Reversal of muscle hypertrophy in the rat urinary bladder after removal of urethral obstruction

Gabella, Giorgio; Uvelius, Bengt

doi:10.1007/bf00327781

Cited by 40 publications

(20 citation statements)

References 18 publications

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“…Many clinicians favor decompressing the bladder for a week or more to improve the likelihood of a successful voiding trial 67 . Animal studies indicate that retention results in detrusor damage, collagen infiltration, and decreased contractility 47,70 . Many of these changes improve after relief of obstruction 70 .…”

Section: Management Issuesmentioning

confidence: 99%

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Detrusor Underactivity: Clinical Features and Pathogenesis of an Underdiagnosed Geriatric Condition

Taylor

Kuchel

2006

J American Geriatrics Society

190

137

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Urinary incontinence and other lower urinary tract symptoms exert a major influence on the health and independence of frail older people. Detrusor underactivity (DU) is defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. DU may influence the clinical presentation and impede the therapy of disorders as common and as disparate as detrusor overactivity, urinary retention, and benign prostatic hyperplasia. Urodynamically, nearly two-thirds of incontinent nursing home residents exhibit DU. The clinical diagnosis of DU when present alone or in association with other bladder conditions such as detrusor overactivity (detrusor hyperactivity with impaired contractility (DHIC)) is challenging, because symptoms lack adequate precision. A catheterized and increasingly noninvasive ultrasound-based postvoid residual assessment allows a bedside diagnosis of retention and may suggest the presence of DU in individuals (mostly women) with a low likelihood of bladder outlet obstruction (BOO). Nevertheless, it cannot differentiate primary DU from retention secondary to BOO. The management of individuals with DHIC remains unsatisfactory, because antispasmodic anticholinergic medications may worsen retention, whereas bethanechol does not improve bladder emptying. Human detrusor biopsies reveal axonal degeneration, muscle loss, and fibrosis in DU. Animal studies suggest that multiple risk factors, including retention itself, lack of estrogen, infection, inflammation, and aging, may contribute to DU. Priority areas for future research include efforts to facilitate clinical nonurodynamic diagnosis of probable DU plus translational research designed to address the pathogenesis of this complex multifactorial geriatric syndrome.

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Section: Management Issuesmentioning

confidence: 99%

“…Animal studies indicate that retention results in detrusor damage, collagen infiltration, and decreased contractility 47,70 . Many of these changes improve after relief of obstruction 70 . It has been proposed that bladder decompression may facilitate healing and promote the restoration of normal detrusor contractility.…”

Section: Management Issuesmentioning

confidence: 99%

Detrusor Underactivity: Clinical Features and Pathogenesis of an Underdiagnosed Geriatric Condition

Taylor

Kuchel

2006

J American Geriatrics Society

190

137

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“…With respect to the application of hSlo myocyte gene therapy to bladder function, one might not, at first glance, anticipate a similar degree of physiological success. One obvious reason for skepticism is related to the apparent absence of the morphological and structural correlates of gap junctions in human (18,21) and rat bladder (28,29). In this regard, a recent report has shown that mRNA for the gap junction protein Cx43 can be detected in the normal rat bladder using RT-PCR techniques (16).…”

Section: Why Does Gene Therapy With Hslo Ameliorate Bladder Overactivmentioning

confidence: 99%

Bladder injection of “naked”hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo

