Document Detail

Histamine H3-receptor-mediated inhibition of calcitonin gene-related peptide release from cardiac C fibers. A regulatory negative-feedback loop.
MedLine Citation:
PMID:  8620607     Owner:  NLM     Status:  MEDLINE    
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.
M Imamura; N C Smith; M Garbarg; R Levi
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation research     Volume:  78     ISSN:  0009-7330     ISO Abbreviation:  Circ. Res.     Publication Date:  1996 May 
Date Detail:
Created Date:  1996-06-18     Completed Date:  1996-06-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  863-9     Citation Subset:  IM    
Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
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MeSH Terms
Atrial Function / drug effects
Bradykinin / pharmacology
Calcitonin Gene-Related Peptide / antagonists & inhibitors*,  physiology
Capsaicin / pharmacology
Feedback / physiology
Guinea Pigs
Heart Conduction System / drug effects,  metabolism*,  physiology
Heart Rate / drug effects
Myocardial Contraction / drug effects
Nerve Fibers / drug effects,  metabolism*,  physiology
Receptors, Histamine H3 / physiology*
Grant Support
Reg. No./Substance:
0/Receptors, Histamine H3; 404-86-4/Capsaicin; 58-82-2/Bradykinin; 83652-28-2/Calcitonin Gene-Related Peptide

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