Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia.
OBJECTIVE
Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists.


METHODS
We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil.


RESULTS
In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED(15)/ID(50)) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65).


CONCLUSIONS
Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients.
Tatemichi
Satoshi
S
Pharmacology Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. satoshi_tatemichi@pharm.kissei.co.jp
Tomiyama
Yoshitaka
Y
Maruyama
Itaru
I
Kobayashi
Shinya
S
Kobayashi
Kumi
K
Maezawa
Ayaka
A
Kobayashi
Mamoru
M
Yamazaki
Yoshinobu
Y
Shibata
Nobuo
N
D058646:Adrenergic alpha-1 Receptor Agonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017536:Carotid Artery, Common / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004285:Dogs; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D007001:Hypogastric Plexus / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D009928:Organ Specificity; D010879:Piperazines / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects*; D011470:Prostatic Hyperplasia / Q000150:complications*; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin; D014521:Urethra / Q000187:drug effects; D014524:Urethral Obstruction / Q000188:drug therapy* / Q000209:etiology*; D014551:Urinary Tract / Q000187:drug effects*
D058646:Adrenergic alpha-1 Receptor Agonists; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D009281:Naphthalenes; D010879:Piperazines; D013449:Sulfonamides; C095285:silodosin; D000077409:Tamsulosin; C064357:naftopidil; D009638:Norepinephrine