Christ

Day²,

Day³

et al. 2001

American Journal of Physiology-Regulatory, Integrative and Comp

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The goal of these studies was to examine the potential utility of bladder instilled K+ channel gene therapy with hSlo cDNA (i.e., the maxi-K channel) to ameliorate bladder overactivity in a rat model of partial urinary outlet obstruction. Twenty-two female Sprague-Dawley rats were subjected to partial urethral (i.e., outlet) obstruction, with 17 sham-operated control rats run in parallel. After 6 wk of obstruction, suprapubic catheters were surgically placed in the dome of the bladder in all rats. Twelve obstructed rats received bladder instillation of 100 microg of hSlo/pcDNA in 1 ml PBS during catheterization, and another 10 obstructed rats received 1 ml PBS (7 rats) or 1 ml PBS containing pcDNA only (3 rats). Two days after surgery cystometry was performed on all animals to examine the characteristics of the micturition reflex in conscious and unrestrained rats. Obstruction was associated with a three- to fourfold increase in bladder weight and alterations in virtually every micturition parameter estimate. PBS-injected obstructed rats routinely displayed spontaneous bladder contractions between micturitions. In contrast, hSlo injection eliminated the obstruction-associated bladder hyperactivity, without detectably affecting any other cystometric parameter. Presumably, expression of hSlo in rat bladder functionally antagonizes the increased contractility normally observed in obstructed animals and thereby ameliorates bladder overactivity. These initial observations indicate a potential utility of gene therapy for urinary incontinence.

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“…Clinical treatments focus on mitigating the source of out‐flow obstruction, yet removal of the anatomical PBO itself does not completely reverse the pathology and dysfunction, in a large proportion of BPH and PUV patients, even months or years following REL. The failure to resolve after REL is seen at multiple levels (matrix, neural input, and smooth muscle cellular phenotype) and leads to ongoing sequelae such as increased residual volumes and altered activity …”

Section: Introductionmentioning

confidence: 99%

Persistent myopathy despite release of partial obstruction: in vivo reversal of dysfunction and transcriptional responses using rapamycin

et al. 2020

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Current and potential medical therapy for obstruction‐induced myopathic bladder dysfunction (from benign prostatic hyperplasia or posterior urethral valves) focuses on symptoms. The persistent tissue pathology and dysfunction after release of obstruction is often deemed irreversible without any systematic therapeutic approaches. As rapamycin can attenuate bladder smooth muscle hypertrophy and dysfunction during the genesis of partial obstruction in vivo, we tested whether rapamycin could improve persistent function after release of obstruction (de‐obstruction or REL). Female Sprague‐Dawley rat bladders were partially obstructed (PBO) by suturing around both the urethra and a para‐urethral steel rod, then removing the rod. One day prior to release of obstruction (preREL), voiding parameters and residual urine volume of preREL+future rapa, preREL+future veh groups were recorded. Release of obstruction (REL) was performed by suture removal following 6 weeks of PBO. For 4 more weeks after the de‐obstruction, REL animals were randomized to rapamycin (REL+rapa) or vehicle (REL+veh). PBO for 6 weeks were used as positive controls. In shams, the urethra was exposed, but no suture tied. Voiding parameters and residual urine volume were measured prior to sacrifice of sham and REL+veh or REL+rapa, and PBO. Rapamycin efficacy was tested by pair‐wise comparison of changes in individual voiding data from preREL+future veh or preREL+future rapa versus REL+veh or REL+rapa, respectively, as well as by comparisons of REL+veh to REL+rapa groups. Bladders were weighed and processed for a high‐throughput QPCR array, and histopathology. Bladder/body mass ratios with PBO increased significantly and remained higher in the release phase in REL+veh animals. REL+rapa versus REL+veh improved residual volumes and micturition fractions toward sham levels. Three genes encoding extracellular proteins, BMP2, SOD3, and IGFBP7, correlated with functional improvement by Pearson's correlations. The promoters of these genes showed enrichment for several motifs including circadian E‐boxes. While obstruction and REL augmented CLOCK and NPAS2 expression above sham levels, rapamycin treatment during release significantly blocked their expression. This experimental design of pharmaco‐intervention during the de‐obstruction phase revealed a novel pathway dysregulated during the clinically relevant treatment phase of obstructive bladder myopathy.

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Reversal of muscle hypertrophy in the rat urinary bladder after removal of urethral obstruction

Cited by 40 publications

References 18 publications

Detrusor Underactivity: Clinical Features and Pathogenesis of an Underdiagnosed Geriatric Condition

Detrusor Underactivity: Clinical Features and Pathogenesis of an Underdiagnosed Geriatric Condition

Bladder injection of “naked”hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo

Persistent myopathy despite release of partial obstruction: in vivo reversal of dysfunction and transcriptional responses using rapamycin

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