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Physiological paradoxes, such as preserved organ function after denervation or transplantation, challenge a purely autonomic paradigm and point to intrinsic, tissue\u2010based catecholaminergic control mechanisms. This review critically examines and integrates the emerging concept of endothelium\u2010 and epithelium\u2010derived 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\u2010nitrodopamine (6\u2010ND) and 6\u2010cyanodopamine (6\u2010CYD), is discussed. Endothelium\u2010derived 6\u2010ND and 6\u2010CYD emerges as highly potent and long\u2010lasting 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\u2010ND selectively antagonises dopamine\u2010induced contractile responses and promotes smooth muscle relaxation through mechanisms largely independent of the canonical sGC\u2010cGMP pathway. Notably, agarose\u2010coupled 6\u2010ND identified cyclase\u2010associated proteins (CAPs) in cardiomyocyte membranes, linking 6\u2010ND signalling to adenylyl cyclase regulation. In parallel, epithelium\u2010derived catecholamines, including 6\u2010ND and 6\u2010CYD, 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.<\/jats:p>","DOI":"10.1111\/bph.70503","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T05:50:46Z","timestamp":1779515446000},"page":"4091-4110","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Endothelium\u2010 and epithelium\u2010derived novel endogenous catecholamines as modulators of the autonomic nervous system"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2226-2530","authenticated-orcid":false,"given":"Mariana G.","family":"de Oliveira","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology S\u00e3o Francisco University (USF)  Bragan\u00e7a 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