Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications

Abstract

The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the “NO-paradox”, referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.

Plasma Cyclic Guanosine Monophosphate Is a Promising Biomarker of Clinically Significant Portal Hypertension in Patients With Liver Cirrhosis

“…Cirrhotic patients with and without CSPH were of comparable age and gender distribution with a median age of 60 (55-67) and 61 (54-67) years (p = 0.925) and a majority of 49 (70.0%) and 15 (71.4%) males, respectively (p = 0.900). As to be expected, patients with CSPH had more advanced liver disease, highlighted by a MELD score of 11(8)(9)(10)(11)(12)(13)(14) in comparison to patients without CSPH with a MELD score of 7 (7-8; p = 0.007). Alcoholic liver disease was the leading etiology in patients with CSPH (n = 45, 64.3 %), while cirrhotic patients without CSPH mostly had viral liver disease (n = 15, 71.4 %).…”

“…Various studies in the animal model of portal hypertension have demonstrated decreased hepatic cGMP activity with reflectively increased splanchnic and systemic cGMP activity ( 4 – 7 ). These alterations are believed to be a major contributing factor to the state of profuse hepatic vascular resistance and hyperdynamic splanchnic and systemic circulation that characterizes cirrhotic portal hypertension ( 12 , 13 ). This pathophysiological background suggests that cGMP could be a biomarker of portal hypertension.…”

“…Graphical exploration revealed no unequivocal link of plasma cGMP to pre-TIPS PSG measurements; Supplementary Figure 1. TIPS placement reduced the patients' PSG to 11 (10)(11)(12) mmHg. Following TIPS implantation, plasma cGMP showed a decrease in 10 out of 13 patients (76.9 %); Figure 4.…”

Emerging Therapeutic Targets for Portal Hypertension

“…PDE5 is an enzyme which converts vasodilating cGMP into its inactive form and is increased in the cirrhotic liver. Its modulation using PDE5-inhibitors may have potential in the treatment of ACLD, as highlighted in a recent review [ 155 ]. In the clinical setting, results have been mixed, with some studies showing no change in HVPG [ 59 , 156 ], while others observed a decrease [ 41 , 60 ].…”

Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer

“…The latter (i.e., sildenafil, vardenafil, tadalafil,) are mostly known for their clinical use in the treatment of erectile dysfunction [ 54 ]. They are also applied in other diseases, such as male lower urinary tract symptoms (LUTS), psoriasis arthritis, nonalcoholic fatty liver disease (NAFLD), liver cirrhosis, pulmonary arterial hypertension (PAH) [ 55 , 56 , 57 , 58 , 59 , 60 ]. Nevertheless, these compounds, alone or in combination with chemotherapeutics, have been heralded as promising drugs for the treatment of several malignancies, including breast cancer, although their role is yet to be fully clarified [ 61 , 62 , 63 , 64 ].…”