Sildenafil, a type-5 CGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro
Sildenafil, a type-5 CGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro
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DOI：
10.1016/s0022-5347(01)63100-8
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发表时间：
1998-07-01
影响因子：
6.6
通讯作者：
Steers, WD
中科院分区：
文献类型：
--
作者：
Chuang, AT;Strauss, JD;Steers, WD
目的：海绵体平滑肌（CCSM）松弛和阴茎勃起的主要机制依赖于一氧化氮（NO）诱导的肌浆环鸟苷单磷酸（cGMP）的升高。增强NO-cGMP信号转导通路的药物可能对治疗勃起功能障碍有益。西地那非是一种选择性的5型cGMP磷酸二酯酶抑制剂，研究了该化合物治疗阳痿的具体机制。材料与方法：用苯肾上腺素等距刺激兔海绵体离体条。使用不同浓度的硝普钠（SNP）单独或与西地那非联合诱导分级松弛。在固定时间，将组织快速冷冻，并使用Western blot等电聚焦分析进行肌球蛋白轻链（MLC）磷酸化，使用放射免疫分析技术进行cGMP含量测定。结果：西地那非降低了未刺激CCSM的自发张力，但对无NO供体（SNP）时苯肾上腺素诱导的等长张力影响不大。西地那非使组织对SNP致敏松弛，但松弛与[cGMP]之间的关系在西地那非的作用下没有改变。峰等距力的松弛与[cGMP]相关，但与MLC磷酸化无关。结论：西地那非通过放大正常内源性cGMP依赖性松弛机制的作用而使CCSM松弛。
Purpose: 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.Materials and Methods: 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.Results: 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.Conclusions: Sildenafil relaxes CCSM by amplifying the effects of the normal, endogenous cGMP dependent relaxation mechanisms.