Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability.
Increasing NO bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of NO with a reduction in hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to NO in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our present study aims to evaluate the effects and mechanisms of administration of sildenafil for 1 week on the hepatic microcirculation of cirrhotic rats. Cirrhosis was induced by bile duct ligation with sham-operated rats serving as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phospho-eNOS (endothelial NO synthase), iNOS (inducible NO synthase), phospho-Akt, PDE-5 (phosphodiesterase-5) and sGC (soluble guanylate cyclase) were determined by Western blot analysis. Biosynthesis of BH4 (tetrahydrobiopterin) and GTPCH-I (GTP cyclohydrolase I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, and the protein expression of phospho-Akt, phospho-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 any significant change in these measurements. In conclusion, sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in the hepatic microcirculation.
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Kuei-Chuan
KC
Lee
Ying-Ying
YY
Yang
Yi-Tsau
YT
Huang
Fa-Yauh
FY
Lee
Ming-Chih
MC
Hou
Han-Chieh
HC
Lin
Shou-Dong
SD
Lee
D000818:Animals; D001682:Biological Availability; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects* / Q000502:physiology; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017082:Portal Pressure / Q000187:drug effects; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate