Tatemichi Satoshi, Akiyama Katsuyoshi, Kobayashi Mamoru, Yamazaki Yoshinobu, Yokoyama Osamu, Uruno Tsutomu
Pharmacology Research R & D, Kissei Pharmaceutical Co., Ltd., 4365-1 Kashiwabara, Hotaka, Azumino-City, Nagano Prefecture 399-8304, Japan.
J Urol. 2006 Sep;176(3):1236-41. doi: 10.1016/j.juro.2006.04.029.
Alpha(1)-adrenoceptor antagonists relax the obstructed prostatic urethra and suppress the irritative symptoms frequently observed in patients with benign prostatic hyperplasia. We investigated the effects of 3 alpha(1)-adrenoceptor antagonists on urodynamics in rats with hormone induced benign prostatic hyperplasia to determine which alpha(1)-adrenoceptor subtype selective antagonists would suppress irritative symptoms.
Rats were treated with testosterone and 17beta-estradiol by weekly intramuscular injections. After 4 weeks a pressure flow study was done and the effects of the alpha(1)-adrenoceptor antagonists KMD-3213 silodosin, tamsulosin and prazosin on urodynamics were compared. We especially investigated the involvement of the bladder and prostatic urethra to clarify the mechanism of detrusor overactivity expression.
Hormone treatment induced benign prostatic hyperplasia and resulted in detrusor overactivity, as determined by cystometry. Baseline perfusion urethral pressure and the phenylephrine induced increase in it were significantly higher in rats with vs without benign prostatic hyperplasia. Cystometry in hormone treated female rats did not show detrusor overactivity. KMD-3213 decreased detrusor overactivity, similar to other alpha(1)-adrenoceptor antagonists.
These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.
α1肾上腺素能受体拮抗剂可松弛梗阻的前列腺尿道，并抑制良性前列腺增生患者常见的刺激性症状。我们研究了3种α1肾上腺素能受体拮抗剂对激素诱导的良性前列腺增生大鼠尿动力学的影响，以确定哪种α1肾上腺素能受体亚型选择性拮抗剂能抑制刺激性症状。
通过每周肌肉注射睾酮和17β-雌二醇对大鼠进行处理。4周后进行压力流研究，比较α1肾上腺素能受体拮抗剂KMD-3213（西洛多辛）、坦索罗辛和哌唑嗪对尿动力学的影响。我们特别研究了膀胱和前列腺尿道的参与情况，以阐明逼尿肌过度活动表达的机制。
激素治疗诱导了良性前列腺增生，并导致逼尿肌过度活动，这通过膀胱测压确定．与未患良性前列腺增生的大鼠相比，患良性前列腺增生大鼠的基线灌注尿道压力及其由去氧肾上腺素诱导的升高显著更高。激素处理的雌性大鼠的膀胱测压未显示逼尿肌过度活动。与其他α1肾上腺素能受体拮抗剂类似，KMD-3213降低了逼尿肌过度活动。
这些结果表明，肥大前列腺中主要通过α1A肾上腺素能受体介导的对交感神经刺激的过度反应会导致逼尿肌过度活动。此外，α1A肾上腺素能受体选择性拮抗剂KMD-3213可能适合改善良性前列腺增生患者的刺激性症状。
