Helmy A, Newby D E, Jalan R, Hayes P C, Webb D J
Liver Unit, Department of Medicine, Royal Infirmary of Edinburgh, and Clinical Pharmacology Unit and Research Centre, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Gut. 2003 Mar;52(3):410-5. doi: 10.1136/gut.52.3.410.
Patients with advanced cirrhosis have systemic vasodilatation and increased nitric oxide (NO) production despite activated vasopressor systems, including the endothelin system. The aims of this study were to assess the contribution of endogenous endothelin 1 (ET-1) and NO to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis (n=7) and in age and sex matched healthy controls (n=7).
Using venous occlusion plethysmography, forearm blood flow (FBF) responses to subsystemic locally active intra-arterial infusion of BQ-123 (a selective endothelin type A receptor (ET(A)) receptor antagonist; 10 nmol/min) were measured before and during application of an "NO clamp": a balanced co-infusion of L-N(G)-monomethyl-arginine (a selective NO synthase inhibitor) and sodium nitroprusside (an exogenous NO donor) to block endogenous NO production and restore NO mediated basal FBF, respectively.
L-NMMA infusion produced a reduction in FBF (p<0.001) which was similar in both groups. Before applying the "NO clamp", BQ-123 caused an increase in FBF in both groups (p<0.001) that was greater in patients with cirrhosis (p<0.01). During the "NO clamp", BQ-123 induced vasodilatation was abolished in controls and attenuated in patients (p<0.001) but remained significantly greater in patients with cirrhosis (p<0.01).
These findings indicate a greater ET(A) mediated contribution of endogenous ET-1 to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis. In addition, enhanced vasodilatation to ET(A) receptor antagonism in cirrhosis cannot be entirely attributed to NO release but is likely to be related to reversal of direct ET-1 mediated tone.
晚期肝硬化患者尽管血管升压系统（包括内皮素系统）被激活，但仍存在全身血管舒张和一氧化氮（NO）生成增加的情况。本研究的目的是评估内源性内皮素1（ET-1）和NO对腹水前期肝硬化患者（n = 7）以及年龄和性别匹配的健康对照者（n = 7）前臂基础血管张力维持的作用。
采用静脉阻断体积描记法，在应用“NO钳夹”（一种平衡输注L-N(G)-单甲基精氨酸（一种选择性NO合酶抑制剂）和硝普钠（一种外源性NO供体）以分别阻断内源性NO生成和恢复NO介导的基础前臂血流量）之前和期间，测量前臂血流量（FBF）对动脉内局部活性输注BQ-123（一种选择性A型内皮素受体（ET(A)）拮抗剂；10 nmol/min）的反应。
输注L-NMMA导致两组的FBF均降低（p<0.001）。在应用“NO钳夹”之前，BQ-123使两组的FBF均增加（p<0.001），且在肝硬化患者中增加幅度更大（p<0.01）。在“NO钳夹”期间，对照组中BQ-123诱导的血管舒张被消除，而在患者中减弱（p<0.001），但在肝硬化患者中仍显著更大（p<0.01）。
这些发现表明，内源性ET-1通过ET(A)介导，对腹水前期肝硬化患者前臂基础血管张力的维持作用更大。此外，肝硬化中对ET(A)受体拮抗的血管舒张增强不能完全归因于NO释放，而可能与直接的ET-1介导的张力逆转有关。
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