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(Circulation Research. 1996;78:863-869.)
© 1996 American Heart Association, Inc.

Articles

Histamine H₃-Receptor–Mediated Inhibition of Calcitonin Gene-Related Peptide Release From Cardiac C Fibers

A Regulatory Negative-Feedback Loop

Michiaki Imamura, Neil C.E. Smith, Monique Garbarg, Roberto Levi

From the Department of Pharmacology (M.I., N.C.E.S., R.L.), Cornell University Medical College, New York, NY, and Unité de Neurobiologie et Pharmacologie (M.G.), INSERM U109, Paris, France.

Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi@med.cornell.edu.

Abstract 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 release 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.

Key Words: histamine H₃-receptors • calcitonin gene-related peptide release • bradykinin • sensory C-fiber endings • mast cells

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