Uckert Stefan, Bazrafshan Siamak, Scheller Friedemann, Mayer Margit E, Jonas Udo, Stief Christian G
Department of Urology, Hannover Medical School, Hannover, Germany.
Urology. 2007 Jul;70(1):185-9. doi: 10.1016/j.urology.2007.02.049.
To further elucidate the significance of the cyclic nucleotide-mediated signal transduction, we examined the in vitro functional responses of isolated seminal vesicle (SV) smooth muscle tissue to selective phosphodiesterase (PDE) inhibitors.
Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE inhibitors vinpocetine (PDE1 inhibitor), rolipram (PDE4 inhibitor), and sildenafil and vardenafil (PDE5 inhibitors) on the tension induced by 10 microM of norepinephrine on SV tissue strips were investigated. To examine the drug effects on the tissue levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), the SV strips were exposed to different concentrations of the compounds (0.1, 1, and 10 microM). After freezing, homogenization, and extraction of cyclic nucleotides, cAMP and cGMP were measured using radioimmunoassays. In the experiments, sodium nitroprusside and forskolin were used as reference compounds.
The norepinephrine-induced tension was reversed by the drugs in a dose-dependent manner. The rank order of efficacy was rolipram greater than sildenafil greater than vardenafil greater than or equal to vinpocetine greater than sodium nitroprusside greater than forskolin. The reversion of the norepinephrine-induced tension at maximum drug concentration ranged from 79% (rolipram) to 32% (forskolin). Only rolipram and sildenafil reached a median effective concentration. The effects of the PDE inhibitors were paralleled by a 1.7-fold to 173-fold increase in tissue cGMP or cAMP.
Our results have demonstrated that PDE inhibitors can reverse the adrenergic tension of human SV tissue and increase levels of cyclic nucleotides. This outlines the potential significance of cAMP and cGMP in the control of SV smooth muscle function. These findings might be of importance with regard to the pharmacologic treatment of premature ejaculation.
为了进一步阐明环核苷酸介导的信号转导的意义，我们检测了分离的精囊（SV）平滑肌组织对选择性磷酸二酯酶（PDE）抑制剂的体外功能反应。
采用器官浴技术，研究了PDE抑制剂长春西汀（PDE1抑制剂）、咯利普兰（PDE4抑制剂）、西地那非和伐地那非（PDE5抑制剂）浓度增加（1 nM至10 μM）对10 μM去甲肾上腺素诱导的SV组织条张力的影响。为了检测药物对环鸟苷单磷酸（cGMP）和环腺苷单磷酸（cAMP）组织水平的影响，将SV条暴露于不同浓度的化合物（0.1、1和10 μM）。在冷冻、匀浆和提取环核苷酸后，使用放射免疫测定法测量cAMP和cGMP。在实验中，硝普钠和福斯高林用作参考化合物。
药物以剂量依赖性方式逆转了去甲肾上腺素诱导的张力。疗效顺序为咯利普兰＞西地那非＞伐地那非≥长春西汀＞硝普钠＞福斯高林。在最大药物浓度下，去甲肾上腺素诱导的张力逆转范围为79%（咯利普兰）至32%（福斯高林）。只有咯利普兰和西地那非达到了半数有效浓度。PDE抑制剂的作用伴随着组织cGMP或cAMP增加1.7倍至173倍。
我们的结果表明，PDE抑制剂可以逆转人SV组织的肾上腺素能张力并增加环核苷酸水平。这概述了cAMP和cGMP在控制SV平滑肌功能中的潜在意义。这些发现可能对早泄的药物治疗具有重要意义。
