Objective: To investigate the nitric oxide synthase (NOS)/nitric oxide (NO) and heme oxygenase (HO)/carbon monoxide (CO) pathways in the human isolated ureter. Methods: Immunohistochemical studies were performed. NOS activity was measured by monitoring the converison of [3H]-arginine to [3H]-citrulline. Functional inhibitory effects mediated by NO and CO were assessed, and correlated with cyclic nucleotide levels. Results: The overall innervation of the ureter was moderate, however more prominent in the distal segment. Relative to overall innervation, neuronal NOS-immunoreactive (-IR) nerves were few. In the submucosa, neuronal NOS-IR varicose nerves were found closely together with varicose nerves containing calcitonin gene-related peptide immunoreactivity. In the distal ureter, nerve trunks were demonstrated, expressing immunoreactivity for HO-2. Ca2+-dependent NOS activity was 53 ± 13 pM/mg protein/h. In isolated preparations, NO decreased endothelin-1-induced contractions in a concentration-dependent manner. In strips exposed to NO, there was a 6-fold increase of the cyclic GMP levels in comparison to control preparations (p < 0.001). CO exerted no effect on induced ureteral tone. Conclusions: Neuronal NOS- and HO-2-IR nerves can be demonstrated in the human ureter, where NO, but probably not CO, may contribute to the regulation of tone. Although the physiological roles for NO and CO remain to be established, the NOS/NO/cyclic GMP pathway may be a target for drugs producing relaxation of the human ureter. The richer innervation of the distal ureter may be of importance for the coordination of ureteral peristalsis and the motility of the ureterovesical junction.

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