{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:12:36Z","timestamp":1790885556479,"version":"4.1.0"},"reference-count":45,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,7,1]]},"abstract":"<jats:p>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\u00a0week 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.<\/jats:p>","DOI":"10.1042\/cs20090601","type":"journal-article","created":{"date-parts":[[2010,2,5]],"date-time":"2010-02-05T14:22:32Z","timestamp":1265379752000},"page":"45-55","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability"],"prefix":"10.1042","volume":"119","author":[{"given":"Kuei-Chuan","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"},{"name":"Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, Taiwan"},{"name":"Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Tsau","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fa-Yauh","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"},{"name":"Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chih","family":"Hou","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Chieh","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-Dong","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2010,4,7]]},"reference":[{"key":"2021113010124592700_B1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0168-8278(00)80422-5","article-title":"Complications of cirrhosis. 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Gastroenterol."},{"key":"2021113010124592700_B8","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1056\/NEJM199312303292706","article-title":"The L-arginine\u2013nitric oxide pathway","volume":"329","author":"Moncada","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"2021113010124592700_B9","first-page":"47","article-title":"Sildenafil: an orally active type\u00a05 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction","volume":"8","author":"Boolell","year":"1996","journal-title":"Int. J. Impot. Res."},{"key":"2021113010124592700_B10","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.jhep.2006.01.032","article-title":"Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers","volume":"44","author":"Loureiro-Silva","year":"2006","journal-title":"J. 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