Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium

Sellers, Donna; Chess-Williams, Russ; Michel, Martin C.

doi:10.1007/s00210-018-1510-8

Cited by 44 publications

(30 citation statements)

References 209 publications

(316 reference statements)

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“…Cyclophosphamide and ifosfamide treatment are associated with bladder toxicity. The urothelium has been shown to be able to communicate with the detrusor, myofibroblasts and sensory nerves by releasing ATP, ACh and PGE2 among other mediators (Sellers et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde’s contribution to urothelial dysfunction in vitro

2019

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The clinical use of cyclophosphamide and ifosfamide is limited by a resultant bladder toxicity which has been attributed to the metabolite acrolein. Another metabolite chloroacetaldehyde (CAA) associated with nephrotoxicity, has not been investigated for toxicity in the bladder and this study investigates the effects of acrolein and CAA on human urothelial cells in vitro. Human urothelial cells (RT4 and T24) were treated with acrolein or CAA and changes in cell viability, reactive oxygen species, caspase-3 activity and release of urothelial mediators ATP, acetylcholine, PGE2 were measured. The protective effects of N-acetyl cysteine (NAC) were also assessed. Both metabolites were toxic to human urothelial cells however, CAA significantly decreased cell viability at a 10-fold lower concentration (10µM) than acrolein (100µM). This was associated with increased ROS production and caspase-3 activity. NAC protected cells from these changes. In RT4 cells 100µM acrolein caused a significant increase in basal and stretch-induced ATP, Ach and PGE2 release. In T24 cells chloroacetaldehyde (10µM) increased basal and stimulated ATP and PGE2 levels. Again, NAC protected against changes in urothelial mediator release following acrolein or CAA. This study is the first to report that CAA in addition to acrolein contributes to the urotoxicity of cyclophosphamide and ifosfamide. Both metabolites altered urothelial mediator levels which could contribute to the sensory and functional bladder changes experienced by patients after treatment with cyclophosphamide or ifosfamide. Alterations in urothelial cell viability and mediator release may be causally linked to oxidative stress, with NAC providing protection against these changes.

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Section: Discussionmentioning

confidence: 99%

Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde’s contribution to urothelial dysfunction in vitro

2019

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“…Thus, a negligible effect of the urothelium on passive whole bladder wall properties is expected. However, the urothelium has a modulating effect on smooth muscle contraction and relaxation (Sellers et al, 2018). In the present study, experiments were conducted on whole tissue strips without removal of the urothelium to ensure functional integrity.…”

Section: Discussionmentioning

confidence: 99%

Locational and Directional Dependencies of Smooth Muscle Properties in Pig Urinary Bladder

et al. 2019

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The urinary bladder is a distensible hollow muscular organ, which allows huge changes in size during absorption, storage and micturition. Pathological alterations of biomechanical properties can lead to bladder dysfunction and loss in quality of life. To understand and treat bladder diseases, the mechanisms of the healthy urinary bladder need to be determined. Thus, a series of studies focused on the detrusor muscle, a layer of urinary bladder made of smooth muscle fibers arranged in longitudinal and circumferential orientation. However, little is known about whether its active muscle properties differ depending on location and direction. This study aimed to investigate the porcine bladder for heterogeneous (six different locations) and anisotropic (longitudinal vs. circumferential) contractile properties including the force-length-(FLR) and force-velocity-relationship (FVR). Therefore, smooth muscle tissue strips with longitudinal and circumferential direction have been prepared from different bladder locations (apex dorsal, apex ventral, body dorsal, body ventral, trigone dorsal, trigone ventral). FLR and FVR have been determined by a series of isometric and isotonic contractions. Additionally, histological analyses were conducted to determine smooth muscle content and fiber orientation. Mechanical and histological examinations were carried out on 94 and 36 samples, respectively. The results showed that maximum active stress (pact) of the bladder strips was higher in the longitudinal compared to the circumferential direction. This is in line with our histological investigation showing a higher smooth muscle content in the bladder strips in the longitudinal direction. However, normalization of maximum strip force by the cross-sectional area (CSA) of smooth muscle fibers yielded similar smooth muscle maximum stresses (165.4 ± 29.6 kPa), independent of strip direction. Active muscle properties (FLR, FVR) showed no locational differences. The trigone exhibited higher passive stress (ppass) than the body. Moreover, the bladder exhibited greater ppass in the longitudinal than circumferential direction which might be attributed to its microstructure (more longitudinal arrangement of muscle fibers). This study provides a valuable dataset for the development of constitutive computational models of the healthy urinary bladder. These models are relevant from a medical standpoint, as they contribute to the basic understanding of the function of the bladder in health and disease.

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“…Locally, the urothelium can influence contractility of the underlying smooth muscle, for example via the release of a urothelium‐derived inhibitory factor (UDIF), found in porcine and human bladders, but as yet unidentified. Using urothelium‐intact and denuded bladder strips we investigated whether diabetes alters this influence of the urothelium on bladder contractility.…”

Section: Discussionmentioning

confidence: 99%

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

Lee

Rose’Meyer

McDermott

et al. 2018

Clin Exp Pharma Physio

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Up to 80% of patients with diabetes mellitus develop lower urinary tract complications, most commonly diabetic bladder dysfunction (DBD). The aim of this study was to investigate the impact of diabetes on the function of the inner bladder lining (urothelium). Bladder compliance and intraluminal release of urothelial mediators, adenosine triphosphate (ATP) and acetylcholine (ACh) in response to distension were investigated in whole bladders isolated from 2- and 12-week streptozotocin (STZ)-diabetic rats. Intact and urothelium-denuded bladder strips were used to assess the influence of the urothelium on bladder contractility. Intraluminal ATP release was significantly enhanced at 2 weeks of diabetes, although not at 12 weeks. In contrast, intraluminal ACh release was unaltered by diabetes. Bladder compliance was also significantly enhanced at both 2 and 12 weeks of diabetes, with greatly reduced intravesical pressures in response to distension. Nerve-evoked contractions of bladder strips were significantly greater at 2 weeks of diabetes. When the urothelium was absent, nerve-evoked contractions were reduced, but contractions remained significantly elevated at lower frequencies of stimulation (<5 Hz) in diabetics. Interestingly, although relaxations of bladder strips to isoprenaline were unaltered by diabetes, removal of the urothelium unmasked significantly enhanced relaxations in strips from 2- and 12-week diabetic animals. In conclusion, diabetes alters urothelial function. Enhanced urothelial ATP release may be involved in the hypercontractility observed at early time points of diabetes. These alterations are time-dependent and may contribute to the mechanisms at play during the development of diabetic bladder dysfunction.

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Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium

Cited by 44 publications

References 209 publications

Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde’s contribution to urothelial dysfunction in vitro

Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde’s contribution to urothelial dysfunction in vitro

Locational and Directional Dependencies of Smooth Muscle Properties in Pig Urinary Bladder

Diabetes‐induced alterations in urothelium function: Enhanced ATP release and nerve‐evoked contractions in the streptozotocin rat bladder

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