Loureiro-Silva Mauricio R, Iwakiri Yasuko, Abraldes Juan G, Haq Omar, Groszmann Roberto J
Hepatic Hemodynamic Laboratory, VA Medical Center, West Haven, CT 06516, USA.
J Hepatol. 2006 May;44(5):886-93. doi: 10.1016/j.jhep.2006.01.032. Epub 2006 Feb 28.
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.
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).
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.
Increased PDE-5 expression is involved in the decreased vascular response to NO in cirrhotic livers.
背景/目的：肝硬化肝脏对一氧化氮（NO）的血管舒张反应不足。NO的血管舒张作用通常受到磷酸二酯酶对其第二信使环磷酸鸟苷3'，5'-单磷酸的降解的限制。我们研究了（1）正常和肝硬化大鼠肝脏中磷酸二酯酶-5（PDE-5）的表达，（2）肝硬化肝脏中对NO反应不足的部位，以及（3）PDE-5抑制剂枸橼酸西地那非对这种反应不足的影响。
对正常和腹水型肝硬化大鼠进行肝脏灌注，并持续测量灌注压和肝窦（楔形肝）压力。在用N-单甲基-L-精氨酸孵育并经甲氧明预收缩后，在不存在或存在西地那非（10⁻⁸M）的情况下，获得对自发性NO供体S-亚硝基-N-乙酰青霉胺的浓度-反应曲线。
肝硬化肝脏中PDE-5的表达（蛋白质印迹法）高于正常肝脏（P = 0.042）。与正常肝脏相比，肝硬化肝脏在肝窦前区域对S-亚硝基-N-乙酰青霉胺的反应降低（P = 0.003），但在肝窦/肝窦后区域无此现象（P = 0.433）。在存在西地那非的情况下，正常和肝硬化肝脏对S-亚硝基-N-乙酰青霉胺的肝窦前（P = 0.419）和肝窦/肝窦后（P = 0.875）反应相似。
PDE-5表达增加与肝硬化肝脏中血管对NO的反应降低有关。
