This proposal comprises a two center international collaboration to draw upon complementary expertise in answering key issues of pathophysiological mechanisms and therapeutic potentials in overactive bladder (OAB) and neurogenic bladder dysfunction (NBD). The collaboration will study the influence of phosphodiesterase type 5 (PDE5) inhibitors on sensory and motor behavior of the lower urinary tract (LUT) using established models of T8-T9 spinal cord transection (SCT) for NBD and intravesically instilled transient receptor potential ankyrin 1 (TRPA1) receptor agonist, acrolein, for OAB. The University of Pittsburgh group has developed new in vitro approaches for studying peripheral LUT function using isolated tissues and cells, while the University of Bristol team has developed new in situ approaches for studying CNS sensory and motor function and the reflexes controlling the LUT. The two research teams have a good record of collaboration, evidenced by successfully obtaining preliminary data in this technically challenging scientific area, funded in part, by a pilot grant from the International Continence Society to the Co-PI's. Further collaboration between these centers will increase our knowledge of integrative (patho) physiology of the LUT and the potential therapeutic role of PDE5 inhibitors. There are three specific aims:
Specific Aim1 : To measure effects of PDE5 inhibition on A?- versus C-fiber afferent firing and neuropeptide release, in whole bladder sheets and cross sections from normal, SCT and acrolein instilled mice.
Specific Aim2 : To measure effects of PDE5 inhibition on storage and voiding reflexes in normal and acrolein instilled decerebrate arterially perfused mice (DAPM) before and after acute brainstem/SCT.
Specific Aim3 : To measure effects of PDE5 inhibition on in-line dissociated urothelial, interstitial and smooth muscle cells and bladder wall cross sections from control versus SCT mice.
Overactive bladder (OAB) is highly prevalent and has a severe effect on the quality of life. A multinational epidemiology study of lower urinary tract (LUT) symptoms estimated that 29.8 million adults aged e40 years in the USA have bothersome OAB symptoms (PMID: 19281467). Neurogenic bladder dysfunction (NBD) is present in the majority of people with neurological disease and is one of its most troubling aspects. Current treatments are often of limited efficacy and/or have adverse effects. Consequently, many people need containment, i.e., pads/diapers/catheters. Thus, OAB/NBD impacts on the personal quality of living and work productivity, and is expensive for the healthcare economy (estimated in billions of dollars). This proposal will focus on phosphodiesterase type 5 (PDE5) inhibitors (e.g., Viagra), whose use clinically to treat erectile dysfunction has been found to improve LUT symptoms. However, the sites-of-action of PDE5 inhibitors in decreasing these symptoms are not known. We propose to investigate several potential mechanisms in normal animals and models of OAB/NBD. The Pittsburgh and Bristol teams collaborated enthusiastically and effectively on a grant from the International Continence Society, and assert their ongoing commitment to joint research and knowledge/skills exchange within the proposed project, and knowledge sharing with the wider research community. Accordingly, the synergy of the research teams promises substantial progress.