scholarly journals NMDAR in bladder smooth muscle is not a pharmacotherapy target for overactive bladder in mice

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11684
Author(s):  
Xiang Xie ◽  
Chuang Luo ◽  
Jia Yu Liang ◽  
Run Huang ◽  
Jia Li Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Overactive Bladder ◽  
Bladder Wall ◽  
Bladder Function ◽  
Wild Type ◽  
Bladder Smooth Muscle ◽  
Aspartate Receptor ◽  
The Common ◽  
And Function ◽  
Common Pathogenesis

Overactive bladder (OAB) is a common condition that affects a significant patient population. The N-methyl-D-aspartate receptor (NMDAR) has a role in developing bladder overactivity, pharmacological inhibition of which inhibits bladder overactivity. The common pathogenesis of OAB involves bladder smooth muscle (BSM) overactivity. In this study, a smooth muscle–specific NMDAR knockout (SMNRKO) mouse model was generated. The bladders from SMNRKO mice displayed normal size and weight with an intact bladder wall and well-arranged BSM bundles. Besides, SMNRKO mice had normal voiding patterns and urodynamics and BSM contractility, indicating that NMDAR in BSM was not essential for normal physiological bladder morphology and function. Unexpectedly, cyclophosphamide (CYP)-treated SMNRKO and wild-type (WT) mice had similar pathological changes in the bladder. Furthermore, SMNRKO mice displayed similar altered voiding patterns and urodynamic abnormalities and impaired BSM contractility compared with WT mice after CYP treatment. MK801 partially reversed the pathological bladder morphology and improved bladder dysfunction induced by CYP, but did not cause apparent differences between WT mice and SMNRKO mice, suggesting that NMDAR in BSM was not involved in pathological bladder morphology and function. Moreover, the direct instillation of NMDAR agonists or antagonists into the CYP-induced OAB did not affect bladder urodynamic function, indicating that NMDAR in BSM was not the pharmacotherapy target of MK801 for CYP-induced cystitis. The findings indicated that NMDAR in BSM was not essential for normal physiological or pathological bladder morphology and function, and MK801 improving pathological bladder function was not mediated by an action on NMDAR in BSM.

scholarly journals Protective Effects of Antimuscarinics on the Bladder Remodeling After Bladder Outlet Obstruction

2017 ◽  
Vol 44 (3) ◽  
pp. 907-919 ◽  
Author(s):  
Qiang Liu ◽  
Deyi Luo ◽  
Tongxin Yang ◽  
Banghua Liao ◽  
Hong Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Bladder Outlet Obstruction ◽  
Outlet Obstruction ◽  
Structure And Function ◽  
Bladder Function ◽  
Bladder Smooth Muscle ◽  
M3 Receptors ◽  
And Function

Background/Aims: Overactive bladder associated with bladder outlet obstruction (BOO) is a highly prevalent condition, which is usually treated with antimuscarinics. However, the potential effects of antimuscarinics on the structure and function of bladder have not been investigated thus far. Methods: Sprague-Dawley(R) rats accepted bladder neck obstruction surgery or sham surgery, and then received treatment of three different antimuscarinics (Solifenacin, Darifenacin, and Tolterodine) or vehicle. After 3, 6 and 12 weeks, the bladder function and structure were measured. The effect of antimuscarinics on cellular alteration in vitro was observed under mechanical stimulation. Bladder morphology were examined by immunohistochemistry, and the bladder function were investigated by cystometry and strip contractility test. The expression of muscarinic receptors and inflammatory cytokines were measured by PCR and Western blotting. Results: Here we demonstrate, both in vitro and in vivo, that antimuscarinics are protective regulators for the bladder structure and function. Antimuscarinics decrease the weight of bladders with BOO. Antimuscarinics improve the voiding parameter and enhance the contraction of bladder smooth muscle. The results also show that antimuscarinics inhibit the proliferation of bladder smooth muscle cells both in vivo and in vitro, it can reduce the collagen deposition and inflammatory cytokines in bladders with BOO. During this process, the expression of M2 and M3 receptors was altered by antimuscarinics. Conclusion: Antimuscarinics could reverse the structural and functional changes of BOO bladder wall at cellular and tissue level, and the alteration of M2 and M3 receptors may be involved in this biological process.

