Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers.
OBJECTIVE
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 pre-constriction 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.
Hepatic Hemodynamic Laboratory, VA Medical Center, West Haven, CT 06516, USA.
Mauricio R
MR
Loureiro-Silva
Yasuko
Y
Iwakiri
Juan G
JG
Abraldes
Omar
O
Haq
Roberto J
RJ
Groszmann
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008102:Liver Circulation / Q000502:physiology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat