Endothelial β3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation β-blocker nebivolol
Endothelial β3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation β-blocker nebivolol
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DOI：
10.1161/circulationaha.104.532960
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发表时间：
2005-08-23
期刊：
影响因子：
37.8
通讯作者：
Balligand, JL
中科院分区：
文献类型：
--
作者：
Dessy, C;Saliez, J;Balligand, JL
背景-非特异性β受体阻滞剂的治疗效果受到血管收缩的限制，因此证明了对具有辅助血管舒张特性的分子的兴趣。奈必洛尔是一种选择性β（1）-肾上腺素受体拮抗剂，通过不完全表征的机制释放一氧化氮（NO）。我们在人冠状微动脉中鉴定了介导内皮和NO依赖性舒张的内皮β（3）-肾上腺素受体，并假设奈必洛尔激活这些β（3）-肾上腺素受体。（10 μ mol/L，前列腺素F2 α收缩的-86 +/- 6%）;这对NO合酶（NOS）抑制敏感，不受β（1-2）-阻断剂纳多洛尔的影响，β-（1-2-3）受体阻滞剂布萘洛尔（P < 0.05; n = 3 ~ 8）可抑制上述作用。重要的是，奈必洛尔不能舒张β 3肾上腺素受体缺陷小鼠的微动脉。奈必洛尔（10 μ mol/L）也松弛人冠状动脉微血管（KCl收缩的-71 +/- 5%）;这依赖于功能性内皮和NO合酶，但对β（1-2）-阻滞剂不敏感（所有P < 0.05）。在小鼠主动脉环新生血管生成试验中，奈必洛尔诱导野生型小鼠主动脉环中新毛细血管管形成，但β（3）-肾上腺素受体或内皮NOS缺陷小鼠未诱导。在培养的内皮细胞，10 μ mol/L奈必洛尔增加NO释放的200%，通过电子顺磁自旋捕获，这也被逆转的NOS抑制。同时，内皮NOS在苏氨酸（495）上脱磷酸化，fura-2钙荧光增加91.8 +/- 23.7%;这种作用不受β（1-2）-阻断的影响，但被β（1-2-3）-阻断所消除结论：奈必洛尔通过对内皮β（3）的激动剂作用扩张人和啮齿动物的冠状动脉阻力微动脉。肾上腺素受体释放NO和促进新血管生成。这些性质可能被证明是特别有益的治疗缺血性和心力衰竭疾病，通过保存冠状动脉储备。
Background - The therapeutic effects of nonspecific beta-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective beta(1)-adrenoreceptor antagonist that releases nitric oxide ( NO) through incompletely characterized mechanisms. We identified endothelial beta(3)-adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these beta(3)-adrenoreceptors.Methods and Results - Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 mu mol/L, -86 +/- 6% of prostaglandin F2 alpha contraction); this was sensitive to NO synthase ( NOS) inhibition, unaffected by the beta(1-2)-blocker nadolol, and prevented by the beta(1-2-3)-blocker bupranolol (P < 0.05; n = 3 to 8). Importantly, nebivolol failed to relax microarteries from beta(3)-adrenoreceptor-deficient mice. Nebivolol (10 mu mol/L) also relaxed human coronary microvessels (-71 +/- 5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to beta(1-2)-blockade ( all P < 0.05). In a mouse aortic ring assay of neoangiogenesis, nebivolol induced neocapillary tube formation in rings from wild-type but not beta(3)-adrenoreceptor - or endothelial NOS - deficient mice. In cultured endothelial cells, 10 mu mol/L nebivolol increased NO release by 200% as measured by electron paramagnetic spin trapping, which was also reversed by NOS inhibition. In parallel, endothelial NOS was dephosphorylated on threonine(495), and fura-2 calcium fluorescence increased by 91.8 +/- 23.7%; this effect was unaffected by beta(1-2)-blockade but abrogated by beta(1-2-3)-blockade ( all P < 0.05).Conclusions - Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial beta(3)-adrenoreceptors to release NO and promote neoangiogenesis. These properties may prove particularly beneficial for the treatment of ischemic and cardiac failure diseases through preservation of coronary reserve.