Obstruction enhances rho‐kinase pathway and diminishes protein kinase C pathway in carbachol‐induced calcium sensitization in contraction of α‐toxin permeabilized guinea pig detrusor smooth muscle

Shahab, Nouval; Kajioka, Shunichi; Takahashi-Yanaga, Fumi; Onimaru, Manabu; Matsuda, Miho; Seki, Nobuhiko; Naito, Seiji

doi:10.1002/nau.21193

Cited by 9 publications

(13 citation statements)

References 30 publications

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“…5). This observation is consistent with the recent report that PBOO enhanced ROCK pathway and disturbed the PKC pathway (41). PDBu induced a biphasic effect on tone in control group and lowered the tone at low concentrations (1-10 nM), whereas it increased the tone at higher concentrations (30 -300 nM) as previously reported ( Fig.…”

Section: -Dmag Treatment Alleviated An Increase In Bladder Weight Asupporting

confidence: 93%

Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction

Iguchi

Dönmez

Malykhina

et al. 2017

American Journal of Physiology-Renal Physiology

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Posterior urethral valves are the most common cause of partial bladder outlet obstruction (PBOO) in the pediatric population. Pathological changes in the bladder developed during PBOO are responsible for long-lasting voiding dysfunction in this population despite early surgical interventions. Increasing evidence showed PBOO induces an upregulation of hypoxia-inducible factors (HIFs) and their transcriptional target genes, and they play a role in pathophysiological changes in the obstructed bladders. We hypothesized that blocking HIF pathways can prevent PBOO-induced bladder dysfunction. PBOO was surgically created by ligation of the bladder neck in male C57BL/6J mice for 2 wk. PBOO mice received intraperitoneal injection of either saline or 17-DMAG (alvespimycin, 3 mg/kg) every 48 h starting from postsurgery. Sham-operated animals received injection of saline on the same schedule as PBOO mice and served as controls. The bladders were harvested after 2 wk, and basal activity and evoked contractility of the detrusor smooth muscle (DSM) were evaluated in vitro. Bladder function was assessed in vivo by void spot assay and cystometry in conscious, unrestrained mice. Results indicated the 17-DMAG treatment preserved DSM contractility and partially prevented the development of detrusor over activity in obstructed bladders. In addition, PBOO caused a significant increase in the frequency of micturition, which was significantly reduced by 17-DMAG treatment. The 17-DMAG treatment improved urodynamic parameters, including increases in the bladder pressure at micturition and nonvoid contractions observed in PBOO mice. These results demonstrate that treatment with 17-DMAG, a HIF inhibitor, significantly alleviated PBOO-induced bladder pathology in vivo.

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Section: -Dmag Treatment Alleviated An Increase In Bladder Weight Asupporting

confidence: 93%

Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction

Iguchi

Dönmez

Malykhina

et al. 2017

American Journal of Physiology-Renal Physiology

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“…Of interest, in spontaneously hypertensive rats, hydroxyfasudil treatment was recently shown to inhibit the production of growth factors (TGF‐β1 and bFGF) and IL‐6 in ventral prostates, two important components involved in the prostatic hyperplasia progression . Activation of PKC leads to phosphorylation of CPI‐17 regulatory protein, which inhibits MLCP, increasing smooth muscle contractions independently of Ca 2+ . The PKC inhibitor GF109203X significantly reduced the contractions in control and middle‐age groups, but the contractile responses to phenylephrine remained increased in middle‐aged rats, suggesting that PKC does not take part in the prostate hypercontractility in middle‐age.…”

Section: Discussionmentioning

confidence: 99%

Implication of Rho‐kinase and soluble guanylyl cyclase enzymes in prostate smooth muscle dysfunction in middle‐aged rats

