© 1995 American Heart Association, Inc.
Articles |
Functional Identification of Histamine H3-Receptors in the Human Heart
From the Department of Pharmacology, Cornell University Medical College, New York, NY.
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 Norepinephrine release contributes to
ischemic cardiac dysfunction and arrhythmias. Because
activation of histamine H3-receptors inhibits
norepinephrine release, we searched for the presence of
H3-receptors directly in sympathetic nerve endings (cardiac
synaptosomes) isolated from surgical specimens of human atria.
Norepinephrine was released by depolarization with
K+. The presence of H3-receptors was
ascertained because the selective H3-receptor agonists
(R)
-methylhistamine and imetit reduced
norepinephrine release, and the specific
H3-receptor antagonist thioperamide blocked
this effect. Norepinephrine release was exocytotic, since
it was inhibited by the N-type Ca2+-channel blocker
-conotoxin and the protein kinase C inhibitor Ro31-8220.
Functional relevance of these H3-receptors was obtained by
showing that transmural electrical stimulation of sympathetic nerve
endings in human atrial tissue increased contractility,
an effect blocked by propranolol and attenuated in a
concentration-dependent manner by (R)-methylhistamine.
Also, thioperamide antagonized the effect of
(R)-methylhistamine. Our findings are the first
demonstration that H3-receptors are present in
sympathetic nerve endings in the human heart, where they modulate
adrenergic responses by inhibiting norepinephrine release.
Since myocardial ischemia causes intracardiac histamine
release, H3-receptor–induced attenuation of sympathetic
neurotransmission may be clinically relevant.
Key Words: cardiac synaptosomes • histamine H3-receptors • norepinephrine release • sympathetic nerve endings • myocardial ischemia
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