Angiotensinergic Innervation of the Human Right Atrium: Implications for Cardiac Reflexes.

Background: The right atrium is densely innervated and provides sensory input to important cardio-circulatory reflexes controlling cardiac output and blood pressure. Its angiotensin (Ang) II-expressing innervation may release Ang II as a neuropeptide co-transmitter to modulate reflexes but has not yet been characterized. Methods: Intraoperative surgical biopsies from human right atria (n=7) were immunocytologically stained for Ang II, tyrosine hydroxylase (TH) and synaptophysin (SYN). Tissue angiotensins were extracted and quantified by radioimmunoassay. Results: Angiotensinergic fibers were frequent in epicardial nerves and around vessels with variable TH co-localization (none to >50%/bundle). Fibers were also widely distributed between cardiomyocytes and in the endocardium where they were typically non-varicose, TH/SYN-negative and usually accompanied by varicose catecholaminergic fibers. In the endocardium, some showed large varicosities and were partially TH or SYN-positive. A few endocardial regions showed scattered non-varicose Ang fibers ending directly between endothelial cells. Occasional clusters of thin varicose terminals co-localizing SYN or TH were located underneath, or protruded into, the endothelium. Endocardial density of Ang and TH-positive fibers was 30–300 vs. 200–450/mm 2. Atrial Ang II, III and I concentrations were 67, 16 and 5 fmol/g (median) while Ang IV and V were mostly undetectable. Conclusions: The human right atrium harbours an abundant angiotensinergic innervation and a novel potential source of atrial Ang II. Most peripheral fibers were non-catecholaminergic afferents or preterminal vagal efferents and a minority was presumably sympathetic. Neuronal Ang II release from these fibers may modulate cardiac and circulatory reflexes independently from plasma and tissue Ang II sources.