Leal Marcos A, Balarini Camille M, Dias Ananda T, Porto Marcella L, Gava Agata L, Pereira Thiago M C, Meyrelles Silvana S, Vasquez Elisardo C
Laboratory of Translational Physiology, Health Sciences Center, Federal University of Espirito Santo, Av Marechal Campos 1468, 29042-755 Vitoria, ES, Brazil.
Curr Pharm Biotechnol. 2015;16(6):517-30. doi: 10.2174/138920101606150407113458.
Sildenafil ameliorates aortic relaxations in apolipoprotein E knockout (apoE) mice. Now, we tested the hypothesis that endothelial dysfunction (ED) in this model is characterized by contractile hyperresponsiveness to phenylephrine (PE) and that this abnormality may be repaired using sildenafil. The aortic rings were evaluated in apoE mice treated with sildenafil (apoE-sil, 40 mg/kg/day) and compared with apoE and wild-type (WT) mice administered with vehicle (veh). The apoE-veh mice exhibited an imbalance of nitric oxide and reactive oxygen species (NO/ROS) levels and an increased maximum response (Rmax, 20%) and sensitivity (7%) to PE, which were not modified by endothelial removal. Under the prostanoids blockade, vasocontraction was decreased more in apoE-veh (-37%) than in WT (-27%) and apoE-sil (-30%) mice. NADPH-oxidase blockade abolished the enhanced contractile responsiveness in apoE-veh (-33%), without effects in WT and apoE-sil groups. The atherosclerotic lesions and the imbalance of NO/ROS were reduced (40%) in apoE-sil mice. In conclusion, ED in apoE mice was characterized by decreased NO-bioavailability and contractile hyperresponsiveness, due to thromboxane and oxidative stress, and was normalized by sildenafil. The beneficial effects of this phosphodiesterase-5 inhibitor on ED and lipid deposition provide new insights for its use as adjuvant in the treatment of atherosclerosis.
西地那非可改善载脂蛋白E基因敲除（apoE）小鼠的主动脉舒张功能。现在，我们验证了这样一个假设：该模型中的内皮功能障碍（ED）表现为对去氧肾上腺素（PE）的收缩反应性增强，并且这种异常情况可能可以用西地那非修复。对用西地那非治疗的apoE小鼠（apoE-sil，40毫克/千克/天）的主动脉环进行评估，并与给予赋形剂（veh）的apoE和野生型（WT）小鼠进行比较。apoE-veh小鼠表现出一氧化氮和活性氧（NO/ROS）水平失衡，对PE的最大反应（Rmax，增加20%）和敏感性（增加7%）增强，而内皮去除并未改变这些情况。在前列腺素阻断作用下，apoE-veh小鼠（-37%）的血管收缩降低幅度大于WT小鼠（-27%）和apoE-sil小鼠（-30%）。NADPH氧化酶阻断消除了apoE-veh小鼠增强的收缩反应性（-33%），对WT和apoE-sil组无影响。apoE-sil小鼠的动脉粥样硬化病变和NO/ROS失衡减少了（40%）。总之，apoE小鼠的ED表现为NO生物利用度降低和收缩反应性增强，这是由血栓素和氧化应激引起的，而西地那非可使其恢复正常。这种磷酸二酯酶-5抑制剂对ED和脂质沉积的有益作用为其作为动脉粥样硬化治疗辅助药物的应用提供了新的见解。
