Inhibitors of phosphodiesterase 5 (PDE 5) inhibit the nerve-induced release of nitric oxide from the rabbit corpus cavernosum
Inhibitors of phosphodiesterase 5 (PDE 5) inhibit the nerve-induced release of nitric oxide from the rabbit corpus cavernosum
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DOI：
10.1038/sj.bjp.0706991
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发表时间：
2007-02-01
影响因子：
7.3
通讯作者：
Gustafsson, L. E.
中科院分区：
文献类型：
--
作者：
Hallen, K.;Wiklund, N. P.;Gustafsson, L. E.
背景和目的：氮能神经元在海绵体勃起反应和信号传递受损导致勃起功能障碍中起重要作用，目前通过口服选择性磷酸二酯酶5(PDE 5)抑制剂西地那非、他达拉非和伐地那非成功地治疗了该疾病。尽管氮能神经元在泌尿生殖功能中的重要性已经变得明显，但PDE-5抑制剂是否影响神经诱导的一氧化氮(NO)释放还没有被研究。在以前的研究中，我们发现可溶性鸟苷环化酶(SGC)/环鸟苷3‘，5’-单磷酸(CGMP)通路可能调节神经诱导的海绵体组织NO的释放。实验方法：电场刺激(场强5 Hz，40V，0.3ms脉冲，每隔2min 25个脉冲)在东莨菪碱(10(-5)M)、胍乙定(10(-5)M)和苯肾上腺素(3×10(-6)M)存在下，诱发可复制的神经介导的松弛。在灌流实验中，神经刺激海绵体组织(20 Hz，40V，1ms)引起NO/NO2-的释放，用化学发光法测定。关键结果：西地那非、他达拉非和伐地那非降低肌肉张力，延长对神经刺激的松弛。加入西地那非、他达拉非和伐地那非(均为10(-4)4M，n=6-8，p<；0.05)后，诱发的NO释放分别减少到对照组的72+/-11%、55+/-16%和61+/-14%。结论和意义：选择性PDE-5抑制剂可能通过cGMP介导的负反馈影响神经诱导的NO释放。这种负反馈可能解释了为什么在PDE抑制剂的单一治疗中没有出现异常勃起。
Background and purpose: Nitrergic neurons are important for erectile responses in the corpus cavernosum and impaired signalling results in erectile dysfunction, today treated successfully by oral administration of the selective phosphodiesterase 5 (PDE 5) inhibitors sildenafil, tadalafil and vardenafil. Although the importance of nitrergic neurons in urogenital function has become evident, it has not been investigated if the PDE 5 inhibitors affect the nerve-induced release of nitric oxide (NO). In a previous study we found that the soluble guanylate cyclase (sGC)/cyclic guanosine 3', 5'-monophosphate (cGMP) pathway might modulate nerve-induced release of NO in isolated cavernous tissue.Experimental approach: Electrical field stimulation (EFS 5 Hz, 40 V, 0.3 ms pulse duration, 25 pulses at intervals of 2 min) of rabbit isolated cavernous tissue elicited reproducible, nerve-mediated relaxations in the presence of scopolamine (10(-5) M), guanethidine (10(-5) M) and phenylephrine (3 x 10(-6) M). In superfusion experiments, nerve stimulation (20 Hz, 40 V, 1 ms) of the cavernous tissue evoked release of NO/NO2-, measured by chemiluminescence.Key results: Sildenafil, tadalafil and vardenafil decreased the muscular tone and prolonged the relaxations to nerve stimulation. The evoked release of NO decreased to 72 +/- 11%, 55 +/- 16% and 61 +/- 14% of control, respectively after addition of sildenafil, tadalafil or vardenafil (all 10(-4) 4 M, n = 6-8, p < 0.05).Conclusions and Implications: Selective PDE 5 inhibitors influence the nerve-induced release of NO, probably via cGMP-mediated negative feedback. This negative feedback might explain why priapism is not seen during monotherapy with the PDE inhibitors.