We have previously demonstrated that nitric oxide (NO) is elevated in the urine from bladder cancer patients. As the inducible nitric oxide synthase (iNOS) produces high NO output, the aim of this study was to examine iNOS expression and activity in tumoral (BT) and non-tumoral bladder tissue (NT). iNOS expression was determined by Western blot in 42 BT, 22 NT, and 4 normal bladders (normal B). iNOS activity was evaluated by conversion of [(14)C]l-arginine to [(14)C]l-citrulline plus NO, in additional 15 BT, 8 NT, and 1 normal B. iNOS tissue localization was studied by immunohistochemistry. iNOS expression and activity were found in almost 50% of bladder cancer patients, in both BT and in NT. A similar positive or negative iNOS expression in each pair of NT and BT tissue compared was observed, suggesting that high urine NO levels could be generated by an active iNOS present not only in the tumor but also in the non-tumoral bladder tissue. By immunohistochemistry, heterogeneous iNOS staining was detected in tumor cells from superficial and invasive tumors, while it was not evident in the normal bladder epithelium. A follow-up of 21 patients during 2 years showed recurrences in 80% with positive iNOS. On the contrary, no recurrences were observed in 73% of iNOS negative patients. Our results suggest that iNOS expression in bladder tissue may predispose to cancer recurrences.
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