Endothelium‐ and epithelium‐derived novel endogenous catecholamines as modulators of the autonomic nervous system

Catecholamines are classically viewed as neuronal transmitters and adrenal hormones; however, accumulating evidence demonstrates that sources other than nerve fibres and adrenal medulla play a fundamental role in local organ regulation. Physiological paradoxes, such as preserved organ function after denervation or transplantation, challenge a purely autonomic paradigm and point to intrinsic, tissue-based catecholaminergic control mechanisms. This review critically examines and integrates the emerging concept of endothelium- and epithelium-derived catecholamines, with a particular emphasis on the cardiovascular, genitourinary and respiratory systems. Experimental evidence supporting the biosynthesis, release, metabolism and functional roles of novel endogenous catecholamines, including 6-nitrodopamine (6-ND) and 6-cyanodopamine (6-CYD), is discussed. Endothelium-derived 6-ND and 6-CYD emerges as highly potent and long-lasting modulators of cardiovascular function, exerting positive chronotropic and inotropic effects, whilst uniquely potentiating the actions of classical catecholamines. In vascular tissues, including corpus cavernosum, 6-ND selectively antagonises dopamine-induced contractile responses and promotes smooth muscle relaxation through mechanisms largely independent of the canonical sGC-cGMP pathway. Notably, agarose-coupled 6-ND identified cyclase-associated proteins (CAPs) in cardiomyocyte membranes, linking 6-ND signalling to adenylyl cyclase regulation. In parallel, epithelium-derived catecholamines, including 6-ND and 6-CYD, have been identified throughout the genitourinary and respiratory systems, where they modulate smooth muscle tone. This review proposes a revised framework of autonomic regulation in which neural signalling is integrated with locally produced catecholamines acting in a paracrine and autocrine manner, underscoring their relevance as endogenous regulators and potential therapeutic targets.