Identification of alpha-1L and alpha-1A adrenoceptors in human prostate by tissue segment binding.
OBJECTIVE
Silodosin (KMD-3213 or [(-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide]) (Kissei Pharmaceutical Co., Ltd., Matsumoto, Japan) is a selective antagonist for alpha-1A and alpha-1L adrenoceptors. Using this tritiated ligand the 2 alpha-1 adrenoceptors were examined in binding studies with intact tissue segments and membrane preparations of human prostate, and compared with functionally identified alpha-1 adrenoceptor.


METHODS
Binding assays with tissue segments and membrane preparations of human prostate samples were performed using [3H]-silodosin and binding affinities for various drugs were estimated. In functional experiments antagonist affinities were evaluated from the inhibitory potency against the contractile response to noradrenaline.


RESULTS
[3H]-silodosin bound to intact segments and membrane preparations of human prostate with subnanomolar affinity. [3H]-silodosin binding sites in intact segments were divided into 2 distinct components with different affinities for prazosin and RS-17053 (N-[2(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl1H-indole-3-ethanamine hydrochloride) (Research Biochemicals International, Natick, Massachusetts), while binding in membrane preparations showed single high affinity for these drugs. [3H]-silodosin binding sites also showed high affinity for silodosin and tamsulosin but low sensitivity to BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4.5)decane-7,9-dione) (Research Biochemicals International) in intact segments and in membrane preparations. In functional experiments silodosin and tamsulosin potently inhibited the contractile response to noradrenaline but prazosin, RS-17053 and BMY 7378 showed low antagonistic affinity.


CONCLUSIONS
The current binding studies in human prostate samples clearly show that alpha-1L and alpha-1A adrenoceptors coexist as pharmacologically distinct entities in intact tissues but not in crude membrane preparations. Also, alpha-1 adrenoceptors involved in the contractile response to noradrenaline are the alpha-1L subtype.
Morishima
Shigeru
S
Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, and Division of Urology, Department of Surgery, School of Medicine, University of Fukui, Matsuoka, Fukui, Japan.
Tanaka
Takashi
T
Yamamoto
Hatsumi
H
Suzuki
Fumiko
F
Akino
Hironobu
H
Yokoyama
Osamu
O
Muramatsu
Ikunobu
I
D006801:Humans; D008297:Male; D011467:Prostate / Q000737:chemistry*; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000032:analysis* / Q000302:isolation & purification
D018340:Receptors, Adrenergic, alpha-1