Aging Changes in Bladder Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Are Associated With Increasing Heterogeneity of Adrenergic/Mucosal Influence on Detrusor Control in the Mouse

Abstract

A geroscience-informed approach to the increasing prevalence of bladder control problems in older adults requires understanding the impact of aging on dynamic mechanisms that ensure resilience in response to stressors challenging asymptomatic voluntary control over urine storage and voiding. Bladder control is predicated on sensory neural information about bladder volume. Modulation of volume-induced bladder wall tensions by autonomic and mucosal factors controls neural sensitivity to bladder volume. We hypothesized that HCN (hyperpolarization-activated cyclic nucleotide-gated) channels integrate these factors and thereby mediate adrenergic detrusor tension control. Furthermore, loss of HCN expression compromises that integration, and could result in loss of precision of detrusor control. Using a lifespan mouse model, RT-qPCR and pharmacologic studies in pre-tensioned intact and mucosa-denuded bladder strips were made. The dominant hcn1 expression declines with maturation and aging, however aging is also associated with increased variance around mean values. In strips from mature animals, isoproterenol had less effect in denuded muscle strips than in intact strips, and HCN blockade diminished isoproterenol responsiveness. With aging, variances about mean response values significantly increased, paralleling hcn1 expression. Our findings support a role for HCN in providing neuroendocrine/paracrine integration and suggest an association of increased heterogeneity of HCN expression in aging with reductions in response precision to neuroendocrine control. The functional implication is an increased risk of dysfunction of brainstem/bladder regulation of neuronal sensitivity to bladder volume. This supports the clinical model of the aging bladder phenotype as an expression of loss of resilience, and not as emerging bladder pathology with aging.

The brain, gut, and bladder health nexus: A conceptual model linking stress and mental health disorders to overactive bladder in women

“…Conceptual work highlights resilience with respect to female urinary microbiota 81 and age‐related changes to bladder function 82 . Indeed, Hardy and colleagues suggest that age‐related changes to bladder function are due to loss of resilience as opposed to emerging pathology 83 . It is plausible that neuropsychological resilience in the context of stress would confer some protection from the development of OAB and UI; however, research is needed to test this hypothesis.…”

Aging and urinary control: Alterations in the brain–bladder axis

“…Response heterogeneity has been previously associated with alterations in ion channel expression, as variances about mean responses to adrenergic stimuli in strip studies paralleled decreasing expression of Hcn1 , encoding the hyperpolarization‐activated cyclic nucleotide‐gated channel 1 protein (Hardy et al, 2021 ), which has previously been shown to play an important role in adrenergic detrusor tension control with aging in B6 mice (Al‐Naggar et al, 2019 ; Lemtiri‐Chlieh et al, 2022 ; Mader et al, 2018 ; Singh et al, 2022 ). Apart from tissue‐level responses, heterogeneity is also exhibited in response to the stressor of cystometry.…”

“…In B6 mice, expression of muscarinic and adrenergic receptors have been reported to decrease with aging (Kamei et al, 2018 ). Decreased receptor expression may provide insight into the decreased responses to excitatory and relaxatory stimuli seen in aged bladder strips from B6 mice (Hardy et al, 2019 , 2021 ), Sprague–Dawley rats (Durlu‐Kandilci et al, 2015 ), and humans (Yoshida et al, 2001 ). Increased agrin—an essential element of the neuromuscular junction—is observed at the neuromuscular junctions of the developing rodent bladder (Gingras et al, 2005 ) and is required for neuromuscular junction integrity (Hoch, 1999 ).…”

Alternative therapies for recurrent cystitis in menopausal women

“…Но природа неумолима, и с прекращением репродуктивной функции наступают изменения физиологии и функций многих клеток. Мы рассмотрим мочеполовую систему, а точнее -мочевой пузырь и влагалище, имеющие единую онто-филогенетическую природу и зависимость от эстрогенов [3][4][5]. Что происходит с мочевым пузырем в менопаузу?…”