Ballard S A, Gingell C J, Tang K, Turner L A, Price M E, Naylor A M
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, United Kingdom.
J Urol. 1998 Jun;159(6):2164-71. doi: 10.1016/S0022-5347(01)63299-3.
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.
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 [3H]-cGMP or [3H]-cAMP to their respective [3H]-5'-mononucleotides.
Sildenafil (0.001 to 1 microM) 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 microM 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.
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.
西地那非是一种环磷酸鸟苷特异性磷酸二酯酶5（PDE5）抑制剂，目前正作为阴茎勃起功能障碍的口服治疗药物进行评估。本研究的目的是在体外研究西地那非对人海绵体（HCC）神经源性舒张的作用机制，并确定西地那非对全系列磷酸二酯酶同工酶的活性。
用去氧肾上腺素预收缩HCC组织条。然后在有和没有西地那非的情况下测定电场刺激（EFS）引起的舒张反应。通过测量[3H]-环磷酸鸟苷或[3H]-环磷酸腺苷向其各自的[3H]-5'-单核苷酸的转化，来确定西地那非对从人体组织制备的磷酸二酯酶1至5以及牛视网膜磷酸二酯酶6的影响。
西地那非（0.001至1微摩尔）以浓度依赖的方式增强了EFS诱导的、一氧化氮（NO）依赖的HCC舒张，在1微摩尔西地那非时最大舒张幅度达到预处理水平的3倍。与早期的磷酸二酯酶5抑制剂扎普司特相比，西地那非的效力约高240倍，对HCC中磷酸二酯酶5的抑制几何平均半数抑制浓度（IC50）为3.5纳摩尔。对于西地那非，抑制磷酸二酯酶1至4的IC50值比对磷酸二酯酶5的IC50值大80至8500倍以上，而对磷酸二酯酶6的IC50（33纳摩尔）约大9倍。
数据支持这样的观点，即西地那非在勃起功能障碍患者中增强阴茎勃起涉及在性刺激期间增强介导海绵体平滑肌舒张的NO刺激的环磷酸鸟苷信号。西地那非是HCC中磷酸二酯酶5的有效抑制剂，相对于其他磷酸二酯酶同工酶对磷酸二酯酶5具有高选择性。
