Effects of propiverine hydrochloride, an anticholinergic agent, on urethral continence mechanisms and plasma catecholamine concentration in rats.

INTRODUCTION AND HYPOTHESIS: Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats. METHODS: Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested. RESULTS: Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased. CONCLUSIONS: Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.

Mirabegron, a ß3-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder.

Mirabegron (YM-178), currently in development by Astellas Pharma Inc, is an orally active ß3-adrenoceptor (AR) agonist for the potential symptomatic treatment of overactive bladder (OAB). Mirabegron demonstrates nanomolar EC50 values against the human ß3-AR in biochemical assays with potent selectivity over the ß1- and ß2-ARs. Originally developed as a treatment for diabetes, the development of mirabegron was later refocused to OAB. Cystometric experiments in rats reported a reduction in resting intravesical pressure and contraction frequency in anesthetized rats, without any effect on the amplitude of micturition contraction. Mirabegron also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction. Top-line results from clinical trials to date indicate that mirabegron has been well tolerated with significant efficacy in reducing the number of incontinence episodes and mean micturition frequency in patients. Evidence of cytochrome P450 (CYP)2D6 inhibition in clinical trials highlighted a concern for pharmacokinetic interaction with other drugs that are CYP2D6 substrates, as confirmed by a rise in the pharmacokinetic parameters of desipramine with concomitant administration of mirabegron. Mirabegron exhibits a novel mode of action in targeting the ß3-AR for bladder relaxation, and the studies and trials conducted to date suggest mirabegron as a promising new treatment in the management of OAB symptoms, such as increased urinary urgency and frequency, and urgency incontinence.