Overactive bladder mediated by accelerated Ca2+influx mode of Na+/Ca2+exchanger in smooth muscle

2013 ◽  
Vol 305 (3) ◽  
pp. C299-C308 ◽  
Author(s):  
Hisao Yamamura ◽  
William C. Cole ◽  
Satomi Kita ◽  
Shingo Hotta ◽  
Hidemichi Murata ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Overactive Bladder ◽  
Molecular Target ◽  
The Other ◽  
Relative Importance ◽  
Wild Type ◽  
Bladder Smooth Muscle ◽  
Reverse Mode ◽  
Urinary Bladder Smooth Muscle ◽  
Spontaneous Contractions

The Na+/Ca2+exchanger (NCX) is thought to be a key molecule in the regulation of cytosolic Ca2+dynamics. The relative importance of the two Ca2+transport modes of NCX activity leading to Ca2+efflux (forward) and influx (reverse) in smooth muscle, however, remains unclear. Unexpectedly, spontaneous contractions of urinary bladder smooth muscle (UBSM) were enhanced in transgenic mice overexpressing NCX1.3 (NCX1.3tg/tg). The enhanced activity was attenuated by KB-R7943 or SN-6. Whole cell outward NCX current sensitive to KB-R7943 or Ni2+was readily detected in UBSM cells from NCX1.3tg/tgbut not wild-type mice. Spontaneous Ca2+transients in myocytes of NCX1.3tg/tgwere larger and frequently resulted in propagating events and global elevations in cytosolic Ca2+concentration. Significantly, NCX1.3tg/tgmice exhibited a pattern of more frequent urination of smaller volumes and this phenotype was reversed by oral administration of KB-R7943. On the other hand, KB-R7943 did not improve it in KB-R7943-insensitive (G833C-)NCX1.3tg/tgmice. We conclude that NCX1.3 overexpression is associated with abnormal urination owing to enhanced Ca2+influx via reverse mode NCX leading to prolonged, propagating spontaneous Ca2+release events and a potentiation of spontaneous UBSM contraction. These findings suggest the possibility that NCX is a candidate molecular target for overactive bladder therapy.

Strain Induced Bladder Smooth Muscle Remodeling

2007 ◽  
Author(s):  
Rebecca A. Long ◽  
Aron Parekh ◽  
Michael S. Sacks
Keyword(s):  
Smooth Muscle ◽  
Ex Vivo ◽  
Bladder Wall ◽  
Outlet Obstruction ◽  
Tissue Remodeling ◽  
Bladder Function ◽  
Compensatory Mechanism ◽  
Bladder Smooth Muscle ◽  
Cord Injury

Multiple urinary bladder wall (UBW) pathologies, such as overactive bladder, bladder outlet obstruction, spinal cord injury (SCI) and related neurogenic disorders, and diabetes result in tissue remodeling marked by hypertrophic bladder smooth muscle cells (BSMC) and altered extra-cellular matrix components. This remodeling results in changes in UBW biomechanical properties leading to altered bladder function. Our previous studies have revealed that during the initial areflexic phase of SCI the UBW undergoes profound remodeling that appears to be a compensatory mechanism for the increased wall stretch resulting from over-distension [1, 2]. Remodeling in the bladder wall results in changes in biomechanics and ultimately the ability of the organ to normally fill and void [3]. The stimuli and precise mechanisms that are responsible for bladder remodeling in SCI and the aforementioned pathologies remain unknown. The objective of the present study is to determine the effects of varied in vitro strain on ECM production in the ex vivo rat bladder as a first step toward understanding tissue remodeling in response to strain.

