Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat.
OBJECTIVE
Recent evidence indicates that in a number of species detrusor relaxation is mediated through activation of the beta3-adrenergic receptor. We determined whether activation of the beta3-adrenergic receptor would be a useful therapeutic approach for bladder instability. We profiled in vitro activity of the beta3-adrenergic receptor agonist CL-616243 and the efficacy of this compound in experimental models of detrusor instability and bladder hyperreflexia.


METHODS
Isolated rat detrusor strips were contracted by depolarizing the preparations with 20 mM. KCl. CL-316423 was added to the tissue bath in increasing concentrations and contraction inhibition was assessed. Efficacy against bladder instability was evaluated using the obstructed hypertrophied bladder model in the rat. The acetic acid bladder cystometry model was used to assess the efficacy of CL-316423 in bladder hyperreflexia. Isovolumetric contractions were evoked by electrical stimulation using a silver bipolar electrode. Data are expressed as the mean plus or minus standard error of mean.


RESULTS
CL-316243 inhibited spontaneously contracting, isolated rat detrusor strips in a concentration dependent manner with a mean concentration inhibiting 50% of maximal response of 2.65 +/- 0.36 nM. Intrinsic activity relative to forskolin was 1. In vivo CL-316243 administered intravenously or orally significantly increased the voiding interval and bladder compliance. In addition, there was a decrease in the number of spontaneous contractions during the filling phase in a model of neurogenic and obstruction induced bladder instability. The amplitude of electrically evoked isovolumetric contractions was significantly smaller after CL-316243 exposure.


CONCLUSIONS
These data suggest that activating the beta3-adrenergic receptor in rat bladder using CL-316243 may directly inhibit smooth muscle contractility, experimental hyperreflexia and detrusor instability, and be useful for urge urinary incontinence.
Woods
M
M
Urologic Disorders, Wyeth-Ayerst Women's Health Discovery Research, Radnor, Pennsylvania, USA.
Carson
N
N
Norton
N W
NW
Sheldon
J H
JH
Argentieri
T M
TM
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000818:Animals; D004149:Dioxoles / Q000627:therapeutic use*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012021:Reflex, Abnormal / Q000187:drug effects*; D001745:Urinary Bladder Diseases / Q000188:drug therapy* / Q000503:physiopathology
D000318:Adrenergic beta-Agonists; D004149:Dioxoles; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate