosis and architectural distorsion at histological examination. Cirrhotic rats treated with PAG also exhibited significantly lower ALT (23.9 ± 19.7 U/L vs 100.4 ± 21.8 U/L; P < 0.001) and creatinine levels (24.8 ± 7.1 µmol/L versus 34.1 ± 7.8 µmol/L; P = 0.03), with no significant differences in bilirubin levels. Conclusion: In vivo inhibition of H2S synthesis in cirrhotic rats reduces portal pressure, liver fibrosis, and the hepatic expression of markers of inflammation and fibrosis, with no effects on mesenteric vasodilation. These findings suggest that targeting H2S may represent a promising therapeutic strategy for portal hypertension by acting on intrahepatic resistance.