Dysfunctions of the lower urinary tract such as overactive bladder syndrome and incontinence are the product of storage failure. Spontaneous regional bladder wall movements (non-micturition contractions, NMCs) are proposed to generate afferent activity that signals volume status to the CNS. The sympathetic nervous system, via activation of β-adrenoceptors (β-AR), causes bladder relaxation and promotes urine storage. We hypothesised that β-AR regulation of micturition is mediated by suppression of NMCs. We employed an un-anaesthetised decerebrate, artificially perfused rat preparation that allows simultaneous cystometry with external urethral sphincter and pelvic afferent nerve recordings. Systemic isoprenaline (10nM-1μM) increased inter-void 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 (10-100nM) increased inter-void 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 (L748,337), which alone shortened inter-void 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-sensitised bladder preparation and in preparations after loss of spino-bulbar reflex bladder control. The β3-AR-mediated increase in inter-void interval correlated with increased bladder compliance but not with the fall in NMC amplitude. These findings indicate that β3-adrenoceptors have a selective effect to improve urine storage by increasing compliance without affecting the active components of voiding.
- The American Society for Pharmacology and Experimental Therapeutics