2. Academic Validation
  3. The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats

The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats

  • Sci Rep. 2018 Jun 19;8(1):9372. doi: 10.1038/s41598-018-27656-y.
Philipp Schwabl 1 2,  Ksenia Brusilovskaya 1 2,  Paul Supper 1 2,  David Bauer 1 2,  Philipp Königshofer 1 2,  Florian Riedl 1 2,  Hubert Hayden 1 2,  Claudia Daniela Fuchs 1,  Judith Stift 3,  Georg Oberhuber 3,  Stefan Aschauer 4,  Diana Bonderman 4,  Thorsten Gnad 5,  Alexander Pfeifer 5,  Frank Erhard Uschner 6,  Jonel Trebicka 6 7 8 9,  Nataliya Rohr-Udilova 1 2,  Bruno Karl Podesser 10,  Markus Peck-Radosavljevic 1 2,  Michael Trauner 1,  Thomas Reiberger 11 12
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
  • 2 Vienna Hepatic Hemodynamic Laboratory, Vienna, Austria.
  • 3 Department of Pathology, Medical University of Vienna, Vienna, Austria.
  • 4 Division of Cardiology, Dept. of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
  • 5 Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
  • 6 Department of Internal Medicine I, University of Bonn, Bonn, Germany.
  • 7 Department of Gastroenterology, Odense Hospital, University of Southern Denmark, Odense, Denmark.
  • 8 European Foundation of the Study of Chronic Liver Failure - EF CLIF, Barcelona, Spain.
  • 9 Institute for Bioengineering of Catalonia, Barcelona, Spain.
  • 10 Center for Biomedical Research, Medical University of Vienna, Vienna, Austria.
  • 11 Division of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria. [email protected].
  • 12 Vienna Hepatic Hemodynamic Laboratory, Vienna, Austria. [email protected].
PMID: 29921982 DOI: 10.1038/s41598-018-27656-y
Abstract

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble Guanylate Cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

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