Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats

Andrzej Wróbel,Ewa Poleszak,Karol Rojek,Anna Serefko,Urszula Doboszewska,Piotr Wlaź,Ewa Rechberger,Krystyna Skalicka-Woźniak,Jarosław Dudka

doi:10.1007/s00210-017-1361-8

Abstract

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.

Highlights

Hemorrhagic cystitis (HC) is a life-threatening condition defined by lower urinary tract symptoms that include hematuria and bladder detrusor overactivity
As HC may require inpatient management and major procedures, which are not always effective (Payne et al 2013), its prevention is preferred over treatment
Because CYP-induced HC is an inflammatory process (Korkmaz et al 2007), compounds that possess anti-inflammatory properties seem worth taking into account while searching for agents that could be beneficial for reducing adverse effects during CYP therapy

Summary

Introduction

Hemorrhagic cystitis (HC) is a life-threatening condition defined by lower urinary tract symptoms that include hematuria and bladder detrusor overactivity. The severity of HC induced by CYP ranges from mild to severe and may require a variety of procedures like hydration, clot extraction via cystoscopy, continuous bladder irrigation, or cystectomy (Matz and Hsieh 2017); despite those treatment options, can be fatal (Ebiloglu et al 2016). Administration of a sulfhydryl compound MESNA and hyperhydration are two most frequently used methods for the prevention of HC in patients treated with CYP, but they are not always effective and cannot be used in all patient populations (Payne et al 2013). There is a need for novel agents that could be useful to prevent adverse urologic effects during CYP therapy

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