Park Juhyun, Kwon Oh Seong, Cho Sung Yong, Paick Jae-Seung, Kim Soo Woong
Department of Urology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea.
Department of Urology, Hallym University Hangang Sacred Heart Hospital, Seoul, Korea.
PLoS One. 2017 Feb 28;12(2):e0172751. doi: 10.1371/journal.pone.0172751. eCollection 2017.
The efficacy of statins is related to the 'common soil' hypothesis, which proposes oxidative stress and inflammation as main pathophysiologic processes in the disease group of diabetes and endothelial dysfunction. This study evaluated the recovery of erectile function after administration of chronic statin alone in streptozotocin (STZ)-induced diabetes mellitus (DM) rats, focusing on the anti-oxidative effects and consequentially recuperated endothelial function. A total of 45 male Sprague-Dawley rats (8 weeks old) were divided into three groups (n = 15 each): an age-matched normal control group (Control group), an uncontrolled DM group (DM group), and a statin-treated group (Statin group). The rats in the DM and Statin group received an injection of STZ (60 mg/kg). Beginning 10 weeks after the establishment of DM, the Statin group received daily treatment with atorvastatin (10 mg/kg) via oral gavage for four weeks. After 14 weeks, the results of the experiment were evaluated. The ratios of intracavernosal pressure (ICP) to mean arterial pressure (MAP) were recorded with cavernosometry (20 Hz, 3 V, 0.2 msec for 30 seconds) before and after the intravenous administration of udenafil (1 mg/kg). Expression of alpha-smooth muscle actin (α-SMA) was evaluated using cavernosal tissue. In addition, changes in RhoA translocation ratio and myosin phosphatase target subunit 1 (MYPT1) phosphorylation were evaluated with western blot. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were also analyzed as measurements of oxidative stress levels. The ICP/MAP and area under the curve (AUC)/MAP ratios of the Statin group were obviously superior to the DM group, but were not comparable to the Control group (P<0.001). The level of oxidative stress, namely SOD activity, was also significantly lower in the Statin group than in the DM group (P = 0.015), and was comparable to the Control group. In contrast, MDA levels were not considerably different among the groups (P = 0.217). The RhoA translocation ratio was not significantly different among the groups (P = 0.668), whereas MYPT1 phosphorylation in the Statin group was significantly lower than in the DM group (P = 0.030), and similar to the Control group. Expression of α-SMA in the Statin group was higher than in the DM group (P<0.001), and comparable to the Control group. Chronic statin treatment alone showed anti-oxidative effects and helped to restore the erectile mechanism, but did not lead to the full recovery of erectile function in STZ-induced DM rats. Therefore, combination therapy rather than a single agent should be the preferred treatment strategy for DM-associated erectile dysfunction, especially in the setting of severe diabetes.
他汀类药物的疗效与“共同土壤”假说相关，该假说提出氧化应激和炎症是糖尿病和内皮功能障碍疾病组中的主要病理生理过程。本研究评估了在链脲佐菌素（STZ）诱导的糖尿病（DM）大鼠中单独长期给予他汀类药物后勃起功能的恢复情况，重点关注其抗氧化作用以及随之恢复的内皮功能。总共45只雄性Sprague-Dawley大鼠（8周龄）被分为三组（每组n = 15）：年龄匹配的正常对照组（对照组）、未控制的DM组（DM组）和他汀类药物治疗组（他汀组）。DM组和他汀组的大鼠接受STZ注射（60 mg/kg）。在DM建立10周后，他汀组通过口服灌胃每日接受阿托伐他汀（10 mg/kg）治疗，持续四周。14周后，评估实验结果。在静脉注射伐地那非（1 mg/kg）前后，通过海绵体测量法（20 Hz，3 V，0.2毫秒，持续30秒）记录海绵体内压（ICP）与平均动脉压（MAP）的比值。使用海绵体组织评估α-平滑肌肌动蛋白（α-SMA）的表达。此外，通过蛋白质免疫印迹法评估RhoA易位率和肌球蛋白磷酸酶靶向亚基1（MYPT1）磷酸化的变化。还分析了超氧化物歧化酶（SOD）和丙二醛（MDA）水平作为氧化应激水平的测量指标。他汀组的ICP/MAP和曲线下面积（AUC）/MAP比值明显优于DM组，但与对照组不可比（P<0.001）。氧化应激水平，即SOD活性，在他汀组中也显著低于DM组（P = 0.015），且与对照组相当。相比之下，各组间MDA水平没有显著差异（P = 0.217）。各组间RhoA易位率没有显著差异（P = 0.668），而他汀组中MYPT1磷酸化显著低于DM组（P = 0.030），与对照组相似。他汀组中α-SMA的表达高于DM组（P<0.001），且与对照组相当。单独长期给予他汀类药物治疗显示出抗氧化作用，并有助于恢复勃起机制，但在STZ诱导的DM大鼠中并未导致勃起功能完全恢复。因此，联合治疗而非单一药物治疗应是DM相关性勃起功能障碍的首选治疗策略，尤其是在重度糖尿病的情况下。
