Background/Aim: Increasing nitric oxide (NO) bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of nitric oxide (NO) with reduction of hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to nitric oxide in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our study aims to evaluate the effects and mechanisms of administration of sildenafil for one week in the hepatic microcirculation of cirrhotic rats. Methods: Cirrhosis was induced by bile duct ligation. Sham-operated rats served as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible nitric oxide synthase (iNOS), phosphorylated Akt (p-Akt), phosphodiesterase-5 (PDE-5), and soluble guanylyl cyclase (sGC) were determined by Western blot analysis. Biosynthesis of tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GTPCH-I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. Results: In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, protein expression of p-Akt, p-eNOS and sGC. These events were associated with reduced protein expression of PDE-5, portal perfusion pressure, and portal vein pressure. In contrast, sham rats did not produce significant change in these measurements. Conclusions: Sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in hepatic microcirculation.
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Administration of a low dose of sildenafil for one week decreases intrahepatic resistance in rats with biliary cirrhosis: The role of NO…
