Research Center Sanofi-Midy, Exploratory Unit, sanofi R&D, Milano, Italy.
J Transl Med. 2012 Mar 23;10:59. doi: 10.1186/1479-5876-10-59.
RhoA-Rho kinase complex contributes to keep the cavernosus smooth muscle contracted and its inhibition is considered a potential strategy for the therapy of erectile dysfunction (ED).
We compared the effects of SAR407899, the Rho-kinase inhibitor Y-27632 and the PDE5 inhibitor sildenafil for their ability to relax corpus cavernosum strips contracted with phenylephrine in healthy and diabetic animals. Strips were obtained from WKY, spontaneous hypertensive (SHR), control CD, and diabetic CD rats, humans, control and diabetic rabbits. Diabetes was induced by streptozotocin or alloxan injection. In vivo penile erection (length) induced by drugs was measured in conscious rabbits.
SAR407899 dose-dependently relaxed the pre-contracted corpora cavernosa in all species, with similar potency and efficacy in healthy vs diabetic rats, WKY vs SHR rats, healthy vs diabetic rabbits (IC(50) range from 0.05 to 0.29 μM, Emax range 89 to 97%). In the presence of the NO-synthase (NOS) inhibitor, L-NAME, the SAR407899 response did not decrease in any of the species or experimental conditions. The effect was confirmed in human strips where sildenafil was significantly less potent and effective, with IC50 respectively 0.13 and 0.51 μM; Emax 92 and 43%. Unlike SAR407899, the potency and efficacy of sildenafil and Y27632 were significantly reduced by diabetes and L-NAME. In vivo, SAR407899 dose-dependently induced rabbit penile erection, with greater potency and longer duration of action than sildenafil. Sildenafil, but not SAR407899, was less effective in alloxan-induced diabetes.
The induction of penile erection by SAR407899, unlike that by sildenafil, is largely independent of e-NO activity. This suggests its use in erectile dysfunction for diabetic and hypertensive patients where e-NO activity is impaired.
RhoA-Rho 激酶复合物有助于保持海绵体平滑肌收缩，抑制其活性被认为是治疗勃起功能障碍（ED）的一种潜在策略。
我们比较了 Rho 激酶抑制剂 SAR407899、Y-27632 和 PDE5 抑制剂西地那非对去甲肾上腺素诱导的健康和糖尿病动物海绵体肌条收缩的舒张作用。标本取自 WKY、自发性高血压（SHR）、对照型糖尿病（CD）和糖尿病 CD 大鼠、人和对照型及糖尿病兔。糖尿病通过链脲佐菌素或阿霉素注射诱导。在清醒兔中测量药物诱导的阴茎勃起（长度）。
SAR407899 剂量依赖性地舒张所有物种的预收缩海绵体，在健康和糖尿病大鼠、WKY 和 SHR 大鼠、健康和糖尿病兔中，其效力和效能相似（IC50 范围为 0.05 至 0.29 μM，Emax 范围为 89 至 97%）。在一氧化氮合酶（NOS）抑制剂 L-NAME 存在的情况下，SAR407899 在任何物种或实验条件下的反应都没有减弱。在人海绵体肌条中得到了证实，西地那非的效力和效能明显降低，IC50 分别为 0.13 和 0.51 μM；Emax 为 92%和 43%。与 SAR407899 不同，西地那非和 Y27632 的效力和效能在糖尿病和 L-NAME 存在的情况下显著降低。在体内，SAR407899 剂量依赖性地诱导兔阴茎勃起，其效力和作用持续时间均大于西地那非。西地那非，而不是 SAR407899，在阿霉素诱导的糖尿病中效果较差。
与西地那非不同，SAR407899 诱导阴茎勃起在很大程度上独立于 e-NO 活性。这表明它可用于治疗糖尿病和高血压患者的勃起功能障碍，这些患者的 e-NO 活性受损。
