Therapeutic options targeting intrahepatic resistance
Therapeutic options targeting intrahepatic resistance are very limited. Theoretically, the NO-cGMP pathway may be influenced at several sites. Yet, most strategies did not reach clinical practice or yielded disappointing results, such as activators of soluble guanylate cyclase , NO releasing derivates , or statins . Organic nitrates reduce the hepatic venous pressure gradient (HVPG). However, they also act on the systemic circulation and lead to arterial hypotension. They are not recommended as monotherapy for secondary prophylaxis of variceal bleeding, while combination with non-selective beta-blockers (NSBB) is seemingly not better than monotherapy with NSBB or variceal ligation alone , .
NSBB, currently the mainstay of medical therapy of portal hypertension, act by lowering everolimus rate, antagonizing mesenteric vasodilatation and reducing portal tributary blood flow , .
Phosphodiesterase-5-inhibitors (PDE-5-I) block the key enzyme that terminates the action of the NO-cGMP system converting cGMP to the inactive 5′-GMP  and prolong the vasodilating effect of NO. PDE-5-Is have been approved for treatment of erectile dysfunction  and pulmonary arterial hypertension .
Udenafil is a highly specific PDE-5-I with fast onset of action and long elimination half-life. Like other PDE-5-Is, it is a substrate of cytochrome P450-3A and has a marked first pass effect in the liver . As no systematic data exists with respect to appropriate dosage of udenafil in portal hypertension, we performed a phase II dose-finding trial. Ascending doses of udenafil were given to patients with compensated liver cirrhosis and HVPG≥12mmHg over one week. The primary efficacy variable was the rate of patients showing response defined as final HVPG reduction by ≥20% compared to day 0 or final HVPG reduction to ≤12mmHg at the end of treatment . In addition, we analyzed the change of HVPG one hour after intake of udenafil on days 0 and 6 (acute setting).
Materials and methods
Discussion In patients with compensated liver cirrhosis oral administration of 75mg or 100mg udenafil, a PDE-5-I with a long elimination half-life, induced a statistically significant decrease of HVPG in the acute setting by 20%. According to previous studies, this reduction predicts a beneficial long-term effect to prevent esophageal variceal bleeding , , . Doses of 12.5mg to 50mg were less effective. Due to administrative restrictions we could not perform a placebo-controlled trial which is a limitation of the present study. However, we tried to avoid a possible bias by blinded analysis of the HVPG pressure tracings by an independent person familiar with HVPG measurements. Theoretical considerations about action and localization of the NO-cGMP system suggest that a modulation of the NO-cGMP pathway might influence sinusoidal blood flow and intrahepatic resistance , . PDE-5-Is, which inhibit the conversion of cGMP to inactive GMP, were expected to have an effect on portal pressure. Colle supposed that sildenafil may even increase the portal pressure in animals with liver cirrhosis . In contrast, Halverscheid showed that at least in the healthy liver, vardenafil and sildenafil increase portal venous and sinusoidal blood flow and the total liver blood flow/cardiac output ratio, and decrease hepatic resistance with a tendency to lower portal pressure . The first clinical study dealing with the effect of a PDE-5-I on hepatic haemodynamics showed in 18 healthy individuals and 18 patients with Child A liver cirrhosis  that an oral 10mg dose of the PDE-5-I vardenafil induced a ≥20% increase of portal venous blood flow in cirrhotics and healthy individuals. In five patients we showed that 10mg vardenafil reduced HVPG after one hour by 19%. Sildenafil or tadalafil showed comparable effects on portal blood flow . Both vardenafil and tadalafil induced a marked reduction of HVPG and pulmonary arterial pressure in a patient with porto-pulmonary hypertension . This suggested that PDE-5-Is could be a therapeutic option for portal hypertension.