[Effects of silodosin (KMD-3213) on phenylephrine-induced increase in intraurethral pressure and blood pressure in rats--study of the selectivity for lower urinary tract].
The effects of silodosin, an alpha(1A)-adrenoceptor (AR) antagonist, and of other alpha(1)-AR antagonists on the phenylephrine (PE)-induced increase in intraurethral pressure (IUP) and on blood pressure (BP) were studied in anesthetized rats. The drugs were administered intravenously (i.v. study) or intraduodenally (i.d. study). IUP and BP were measured via catheters inserted into the prostatic urethra and common carotid artery, respectively. In the i.v. study, drugs were administered every 30 min for effects on BP, and 5 min before each PE-injection (30 microg/kg, every 60 min) with stepwise increases in dose for effects on IUP. In the i.d. study, one dose of drug was administered per rat, then IUP and BP were observed for 4 h [IUP being measured time-dependently following PE-injection (30 microg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID(50) for IUP and ED(15) for BP were calculated, and uroselectivity was determined as ED(15)/ID(50) for each drug. All drugs both inhibited the IUP increase and lowered BP, each effect being dose-dependent. The order of uroselectivities was silodosin (11.7)>tamuslosin (2.24)>naftopidil (0.133) in the i.v. study, and silodosin (26.0)>tamuslosin (3.82)>naftopidil (1.39) in the i.d. study. Selectivity for the lower urinary tract (LUT) was higher for silodosin than for tamsulosin (alpha(1A)/alpha(1D)-AR), naftopidil (alpha(1D)-AR), or prazosin (non-selective alpha(1)-AR). These results suggested that an alpha(1A)-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.
Tatemichi
Satoshi
S
Pharmacology Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., Azumino City, Japan. satoshi_tatemichi@pharm.kissei.co.jp
Kobayashi
Kumi
K
Maruyama
Itaru
I
Kobayashi
Mamoru
M
Yamazaki
Yoshinobu
Y
Shibata
Nobuo
N
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011224:Prazosin / Q000008:administration & dosage / Q000494:pharmacology; D011312:Pressure; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000077409:Tamsulosin; D014521:Urethra / Q000187:drug effects*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D009281:Naphthalenes; D010879:Piperazines; D013449:Sulfonamides; D010656:Phenylephrine; C095285:silodosin; D000077409:Tamsulosin; C064357:naftopidil; D011224:Prazosin