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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 (pEC50) and maximal responses (Emax) 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 pEC50 of 5.89 and an Emax of 37%. Conclusions: These data support the potential of besipirdine as a new drug for LUT dysfunctions such as stress and mixed urinary incontinence.

Introduction: Parathyroid-hormone-related protein (PTHrP) is considered as an autocrine/paracrine regulator of growth and/or differentiation in normal and malignant tissues. We determined the distribution and density of the expression of PTHrP in the rabbit bladder during growth in response to partial outlet obstruction and its relation with the smooth muscle/collagen ratio. Materials and Methods: A total of 30 male New Zealand White rabbits were studied. After 7, 14, 28 or 56 days of obstruction, 6 rabbits per group were sacrificed and the bladder extracted. Six sham-operated rabbits served as controls. The expression and localization of PTHrP or collagen type III were detected by immunohistochemistry using specific antibodies. Results: The levels of PTHrP were progressively increased by 14 days of obstruction, whereas they decreased after 14 days, although the PTHrP positivity was higher than in sham controls by 28 and 56 days of obstruction. PTHrP staining was related to the smooth muscle/collagen ratio, both showing a peak in rabbits obstructed for 14 days. Conclusions: These data indicate that PTHrP may play an important regulatory role in the cellular and vascular response to partial outlet obstruction.