Rizzi Elen, Guimaraes Danielle A, Ceron Carla S, Prado Cibele M, Pinheiro Lucas C, Martins-Oliveira Alisson, Gerlach Raquel F, Tanus-Santos Jose E
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, 14049-900 Ribeirao Preto, SP, Brazil.
Free Radic Biol Med. 2014 Aug;73:308-17. doi: 10.1016/j.freeradbiomed.2014.05.024. Epub 2014 Jun 13.
Hypertension induces left-ventricular hypertrophy (LVH) by mechanisms involving oxidative stress and unbalanced cardiac matrix metalloproteinase (MMP) activity. We hypothesized that β1-adrenergic receptor blockers with antioxidant properties (nebivolol) could reverse hypertension-induced LVH more effectively than conventional β1-blockers (metoprolol) when used at doses that exert similar antihypertensive effects. Two-kidney one-clip (2K1C) hypertension was induced in male Wistar rats. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1)day(-1)) or metoprolol (20 mg kg(-1)day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly by tail-cuff plethysmography. LV structural changes and fibrosis were studied in hematoxylin/eosin- and picrosirius-stained sections, respectively. Cardiac MMP levels and activity were determined by in situ zymography, gel zymography, and immunofluorescence. Dihydroethidium and lucigenin-derived chemiluminescence assays were used to assess cardiac reactive oxygen species (ROS) production. Nitrotyrosine levels were determined in LV samples by immunohistochemistry and green fluorescence and were evaluated using the ImageJ software. Cardiac protein kinase B/Akt (AKT) phosphorylation state was assessed by Western blot. Both β-blockers exerted similar antihypertensive effects and attenuated hypertension-induced cardiac remodeling. Both drugs reduced myocyte hypertrophy and collagen deposition in 2K1C rats. These effects were associated with lower cardiac ROS and nitrotyrosine levels and attenuation of hypertension-induced increases in cardiac MMP-2 levels and in situ gelatinolytic activity after treatment with both β-blockers. Whereas hypertension increased AKT phosphorylation, no effects were found with β-blockers. In conclusion, we found evidence that two β1-blockers with different properties attenuate hypertension-induced LV hypertrophy and cardiac collagen deposition in association with significant cardiac antioxidant effects and MMP-2 downregulation, thus suggesting a critical role for β1-adrenergic receptors in mediating those effects. Nebivolol is not superior to metoprolol, at least with respect to their capacity to reverse hypertension-induced LVH.
高血压通过涉及氧化应激和心脏基质金属蛋白酶（MMP）活性失衡的机制诱导左心室肥厚（LVH）。我们假设，具有抗氧化特性的β1肾上腺素能受体阻滞剂（奈必洛尔）在使用产生相似降压效果的剂量时，比传统β1阻滞剂（美托洛尔）能更有效地逆转高血压诱导的LVH。在雄性Wistar大鼠中诱导两肾一夹（2K1C）高血压。手术后六周，高血压大鼠和假手术大鼠用奈必洛尔（10 mg kg⁻¹天⁻¹）或美托洛尔（20 mg kg⁻¹天⁻¹）治疗4周。每周通过尾袖体积描记法监测收缩压。分别在苏木精/伊红和苦味天狼星染色切片中研究LV结构变化和纤维化。通过原位酶谱法、凝胶酶谱法和免疫荧光法测定心脏MMP水平和活性。使用二氢乙锭和光泽精衍生的化学发光测定法评估心脏活性氧（ROS）产生。通过免疫组织化学和绿色荧光测定LV样品中的硝基酪氨酸水平，并使用ImageJ软件进行评估。通过蛋白质印迹法评估心脏蛋白激酶B/Akt（AKT）的磷酸化状态。两种β阻滞剂都发挥了相似的降压作用，并减轻了高血压诱导的心脏重塑。两种药物都减少了2K1C大鼠的心肌细胞肥大和胶原沉积。这些作用与较低的心脏ROS和硝基酪氨酸水平以及两种β阻滞剂治疗后高血压诱导的心脏MMP-2水平和原位明胶酶活性增加的减弱有关。虽然高血压增加了AKT磷酸化，但β阻滞剂未发现有影响。总之，我们发现证据表明，两种具有不同特性的β1阻滞剂减轻高血压诱导的LV肥大和心脏胶原沉积，同时具有显著的心脏抗氧化作用和MMP-2下调，因此表明β1肾上腺素能受体在介导这些作用中起关键作用。至少在逆转高血压诱导的LVH的能力方面，奈必洛尔并不优于美托洛尔。
