Halothane-anesthetized rabbit: a new experimental model to test the effects of besipirdine and duloxetine on lower urinary tract function.

Introduction: The effects of besipirdine and its main metabolite, HP-748, as well as duloxetine and tomoxetine in the lower urinary tract (LUT) were studied using in vitro and in vivo techniques.

Materials And Methods: For in vivo studies, besipirdine or duloxetine effects on cystometric parameters and striated sphincter electromyographic (SS-EMG) activity were investigated. On the isolated urethra, norepinephrine (NE) concentration-response curves (CRC) were performed in the presence of besipirdine, duloxetine or tomoxetine. Moreover, CRC to HP-748 were constructed in the absence or presence of prazosin. Potency (pEC(50)) and maximal responses (E(max)) were determined.

Results: Besipirdine at 1, 3 and 5 mg/kg intravenously (i.v.) induced a significant increase in SS-EMG activity (250, 273 and 241%, respectively), bladder capacity (172, 197, and 235%, respectively), intercontraction interval (ICI; 208, 242, and 400%, respectively), and residual volume (181, 191, and 236%, respectively). Duloxetine at 2 mg/kg i.v. increased significantly SS-EMG activity (219%), micturition volume (222%), and ICI (205%). In the isolated urethra, besipirdine, tomoxetine and duloxetine significantly displaced to the left the NE CRC. In addition, HP-748 induced contraction of the isolated urethra with a pEC(50) of 5.89 and an E(max) of 37%.

Conclusions: These data support the potential of besipirdine as a new drug for LUT dysfunctions such as stress and mixed urinary incontinence.