Abstract
You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology (PD27)1 Sep 2021PD27-07 BEDSIDE TO BENCHTOP RESEARCH UNCOVERS THE FUNCTIONAL ROLE OF HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED GATED (HCN) CHANNELS IN AGING BLADDER PHENOTYPE Nishant Singh, Irina Zabbarova, Anthony Kanai, Christopher Chermansky, Naoki Yoshimura, and Pradeep Tyagi Nishant SinghNishant Singh More articles by this author , Irina ZabbarovaIrina Zabbarova More articles by this author , Anthony KanaiAnthony Kanai More articles by this author , Christopher ChermanskyChristopher Chermansky More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , and Pradeep TyagiPradeep Tyagi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002020.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The aging bladder phenotype in detrusor overactivity, detrusor underactivity or detrusor hyperactivity with impaired contractility patients is characterized by detrusor instability with or without the loss of bladder volume sensitivity. Since separate studies reported age related downregulation of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in mouse and human bladder, we examined the functional significance of age related reduction in HCN activity with multiple oral dosing of FDA approved HCN blocker, Ivabradine. METHODS: Aged male Fisher 344 rats (n=15) and young rats of both genders (n=15) were left untreated or treated daily with oral gavage of either vehicle or Ivabradine 6mg/kg (n=5) for 7 days prior to assessing nocturnal urination followed by awake cystometry on 7th day and quantitative RT-PCR and Western blot of HCN subtypes of untreated aged and young rats. RESULTS: Untreated aged aged rats (n=10) voided nearly double the volume of individual voids of young rats at night time (0.82±0.22 mL vs 0.41±0.12 mL, p<0.05), which was confirmed by a significant increase (p<0.05) in the micturition volume threshold (VT) in awake cystometry of aged rats. Increase in VT of aged rats coincided with a doubling of non-voiding contraction (NVC) frequency (p<0.05) while maximum voiding pressure (MVP) did not change with age. The age- related alterations in cystometry parameters correlated with the significant downregulation of cAMP sensitive HCN1and HCN2 subtype (40%) and the upregulation of cAMP insensitive HCN3 (60%) subtype. Ivabradine treatment significantly increased the VT (p<0.005), NVC frequency (p<0.001) and MVP (p<0.0001) in young and aged rats to different extents. CONCLUSIONS: A critical role for the altered bladder expression of HCN subtypes in the manifestation of aging bladder phenotype is supported by the dramatic changes in the bladder function following pharmacological blockade of HCN channels in young rats. The dramatic effect of Ivabradine on VT and MVP of aged rats in this bedside to benchtop research provides a basis for the therapeutic benefit of Ivabradine on detrusor underactivity of a male patient (Int Urol Nephrol, 40: 333, 2008). Source of Funding: NIA- AG062971 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e446-e446 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nishant Singh More articles by this author Irina Zabbarova More articles by this author Anthony Kanai More articles by this author Christopher Chermansky More articles by this author Naoki Yoshimura More articles by this author Pradeep Tyagi More articles by this author Expand All Advertisement Loading ...
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