Nebivolol:: A third-generation β-blocker that augments vascular nitric oxide release endothelial β2-adrenergic receptor-mediated nitric oxide production
Nebivolol:: A third-generation β-blocker that augments vascular nitric oxide release endothelial β2-adrenergic receptor-mediated nitric oxide production
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DOI：
10.1161/01.cir.102.6.677
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发表时间：
2000-08-08
期刊：
影响因子：
37.8
通讯作者：
van der Zee, R
中科院分区：
文献类型：
--
作者：
Broeders, MAW;Doevendans, PA;van der Zee, R
背景-奈必洛尔是一种β-选择性肾上腺素能受体拮抗剂，在人体中具有一氧化氮（NO）介导的血管舒张特性。在这项研究中，我们探讨了奈必洛尔是否真的诱导NO的产生，如果是这样，通过什么机制。我们假设，而不是奈必洛尔本身，而是它的代谢产物增加NO production.Methods和Results-Mouse胸主动脉段沐浴在一个器官室。奈必洛尔给药不影响NO的产生。当奈必洛尔在小鼠体内代谢时，加入这些小鼠的血浆导致NO释放持续增加2倍。有趣的是，选择性β（2）-肾上腺素能受体拮抗剂（butoxamine）的共同管理，防止反应。免疫组织化学和Western印迹分析表明内皮细胞上存在β（2）-肾上腺素能受体，但不存在β（1）-肾上腺素能受体。在没有钙的情况下，代谢奈必洛尔未能增加NO的产生，这表明钙依赖性NO合酶的作用。与数字荧光成像，在内皮细胞胞浆游离Ca 2+浓度的快速和持续的上升后，观察到代谢奈必洛尔，这也被废除了butoxamine pretreatment. Conclusions，在体内代谢奈必洛尔增加血管NO的生产。这种现象涉及内皮β 2-肾上腺素能受体连接，随后内皮游离[Ca 2 +]和内皮NO脱氢酶依赖性NO产生增加。这可能是奈必洛尔诱导的NO介导的人体动脉扩张的重要机制。
Background-Nebivolol is a beta-selective adrenergic receptor antagonist with proposed nitric oxide (NO)-mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production.Methods and Results-Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective beta(2)-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of beta(2)- but not beta(1)-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca2+ concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment.Conclusions-In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial Pz-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca2+], and endothelial NO synthasedependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.