Participation of endogenous endothelin and ETA receptor in premicturition contractions in rats with bladder outlet obstruction.
A relationship between endogenous endothelins and bladder overactivity has recently been suggested, but the related endothelin receptor subtype has not been identified. Here, to evaluate the involvement of endothelin-1 and its receptors in bladder overactivity, we investigated endothelin-1 levels and the expression of its receptors in the bladder of rats with bladder outlet obstruction (BOO), a model for bladder overactivity. We also investigated the effects of a selective endothelin ET(A) receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on bladder functions in conscious BOO rats. Partial obstruction of the urethra led to a progressive increase in bladder weight from weeks 1 to 6. Binding assays performed using plasma membranes prepared from these bladders to estimate endothelin receptor density from the maximum [(125)I]endothelin-1 binding showed increased endothelin receptor density (about double) at 1, 2, and 6 weeks after the operation in the BOO bladder. The densities of endothelin ET(A) receptors in the bladder of sham-operated and BOO rats at 2 weeks after operation were about 3.5 and 5 times those of endothelin ET(B) receptors respectively. Furthermore, the endothelin-1 level was also increased in the BOO bladder. Two weeks after operation, BOO rats showed an increase in maximum bladder capacity and micturition volume and the generation of premicturition contractions. The frequency of premicturition contractions was dose-dependently reduced by YM598 (0.1-3 mg/kg, i.v.) without any effect on other voiding parameters in BOO rats. These data suggest that endothelin-1 and endothelin ET(A) receptors might be involved in the generation of premicturition contractions in BOO rats, and that endothelin ET(A) receptor antagonists such as YM598 may have ameliorating effects in patients with bladder overactivity associated with BOO.
Ukai
Masashi
M
Pharmacology Research Labs, Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. masashi.ukai@jp.astellas.com
Yuyama
Hironori
H
Noguchi
Yukiko
Y
Someya
Akiyoshi
A
Okutsu
Hiroko
H
Watanabe
Mai
M
Yoshino
Taiji
T
Ohtake
Akiyoshi
A
Suzuki
Masanori
M
Sato
Shuichi
S
Sasamata
Masao
M
D000818:Animals; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D009929:Organ Size; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides