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

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.

Soluble Guanylate Cyclase Stimulators and Activators

“…sGC agonists have shown promising effects in preclinical models of liver fibrosis (Knorr et al 2008;Hall et al 2017). The sGC stimulator riociguat was shown to reduce liver fibrosis and portal pressure in cirrhotic rats (Schwabl et al 2018) and mechanistic studies suggest that sGC modulators may inhibit fibrotic differentiation of hepatic stellate cells (Xiao et al 2015;Hall et al 2017). Nonalcoholic steatohepatitis (NASH) is a liver disease with characteristics of steatosis, inflammation, and fibrosis, and is a growing health concern globally.…”

Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit

“…Recently, we and others have demonstrated that modulation of cyclic guanosine-3′,5′-monophosphate (cGMP) exerts antiinflammatory and antifibrogenic effects in models of NASH and reduces portal pressure and fibrogenesis in cirrhotic rats (3)(4)(5). In these studies, small molecules with the ability to stimulate soluble guanylate cyclase (sGC), an enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cGMP, proved to be efficacious in the prevention as well as in the treatment of hepatic inflammation and fibrosis (3)(4)(5). In particular, using an optimized experimental model of NASH induced by a cholinedeficient L-amino acid-defined high-fat diet (CDAHFD) (6), we recently demonstrated that administration of the sGC stimulator praliciguat (PRL) delayed, in a dose-dependent manner, the development of liver inflammation and fibrosis (3).…”

Vascular Targets for the Treatment of Portal Hypertension

“…91 Primary cell isolation experiments revealed sGC expression in hepatocytes and HSCs and to a lower extent also in LSECs and KCs. 92 Activation of the sGC by NO results in the production of cyclic guanosine monophosphate (cGMP) and vasodilation. In oxidative stress conditions, as often present in liver diseases, NO signaling and affinity of NO to sGC is disturbed, which contributes to sinusoidal endothelial dysfunction and intrahepatic vasoconstriction.…”

“…105,106 Data obtained from two rat models of PHT (biliary and toxic liver cirrhosis), suggest promising effects of riociguat (sGC stimulator) on the reduction of PP and liver fibrosis. 92 Riociguat decrease hepatic necroinflammation and sinusoidal vascular remodeling, especially in cholestatic cirrhosis. 92 Of note, the safety of riociguat was already investigated and confirmed in patients with up to Child-Pugh B cirrhosis.…”

“…92 Riociguat decrease hepatic necroinflammation and sinusoidal vascular remodeling, especially in cholestatic cirrhosis. 92 Of note, the safety of riociguat was already investigated and confirmed in patients with up to Child-Pugh B cirrhosis. 107 Another sGC stimulator IW-1973 has been shown to have a protective effect of the on hepatic steatosis, inflammation, and fibrosis in the NASH animal model.…”