Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers

Background/Aims: Cirrhotic livers have a deficient vasodilator response to nitric oxide (NO). The vasodilator effect of NO is normally limited by the degradation of its second messenger cyclic guanosine 3', 5' monophosphate by phosphodiesterases. We investigated (1) the phosphodiesterase-5 (PDE-5) expression in normal and cirrhotic rat livers, (2) the location of the deficient response to NO in cirrhotic livers, and (3) the effect of the PDE-5 inhibitor Sildenafil citrate on this deficient response. Methods: Normal and ascitic cirrhotic rats were subjected to liver perfusion with continuous measurement of both perfusion and sinusoidal (wedge hepatic) pressures. After incubation with N-monomethyl-L-arginine and preconstriction with Methoxamine, concentration-response curves to the spontaneous NO donor S-nitroso-N-acetylpenicillamine were obtained in the absence or presence of Sildenafil (10(-8) M). Results: PDE-5 expression (Western blot) in cirrhotic livers was higher than in normal livers (P = 0.042). Compared to normal livers, cirrhotic livers showed a decreased response to S-nitroso-N-acetylpenicillamine in the pre-sinusoidal area (P = 0.003) but not in the sinusoidal/post-sinusoidal area (P = 0.433). In the presence of Sildenafil, normal and cirrhotic livers showed similar pre-sinusoidal (P = 0.419) and sinusoidal/post-sinusoidal (P = 0.875) responses to S-nitroso-N-acetylpenicillamine. Conclusions: Increased PDE-5 expression is involved in the decreased vascular response to NO in cirrhotic livers. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.