The effect of combined treatment with a β3 AR agonist and a ROCK inhibitor on detrusor overactivity.

Abstract

The objective of the study was to evaluate the efficacy and safety of the combined treatment with the β3 AR agonist and ROCK inhibitor in the rat model of detrusor overactivity induced by retinyl acetate instillation. The ROCK inhibitor (GSK 269962) and/or the β3 AR agonist (BRL 37344) were administered in single doses and a cystometry was carried out, along with a 24 hr measurement of cardiovascular parameters and diuresis. The combined use of GSK 269962 and BRL 37344 in doses ineffective in monotherapies, ameliorated DO. An increase was found in voided volume, voiding efficiency, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions, accompanied by a decrease in basal pressure, threshold pressure, detrusor overactivity index, nonvoiding contractions amplitude, and frequency. The combination therapy in question proved to have no effect on micturition voiding pressure, post-void residual, bladder contraction duration, or relaxation time. A 24 hr observation of female rats who received GSK 269962 and/or BRL 37344 did not show any significant changes in urine production. BRL 37344 increased heart rate and blood pressure proportionately to the applied dose. The assessment of the combined treatment with GSK 269962 and BRL 37344 revealed a significant drop of cardiovascular parameters when compared to the rats which only received BRL 37344. The combined use of β3 AR agonists and ROCK inhibitors may improve overactive bladder treatment efficacy and minimize side effects. This polytherapy appears to improve urine storage with no impairment of voiding function. Neurourol. Urodynam. 36:580-588, 2017. © 2016 Wiley Periodicals, Inc.