De Young L, Yu D, Freeman D, Brock G B
Department of Urology, St Joseph's Health Care, Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada.
Int J Impot Res. 2003 Oct;15(5):347-54. doi: 10.1038/sj.ijir.3901026.
Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.
磷酸二酯酶（PDE）抑制剂是勃起功能障碍（ED）治疗领域的一项重要进展。尽管其应用广泛且疗效总体良好，但作为一类药物，仍有15%至57%的男性使用无效。患有严重血管性或神经性基础ED的特定患者群体，如糖尿病男性或接受过根治性盆腔手术的患者，对PDE抑制治疗的反应率较低。我们认为，通过输送足够浓度的游离氧自由基清除分子（如维生素E），可以提高循环中的一氧化氮（NO）水平。理论上，较高水平的NO应能增加阴茎血流量，与PDE5抑制剂联合使用时可能产生协同效应。基于这一假设，将20只成年雄性Sprague-Dawley大鼠通过腹腔注射链脲佐菌素（60mg/kg）诱导为糖尿病大鼠，并分为四个治疗组（每组n = 5）。第一组为对照组，动物接受花生油；第二组每天口服维生素E 20IU；第三组每天口服西地那非5mg/kg；第四组每天口服维生素E 20IU加西地那非5mg/kg，持续3周。通过海绵体神经电刺激后海绵体内压的升高来评估勃起功能。采集阴茎组织以确定组织形态的变化，包括神经元型一氧化氮合酶、平滑肌α-肌动蛋白和内皮细胞完整性。测量PDE5蛋白含量和活性。接受维生素E加西地那非联合治疗的动物海绵体内压显著升高。免疫组织化学染色显示神经元型一氧化氮合酶、内皮细胞和平滑肌细胞染色增加。蛋白质印迹分析显示各组之间PDE5蛋白无显著差异。然而，西地那非组的PDE5活性较高，而接受维生素E加西地那非治疗的组中PDE5活性较低。在这个糖尿病动物模型中，维生素E以有意义的方式增强了PDE5抑制剂的治疗效果。这项研究表明了一种挽救对西地那非难治的患者勃起功能的潜在方法。
