A selective alpha1A-adrenoceptor antagonist inhibits detrusor overactivity in a rat model of benign prostatic hyperplasia.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tatemichi
Satoshi
S
Pharmacology Research R & D, Kissei Pharmaceutical Co., Ltd., 4365-1 Kashiwabara, Hotaka, Azumino-City, Nagano Prefecture 399-8304, Japan. satoshi_tatemichi@pharm.kissei.co.jp
Akiyama
Katsuyoshi
K
Kobayashi
Mamoru
M
Yamazaki
Yoshinobu
Y
Yokoyama
Osamu
O
Uruno
Tsutomu
T
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D011224:Prazosin / Q000627:therapeutic use*; D011470:Prostatic Hyperplasia / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides / Q000627:therapeutic use*; D000077409:Tamsulosin; D014549:Urinary Incontinence / Q000209:etiology* / Q000517:prevention & control*
C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; C095285:silodosin; D000077409:Tamsulosin; D011224:Prazosin