HISTAMINE H-3 RECEPTOR-MEDIATED INHIBITION OF CALCITONIN-GENE-RELATEDPEPTIDE RELEASE FROM CARDIAC C-FIBERS - A REGULATORY NEGATIVE-FEEDBACK LOOP

Antidromic stimulation of cardiac sensory C fibers releases calcitonin gene-related peptide (CGRP), which increases heart rate, contractilit y, and coronary flow. C-fiber endings are closely associated with mast cells, and CGRP may release mast-cell histamine. Because prejunctiona l histamine H-3-receptors inhibit transmitter release from autonomic n erves, we tested the hypothesis that H-3-receptors modulate CGRP relea se 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 effec ts, respectively. Capsaicin significantly enhanced the overflow of CGR P (fivefold) and histamine (twofold) into the coronary effluent. All o l these effects were prevented by prior chemical destruction of C fibe rs in vivo. The H-3-receptor agonist imetit attenuated the inotropic r esponse to bradykinin by 50%. Imetit also decreased the capsaicin-indu ced tachycardia and the increase in CGRP overflow by 50%. Imetit, howe ver, did not modify the response to exogenous CGRP. The effects of ime tit were blocked by the H-3-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 his tamine from cardiac mast cells and histamine in turn inhibits CGRP rel ease by activating H-3-receptors on C-fiber terminals. Because CGRP re lease is augmented in pathophysiological conditions, such as septic sh ock, heart failure, and acute myocardial infarction, modulation of CGR P release may be clinically relevant.