Nonadrenergic noncholinergic innervation. Anatomic distribution of calcitonin gene-related peptide-immunoreactive tissue in the dog heart.

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Abstract
Calcitonin gene-related peptide (CGRP) has inotropic and chronotropic effects in rat and guinea pig hearts. It also may mediate nonadrenergic noncholinergic regulation of canine cardiac electrophysiology. In this study, immunohistochemistry was used to determine the anatomic distribution of CGRP in mature dog heart and autonomic ganglia controlling cardiac function. The stellate ganglia had scattered CGRP-immunoreactive cells and nerve processes; intracardiac ganglia contained stained nerve processes but no CGRP-immunoreactive cells. Although the extramural coronary arteries were modestly innervated by varicose individual nerve processes, the great majority of CGRP-immunoreactive neural tissue in the heart existed adjacent to the sinoatrial node where varicose nerve processes coursed in numerous large nerve bundles. Each bundle contained only a few stained processes, however, indicating that CGRP-immunoreactive nerve processes were accompanying another type of autonomic tissue. Double staining and immunoultrastructure confirmed that the nerve bundles were heterogeneous. Similar nerve bundles were fewer in the left atrium, the region of the atrioventricular node, atrioventricular bundle, and the ventricles. In contrast to the distribution of sympathetic neural tissue, CGRP-immunoreactive nerve processes virtually were nonexistent among muscle fibers. We conclude that 1) CGRP-immunoreactive neural tissue likely affects sympathetic and parasympathetic ganglia that control cardiac function, 2) the preponderance of this nonadrenergic noncholinergic tissue near regions of specialized muscle (especially the sinoatrial node) suggests an efferent function in the canine heart, and 3) the presence of varicosities along CGRP-immunoreactive nerve processes within heterogeneous nerve bundles may indicate that direct axo-axonal contact is the mechanism by which these nonadrenergic noncholinergic nerve processes modulated other autonomic neural tissue.