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We investigated if sGC stimulation (riociguat (RIO)), sGC activation (cinaciguat (CINA)) or phosphodiesterase (PDE)\u20105\u00a0inhibition (tadalafil (TADA)) improves portal hypertension (PHT) and liver fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty male Sprague\u2013Dawley rats underwent bile\u2010duct ligation (BDL) or sham operation. RIO (0.5\u2009mg\/kg), CINA (1\u2009mg\/kg), TADA (1.5\u2009mg\/kg) or vehicle (VEH) was administered from weeks 2 to 4 after BDL. At week 4, invasive haemodynamic measurements were performed, and liver fibrosis was assessed by histology (chromotrope\u2010aniline blue (CAB), Picro\u2010Sirius red (PSR)) and hepatic hydroxyproline content.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cirrhotic bile duct\u2013ligated rats presented with PHT (13.1\u2009\u00b1\u20091.0\u2009mmHg) and increased IHVR (4.9\u2009\u00b1\u20090.5\u2009mmHg\u22c5min\/mL). Both RIO (10.0\u2009\u00b1\u20090.7\u2009mmHg, <jats:italic>p<\/jats:italic> \u2009=\u20090.021) and TADA (10.3\u2009\u00b1\u20090.9\u2009mmHg, <jats:italic>p<\/jats:italic> \u2009=\u20090.050) decreased portal pressure by reducing IHVR (RIO: \u201341%, <jats:italic>p<\/jats:italic> \u2009=\u20090.005; TADA: \u201321%, <jats:italic>p<\/jats:italic> \u2009=\u20090.199) while not impacting heart rate, mean arterial pressure and portosystemic shunting. Hepatic cGMP levels increased upon RIO (+239%, <jats:italic>p<\/jats:italic> \u2009=\u20090.006) and TADA (+32%, <jats:italic>p<\/jats:italic> \u2009=\u20090.073) therapy. In contrast, CINA dosed at 1\u2009mg\/kg caused weight loss, arterial hypotension and hyperlactataemia in bile duct\u2013ligated rats. Liver fibrosis area was significantly decreased by RIO (CAB: \u201348%, <jats:italic>p<\/jats:italic> \u2009=\u20090.011; PSR: \u201327%, <jats:italic>p<\/jats:italic> \u2009=\u20090.121) and TADA (CAB: \u201321%, <jats:italic>p<\/jats:italic> \u2009=\u20090.342; PSR: \u201352%, <jats:italic>p<\/jats:italic> \u2009=\u20090.013) compared to VEH\u2010treated bile duct\u2013ligated rats. Hepatic hydroxyproline content was reduced by RIO (from 503\u2009\u00b1\u200920 to 350\u2009\u00b1\u200930\u2009\u00b5g\/g, <jats:italic>p<\/jats:italic> \u2009=\u20090.003) and TADA (282\u2009\u00b1\u200950\u2009\u00b5g\/g, p\u2009=\u20090.003), in line with a reduction of the hepatic stellate cell activation markers smooth\u2010muscle actin and phosphorylated moesin. Liver transaminases decreased under RIO (AST: \u201336%; ALT: \u201332%) and TADA (AST: \u201324%; ALT: \u201327%) treatment. Hepatic interleukin 6 gene expression was reduced in the RIO group (\u201356%, <jats:italic>p<\/jats:italic> \u2009=\u20090.053).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In a rodent model of biliary cirrhosis, the sGC stimulator RIO and the PDE\u20105\u00a0inhibitor TADA improved PHT. The decrease of sinusoidal vascular resistance was paralleled by a reduction in liver fibrosis and hepatic inflammation, while systemic haemodynamics were not affected.<\/jats:p><\/jats:sec>","DOI":"10.1177\/2050640620944140","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T05:41:18Z","timestamp":1599111678000},"page":"1174-1185","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":35,"title":["Soluble guanylyl cyclase stimulation and phosphodiesterase\u20105\u00a0inhibition improve portal hypertension and reduce liver fibrosis in bile duct\u2013ligated rats"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8234-5875","authenticated-orcid":false,"given":"Ksenia","family":"Brusilovskaya","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine III Medical University of Vienna Vienna 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