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Functional identification of histamine H3-receptors in the human heart
M Imamura1, N Seyedi, H M Lander
1Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
Insights
Histamine H3-receptors are present in human heart sympathetic nerve endings. Activation of these receptors inhibits norepinephrine release, potentially mitigating cardiac dysfunction during ischemia.
Area of Science:
- Cardiovascular Pharmacology
- Neuroscience
- Molecular Biology
Background:
- Norepinephrine release exacerbates ischemic cardiac dysfunction and arrhythmias.
- Histamine H3-receptors are known to inhibit norepinephrine release.
- The presence and function of H3-receptors in the human heart's sympathetic nerve endings were previously uncharacterized.
Purpose of the Study:
- To investigate the presence of histamine H3-receptors in human cardiac sympathetic nerve endings.
- To determine if H3-receptors modulate norepinephrine release from these nerve endings.
- To assess the functional relevance of cardiac H3-receptors in adrenergic responses.
Main Methods:
- Isolation of cardiac synaptosomes from human atrial tissue.
- Measurement of norepinephrine release induced by K+ depolarization.
- Use of selective H3-receptor agonists ((R) alpha-methylhistamine, imetit) and antagonist (thioperamide).
- Assessment of exocytotic norepinephrine release using omega-conotoxin and Ro31-8220.
- Electrical field stimulation of human atrial tissue to measure contractility changes.
Main Results:
- Selective H3-receptor agonists reduced norepinephrine release, while the antagonist thioperamide blocked this effect, confirming H3-receptor presence.
- Norepinephrine release was confirmed to be exocytotic.
- Electrical stimulation increased atrial contractility, an effect attenuated by (R) alpha-methylhistamine and blocked by propranolol.
- Thioperamide antagonized the inhibitory effect of (R) alpha-methylhistamine on contractility.
Conclusions:
- This study provides the first evidence for functional histamine H3-receptors on sympathetic nerve endings in the human heart.
- These H3-receptors inhibit norepinephrine release, thereby modulating adrenergic responses.
- H3-receptor-mediated attenuation of sympathetic neurotransmission may hold clinical significance for managing myocardial ischemia.
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) alpha-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 Ca(2+)-channel blocker omega-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) alpha-methylhistamine. Also, thioperamide antagonized the effect of (R) alpha-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.