Oxybutynin and Propiverine Suppress Adenosine Triphosphate-induced Bladder Overactivity Other Than Through Antimuscarinic Mechanisms

Abstract

Adenosine triphosphate (ATP) is released from bladder urothelium in response to stretch and may act as a sensory neurotransmitter. ATP release from the bladder urothelium is augmented in many pathophysiologic conditions, resulting in bladder overactivity. Patients who have bladder overactivity are treated with antimuscarinics with symptom improvement. We investigated the effects of oxybutynin and propiverine on bladder overactivity induced by intravesical instillation of ATP. Under urethane anesthesia, cystometry was performed in female Sprague-Dawley rats. After a 2-hour baseline period, protamine sulfate (10 mg/mL) was instilled for 1 hour, and then ATP (60 mM, pH 6.0) was instilled intravesically. Oxybutynin, propiverine, pyridoxal-(5) phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), atropine, 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), and methoctramine were given intravenously when ATP-induced bladder overactivity was stable. When protamine sulfate was infused intravesically, the intercontraction interval (ICI) did not decrease significantly, but intravesical instillation of ATP after protamine sulfate treatment decreased the ICI compared with baseline. Oxybutynin, propiverine, and PPADS given intravenously reversed the ATP-induced ICI reduction in a dose-dependent manner. In contrast, ATP-induced ICI reduction was not reversed by intravenous atropine, 4-DAMP, or methoctramine. Maximum voiding pressure did not change with ATP but decreased with antimuscarinics. Pressure threshold (PT) decreased with ATP and stayed reduced after dose of oxybutynin or propiverine. Bladder overactivity induced by intravesical instillation of ATP with protamine pretreatment was suppressed by oxybutynin, propiverine, and PPADS, and not by atropine, 4-DAMP, and methoctramine. Oxybutynin and propiverine suppress ATP-induced bladder overactivity other than through antimuscarinic mechanisms.