Efficacy of the beta 3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat

Purpose: Recent evidence indicates that in a number of species detrusor rel axation 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 a ctivity of the beta3-adrenergic receptor agonist CL-616243 and the efficacy of this compound in experimental models of detrusor instability and bladde r hyperreflexia. Materials and Methods: Isolated rat detrusor strips were contracted by depo larizing the preparations with 20 mM. KCl. CL-316423 was added to the tissu e bath in increasing concentrations and contraction inhibition was assessed . Efficacy against bladder instability was evaluated using the obstructed h ypertrophied bladder model in the rat. The acetic acid bladder cystometry m odel was used to assess the efficacy of CL-316423 in bladder hyperreflexia. Isovolumetric contractions were evoked by electrical stimulation using a s ilver bipolar electrode. Data are expressed as the mean plus or minus stand ard error of mean. Results: CL-316243 inhibited spontaneously contracting, isolated rat detrus or strips in a concentration dependent manner with a mean concentration inh ibiting 50% of maximal response of 2.65 +/- 0.36 nM. Intrinsic activity rel ative to forskolin was 1. In vivo CL-316243 administered intravenously or o rally 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 con tractions was significantly smaller after CL-316243 exposure. Conclusions: These data suggest that activating the beta3-adrenergic recept or in rat bladder using CL-316243 may directly inhibit smooth muscle contra ctility, experimental hyperreflexia and detrusor instability, and be useful for urge urinary incontinence.