The soluble guanylyl cyclase stimulator riociguat reduces liver fibrosis and portal pressure in cirrhotic rats

P Schwabl; K Brusilovskaya; F Riedl; D Bauer; B Strobel; S Fida; P Supper; H Hayden; M Trauner; M Peck-Radosavljevic; T Reiberger

doi:10.1055/s-0035-1551789

Zeitschrift für Gastroenterologie, Table of Contents

The soluble guanylyl cyclase stimulator riociguat reduces liver fibrosis and portal pressure in cirrhotic rats

P Schwabl ¹, K Brusilovskaya ¹, F Riedl ¹, D Bauer ¹, B Strobel ¹, S Fida ¹, P Supper ¹, H Hayden ¹, M Trauner ¹, M Peck-Radosavljevic ¹, T Reiberger ¹

¹Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

Abstract

Background: In liver cirrhosis nitric oxide (NO) signaling, including function of its receptor soluble guanylyl cyclase (sGC), is distorted. The sGC stimulator riociguat (RIO) is used as treatment for pulmonary hypertension and it has been shown that RIO acts antifibrotic. We thus aimed to investigate effects of RIO on experimental liver cirrhosis and portal hypertension.

Methods: Cirrhosis was induced by carbontetrachloride injections (CCl4, 8 weeks) or by bile duct ligation (BDL, 3 weeks) in Sprague Dawley rats. Controls received olive-oil (OO) or underwent sham operation (SO). RIO (1 mg/kg) or placebo were gavaged daily from week 6 – 8 (in CCl4) or from week 2 – 3 (in BDL), respectively. Then mean arterial pressure (MAP), heart rate (HR), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Porto-systemic and spleno-renal shunting were assessed by colored microspheres. Liver fibrosis was assessed by hepatic hydroxyproline content (HP).

Results: CCl4 rats presented with marked cirrhosis, hyperdynamic circulation, portal hypertension and elevated SMABF compared to OO animals. In CCl4 rats, RIO had no effect on HR, MAP and PP but significantly decreased SMABF (74 ± 11 vs. 43 ± 6mL/min; p = 0.036). Further, in CCl4 cirrhosis RIO significantly decreased spleen (1.3 ± 0.1 vs. 1.0 ± 0.1 g; p = 0.008) and liver (16.7 ± 1.2 vs. 11.5 ± 2.4 g; p = 0.015) weight.

BDL rats presented with hepatosplenomegaly and portal hypertension. RIO significantly increased MAP (108 ± 14 vs. 85 ± 17 mmHg; p = 0.016) and decreased PP (13.2 ± 2.5 vs. 10.1 ± 2.4 mmHg; p = 0.048), but had no effect on HR, SMABF and shunting. While organ weights were similar, HP was significantly lower (286 ± 147 vs. 144 ± 74 µg; p = 0.039) in BDL-RIO rats, compared to BDL control animals.

Conclusions: RIO treatment significantly reduced liver damage and ameliorated hyperdynamic circulation and portal pressure in biliary cirrhosis. In toxic cirrhosis RIO reduced hepatosplenomegaly and splanchnic blood inflow.