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Background: Cardiac conduction is influenced by peptidergic mechanisms as well as classic neurotransmitters. The distribution of peptide-containing nerves has not been well defined., Methods and Results: Immunofluorescence and histochemical techniques were used to visualize the innervation of the human conduction system and to distinguish nerve subpopulations according to their peptide and enzyme content. Nerve fibers and fascicles displaying immunoreactivity for protein gene product 9.5 (PGP 9.5) were more numerous in the sinus and atrioventricular nodes than in the penetrating bundle, bundle branches, and adjacent myocardium. The relative density of innervation was greater in the central region of the sinus node than in the peripheral regions. Nerve densities were also higher in the transitional region of the atrioventricular node compared with its compact region. Acetylcholinesterase (AChE)-positive nerves were the main subtype identified in the sinus and atrioventricular nodes, representing half to two thirds of the stained area occupied by PGP 9.5-immunoreactive nerves. Neuropeptide Y-immunoreactive nerves represented the main peptide-containing subpopulation and occurred throughout the conduction system, displaying a similar pattern of distribution and relative density to those demonstrating tyrosine hydroxylase immunoreactivity. Nerve fibers showing immunoreactivity for vasoactive intestinal polypeptide, somatostatin, substance P, or calcitonin gene-related peptide exhibited distinct patterns of distribution and comprised a relatively minor component of the innervation, the percentage of stained area being 10- to 40-fold lower than that occupied by neuropeptide Y- and PGP 9.5-immunoreactive nerves, respectively., Conclusions: The innervation of human conduction tissues exhibits significant regional variation and comprises putative parasympathetic nerves and intrinsic neurons (AChE positive), sympathetic efferent nerves (neuropeptide Y- and tyrosine hydroxylase-immunoreactive nerves), and other peptide-containing nerves, some of which (substance P and calcitonin gene-related peptide containing) are considered to represent afferent nerves. Locally released peptides may be involved in the neural modulation of the human conduction system.