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

Philipp Schwabl,Florian Riedl,Paul Supper,Philipp Königshofer,Claudia D Fuchs ,Bruno K Podesser ,Nataliya Rohr-Udilova,Georg Oberhuber,Frank Erhard Uschner,Stefan Aschauer,Diana Bonderman,Jonel Trebicka,Judith Stift,Hubert Hayden,Ksenia Brusilovskaya,Michael Trauner,Alexander Pfeifer,Markus Peck‐Radosavljevic ,Thorsten Gnad,Dávid Bauer ,Thomas Reiberger

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.

Highlights

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited
All cirrhotic rats presented with significantly elevated portal pressure (PP) compared to healthy controls and the degree of PHT increased with longer BDL duration and higher toxin exposure (Table 1)
Impairment of the Nitric oxide (NO)/Soluble guanylate cyclase (sGC)/cGMP pathway represents a major determinant of the increased intrahepatic vascular resistance in patients with cirrhosis, and is a promising target for the treatment of portal hypertension[11]

Summary

Introduction

Portal hypertension (PHT) deteriorates survival, yet treatment options are limited. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. Two experimental studies investigated the effects of the sGC activator BAY 60–2770 in experimental cirrhosis: Knorr et al demonstrated first, that BAY 60–2770 exhibits antifibrotic effects in rat models of CCl4-fibrosis and pig-serum induced liver injury[23]. PDE5i reduced liver fibrosis, improved endothelial dysfunction and decreased PHT in cirrhotic rats[27,28]. We investigate the effects of RIO on PHT and liver fibrosis in rats with early and advanced biliary (BDL) and hepatotoxic (CCl4) cirrhosis (Fig. 1). We aim to dissect the molecular mechanisms involved in RIO-induced modulation of sinusoidal vasotonus, angiogenesis, and inflammation

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