Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis

Purpose: This study was conducted to examine effects of nitric oxide (NO) d onors on bladder hyperactivity induced by cyclophosphamide (CYP)-induced cy stitis. Materials and Methods: Female Sprague-Dawley rats received a single intrape ritoneal injection of CYP (100 mg./kg.), and then their micturition pattern including mean micturition volume and the number of micturitions during 24 hours was recorded in a metabolic cage before and after CYP treatment. For ty-eight hours after CYP injection, bladder function under urethane anesthe sia was evaluated by cystometry with continuous saline infusion (0.04 mi. p er minute) or under isovolumetric conditions (0.8 mi. bladder volume). NO d onors, S-nitroso-N-acetyl-penicillamine (SNAP, 2 mM) or sodium nitroprussid e (SNP, 1 mM), and an NO synthase (NOS) inhibitor, N-nitro-L-arginine methy l ester (L-NAME, 20 mM) were administered intravesically. Direct action of SNAP on bladder afferent neurons was also tested in a patch-clamp recording study. Results: The number of micturitions significantly increased during the firs t 24 hours after CYP injection (19.0 +/- 0.88 versus 92.1 +/- 16.3 micturit ions/24 hours, mean +/- SE, n = 25) (p <0.001). There was no significant di fference in total micturition volume before (12.3 +/- 1.0 ml./24 hours) and after CYP treatment (15.6 +/- 1.5 ml./24 hours). During continuous infusio n cystometry, intercontraction interval (ICI) was smaller in CYP-injected r ats than in control rats. In CYP-injected animals, NO donors increased the ICI, but did not change the amplitude of bladder contractions. Continuous i ntravesical infusion of the NOS inhibitor did not alter the cystometric par ameters. During cystometry under isovolumetric conditions, contraction freq uency was decreased after NO donor administration. NO donors did not influe nce bladder activity in control rats. Ln patch clamp recordings, when SNAP (500 mu M was directly applied to dissociated afferent neurons innervating the urinary bladder, high-voltage-activated Ca channel currents were suppre ssed by approximately 30%. Conclusions: Intravesical NO donors can suppress CYP-induced bladder hypera ctivity. We hypothesize that the effect of NO donors is not due to smooth m uscle relaxation, but rather due to an inhibitory effect on bladder afferen t pathways that was manifested by an increase in intercontraction interval without changes in contraction amplitude. NO donors may be considered as a possible treatment of CYP-induced and other types of bladder inflammation.