F16357, a novel protease-activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis

Background and PurposeThe aims of the present study were to characterize the role of PAR1 in rat bladder under inflammatory conditions and determine whether a selective PAR1 antagonist, F16357, can prevent the pathophysiological symptoms of cyclophosphamide-induced interstitial cystitis (IC). Experimental ApproachImmunohistochemistry, contractile activity in isolated bladder and urodynamics were determined before and after cyclophosphamide treatment. F16357 was administered intravesically during the acute phase of inflammation, and effects on PAR1 and PAR1-related bladder contraction evaluated 24h after cyclophosphamide injection. Urodynamics and associated voided volumes were recorded 7 and 24h after cyclophosphamide. Key ResultsIn control conditions, PAR1 was present only in some umbrella cells. Cyclophosphamide disrupted the urothelium and expression of PAR1 by all remaining urothelial cells. After F16357 treatment, urothelial damage was absent and PAR1 immunoreactivity similar to control tissues. Thrombin and TFLLR-NH2 induced bladder contractions. These were increased in inflammatory conditions and antagonized by F16357 in a concentration-dependent manner. In telemetric experiments, furosemide increased urine production and voiding frequency for 60min, 7h after cyclophosphamide injection. Intravesical administration of F16357 blocked these changes with a return to a physiological profile; 24h after cyclophosphamide, the volume of micturition was still lower with no increase in number of micturitions. F16357 30M reduced the number of micturitions and improved bladder capacity, but did not affect diuresis. Under similar experimental conditions, lidocaine 2% induced comparable effects. Conclusions and ImplicationsPAR1 is expressed in rat bladder, overactivated in inflammatory conditions and involved in bladder function and sensation. F16357 could represent an interesting candidate for IC treatment