A Functional Analysis of the Influence of β3-adrenoceptors on the Rat Micturition Cycle

Abstract

Dysfunctions of the lower urinary tract, such as overactive bladder syndrome and incontinence, are the product of storage failure. Spontaneous regional bladder wall movements [nonmicturition contractions (NMCs)] are proposed to generate afferent activity that signals volume status to the central nervous system. The sympathetic nervous system, via activation of β-adrenoceptors (β-ARs), causes bladder relaxation and promotes urine storage. We hypothesized that β-AR regulation of micturition is mediated by suppression of NMCs. We used an unanesthetized, decerebrate, artificially perfused rat preparation that allows simultaneous cystometry with external urethral sphincter and pelvic afferent nerve recordings. Systemic isoprenaline (10 nM to 1 µM) increased intervoid interval and bladder compliance accompanied by a decrease in NMC amplitude, voiding pressure, and voiding threshold. Isoprenaline also reduced arterial pressure and increased heart rate. The β3-AR agonist mirabegron (10-100 nM) increased intervoid interval and bladder compliance and reduced NMC amplitude, yet preserved active voiding function and had no effect on arterial pressure or heart rate. All of these effects of mirabegron were blocked by the selective β3-AR antagonist N-[[3-[(2S)-2-hydroxy-3-[[2-[4-[(phenylsulfonyl)amino] phenyl]ethyl]amino]propoxy]phenyl]methyl]-acetamide (L748,337), which alone shortened intervoid interval and decreased bladder compliance-suggesting the presence of a basal β3-AR-mediated sympathetic tone. Similar effects of mirabegron were seen in an acetic acid-sensitized bladder preparation and in preparations after loss of spinobulbar reflex bladder control. The β3-AR-mediated increase in intervoid interval correlated with increased bladder compliance but not with the decrease in NMC amplitude. These findings indicate that β3-adrenoceptors have a selective effect that improves urine storage by increasing compliance without affecting the active components of voiding.