Department of Physiology, Hypertension and Renal Center of Excellence, School of Medicine, Tulane University Medical Center,1430 Tulane Ave., New Orleans, LA 70112, USA.
Am J Physiol Renal Physiol. 2012 Sep;303(5):F775-82. doi: 10.1152/ajprenal.00233.2012. Epub 2012 Jun 6.
Nebivolol is a β(1)-adrenergic blocker that also elicits renal vasodilation and increases the glomerular filtration rate (GFR). However, its direct actions on the renal microvasculature and vasodilator mechanism have not been established. We used the in vitro blood-perfused juxtamedullary nephron technique to determine the vasodilator effects of nebivolol and to test the hypothesis that nebivolol induces vasodilation of renal afferent arterioles via an nitric oxide synthase (NOS)/nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway and the afferent arteriolar vasodilation effect may be mediated through the release of NO by activation of NOS via a β(3)-adrenoceptor-dependent mechanism. Juxtamedullary nephrons were superfused with nebivolol either alone or combined with the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or the NOS inhibitor N(ω)-nitro-l-arginine (l-NNA) or the β-blockers metoprolol (β(1)), butoxamine (β(2)), and SR59230A (β(3)). Nebivolol (100 μmol/l) markedly increased afferent and efferent arteriolar diameters by 18.9 ± 3.0 and 15.8 ± 1.8%. Pretreatment with l-NNA (1,000 μmol/l) or ODQ (10 μmol/l) decreased afferent vasodilator diameters and prevented the vasodilator effects of nebivolol (2.0 ± 0.2 and 2.4 ± 0.6%). Metoprolol did not elicit significant changes in afferent vasodilator diameters and did not prevent the effects of nebivolol to vasodilate afferent arterioles. However, treatment with SR59230A, but not butoxamine, markedly attenuated the vasodilation responses to nebivolol. Using a monoclonal antibody to β(3)-receptors revealed predominant immunostaining on vascular and glomerular endothelial cells. These data indicate that nebivolol vasodilates both afferent and efferent arterioles and that the afferent vasodilator effect is via a mechanism that is independent of β(1)-receptors but is predominantly mediated via a NOS/NO/sGC/cGMP-dependent mechanisms initiated by activation of endothelial β(3)-receptors.
比索洛尔是一种β(1)-肾上腺素能阻滞剂，它还能引起肾血管舒张并增加肾小球滤过率（GFR）。然而，其对肾脏微血管的直接作用和血管舒张机制尚未确定。我们使用体外血液灌注的肾髓质近曲小管技术来确定比索洛尔的血管舒张作用，并测试比索洛尔通过一氧化氮合酶（NOS）/一氧化氮（NO）/可溶性鸟苷酸环化酶（sGC）/环鸟苷酸（cGMP）途径诱导肾入球小动脉舒张的假设，并且入球小动脉舒张效应可能是通过激活 NOS 释放 NO 介导的，这是通过β(3)-肾上腺素能受体依赖性机制。比索洛尔单独或与鸟苷酸环化酶抑制剂 1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）或 NOS 抑制剂 N(ω)-硝基-l-精氨酸（l-NNA）或β-阻滞剂美托洛尔（β(1)）、丁氧胺（β(2)）和 SR59230A（β(3)）联合超射肾髓质近曲小管。比索洛尔（100 μmol/l）显著增加入球和出球小动脉直径 18.9±3.0%和 15.8±1.8%。预先用 l-NNA（1000 μmol/l）或 ODQ（10 μmol/l）处理可降低入球血管舒张直径并防止比索洛尔的血管舒张作用（2.0±0.2%和 2.4±0.6%）。美托洛尔不会引起入球血管舒张直径的显著变化，也不会阻止比索洛尔对入球小动脉的舒张作用。然而，用 SR59230A 处理，但不是丁氧胺，显著减弱了比索洛尔的血管舒张反应。使用单克隆抗体β(3)-受体显示血管和肾小球内皮细胞上主要的免疫染色。这些数据表明，比索洛尔舒张入球和出球小动脉，入球血管舒张效应是通过一种独立于β(1)-受体的机制，但主要是通过激活内皮细胞β(3)-受体启动的 NOS/NO/sGC/cGMP 依赖性机制介导的。