Distinct roles of PMCA isoforms in Ca2+ homeostasis of bladder smooth muscle: evidence from PMCA gene-ablated mice

2007 ◽  
Vol 292 (1) ◽  
pp. C423-C431 ◽  
Author(s):  
Li Liu ◽  
Yukisato Ishida ◽  
Gbolahan Okunade ◽  
Gail J. Pyne-Geithman ◽  
Gary E. Shull ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Smooth Muscle ◽  
Plasma Membrane ◽  
Contractile Response ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Wild Type ◽  
Bladder Smooth Muscle

We previously showed that plasma membrane Ca2+-ATPase (PMCA) activity accounted for 25–30% of relaxation in bladder smooth muscle ( 8 ). Among the four PMCA isoforms only PMCA1 and PMCA4 are expressed in smooth muscle. To address the role of these isoforms, we measured cytosolic Ca2+ ([Ca2+]i) using fura-PE3 and simultaneously measured contractility in bladder smooth muscle from wild-type (WT), Pmca1+/−, Pmca4+/−, Pmca4−/−, and Pmca1+/− Pmca4−/− mice. There were no differences in basal [Ca2+]i values between bladder preparations. KCl (80 mM) elicited both larger forces (150–190%) and increases in [Ca2+]i (130–180%) in smooth muscle from Pmca1+/− and Pmca1+/− Pmca4−/− bladders than those in WT or Pmca4−/−. The responses to carbachol (CCh: 10 μM) were also greater in Pmca1+/− (120–150%) than in WT bladders. In contrast, the responses in Pmca4−/− and Pmca1+/− Pmca4−/− bladders to CCh were significantly smaller (40–50%) than WT. The rise in half-times of force and [Ca2+]i increases in response to KCl and CCh, and the concomitant half-times of their decrease upon washout of agonist were prolonged in Pmca4−/− (130–190%) and Pmca1+/− Pmca4−/− (120–250%) bladders, but not in Pmca1+/− bladders with respect to WT. Our evidence indicates distinct isoform functions with the PMCA1 isoform involved in overall Ca2+ clearance, while PMCA4 is essential for the [Ca2+]i increase and contractile response to the CCh receptor-mediated signal transduction pathway.

scholarly journals Smooth muscle-specific deletion of MnSOD exacerbates diabetes-induced bladder dysfunction in mice

2019 ◽  
Vol 317 (4) ◽  
pp. F906-F912
Author(s):  
Rania A. Elrashidy ◽  
Michael Kavran ◽  
Mervat E. Asker ◽  
Hoda E. Mohamed ◽  
Firouz Daneshgari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Bladder Dysfunction ◽  
Gene Knockout ◽  
Immunoblot Analysis ◽  
Bladder Function ◽  
Detrusor Muscle ◽  
Diabetic Mice ◽  
Wild Type ◽  
Apoptotic Pathways

Bladder dysfunction in diabetes progresses gradually over time. However, the mechanisms of the development are not clear. We tested the hypothesis that oxidative stress plays a key role in the development of diabetic bladder dysfunction using an inducible smooth muscle (SM)-specific superoxide dismutase 2 ( Sod2) gene knockout (SM- Sod2 KO) mouse model. Eight-week-old male Sod2lox/lox, SM-CreERT2(ki)Cre/+ mice and wild-type mice were assigned to diabetic or control groups. 4-Hydroxytamoxifen was injected into Sod2lox/lox, SM-CreERT2(ki)Cre/+ mice to activate CreERT2-mediated deletion of Sod2. Diabetes was induced by injection of streptozotocin, whereas control mice were injected with vehicle. Nine weeks later, bladder function was evaluated, and bladders were harvested for immunoblot analysis. Wild-type diabetic mice presented compensated bladder function along with increased nitrotyrosine and MnSOD in detrusor muscle. Induction of diabetes in SM- Sod2 KO mice caused deteriorated bladder function and even greater increases in nitrotyrosine compared with wild-type diabetic mice. Expression levels of apoptosis regulator Bax and cleaved caspase-3 were increased, but apoptosis regulator Bcl-2 expression was decreased in detrusor muscle of both diabetic groups, with more pronounced effects in SM- Sod2 KO diabetic mice. Our findings demonstrate that exaggerated oxidative stress can accelerate the development of bladder dysfunction in diabetic mice and the enhanced activation of apoptotic pathways in the bladder may be involved in the process.

