Seoul National University College of Medicine-Department of Urology, Seoul, Korea.
J Sex Med. 2011 May;8(5):1352-61. doi: 10.1111/j.1743-6109.2010.02099.x. Epub 2010 Nov 3.
It has been suggested that risk of erectile dysfunction (ED) increases with duration of diabetes and phosphodiesterase type 5 inhibitors (PDE5I) are not as effective in treatment of diabetes-associated ED. However, few studies have investigated time-dependent change in erectile function during the course of diabetes.
To investigate time-dependent change in erectile function and responsiveness to PDE5I in streptozotocin-induced diabetic rats and to understand the pathophysiology of diabetic ED.
At 6, 8, 10, 12, and 14 weeks after diabetic induction, erectile function was assessed by cavernous nerve stimulation before and after administration of DA-8159, a novel PDE5I. Penile tissue was assessed for apoptosis with immunohistochemistry. Protein expression of Rho-kinase 2 (ROCK2), myosin phosphatase targeting subunit 1 (MYPT1), and endothelial nitric oxide synthase (eNOS) was evaluated by Western blot.
Streptozotocin was injected into 50 8-week-old male Sprague-Dawley rats, which were then classified into five diabetic groups according to the observation period.
Diabetic rats maintained normal erectile responses until 6 weeks of diabetes. Following 8 weeks, the rats showed lower erectile responses at higher frequencies of nerve stimulation, which were normalized to control by administration of DA-8159. In contrast, erectile responses were significantly decreased in 10-week diabetic rats, and administration of DA-8159 resulted in partial recovery of normal responses. At more than 12 weeks, rats demonstrated severe deterioration of erectile function, which did not fully respond to PDE5I. Corporal apoptosis was significantly increased after 10 weeks. Upregulation of ROCK2 was found at 6 weeks, and was followed by an increase of MYPT1 phosphorylation. Phosphorylation of eNOS showed marked suppression at 6 weeks and remained lower during the experimental period.
Impairment of erectile function was followed by decreased responsiveness to PDE5I during the course of diabetes. The RhoA/ROCK pathway played an important role in diabetes-associated ED.
有人认为，勃起功能障碍（ED）的风险随着糖尿病病程的延长而增加，而磷酸二酯酶 5 抑制剂（PDE5I）在治疗糖尿病相关 ED 方面的效果并不理想。然而，很少有研究调查糖尿病病程中勃起功能的时间依赖性变化。
研究链脲佐菌素诱导的糖尿病大鼠勃起功能的时间依赖性变化及对 PDE5I 的反应性，探讨糖尿病 ED 的病理生理学机制。
在糖尿病诱导后 6、8、10、12 和 14 周，通过给予新型 PDE5I DA-8159 前后，对海绵体神经刺激评估勃起功能。用免疫组织化学法评估阴茎组织细胞凋亡。通过 Western blot 评估 Rho 激酶 2（ROCK2）、肌球蛋白磷酸酶靶向亚单位 1（MYPT1）和内皮型一氧化氮合酶（eNOS）的蛋白表达。
将链脲佐菌素注射入 50 只 8 周龄雄性 Sprague-Dawley 大鼠，然后根据观察期将其分为五组糖尿病大鼠。
糖尿病大鼠在糖尿病 6 周时仍保持正常的勃起反应。8 周后，随着神经刺激频率的增加，大鼠表现出较低的勃起反应，而给予 DA-8159 则可使反应正常化。相比之下，10 周糖尿病大鼠的勃起反应明显下降，给予 DA-8159 可部分恢复正常反应。12 周以上，大鼠的勃起功能严重恶化，对 PDE5I 无充分反应。10 周后，阴茎细胞凋亡明显增加。6 周时 ROCK2 上调，随后 MYPT1 磷酸化增加。eNOS 磷酸化在 6 周时明显受到抑制，并在整个实验期间保持较低水平。
在糖尿病病程中，勃起功能障碍的损害伴随着对 PDE5I 反应性的降低。RhoA/ROCK 通路在糖尿病相关 ED 中起重要作用。
