Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling.
Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling.
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DOI：
10.1152/ajpendo.00458.2011
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发表时间：
2012-01
期刊：
影响因子：
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通讯作者：
Xinhua Zhang;N. Zang;Yu Wei;Jin-ling Yin;Ruobing Teng;A. Seftel;M. DiSanto
中科院分区：
文献类型：
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作者：
Xinhua Zhang;N. Zang;Yu Wei;Jin-ling Yin;Ruobing Teng;A. Seftel;M. DiSanto
睾酮 (T) 在良性前列腺增生 (BPH) 的发展中发挥着许可作用，临床试验中发现磷酸二酯酶 5 抑制剂 (PDE5is) 对 BPH 和下尿路症状 (LUTS) 有效。本研究调查了 T 对平滑肌 (SM) 收缩和调节信号通路的影响，包括雄性大鼠（假手术、手术去势和补充 T 去势）的 PDE5 表达和前列腺功能活动。进行了体外器官浴研究、实时 RT-PCR、蛋白质印迹分析和免疫组织化学。去势严重削弱了收缩力，包括对去氧肾上腺素的敏感性，SM 肌球蛋白免疫染色显示基质中 SM 细胞排列被破坏。 PDE5 仅免疫定位于前列腺基质中，睾丸切除术显着降低了去势动物中 PDE5 免疫阳性、mRNA 和蛋白质表达以及 nNOS 和 ROKβ mRNA，而增加了 eNOS 加 α(1a) 和 α(1b) 肾上腺素受体表达。在对照大鼠中，PDE5i 扎普司特显着增加一氧化氮供体硝普钠 (SNP) 的前列腺条松弛，但对阉割大鼠没有影响。但与 SNP 加扎普司特治疗的假手术相比，单独使用 SNP 对去势大鼠更有效。 T 补充剂可预防或恢复所有上述变化，包括 SNP 和扎普司特的体外反应性。总之，我们的数据表明，T 正向调节前列腺中的 PDE5 表达和功能活动，并且 T 消融不仅抑制前列腺大小，还降低前列腺 SM 收缩性，其中涉及几种潜在的 SM 收缩/松弛途径。 Zaprinast 的研究结果强烈表明 PDE5/cGMP 在这一信号级联中发挥着重要作用。 PDE5 抑制可能代表治疗 BPH 的新机制。
Testosterone (T) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementation). In vitro organ bath studies, real-time RT-PCR, Western blot analysis, and immunohistochemistry were performed. Castration heavily attenuated contractility, including sensitivity to phenylephrine with SM myosin immunostaining revealing a disrupted SM cell arrangement in the stroma. PDE5 was immunolocalized exclusively in the prostate stroma, and orchiectomy signficantly reduced PDE5 immunopositivity, mRNA, and protein expression, along with nNOS and ROKβ mRNA, whereas it increased eNOS plus α(1a) and α(1b) adrenoreceptor expression in castrated animals. The PDE5i zaprinast significantly increased prostate strip relaxation to the nitric oxide donor sodium nitroprusside (SNP) in control but not castrated rats. But SNP alone was more effective on castrated rats, comparable with sham treated with SNP plus zaprinast. T supplementation prevented or restored all above changes, including SNP and zaprinast in vitro responsiveness. In conclusion, our data show that T positively regulates PDE5 expression and functional activities in prostate, and T ablation not only suppresses prostate size but also reduces prostatic SM contractility, with several potential SM contraction/relaxation pathways implicated. Zaprinast findings strongly suggest a major role for PDE5/cGMP in this signaling cascade. PDE5 inhibition may represent a novel mechanism for treatment of BPH.