scholarly journals Bladder function in mice with inducible smooth muscle-specific deletion of the manganese superoxide dismutase gene

2015 ◽  
Vol 309 (3) ◽  
pp. C169-C178 ◽  
Author(s):  
Guiming Liu ◽  
Rania A. Elrashidy ◽  
Nan Xiao ◽  
Michael Kavran ◽  
Yexiang Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Smooth Muscle ◽  
Manganese Superoxide Dismutase ◽  
Bladder Function ◽  
Antioxidant Systems ◽  
Wild Type ◽  
Manganese Superoxide ◽  
Specific Deletion

Manganese superoxide dismutase (MnSOD) is considered a critical component of the antioxidant systems that protect against oxidative damage. We are interested in the role of oxidative stress in bladder detrusor smooth muscle (SM) in different disease states. In this study, we generated an inducible, SM-specific Sod2−/− mouse model to investigate the effects of MnSOD depletion on the function of the bladder. We crossbred floxed Sod2 ( Sod2lox/lox) mice with mice containing heterozygous knock-in of a gene encoding a tamoxifen-activated Cre recombinase in the SM22α promoter locus [SM-CreERT2(ki)Cre/+]. We obtained Sod2lox/lox,SM-CreERT2(ki)Cre/+ mice and injected 8-wk-old males with 4-hydroxytamoxifen to induce Cre-mediated excision of the floxed Sod2 allele. Twelve weeks later, SM-specific deletion of Sod2 and depletion of MnSOD were confirmed by polymerase chain reaction, immunoblotting, and immunohistochemistry. SM-specific Sod2−/− mice exhibited normal growth with no gross abnormalities. A significant increase in nitrotyrosine concentration was found in bladder SM tissue of SM-specific Sod2−/− mice compared with both wild-type mice and Sod2+/+, SM-CreERT2(ki)Cre/+ mice treated with 4-hydroxytamoxifen. Assessment of 24-h micturition in SM-specific Sod2−/− mice revealed significantly higher voiding frequency compared with both wild-type and SM-specific Cre controls. Conscious cystometry revealed significantly shorter intercontraction intervals and lower functional bladder capacity in SM-specific Sod2−/− mice compared with wild-type mice. This novel model can be used for exploring the mechanistic role of oxidative stress in organs rich in SM in different pathological conditions.

scholarly journals Frequency encoding of cholinergic- and purinergic-mediated signaling to mouse urinary bladder smooth muscle: modulation by BK channels

2007 ◽  
Vol 292 (1) ◽  
pp. R616-R624 ◽  
Author(s):  
Matthias E. Werner ◽  
Anna-Maria Knorn ◽  
Andrea L. Meredith ◽  
Richard W. Aldrich ◽  
Mark T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bk Channels ◽  
Bk Channel ◽  
Detrusor Muscle ◽  
Wild Type ◽  
Bladder Smooth Muscle ◽  
Overactive Detrusor ◽  
Maximal Force ◽  
Urinary Bladder Smooth Muscle

