Antidromic stimulation of cardiac sensory C fibers releases
calcitonin gene-related peptide (CGRP), which increases heart rate, contractility, and coronary flow. C-fiber endings are closely associated with mast cells, and CGRP may release mast-cell
histamine. Because prejunctional
histamine H3-receptors inhibit transmitter release from autonomic nerves, we tested the hypothesis that H3-receptors modulate CGRP release in the heart. CGRP released by
bradykinin in the electrically paced guinea pig left atrium and by
capsaicin in the spontaneously beating isolated heart caused marked positive inotropic and chronotropic effects, respectively.
Capsaicin significantly enhanced the overflow of CGRP (fivefold) and
histamine (twofold) into the coronary effluent. All of these effects were prevented by prior chemical destruction of C fibers in vivo. The H3-receptor agonist
imetit attenuated the inotropic response to
bradykinin by 50%.
Imetit also decreased the
capsaicin-induced
tachycardia and the increase in CGRP overflow by 50%.
Imetit, however, did not modify the response to exogenous CGRP. The effects of
imetit were blocked by the H3-receptor antagonist
thioperamide. Notably,
thioperamide by itself potentiated the
capsaicin-evoked increases in heart rate and CGRP overflow (by 25% and 50%, respectively). Thus, our findings identify a negative-feedback loop, whereby CGRP releases
histamine from cardiac mast cells and
histamine in turn inhibits CGRP releases by activating H3-receptors on C-fiber terminals. Because CGRP release is augmented in pathophysiological conditions, such as
septic shock,
heart failure, and acute
myocardial infarction, modulation of CGRP release may be clinically relevant.