Mollnau Hanke, Schulz Eberhard, Daiber Andreas, Baldus Stephan, Oelze Matthias, August Michael, Wendt Maria, Walter Ulrich, Geiger Carolin, Agrawal Rahul, Kleschyov Andrei L, Meinertz Thomas, Münzel Thomas
Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, University of Hamburg, Hamburg, Germany.
Arterioscler Thromb Vasc Biol. 2003 Apr 1;23(4):615-21. doi: 10.1161/01.ATV.0000065234.70518.26. Epub 2003 Mar 6.
Nebivolol, in contrast to other selective beta1-adrenergic receptor antagonists like atenolol, improves endothelial function in patients with oxidative stress within vascular tissue. With the present studies we sought to determine whether beta receptor blockade with nebivolol may improve endothelial function in hyperlipidemia and whether this is attributable to reductions in vascular oxidative stress.
Watanabe heritable hyperlipidemic rabbits (WHHL) were treated with nebivolol (10 mg/kg per day for 8 weeks). New Zealand white rabbits (NZWR) served as controls. Nebivolol improved endothelial function, reduced vascular superoxide and vascular macrophage infiltration, and prevented NO synthase uncoupling in WHHL. Nebivolol treatment did not modify the expression of sGC or cGK-I but improved cGK-I activity (assessed by the phosphorylation state of the VAsodilator Stimulated Phosphoprotein at serine239, P-VASP). NAD(P)H oxidase activity in whole blood and isolated neutrophils was dose-dependently inhibited by nebivolol, whereas atenolol, metoprolol, and carvedilol were markedly less effective.
Nebivolol therapy effectively prevents NO synthase III uncoupling and prevents activation of the neutrophil NAD(P)H oxidase and infiltration of inflammatory cells. These novel antioxidative stress actions of this compound may explain partly the beneficial effects on endothelial function in patients with enhanced vascular oxidative stress.
与阿替洛尔等其他选择性β1肾上腺素能受体拮抗剂不同，奈必洛尔可改善血管组织存在氧化应激的患者的内皮功能。通过本研究，我们试图确定奈必洛尔进行β受体阻滞是否可改善高脂血症患者的内皮功能，以及这是否归因于血管氧化应激的降低。
将渡边遗传性高脂血症兔（WHHL）用奈必洛尔治疗（每天10mg/kg，持续8周）。新西兰白兔（NZWR）作为对照。奈必洛尔改善了WHHL的内皮功能，减少了血管超氧化物和血管巨噬细胞浸润，并防止了一氧化氮合酶解偶联。奈必洛尔治疗未改变可溶性鸟苷酸环化酶（sGC）或蛋白激酶G-I（cGK-I）的表达，但改善了cGK-I活性（通过血管舒张刺激磷蛋白在丝氨酸239处的磷酸化状态，即磷酸化血管舒张刺激磷蛋白（P-VASP）来评估）。奈必洛尔剂量依赖性地抑制全血和分离的中性粒细胞中的烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）氧化酶活性，而阿替洛尔、美托洛尔和卡维地洛的效果明显较差。
奈必洛尔治疗可有效防止一氧化氮合酶III解偶联，防止中性粒细胞NAD(P)H氧化酶激活和炎症细胞浸润。该化合物这些新的抗氧化应激作用可能部分解释了其对血管氧化应激增强患者内皮功能的有益影响。
