Pharmacological Targeting of Hyperpolarization-Activated Cyclic Nucleotide-Gated Cation Channels on Bladder Afferent Sensory Transmission

IF 1.5 4区医学 Q3 UROLOGY & NEPHROLOGY

LUTS: Lower Urinary Tract Symptoms Pub Date : 2025-08-05 DOI:10.1111/luts.70025

Eric Woon, Jorge Villalobos Santeli, Jia Liu, Longtu Chen, George Kuchel, Bin Feng

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Abstract

Objective

This study aimed to investigate the potential role of cesium chloride (CsCl), ivabradine (IVA), and isoproterenol (ISO) on the sensory transmission of bladder afferents to graded urinary bladder distension (UBD). We specifically selected these drugs to target the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels to determine their role in afferent encoding.

Methods

The bladders of C57BL/6 female mice were harvested with attached pelvic nerves in continuity, and the stimulus–response function (SRF) of bladder afferents to stepped bladder distension (20, 40, 60, 80 cmH₂O) was recorded by single-fiber recordings. Their changes in SRF to bath application of CsCl, IVA, and ISO were then evaluated. The presence of HCN on bladder afferent endings was assessed through immunohistological staining on bladder sections from mice with genetically labeled bladder afferents.

Results

IVA and ISO did not significantly reduce afferent responses to UBD, whereas CsCl increased afferent responses. Bladder afferents in the pelvic nerve pathway were categorized into low-firing (LF, < 10 Hz) and high-firing (HF, > 10 Hz) groups. SRF in both the LF and HF groups showed similar trends with no significant changes in response to IVA and ISO. CsCl increased SRF only in the HF group but not in the LF group. Immunohistological staining revealed that HCN1 does not extensively co-localize with afferent endings, showing only sporadic presence.

Conclusion

Our targeted pharmacological studies with single-fiber recordings and immunohistological staining collectively suggest that HCN channels do not play a significant role in bladder afferent sensory transmission.

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超极化激活环核苷酸门控阳离子通道对膀胱传入感觉传递的药理靶向作用

目的探讨氯化铯（CsCl）、伊伐布雷定（IVA）和异丙肾上腺素（ISO）在膀胱传入神经对分级膀胱膨胀（UBD）的感觉传递中的潜在作用。我们特别选择这些药物来靶向超极化激活的环核苷酸门控（HCN）阳离子通道，以确定它们在传入编码中的作用。方法取C57BL/6雌性小鼠膀胱，连续连接盆腔神经，单纤维记录膀胱传入神经对膀胱扩张（20、40、60、80 cmH2O）的刺激反应功能（SRF）。然后评估他们的SRF在CsCl、IVA和ISO应用后的变化。通过对基因标记膀胱传入的小鼠膀胱切片进行免疫组织学染色，评估HCN在膀胱传入末梢的存在。结果IVA和ISO没有显著降低UBD的传入反应，而CsCl则增加了传入反应。盆腔神经通路膀胱传入神经分为低放电（LF, < 10 Hz）组和高放电（HF, > 10 Hz）组。LF组和HF组的SRF表现出相似的趋势，IVA和ISO对SRF的反应没有显著变化。CsCl仅在HF组增加SRF，而在LF组没有增加。免疫组织染色显示HCN1不广泛地与传入末梢共定位，仅显示零星存在。结论我们的单纤维记录和免疫组织染色的靶向药理学研究共同表明，HCN通道在膀胱传入感觉传递中没有显着作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

LUTS: Lower Urinary Tract Symptoms UROLOGY & NEPHROLOGY-

CiteScore

3.00

自引率

7.70%

发文量

审稿时长

>12 weeks

期刊介绍： LUTS is designed for the timely communication of peer-reviewed studies which provides new clinical and basic science information to physicians and researchers in the field of neurourology, urodynamics and urogynecology. Contributions are reviewed and selected by a group of distinguished referees from around the world, some of whom constitute the journal''s Editorial Board. The journal covers both basic and clinical research on lower urinary tract dysfunctions (LUTD), such as overactive bladder (OAB), detrusor underactivity, benign prostatic hyperplasia (BPH), bladder outlet obstruction (BOO), urinary incontinence, pelvic organ prolapse (POP), painful bladder syndrome (PBS), as well as on other relevant conditions. Case reports are published only if new findings are provided. LUTS is an official journal of the Japanese Continence Society, the Korean Continence Society, and the Taiwanese Continence Society. Submission of papers from all countries are welcome. LUTS has been accepted into Science Citation Index Expanded (SCIE) with a 2011 Impact Factor.