In the urinary bladder, contractions of the detrusor muscle and urine voiding are induced by the neurotransmitters ACh and ATP, released from parasympathetic nerves. Activation of K+ channels, in particular the large-conductance Ca2+-activated K+ (BK) channels, opposes increases in excitability and contractility of urinary bladder smooth muscle (UBSM). We have shown that deleting the gene mSlo1 in mice ( Slo−/−), encoding the BK channel, leads to enhanced nerve-mediated and neurotransmitter-dependent contractility of UBSM ( 38 ). Here, we examine the location of the BK channel in urinary bladder strips from mouse. Immunohistochemical analysis revealed that the channel is expressed in UBSM but not in nerves that innervate the smooth muscle. The relationship between electrical field stimulation and force generation of the cholinergic and purinergic pathways was examined by applying blockers of the respective receptors in UBSM strips from wild-type and from Slo−/− (knockout) mice. In wild-type strips, the stimulation frequency required to obtain a half-maximal force was significantly lower for the purinergic (7.2 ± 0.3 Hz) than the cholinergic pathway (19.1 ± 1.5 Hz), whereas the maximum force was similar. Blocking BK channels with iberiotoxin or ablation of the Slo gene increased cholinergic- and purinergic-mediated force at low frequencies, i.e., significantly decreased the frequency for a half-maximal force. Our results indicate that the BK channel has a very significant role in reducing both cholinergic- and purinergic-induced contractility and suggest that alterations in BK channel expression or function could contribute to pathologies such as overactive detrusor.

scholarly journals Urinary Bladder Contraction and Relaxation: Physiology and Pathophysiology

2004 ◽  
Vol 84 (3) ◽  
pp. 935-986 ◽  
Author(s):  
Karl-Erik Andersson ◽  
Anders Arner
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bladder Wall ◽  
Outlet Obstruction ◽  
Hormonal Control ◽  
Membrane Properties ◽  
Bladder Function ◽  
Future Research ◽  
Detrusor Smooth Muscle ◽  
Functional Changes

The detrusor smooth muscle is the main muscle component of the urinary bladder wall. Its ability to contract over a large length interval and to relax determines the bladder function during filling and micturition. These processes are regulated by several external nervous and hormonal control systems, and the detrusor contains multiple receptors and signaling pathways. Functional changes of the detrusor can be found in several clinically important conditions, e.g., lower urinary tract symptoms (LUTS) and bladder outlet obstruction. The aim of this review is to summarize and synthesize basic information and recent advances in the understanding of the properties of the detrusor smooth muscle, its contractile system, cellular signaling, membrane properties, and cellular receptors. Alterations in these systems in pathological conditions of the bladder wall are described, and some areas for future research are suggested.

Contractile and cytoskeletal proteins in smooth muscle during hypertrophy and its reversal

1991 ◽  
Vol 260 (5) ◽  
pp. C1085-C1093 ◽  
Author(s):  
U. Malmqvist ◽  
A. Arner ◽  
B. Uvelius
Keyword(s):  
Smooth Muscle ◽  
Bladder Wall ◽  
Relative Proportion ◽  
Relative Volume ◽  
Cytoskeletal Proteins ◽  
Intermediate Filament Protein ◽  
Bladder Smooth Muscle ◽  
Rat Urinary Bladder ◽  
Urinary Bladder Smooth Muscle ◽  
Bladder Weight

Hypertrophy of rat urinary bladder smooth muscle was induced by partial urethral obstruction. Bladder weight increased from 70 to 240 mg after 10 days and to 700 mg after 7 wk. Removal of the obstruction after 10 days caused a regression of bladder weight to 130 mg. The relative volume of smooth muscle in the bladder wall increased during hypertrophy. The concentration of myosin in the smooth muscle cells decreased in 10-day hypertrophied bladders, whereas the concentration of actin was unchanged. The actin-myosin ratio was 2.3 in controls, 3.3 in 10-day obstructed bladders, and 2.9 in 7-wk obstructed bladders. After removal of obstruction, the ratio was normalized. Two isoforms of myosin heavy chains were identified (SM1 and SM2). The relative amount of SM2 decreased during hypertrophy. The relative proportion of actin isoforms (alpha, beta, and gamma) was altered toward more gamma and less alpha. These changes were reversible upon removal of the obstruction. Desmin was the dominating intermediate filament protein. The concentration of desmin and filamin increased in the hypertrophic bladders. The increased desmin-actin and filamin-actin ratios in obstructed bladders were normalized after removal of the obstruction. The results suggest that the turnover of contractile and cytoskeletal proteins is fast and can be regulated in response to changes in the functional demands in smooth muscle.

Sign in / Sign up

Export Citation Format

Share Document