The effect of combined treatment with a β 3 AR agonist and a ROCK inhibitor on detrusor overactivity

Neurourology and Urodynamics

Serefko

Bańczerowska‐Górska

et al. 2019

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Aims The main goal of our study was to investigate whether blebbistatin would prevent the cyclophosphamide (CYP)‐induced changes in cystometric and inflammatory parameters indicating the development of bladder inflammation and bladder overactivity. As the nature of CYP‐induced urotoxicity is inflammatory, we assume that agents presenting an anti‐inflammatory potential, such as blebbistatin, are worth special attention. Materials and Methods The experiments were carried out in female Wistar rats. Surgical procedures, cystometric investigations, measurements of bladder edema and urothelium thickness as well as biochemical analyses were performed according to the published literature. Results As expected, an acute administration of CYP (200 mg/kg, intraperitoneally) induced changes in the cystometric parameters and the levels of the tested biomarkers (ie, interleukin 1‐β, interleukin 6, interleukin 10, tumor necrosis factor‐α, nerve growth factor, brain‐derived neurotrophic factor, heparin‐binding epidermal growth factor‐like growth factor, insulin‐like growth factor‐binding protein 3, C‐X‐C motif chemokine 10, orosomucoid‐1, Tamm‐Horsfall protein, hemopexin, and occludin), indicating the development of bladder overactivity and bladder inflammation, respectively. These changes were accompanied by bladder edema and increased urothelium thickness. Intravesical infusion of blebbistatin for 7 days (125 nmol/day) prevented all symptoms of the CYP‐induced urotoxicity. Conclusions Blebbistatin might be a promising novel agent for the treatment of bladder dysfunctions, like CYP‐induced hemorrhage cystitis or bladder overactivity, since it diminished the increased urinary bladder levels of proinflammatory markers and normalized the concentrations of the anti‐inflammatory ones. This effect was accompanied by amelioration of bladder edema and permeability, and normalization of both urothelium thickness and values of the cystometric parameters.

Section: Methodsmentioning

confidence: 99%

Intravesical administration of blebbistatin prevents cyclophosphamide‐induced toxicity of the urinary bladder in female Wistar rats

Neurourology and Urodynamics

Serefko

Bańczerowska‐Górska

et al. 2019

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“…The control rats received volume-matched saline i.p. The doses of the administered agents were chosen based on the literature data and were confirmed/adjusted in our laboratory in preliminary experiments (Hidalgo-Lucas et al 2016; Juszczak et al 2010; Kobayashi et al 2009; Wróbel and Rechberger 2015; Wróbel and Rechberger 2016a; Wróbel and Rechberger 2016b; Wróbel and Rechberger 2016c). …”

Section: Methodsmentioning

confidence: 99%

Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats

Naunyn-Schmiedeberg's Arch Pharmacol

Doboszewska

Rechberger

et al. 2017

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Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CYP). Studies have indicated that Rho kinase (ROCK) inhibitors may suppress detrusor overactivity symptoms and possess anti-inflammatory properties. The aim of the present study was to investigate whether inhibition of ROCK reduces cystometric and histopathological changes associated with CYP-induced cystitis. The rats received GSK 269962, a ROCK inhibitor, at a dose of 30 mg/kg daily, or vehicle for 7 days. Then, acute chemical cystitis leading to bladder overactivity was induced by CYP injection (200 mg/kg i.p.). Following CYP injection, cystometric studies with physiological saline were performed. Moreover, bladder edema (by the Evans Blue dye leakage technique) and urothelium thickness were measured. CYP injection resulted in a significant increase in cystometric parameters: basal pressure, threshold pressure, bladder contraction duration, relaxation time, detrusor overactivity index, non-voiding contractions amplitude, and non-voiding contractions frequency as well as increased Evans Blue extravasation into bladder tissue, whereas micturition voiding pressure, voided volume, post-void residual, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit non-voiding contractions as well as urothelium thickness were significantly decreased in CYP-injected rats. Administration of GSK 269962 normalized the abovementioned CYP injection-induced changes. Inhibition of ROCK was found to ameliorate CYP-induced detrusor overactivity and bladder inflammation. Our data indicate uroprotective effects following ROCK inhibition, which further suggests that this strategy may become an interesting pharmacological tool to prevent urinary adverse effects in patients treated with chemotherapy using CYP.

“…The demonstrated decrease in DOI seems to be very important, considering that an increase in this parameter is a characteristic feature of DO that allows its intensity to be determined. It is believed that DOI reflects the contraction activity of the bladder with far greater precision than ANVC, FNVC, MVP, ICI, BP or BC [18, 19]. The observed increase in VTNVC following administration of duloxetine is very interesting, because this parameter is considered a preclinical equivalent to the volume at the first involuntary detrusor contraction measured during urodynamic investigations in humans [24].…”

Section: Discussionmentioning

confidence: 99%

“…The following cystometric parameters were recorded: basal pressure (BP, cm H 2 O), threshold pressure (TP, cm H 2 O), micturition voiding pressure (MVP, cm H 2 O), voided volume (VV, ml), postvoid residual (PVR, ml), volume threshold (VT, ml), voiding efficiency (VE, %), intercontraction interval (ICI, s), bladder contraction duration (BCD, s), relaxation time (RT, s), bladder compliance (BC, ml/cm H 2 O), and DO index (DOI, cm H 2 O/ml; calculated as the sum of the amplitudes of all detrusor contractions during the filling phase divided by the functional bladder capacity [17–20]), amplitude of nonvoiding contractions (ANVC, cm H 2 O), frequency of nonvoiding contractions (FNVC, times/filling phase), and volume threshold to elicit NVC (VTNVC, %) [19]. …”

Section: Methodsmentioning

confidence: 99%

The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid

Rechberger

2017

Int Urogynecol J

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Introduction and hypothesisThe aim of this study was to assess the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression.MethodsAfter 6 weeks of 13-cis-retinoic acid administration at a dose of 1 mg/kg/day, rats were given duloxetine at a dose of 1 mg/kg. This was followed by conscious cystometry, a forced swim test, and locomotor activity measurement. The levels of corticotropin-releasing factor (CRF) in the hypothalamus, amygdala and plasma were also determined.ResultsDuloxetine treatment led to a reduction in detrusor overactivity symptoms induced by the retinoid. Decreases were observed in cystometric parameters including the detrusor overactivity index, and the amplitude and frequency of nonvoiding contractions, while increases were seen in bladder compliance and the volume threshold to elicit nonvoiding contractions. No statistically significant differences were found in basal pressure, threshold pressure, micturition voiding pressure, postvoid residual , volume threshold, voiding efficiency, intercontraction interval, bladder contraction duration or relaxation time. Duloxetine also reduced the immobility time to that observed in control animals, while it did not affect locomotor activity. Its effects also included lowering of the CRF levels in the hypothalamus, amygdala and plasma, which increased following the prior administration of the retinoid. The plasma level of 13-cis-retinoic acid in rats corresponded to the levels found in humans.ConclusionsThis is the first study showing the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression. Further studies in patients with detrusor overactivity and coexisting depression are warranted to confirm these experimental results.