Uckert Stefan, Sormes Michael, Kedia George, Scheller Friedemann, Knapp Wolfram H, Jonas Udo, Stief Christian G
Department of Urology, Hannover Medical School, Hannover, Germany.
Urology. 2008 Mar;71(3):526-30. doi: 10.1016/j.urology.2007.10.051.
To further evaluate the mechanism of action of phosphodiesterase (PDE) inhibitors on the human prostate, the effects of PDE4 and PDE5 inhibitors on the tension induced by norepinephrine (NE) and on the intracellular levels of cyclic nucleotides in isolated human prostatic tissue were investigated.
Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil and the PDE4 inhibitors rolipram and RP 73401 on the tension induced by NE (40 microM) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays.
The tension induced by NE was dose dependently reversed by the drugs with the following rank order of efficacy: tadalafil greater than RP 73401 greater than rolipram greater than or equal to vardenafil greater than sildenafil. The maximal reversion of tension values ranged from 52.3% (tadalafil) to 17% (sildenafil). Of the PDE inhibitors, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP 73401 (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil, and sildenafil (28-fold, 12-fold, and 3-fold, respectively).
Our results have demonstrated that drugs interfering with the cyclic nucleotide-mediated pathways can reverse the tension induced by NE in isolated prostatic tissue and elevate cyclic adenosine monophosphate and cyclic guanosine monophosphate. Our findings serve to explain how PDE inhibitors can affect symptoms of lower urinary tract symptoms and benign prostatic hyperplasia.
为了进一步评估磷酸二酯酶（PDE）抑制剂对人前列腺的作用机制，研究了PDE4和PDE5抑制剂对去甲肾上腺素（NE）诱导的张力以及对离体人前列腺组织中环核苷酸细胞内水平的影响。
采用器官浴技术，研究了PDE5抑制剂西地那非、他达拉非和伐地那非以及PDE4抑制剂咯利普兰和RP 73401浓度递增（1 nM至10 μM）对前列腺条制剂中NE（40 μM）诱导的张力的影响。通过放射免疫测定法测定药物暴露后环磷酸鸟苷和环磷酸腺苷的积累。
NE诱导的张力被药物剂量依赖性逆转，疗效顺序如下：他达拉非＞RP 734比咯利普兰≥伐地那非＞西地那非。张力值的最大逆转范围为52.3%（他达拉非）至17%（西地那非）。在PDE抑制剂中，只有他达拉非使初始张力逆转了50%。对RP 73401反应时，组织中环磷酸腺苷的最显著增强（11倍），他达拉非、伐地那非和西地那非使环磷酸鸟苷水平显著升高（分别为28倍、12倍和3倍）。
我们的结果表明，干扰环核苷酸介导途径的药物可以逆转离体前列腺组织中NE诱导的张力，并提高环磷酸腺苷和环磷酸鸟苷水平。我们的研究结果有助于解释PDE抑制剂如何影响下尿路症状和良性前列腺增生的症状。
