Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes
Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes
复制标题
DOI：
10.1016/s0022-5347(01)63299-3
复制
发表时间：
1998-06-01
影响因子：
6.6
通讯作者：
Naylor, AM
中科院分区：
文献类型：
--
作者：
Ballard, SA;Gingell, CJ;Naylor, AM
目的：西地那非是一种cgmp特异性磷酸二酯酶5 （PDE5）抑制剂，目前正在评估其作为阴茎勃起功能障碍的口服治疗方法。本研究的目的是探讨西地那非对体外人海绵体（HCC）神经源性松弛的作用机制，并确定西地那非对各种PDE同工酶的活性。材料与方法：用苯肾上腺素预收缩肝细胞癌组织条。然后在西地那非存在和不存在的情况下测定由电场刺激（EFS）引起的松弛反应。通过测定[H-3]-cGMP或[H-3]-cAMP向各自的[H-3]-5′-单核苷酸的转化，测定西地那非对人组织制备的PDE1 -5和牛视网膜制备的PDE6的影响。结果：西地那非（0.001 ~ 1 μ M）以浓度依赖性方式增强efs诱导的一氧化氮（NO）依赖性肝细胞癌松弛，最大可达1 μ M西地那非预处理水平的3倍。与早期PDE5抑制剂zaprinast相比，西地那非的抑制作用约为240倍，抑制肝癌的PDE5，几何平均IC50为3.5 nM。西地那非对PDE1 ~ 4的IC50值是PDE5的80 ~ 8500倍，对PDE6 （33 nM）的IC50值是PDE6的约9倍。结论：这些数据支持了西地那非对勃起功能障碍患者阴茎勃起的增强作用，其机制可能与性刺激时no刺激的cGMP信号的增强有关，cGMP信号介导海绵体平滑肌松弛。西地那非是一种有效的肝癌PDE5抑制剂，相对于其他PDE同工酶，对PDE5具有高选择性。
Purpose: Sildenafil, an inhibitor of cGMP-specific phosphodiesterase 5 (PDE5), is currently undergoing evaluation as an oral therapy for penile erectile dysfunction. The aims of this study were to investigate the mechanism of action of sildenafil on the neurogenic relaxation of human corpus cavernosum (HCC) in vitro and to determine the activity of sildenafil against a full range of PDE isozymes.Materials and Methods: Strips of HCC tissue were precontracted with phenylephrine. Relaxation responses resulting from electrical field stimulation (EFS) were then determined in the presence and absence of sildenafil. The effects of sildenafil on PDE1 to 5 prepared from human tissues and PDE6 from bovine retina were determined by measuring the conversion of [H-3]-cGMP or [H-3]-cAMP to their respective [H-3]-5'-mononucleotides.Results: Sildenafil (0.001 to 1 mu M) enhanced the EFS-induced, nitric oxide (NO) dependent, relaxation of HCC in a concentration-dependent manner to a maximum of 3 times the pretreatment level at 1 mu M sildenafil. Compared with zaprinast, an early PDE5 inhibitor, sildenafil was approximately 240-fold more potent, inhibiting PDE5 from HCC with a geometric mean IC50 of 3.5 nM. For sildenafil, IC50 values for inhibition of PDE1 to 4 were 80 to more than 8500 times greater than that for PDE5 and the IC50 for PDE6 (33 nM) was approximately 9-fold greater.Conclusions: The data support the proposal that enhancement of penile erection by sildenafil in patients with erectile dysfunction involves potentiation of the NO-stimulated cGMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. Sildenafil is a potent inhibitor of PDE5 from HCC, with high selectivity for PDE5 relative to other PDE isozymes.