Gracia-Sancho Jorge, Laviña Bàrbara, Rodríguez-Vilarrupla Aina, Brandes Ralf P, Fernández Mercedes, Bosch Jaume, García-Pagán Joan-Carles
Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Ciberehd and Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
Gastroenterology. 2007 Sep;133(3):959-66. doi: 10.1053/j.gastro.2007.06.021. Epub 2007 Jun 20.
BACKGROUND & AIMS: Increased hepatic vascular resistance in cirrhosis is in part due to reduced nitric oxide (NO) bioavailability. This is related to insufficient NO synthesis from endothelial nitric oxide synthase and to enhanced NO scavenging by superoxide radicals (O(2)(-)). Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase is an important source of O(2)(-) that increases vascular tone in different cardiovascular disorders. Thus, our aims were to study the molecular and biochemical state of NADPH-oxidase in cirrhotic livers and to investigate its possible role in modulating hepatic vascular tone in cirrhosis.
NADPH-oxidase expression and enzymatic activity were determined in control (n = 8) and CCl(4)-cirrhotic (n = 8) rat livers. Additional control (n = 6) and CCl(4)-cirrhotic (n = 10) rats were treated with apocynin (a selective NADPH-oxidase inhibitor) or its vehicle. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow were measured in vivo. Moreover, hepatic endothelial function was evaluated in isolated and perfused rat livers by dose-response curves to acetylcholine. In addition, in 6 control and 6 cirrhotic human livers NADPH-oxidase activity and expression were evaluated.
Rat cirrhotic livers had no increased NADPH-oxidase protein expression or activity in relation to control livers. NADPH-oxidase inhibition did not modify splanchnic or systemic hemodynamics in control or cirrhotic rats and did not improve the impaired endothelial-dependent vasodilatory response to acetylcholine of cirrhotic livers. Human cirrhotic livers also did not exhibit increased NADPH-oxidase expression or activity.
Our study shows that NADPH-oxidase activity is decreased in the cirrhotic livers and therefore cannot explain increased hepatic O(2)(-), endothelial dysfunction, and increased vascular tone in cirrhotic livers.
肝硬化时肝血管阻力增加部分归因于一氧化氮（NO）生物利用度降低。这与内皮型一氧化氮合酶合成NO不足以及超氧阴离子自由基（O₂⁻）对NO的清除增强有关。烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶是O₂⁻的重要来源，在不同的心血管疾病中可增加血管张力。因此，我们的目的是研究肝硬化肝脏中NADPH氧化酶的分子和生化状态，并探讨其在调节肝硬化肝脏血管张力中的可能作用。
测定对照（n = 8）和四氯化碳诱导肝硬化（n = 8）大鼠肝脏中NADPH氧化酶的表达和酶活性。另外的对照（n = 6）和四氯化碳诱导肝硬化（n = 10）大鼠用阿扑辛（一种选择性NADPH氧化酶抑制剂）或其溶媒处理。在体内测量平均动脉压、门静脉压力和肠系膜上动脉血流量。此外，通过对乙酰胆碱的剂量反应曲线评估离体灌注大鼠肝脏的肝内皮功能。另外，评估6例对照和6例肝硬化人肝脏中的NADPH氧化酶活性和表达。
与对照肝脏相比，大鼠肝硬化肝脏中NADPH氧化酶蛋白表达或活性没有增加。NADPH氧化酶抑制对对照或肝硬化大鼠的内脏或全身血流动力学没有影响，也没有改善肝硬化肝脏对乙酰胆碱受损的内皮依赖性血管舒张反应。人肝硬化肝脏也没有表现出NADPH氧化酶表达或活性增加。
我们的研究表明，肝硬化肝脏中NADPH氧化酶活性降低，因此不能解释肝硬化肝脏中O₂⁻增加、内皮功能障碍和血管张力增加的现象。
