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

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP74-03 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 Kabuto Takafumi, So Inamura, Hisato Kobayashi, Xinmin Zha, Keiko Nagase, Minekatsu Taga, Masaya Seki, Nobuki Tanaka, Yoshinaga Okumura, Osamu Yokoyama, and Naoki Tearada Kabuto TakafumiKabuto Takafumi More articles by this author , So InamuraSo Inamura More articles by this author , Hisato KobayashiHisato Kobayashi More articles by this author , Xinmin ZhaXinmin Zha More articles by this author , Keiko NagaseKeiko Nagase More articles by this author , Minekatsu TagaMinekatsu Taga More articles by this author , Masaya SekiMasaya Seki More articles by this author , Nobuki TanakaNobuki Tanaka More articles by this author , Yoshinaga OkumuraYoshinaga Okumura More articles by this author , Osamu YokoyamaOsamu Yokoyama More articles by this author , and Naoki TearadaNaoki Tearada More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003348.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 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-1α), 8-hydroxy-2′-deoxyguanosine (HIF-1α), 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-1α 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-α, TGF-β, IGF-1, and IGF1R were increased at 48 wks versus 36 wks. TA decreased IL-6, TNF-α, 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-1α, 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: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1069 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kabuto Takafumi More articles by this author So Inamura More articles by this author Hisato Kobayashi More articles by this author Xinmin Zha More articles by this author Keiko Nagase More articles by this author Minekatsu Taga More articles by this author Masaya Seki More articles by this author Nobuki Tanaka More articles by this author Yoshinaga Okumura More articles by this author Osamu Yokoyama More articles by this author Naoki Tearada More articles by this author Expand All Advertisement PDF downloadLoading ...