Chronic administration of an oral Rho kinase inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model
Chronic administration of an oral Rho kinase inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model
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DOI：
10.1111/j.1743-6109.2006.00327.x
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发表时间：
2006-11-01
影响因子：
3.5
通讯作者：
Paick, Jae-Seung
中科院分区：
文献类型：
--
作者：
Park, Kwanjin;Kim, Soo Woong;Paick, Jae-Seung
导言。已有研究表明，Rho/Rho激酶钙增敏通路参与了勃起功能障碍和系统性动脉粥样硬化的发病机制。目的：检测长期口服Rho激酶抑制剂(法舒地尔，5-异喹啉磺酰高哌嗪)能否预防血管性勃起功能障碍和盆腔动脉粥样硬化的发生。3月龄大鼠分为3组(每组10只)：对照组(1组)、动脉粥样硬化组(2组)和法舒地尔治疗组(3组)。2组和3组给予动脉粥样硬化倾向治疗(1%胆固醇饮食6周，N-G-硝基-L-精氨酸甲酯[3 mg/m L/d]治疗前2周)，3组同时给予法舒地尔(30 mg/kg/d)治疗6周。测定血管内皮细胞损伤量(血浆von Willebrand因子)和盆腔动脉粥样硬化程度。测定勃起功能、海绵体Rho激酶活性、总一氧化氮合酶和磷酸化内皮型一氧化氮合酶(ENOS)的表达。组2表现为明显的盆腔动脉粥样硬化和血管内皮损伤。大鼠还表现出海绵体Rho激酶活性升高和勃起功能受损。免疫印迹显示eNOS的总表达和磷酸化表达均减少。法舒地尔治疗可部分但明显改善盆腔动脉粥样硬化的进展和血浆von Willebrand因子水平。治疗还使勃起功能、海绵体Rho激酶活性和总eNOS表达正常化。第3组可见磷酸化eNOS的过度表达。这些结果表明，Rho/Rho激酶通路与勃起功能障碍和盆腔动脉粥样硬化的发生密切相关，而法舒地尔的长期治疗可以预防这两种疾病的发生。因此，Rho激酶可能被认为是预防血管性勃起功能障碍的新靶点。
Introduction. It has been shown that the Rho/Rho kinase calcium sensitizing pathway has been implicated in the pathogenesis of erectile dysfunction as well as systemic atherosclerosis.Aims. To test whether chronic treatment of an oral Rho kinase inhibitor (fasudil, 5-Isoquinolinesulfonyl homopiperazine) could prevent the development of both vasculogenic erectile dysfunction and pelvic atherosclerosis in a rat model.Methods. Rats (3 months old) were divided into three groups (N = 10 in each group): control (group 1); atherosclerosis (group 2); and fasudil-treated (group 3). Groups 2 and 3 received atherosclerosis-prone treatment (6 weeks of 1% cholesterol diet and early 2 weeks of N-G-nitro-L-arginine methyl ester [3 mg/mL/day] treatment, but group 3 was concurrently treated with fasudil (30 mg/kg/day) for 6 weeks.Main Outcome Measures. The amount of systemic endothelial injury (plasma von Willebrand factor) and pelvic atherosclerosis was determined. Erectile function, cavernosal Rho kinase activity, and expressions of total and phosphorylated endothelial nitric oxide synthase (eNOS) were also determined.Results. Group 2 showed a significant amount of pelvic atherosclerosis and endothelial injury. The rats also showed elevated cavernosal Rho kinase activity and impaired erectile function. Immunoblot showed a decreased total as well as phosphorylated eNOS expression. The treatment with fasudil partly but significantly ameliorated the development of pelvic atherosclerosis and plasma level of von Willebrand factor. The treatment also normalized the erectile function, cavernosal Rho kinase activity, and total eNOS expression. The overexpression of phospho-eNOS was observed in group 3.Conclusions. These results indicate that the Rho/Rho kinase pathway is substantially involved in the development of erectile dysfunction and pelvic atherosclerosis, both of which could be prevented by chronic treatment with fasudil. Thus, Rho kinase might be considered a novel target for the prevention of vasculogenic erectile dysfunction.