Calmasini

Silva

Alexandre

et al. 2016

Neurourology and Urodynamics

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“…Several recent reports have investigated the role of ROK inhibitors in bladder function in the context of pBOO and overactivity. Studies examining the effects of pBOO on the ROK pathway have reported the overexpression of the ROK in pBOO . These studies highlight the potential use of ROK inhibitors to control OAB associated with pBOO, but also point out the role that the overexpression of the ROK might play in allowing the detrusor muscle to generate adequate force to expel the urine past the obstruction.…”

Section: Introductionmentioning

confidence: 89%

“…The underlying mechanism behind this link has not been shown, but might be related to changes in bladder wall compliance associated with the increased MLC 20 phosphorylation. In the detrusor smooth muscle from pBOO rabbit and Guinea pig, and diabetic rabbit, calcium sensitization has been shown to play a significant role in the increase in MLC 20 phosphorylation, caused by the overexpression of ROK in animal models of lower urinary tract disease . Calcium sensitization results in an increase in MLC 20 phosphorylation independent of intracellular calcium or myosin light chain kinase activity, acting predominantly through the inhibition of the MLCP, although other mechanisms can also play a role in this process .…”

Section: Introductionmentioning

confidence: 99%

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Effects of Rho‐kinase inhibition on myosin light chain phosphorylation and obstruction‐induced detrusor overactivity

et al. 2013

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Abbreviations & Acronyms DMSO = dimethylsulfoxide DO = detrusor overactivity DSM = detrusor smooth muscle EC50 = half maximal effective concentration GSK = GlaxoSmithKlein IEF = isoelectric focusing OAB = overactive bladder MLC20 = myosin light chain 20 kDa MLCP = myosin light chain phosphatase MYPT1 = myosin phosphatase 1 pBOO = partial bladder outlet obstruction ROK = Rho-kinase SHR = spontaneously hypertensive rats Objectives: To study the relationship between myosin light chain phosphorylation of the detrusor muscle and spontaneous smooth muscle contractions in a rabbit model of partial outlet obstruction. Methods: New Zealand white rabbit urinary bladders were partially obstructed for 2 weeks. Rabbits were euthanized, detrusor muscle strips were hung on a force transducer and spontaneous activity was measured at varying concentrations (0-0.03 μM/L) of the Rho-kinase inhibitors GSK 576371 or 0.01 μM/L Y27632. Basal myosin light chain phosphorylation was measured by 2-D gel electrophoresis in control and GSK 576371-treated strips. Results: Both drugs suppressed the force of spontaneous contractions, whereas GSK 576371 had a more profound effect on the frequency of the contractions. The IC50 values for the inhibition of frequency and force of spontaneous contractions were 0.17 μM/L and 0.023 μM/L for GSK 576371, respectively. The compound significantly decreased the basal myosin light chain phosphorylation from 28.0 ± 3.9% to 13.5 ± 1.9% (P < 0.05). At 0.01 μM/L, GSK 576371 inhibited spontaneous bladder overactivity by 50%, but inhibited carbacholelicited contractions force by just 25%. Conclusions: These data suggest that Rho-kinase regulation of myosin light chain phosphorylation contributes to the spontaneous detrusor activity induced by obstruction. This finding could have therapeutic implications by providing another therapeutic option for myogenic, overactive bladder.

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Obstruction enhances rho‐kinase pathway and diminishes protein kinase C pathway in carbachol‐induced calcium sensitization in contraction of α‐toxin permeabilized guinea pig detrusor smooth muscle

Abstract: Our findings provide the first evidence that BOO enhances the ROK pathway and diminishes the PKC pathway in CCh-induced Ca(2+) sensitization in contraction of permeabilized Guinea pig DSM and suggest that inhibitors of ROK might potentially relieve bladder dysfunction related to BOO.

Cited by 9 publications

References 30 publications

Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction

Preventative effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction

Implication of Rho‐kinase and soluble guanylyl cyclase enzymes in prostate smooth muscle dysfunction in middle‐aged rats

Effects of Rho‐kinase inhibition on myosin light chain phosphorylation and obstruction‐induced detrusor overactivity

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