Involvement of stretch‐induced Rho‐kinase activation in the generation of bladder tone

Shiomi, Homare; Takahashi, Norio; Kawashima, Yohei; Ogawa, Soichiro; Haga, Nobuhiro; Kushida, Nobuhiro; Nomiya, Masanori; Yanagida, Takeshi; Ishibashi, Keiichiro; Yamaguchi, Osamu

doi:10.1002/nau.22360

Cited by 10 publications

(15 citation statements)

References 26 publications

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“…This pilot study identified the biomechanical bladder property of dynamic elasticity during a specially designed repeat fill‐and‐empty UD protocol in patients with OAB. Dynamic elasticity is the UD correlate of reversible strain softening (adjustable preload tension) previously identified in isolated human, rabbit, and mouse DSM tissue strips . Using our UD protocol, we were able to generate a novel metric for detrusor muscle function during the filling phase of micturition.…”

Section: Discussionmentioning

confidence: 95%

“…In pre‐clinical studies, adjustable preload tension, the pre‐clinical correlate of dynamic elasticity, has been attributed to cycling actomyosin crossbridges . Furthermore, adjustable preload tension has been shown to be under the influence of the rho‐kinase pathway in multiple species, including humans, and may offer a target for future intervention in these types of voiding dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…In these earlier in vitro studies, an acute reduction in DSM tension (increased compliance) was identified after strain softening, which was reversed with active muscle contraction at shorter muscle lengths . Strain softening is quantified as adjustable preload tension in DSM strips, and strain softening reversal is regulated by rho‐kinase in DSM from multiple species, including humans . We hypothesize that preclinical strain softening measured as adjustable preload tension in DSM strips can be identified clinically as “dynamic elasticity” during UD testing.…”

Section: Introductionmentioning

confidence: 87%

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A pilot study to measure dynamic elasticity of the bladder during urodynamics

Colhoun

Klausner

Nagle

et al. 2016

Neurourology and Urodynamics

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AIMS Previous studies using isolated strips of human detrusor muscle identified adjustable preload tension, a novel mechanism that acutely regulates detrusor wall tension. The purpose of this investigation was to develop a method to identify a correlate measure of adjustable preload tension during urodynamics. METHODS Patients reporting urgency most or all of the time based on ICIq-OAB survey scores were prospectively enrolled in an extended repeat fill-and-empty urodynamics study designed to identify a correlate of adjustable preload tension which we now call “dynamic elasticity.” Cystometric capacity was determined during initial fill. Repeat fills to defined percentages of capacity with passive emptying (via syringe aspiration) were performed to strain soften the bladder. A complete fill with active voiding was included to determine whether human bladder exhibits reversible strain softening. RESULTS Five patients completed the extended urodynamics study. Intravesical pressure (pves) decreased with subsequent fills and was significantly lower during Fill 3 compared to Fill 1 (P =0.008), demonstrating strain softening. Active voiding after Fill 3 caused strain softening reversal, with pves in Fill 4 returning to the baseline measured during Fill 1 (P = 0.29). Dynamic elasticity, the urodynamic correlate of adjustable preload tension, was calculated as the amount of strain softening (or its reversal) per % capacity (Δaverage pves between fills/Δ%capacity). Dynamic elasticity was lost via repeat passive filling and emptying (strain softening) and regained after active voiding regulated the process (strain softening reversal). CONCLUSIONS Improved understanding of dynamic elasticity in the human bladder could lead to both improved sub-typing and novel treatments of overactive bladder.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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A pilot study to measure dynamic elasticity of the bladder during urodynamics

Colhoun

Klausner

Nagle

et al. 2016

Neurourology and Urodynamics

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“…In vitro models of mechanical stretch, where BSM cells are cultured on a deformable membrane, has been used to demonstrate that the phosphatase, and contributes to agonist-induced Ca 2ϩ sensitization in smooth muscle contraction (43,44). The ROCK pathway is constitutively active, and stretch enhances ROCK pathway activation, contributing to myogenic tone generation in bladder wall smooth muscle, thereby affecting bladder compliance (41). Inhibiting ROCK with the inhibitor Y-27632 induced concentration-dependent relaxation of detrusor muscle strips at resting tension (41).…”

Section: Discussionmentioning

confidence: 99%

“…The ROCK pathway is constitutively active, and stretch enhances ROCK pathway activation, contributing to myogenic tone generation in bladder wall smooth muscle, thereby affecting bladder compliance (41). Inhibiting ROCK with the inhibitor Y-27632 induced concentration-dependent relaxation of detrusor muscle strips at resting tension (41). Furthermore, spontaneously tonic smooth muscle, such as internal anal sphincter, has higher levels of RhoA/ROCK activity compared with phasic smooth muscle, indicating a role for ROCK in the maintenance of basal tone (35).…”

