MP74-03: Long-term administration of a PDE-5 inhibitor prevents the development of bladder epithelial ATP increase and decreased detrusor contractility in type 2 diabetic rats
Introduction: We examined a series of pathological conditions of bladder wall in a type 2 diabetes mellitus (T2DM) model (Otsuka Long-Evans Tokushima Fatty [OLEFT] rats) and evaluated the effects of a long-term administration of the PDE-5 inhibitor tadalafil (TA) on these conditions. Methods: Male OLETF and Long-Evans Tokushima Otsuka (LETO) rats were used as T2DM and control groups, respectively. TA was orally administered for 12 weeks (wks) from the age of 36 wks. Bladder blood flow and ATP, prostaglandin E2 (PGE2), and nerve growth factor (NGF) released from the bladder epithelium were measured at 36 and 48 wks of age. Vesicular nucleotide transporter (VNUT), hypoxia-inducible factor-1 alpha (HIF-1a), 8-hydroxy-2'-deoxyguanosine (HIF-1a), the oxidative stress marker 8-OHdG, and the mRNA and protein of pro-inflammatory cytokines and growth factors in the bladder wall were measured by RT-PCRs and ELISAs. Bladder strip contractions to KCl and carbachol were monitored in the OLETF rat bladder. Results: The bladder blood flow in the OLETF rats was decreased at 48 wks compared to 36 wks. TA increased the bladder blood flow. Epithelial ATP was significantly increased in OLETF compared to LETO and decreased by TA in both LETO and OLETF. The bladder VNUT expression was significantly elevated in OLETF versus LETO at 36 wks; it was further enhanced at 48 wks, but a significant decrease occurred with TA in both rat strains. HIF-1a and 8-OHdG of OLETF were upregulated at 48 wks and decreased by TA. In OLETF, the expressions of IL-6, IL-8, bFGF, TNF-a, TGF-ß, IGF-1, and IGF1R were increased at 48 wks versus 36 wks. TA decreased IL-6, TNF-a, IGF-1 and IGF1R. In OLETF, the contractile response of bladder strips to KCl and carbachol decreased at 48 wks versus 36 wks, but it recovered after TA administration. Conclusions: These data suggest that impaired bladder blood flow resulted in increased expressions of HIF-1a, 8-OhdG, and various pro-inflammatory cytokines and growth factors In T2DM. As a result, the bladder epithelial ATP release was enhanced, possibly via VNUT upregulation.A long-term administration of a PDE-5 inhibitor could prevent the development of storage and voiding dysfunction associated with T2DM. This study is the first to suggest that epithelium-derived ATP may be involved in urine storage dysfunction in T2DM and tadalafil inhibits ATP release and improves bladder contraction. SOURCE OF Funding: Non
