Chuang A T, Strauss J D, Murphy R A, Steers W D
Department of Urology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
J Urol. 1998 Jul;160(1):257-61.
The primary mechanism for relaxation of corpus cavernosum smooth muscle (CCSM) and penile erection depends upon nitric oxide (NO)-induced elevation of myoplasmic cyclic guanosine monophosphate (cGMP). Agents that enhance the NO-cGMP signal transduction pathway may prove beneficial in treating erectile dysfunction. Sildenafil, a selective type-5 cGMP phosphodiesterase inhibitor, was investigated to determine the specific mechanism(s) involved in the therapeutic use of this compound to treat impotence.
Isolated strips of rabbit corpus cavernosum were stimulated isometrically with phenylephrine. Graded relaxations were induced using various concentrations of sodium nitroprusside (SNP) alone and in combination with sildenafil. At fixed times, the tissues were rapidly frozen and processed for myosin light chain (MLC) phosphorylation using isoelectric focusing with Western blot analysis, and cGMP content using radioimmunoassay techniques.
Sildenafil alone reduced spontaneous tone in unstimulated CCSM, but had little effect on phenylephrine-induced isometric tension in the absence of a NO donor (SNP). Sildenafil sensitized the tissue to SNP for relaxation, but the relationship between relaxation and [cGMP] was unchanged by sildenafil. Relaxation from peak isometric force was correlated with [cGMP] but not MLC phosphorylation.
Sildenafil relaxes CCSM by amplifying the effects of the normal, endogenous cGMP dependent relaxation mechanisms.
阴茎海绵体平滑肌（CCSM）舒张及阴茎勃起的主要机制取决于一氧化氮（NO）诱导的胞浆环磷酸鸟苷（cGMP）升高。增强NO-cGMP信号转导途径的药物可能对治疗勃起功能障碍有益。研究了西地那非，一种选择性5型cGMP磷酸二酯酶抑制剂，以确定该化合物治疗阳痿的具体作用机制。
用去氧肾上腺素对分离的兔阴茎海绵体条进行等长刺激。单独使用不同浓度的硝普钠（SNP）以及联合西地那非诱导分级舒张。在固定时间，将组织迅速冷冻，并使用等电聚焦结合蛋白质免疫印迹分析处理以检测肌球蛋白轻链（MLC）磷酸化，使用放射免疫测定技术检测cGMP含量。
单独使用西地那非可降低未刺激的CCSM的自发张力，但在无NO供体（SNP）时对去氧肾上腺素诱导的等长张力影响很小。西地那非使组织对SNP诱导的舒张更敏感，但西地那非并未改变舒张与[cGMP]之间的关系。从等长力峰值开始的舒张与[cGMP]相关，但与MLC磷酸化无关。
西地那非通过放大正常内源性cGMP依赖性舒张机制的作用来舒张CCSM。