Section: Discussionmentioning

confidence: 99%

Mechanical stretch upregulates proteins involved in Ca²⁺ sensitization in urinary bladder smooth muscle hypertrophy

Boopathi

Gomes

Zderic

et al. 2014

American Journal of Physiology-Cell Physiology

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Boopathi E, Gomes C, Zderic SA, Malkowicz B, Chakrabarti R, Patel DP, Wein AJ, Chacko S. Mechanical stretch upregulates proteins involved in Ca 2ϩ sensitization in urinary bladder smooth muscle hypertrophy. Am J Physiol Cell Physiol 307: C542-C553, 2014. First published July 16, 2014; doi:10.1152/ajpcell.00033.2014.-Partial bladder outlet obstruction (pBOO)-induced remodeling of bladder detrusor smooth muscle (DSM) is associated with the modulation of cell signals regulating contraction. We analyzed the DSM from obstructed murine urinary bladders for the temporal regulation of RhoA GTPase and Rho-activated kinase (ROCK), which are linked to Ca 2ϩ sensitization. In addition, the effects of equibiaxial cell stretch, a condition thought to be associated with pBOO-induced bladder wall smooth muscle hypertrophy and voiding frequency, on the expression of RhoA, ROCK, and C-kinase-activated protein phosphatase I inhibitor (CPI-17) were investigated. DSM from 1-, 3-, 7-, and 14-day obstructed male mice bladders and benign prostatic hyperplasia (BPH)-induced obstructed human bladders revealed overexpression of RhoA and ROCK-␤ at the mRNA and protein levels compared with control. Primary human bladder myocytes seeded onto type I collagen-coated elastic silicone membranes were subjected to cyclic equibiaxial stretch, mimicking the cellular mechanical stretch in the bladder in vivo, and analyzed for the expression of RhoA, ROCK-␤, and CPI-17. Stretch caused a significant increase of RhoA, ROCK␤, and CPI-17 expression. The stretch-induced increase in CPI-17 expression occurs at the transcriptional level and is associated with CPI-17 promoter binding by GATA-6 and NF-B, the transcription factors responsible for CPI-17 gene transcription. Cell stretch caused by bladder overdistension in pBOO is the likely mechanism for initiating overexpression of the signaling proteins regulating DSM tone. partial bladder outlet obstruction; cell stretch; human bladder; benign prostatic hyperplasia; calcium sensitization DETRUSOR SMOOTH MUSCLE (DSM) hypertrophy is associated with alteration of the signaling pathways that initiate and maintain force in the bladder wall smooth muscle during partial bladder outlet obstruction (pBOO). These alterations have been observed in animal models and men with benign prostatic hyperplasia (BPH)-induced obstruction (7,9,14,19). In both animal models and humans, removal of the obstruction causes regression of smooth muscle hypertrophy, and the bladder function returns relatively to normal in most instances. However, in some cases, bladder function does not return to normal, and the reason for this is unclear. It is most likely due to the failure of altered signaling mechanisms to reverse back to normal, as seen in incomplete reversal of myosin isoform expression after 2-wk pBOO in rabbits (14).In general, activation of smooth muscle requires phosphorylation of the myosin regulatory light chain (MLC 20 ) by Ca 2ϩ / calmodulin-dependent myosin light chain kinase (MLCK) (2, 45). Under certain physiological cond...

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Pelvic Arterial Occlusive Disease Affects the RhoA/Rho-Kinase Pathway in Bladder Smooth Muscle

et al. 2015

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Involvement of stretch‐induced Rho‐kinase activation in the generation of bladder tone

Abstract: This study demonstrates that the ROK pathway is constitutively active and stretch further activates the ROK pathway, which contributes to the generation of bladder tone, thereby affecting bladder compliance.

Cited by 10 publications

References 26 publications

A pilot study to measure dynamic elasticity of the bladder during urodynamics

A pilot study to measure dynamic elasticity of the bladder during urodynamics

Mechanical stretch upregulates proteins involved in Ca²⁺ sensitization in urinary bladder smooth muscle hypertrophy

Pelvic Arterial Occlusive Disease Affects the RhoA/Rho-Kinase Pathway in Bladder Smooth Muscle

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Involvement of stretch‐induced Rho‐kinase activation in the generation of bladder tone

Abstract: This study demonstrates that the ROK pathway is constitutively active and stretch further activates the ROK pathway, which contributes to the generation of bladder tone, thereby affecting bladder compliance.

Cited by 10 publications

References 26 publications

A pilot study to measure dynamic elasticity of the bladder during urodynamics

A pilot study to measure dynamic elasticity of the bladder during urodynamics

Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy

Pelvic Arterial Occlusive Disease Affects the RhoA/Rho-Kinase Pathway in Bladder Smooth Muscle

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Mechanical stretch upregulates proteins involved in Ca²⁺ sensitization in urinary bladder smooth muscle hypertrophy