Combination of phosphodiesterase‐5‐inhibitors and beta blockers improves experimental portal hypertension and erectile dysfunction

Abstract

Background & Aims Phosphodiesterase‐5 inhibitors (PDE‐5‐I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side‐effects have been reported. Non‐selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE‐5‐I with NSBB and its impact on PH and ED in experimental cirrhosis. Methods ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile‐duct‐ligation or carbon‐tetrachloride intoxication in rats. Corpus cavernosum pressure – a surrogate of ED ‐, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE‐5 signalling were analysed using PCR and western Blot. Results ED in humans was related to severity of liver disease and to NSBB treatment. PDE‐5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side‐effects. Conclusions ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE‐5‐I and NSBB improves ED and PH in experimental cirrhosis.

Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension

“…iNOS could not be found in healthy liver, but a marked expression was observed in early and progressed stages of TAA-induced liver damage. A subsequent study of Uschner et al using the BDL-model and the CCl 4 -model of liver cirrhosis confirmed the overexpression of eNOS and iNOS [ 97 ]. The latter data confirm the hypothesis of an iNOS upregulation in response to toxic stimuli.…”

“…Therefore, this paper yielded the molecular basis for the action of PDE-5 inhibitors on PVP in liver cirrhosis. Again, the study of Uschner et al confirmed the overexpression of sGC and PDE-5 in the BDL-model and the CCl 4 -model of liver cirrhosis [ 97 ].…”

“…Heart rate (HR) remained unaltered regardless of the applied dosage. Uschner et al confirmed the effect of udenafil on PVP in the BDL- and CCl 4 -model of liver cirrhosis [ 97 , 156 ]. Their most recent study moreover investigated the acute effects of a combination of udenafil with the NSBB propranolol [ 97 ].…”

“…Uschner et al confirmed the effect of udenafil on PVP in the BDL- and CCl 4 -model of liver cirrhosis [ 97 , 156 ]. Their most recent study moreover investigated the acute effects of a combination of udenafil with the NSBB propranolol [ 97 ]. Administration of udenafil (1 mg/kg oral) reduced PVP by 25–35%, whereas the addition of propranolol led to a further lowering by 40%.…”

“…cGMP as the final dilating agent was found to be elevated both in aortal rings and in plasma of animals with cirrhosis [ 135 ]. The recent study of Uschner et al also reported increased cGMP levels in peripheral blood vessels, which were most likely caused by decreased PDE-5 expression (detected in animals and humans with cirrhosis) [ 97 ].…”