6‐Nitrodopamine as a Novel Mediator of Prostatic Smooth Muscle Function in Mouse and Human

ABSTRACT Background Epithelium‐derived catecholamines contribute to local regulation of genitourinary smooth muscle function, but the role of the endogenous 6‐nitrodopamine (6‐ND) in the prostate remains unknown. Objectives To determine whether 6‐ND is produced by mouse and human prostate and its role in smooth muscle regulation. Methods Catecholamine release was quantified by LC‐MS/MS. Tyrosine hydroxylase (TH) expression was assessed by immunohistochemistry and FISH. Functional responses were evaluated by myography and void spot assay. Results Basal 6‐ND release was detected in mouse and human prostate. In mice, release was partially sensitive to tetrodotoxin (TTX), whereas in human tissues it was largely TTX‐resistant. TH expression was identified in the prostatic epithelium. Functionally, 6‐ND relaxed pre‐contracted tissues, attenuated neurogenic contractions, and reduced noradrenaline potency. Genetic deletion of nitric oxide synthases (e/i/nNOS −/− ) or inhibition was associated with prostatic hypercontractility and reduced voiding frequency. Although 6‐ND‐induced relaxation was independent of the NO‐sGC‐cGMP pathway and did not increase intracellular cAMP, it potentiated forskolin‐induced relaxation. Discussion These findings identify 6‐ND as an endogenous modulator of prostatic smooth muscle function and are consistent with a dual regulatory system integrating neuronal and epithelial catecholamine sources. Conclusion 6‐ND represents a novel pathway involved in local prostate regulation and a potential therapeutic target for prostatic disorders.