Rodríguez-Vilarrupla Aina, Graupera Mariona, Matei Vasilica, Bataller Ramón, Abraldes Juan G, Bosch Jaume, García-Pagán Joan-Carles
Hepatic Hemodynamic Laboratory, Liver Unit, Institut Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Ciberehd, Barcelona, Spain.
Liver Int. 2008 Apr;28(4):566-73. doi: 10.1111/j.1478-3231.2008.01668.x.
Large-conductance calcium-activated potassium (BK(Ca)) channels regulate vascular tone in different vascular systems. Moreover, activated hepatic stellate cells (HSC) contain BK(Ca) channels. The aim of this study was to evaluate the role of BK(Ca) channels in the regulation of vascular tone in control (CT) and carbon tetrachloride-cirrhotic (CH) rat livers.
Changes in intrahepatic vascular resistance were assessed by evaluating the portal perfusion pressure (PP) response to methoxamine (Mtx) in the presence of Iberiotoxin (Ibtx; a BK(Ca) channel blocker), NS1619 (a BK(Ca) channel opener), Ibtx plus the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine (L-NNA) or L-NNA alone. In addition, in CH livers, PP dose-response curves to the NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), were performed after pre-incubation with Ibtx or its vehicle. BK(Ca) mRNA expression was assessed in liver homogenates, and BK(Ca) protein expression in HSC isolated from CT and CH livers.
In CH livers, Ibtx significantly increased baseline PP and exacerbated the PP response to Mtx. Conversely, NS1619 induced a mild nonsignificant decrease of baseline PP and attenuated the hyperresponse to Mtx. CH livers exhibited an upregulation of both mRNA and protein of the alpha-subunit of BK(Ca).
Large-conductance calcium-activated potassium channels are overexpressed in CH livers and might represent a compensatory mechanism modulating the increased hepatic vascular tone of cirrhosis.
大电导钙激活钾（BK(Ca)）通道调节不同血管系统中的血管张力。此外，活化的肝星状细胞（HSC）含有BK(Ca)通道。本研究的目的是评估BK(Ca)通道在对照（CT）和四氯化碳诱导肝硬化（CH）大鼠肝脏血管张力调节中的作用。
通过评估在存在埃博毒素（Ibtx；一种BK(Ca)通道阻滞剂）、NS1619（一种BK(Ca)通道开放剂）、Ibtx加一氧化氮（NO）合酶抑制剂N(G)-硝基-L-精氨酸（L-NNA）或单独使用L-NNA的情况下，甲氧明（Mtx）引起的门静脉灌注压（PP）反应，来评估肝内血管阻力的变化。此外，在CH肝脏中，在用Ibtx或其溶媒预孵育后，进行对NO供体S-亚硝基-N-乙酰-D,L-青霉胺（SNAP）的PP剂量反应曲线测定。在肝脏匀浆中评估BK(Ca) mRNA表达，并在从CT和CH肝脏分离的HSC中评估BK(Ca)蛋白表达。
在CH肝脏中，Ibtx显著增加基线PP，并加剧PP对Mtx的反应。相反，NS1619诱导基线PP轻度非显著性降低，并减弱对Mtx的高反应性。CH肝脏中BK(Ca)α亚基的mRNA和蛋白均上调。
大电导钙激活钾通道在CH肝脏中过表达，可能代表一种调节肝硬化时肝血管张力增加的代偿机制。
