Magdalena Ufniarz

Title: Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats

Abstract

Hemorrhagic cystitis is a frequent complication in patients receiving cyclophosphamide (CYP). Previous research suggests that inhibitors of Rho kinase (ROCK) can reduce symptoms of detrusor overactivity and has anti-inflammatory effects. The purpose of this study was to evaluate whether ROCK inhibition affects cystometric and histopathological alterations associated with CYP-induced cystitis. Rats were treated for 7 days with the ROCK inhibitor GSK 269962 (30 mg/kg/day). Acute chemical cystitis accompanied by bladder overactivity was then induced by an intraperitoneal injection of CYP (200 mg/kg). After CYP injections, cystometric parametres were messured. In addition, bladder edema and urothelial thickness was evaluated.

CYP administration caused an increase in cystometric parameters, including basal pressure, threshold pressure, duration of bladder contractions, relaxation time, detrusor overactivity index, and the amplitude and frequency of non-voiding contractions. It also significantly enhanced Evans Blue leakage into bladder tissue. In contrast, micturition voiding pressure, voided volume, post-void residual volume, volume threshold, intercontraction interval, bladder compliance, volume threshold required to induce non-voiding contractions, and urothelial thickness were significantly decreased in CYP-treated rats. Treatment with GSK 269962 reversed these CYP-induced changes.

Overall, ROCK inhibition reversed CYP-induced detrusor overactivity and bladder inflammation. These findings demonstrate a uroprotective effect of ROCK inhibition and suggest that this approach may represent a promising pharmacological strategy to prevent urinary side effects in patients undergoing cyclophosphamide chemotherapy.

What will the audience take away from your presentation?

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.