Department of Urology, University of Pittsburgh, Pittsburgh, PA, United States of America.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America.
Life Sci. 2022 Jan 15;289:120203. doi: 10.1016/j.lfs.2021.120203. Epub 2021 Dec 4.
To assess the functional role of Hyperpolarization-activated cyclic nucleotide-gated gated channel (HCN) subtypes in the aging bladder phenotype characterized by diminished bladder volume sensation (BVS) with or without the detrusor instability (DI).
Expression of HCN subtypes was examined by quantitative RT-PCR and Western blot in aged male Fisher 344 rats (n = 15) and young rats (n = 15). Nocturnal urination and awake cystometry (CMG) were assessed in presence and absence of a steady state HCN channel blockade achieved with daily oral gavage of vehicle or Ivabradine (HCN blocker) 6 mg/kg for 7 days.
The association of BVS with the age-related downregulation (30%) of cAMP sensitive HCN1, HCN2 subtypes, and (50%) upregulation of cAMP insensitive HCN3 subtype is evinced by the doubling in the mean urine volume of nocturnal voids (0.82 ± 0.22 mL vs 0.41 ± 0.12 mL; n = 10; p < 0.05) predicting an age-related rise in the micturition volume threshold (p < 0.0001) in CMG, which is raised further by Ivabradine treatment (p < 0.0005). Ivabradine also doubled non-voiding contractions (NVC) and maximum voiding pressure (MVP) in young and aged rats, respectively (p < 0.0001) to abolish the age-related, innate two -fold elevation in NVC not accompanied with MVP rise in untreated aged rats (p < 0.005).
The age-related HCN downregulation is mechanistically linked to the exhibition of aging bladder phenotype with the manifestation of DI following steady state blockade of HCN channels in Ivabradine treated young rats. The amplification of MVP in aged rats mediated by FDA approved Ivabradine hints at potential repurposing opportunity in detrusor underactivity.
评估超极化激活环核苷酸门控通道（HCN）亚型在老化膀胱表型中的功能作用，该表型的特征是膀胱容量感觉（BVS）降低，伴有或不伴有逼尿肌不稳定（DI）。
通过定量 RT-PCR 和 Western blot 检测 HCN 亚型在老年雄性 Fisher 344 大鼠（n=15）和年轻大鼠（n=15）中的表达。在存在和不存在稳态 HCN 通道阻断的情况下，通过每日口服给予载体或伊伐布雷定（HCN 阻断剂）6mg/kg，进行夜间排尿和清醒膀胱测压（CMG）评估。
BVS 与年龄相关的 cAMP 敏感 HCN1、HCN2 亚型下调（30%）以及 cAMP 不敏感 HCN3 亚型上调（50%）相关，这表现为夜间排尿的平均尿量增加一倍（0.82±0.22mL 对 0.41±0.12mL；n=10；p<0.05），预示着 CMG 中排尿量阈值的年龄相关性升高（p<0.0001），伊伐布雷定治疗进一步升高（p<0.0005）。伊伐布雷定还使年轻和老年大鼠的非排空收缩（NVC）和最大排空压力（MVP）分别增加一倍（p<0.0001），从而消除了未经治疗的老年大鼠中固有、年龄相关的 NVC 升高两倍，而 MVP 无升高（p<0.005）。
年龄相关的 HCN 下调与 DI 表现的老化膀胱表型的展示在伊伐布雷定治疗的年轻大鼠中通过稳态 HCN 通道阻断机制相关。FDA 批准的伊伐布雷定可放大老年大鼠的 MVP，提示在逼尿肌无力方面具有潜在的再利用机会。
