Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
J Urol. 2013 Mar;189(3):1147-54. doi: 10.1016/j.juro.2012.08.220. Epub 2012 Oct 8.
Men with benign prostatic hyperplasia commonly experience irritative lower urinary tract symptoms, which are due at least in part to enhanced prostatic smooth muscle tone. To provide some insight into the changes that occur in prostatic contractility with age, we examined the contribution of rho-kinase dependent Ca(2+) sensitization in neurogenic and spontaneous contractions of young and aging guinea pig prostates.
We used conventional tension recording and electrophysiological intracellular microelectrode recording techniques.
The Rho-kinase inhibitor Y-27632 (10 and 100 μM) significantly inhibited electrical field stimulated evoked (neurogenic) contractions in the guinea pig prostate in a dose dependent manner. In addition, Y-27632 (1 and 10 μM) similarly suppressed tetrodotoxin insensitive spontaneous contractions in dose dependent fashion. While Y-27632 at 10 μM decreased spontaneous contractions of young and aging guinea pig prostates, as evidenced by a significant decrease in the AUC, there was no significant difference in the degree of inhibition between the 2 age groups. In contrast to contractile activity, Y-27632 did not affect the generation or modulation of spontaneous slow wave electrical activity, which underlies spontaneous contractions.
There are strong indicators that Rho-kinase signaling pathways have a significant role in prostatic smooth muscle contractility, most likely independent of cytosolic Ca(2+) levels. Features of the rho-kinase pathway may well represent alternative, novel future therapeutic targets to reduce prostatic contractility, thereby alleviating the lower urinary tract symptoms arising from benign prostatic hyperplasia.
患有良性前列腺增生的男性常经历刺激性下尿路症状，这些症状至少部分归因于前列腺平滑肌张力增强。为了深入了解前列腺收缩性随年龄变化而发生的变化，我们研究了神经源性和自发性收缩中青年和老年豚鼠前列腺中 Rho 激酶依赖性 Ca（2+）敏化的作用。
我们使用了常规张力记录和电生理细胞内微电极记录技术。
Rho 激酶抑制剂 Y-27632（10 和 100 μM）以剂量依赖的方式显著抑制豚鼠前列腺的电场刺激诱发的（神经源性）收缩。此外，Y-27632（1 和 10 μM）也以剂量依赖的方式类似地抑制了河豚毒素不敏感的自发性收缩。虽然 Y-27632 在 10 μM 时降低了青年和老年豚鼠前列腺的自发性收缩，这表现为 AUC 显著降低，但在 2 个年龄组之间抑制程度没有显著差异。与收缩活性相反，Y-27632 不影响自发性慢波电活动的产生或调节，后者是自发性收缩的基础。
有强烈的迹象表明 Rho 激酶信号通路在前列腺平滑肌收缩性中具有重要作用，可能独立于细胞质 Ca（2+）水平。Rho 激酶途径的特征很可能代表减少前列腺收缩性的替代、新颖的未来治疗靶点，从而缓解良性前列腺增生引起的下尿路症状。
