An alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate-receptor antagonist can inhibit premicturition contractions in rats with bladder outlet obstruction.
OBJECTIVE
To explore the possible involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) glutamate-receptors in bladder dysfunction associated with bladder outlet obstruction (BOO), as detrusor overactivity (DO) is common in men with benign prostatic hyperplasia.


METHODS
Proposed mechanisms of DO include the myogenic or neurogenic theory, and the autonomous bladder hypothesis. In rats, BOO produces premicturition contractions (PMCs) that are assumed to be a consequence of inappropriate non-micturition activity during the filling phase. Using pharmacology, we explored the cause of PMCs to provide new insights into DO in humans. BOO was created in female Wistar rats; 6 weeks after obstruction we evaluated them using conscious-filling cystometry. A specific AMPA receptor antagonist, 1-(4'-aminophenyl)- 3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (CFM-2) was administered intravenously (i.v.) (0.003-3 mg/kg) or intrathecally (i.t.) (0.01-10 microg).


RESULTS
The i.v. administration of CFM-2 in rats with BOO significantly decreased the threshold pressure and micturition pressure. The most remarkable findings were that i.v. administration of CFM-2 in rats with BOO significantly and dose-dependently decreased the amplitude and number of PMCs. The highest dose of CFM-2 almost completely eliminated PMCs. The i.t. administration of CFM-2 had no significant effect on PMCs.


CONCLUSIONS
AMPA receptors have never been suggested as a neural mechanism of bladder dysfunction associated with BOO. Although PMCs in rats with BOO have been assumed to be mainly of myogenic origin, PMCs were suppressed by the i.v. administration of CFM-2. Thus, we think that PMCs have neurogenic components that are linked with AMPA receptors. In the present study, i.v. but not i.t. administration of CFM-2 suppressed PMCs, suggesting peripheral and/or supraspinal sites of inhibitory action of CFM-2 on PMCs.
Kitta
Takeya
T
Department of Urology, Hokkaido University Graduate School of Medicine, North-15 West-7 Kita-Ku, Sapporo 060-8638, Japan. kitta@fb3.so-net.ne.jp
Kakizaki
Hidehiro
H
Tanaka
Hiroshi
H
Sano
Hiroshi
H
Furuno
Tsuyoshi
T
Mitsui
Takahiko
T
Moriya
Kimihiko
K
Nonomura
Katsuya
K
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D009119:Muscle Contraction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*; D053201:Urinary Bladder, Overactive / Q000503:physiopathology*; D014554:Urination / Q000502:physiology; D014563:Urodynamics
D001570:Benzodiazepinones; C119033:CFM 2; D018091:Receptors, AMPA