Functional Identification of Histamine H 3 -Receptors in the Human Heart

Abstract

Abstract Norepinephrine release contributes to ischemic cardiac dysfunction and arrhythmias. Because activation of histamine H 3 -receptors inhibits norepinephrine release, we searched for the presence of H 3 -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 H 3 -receptors was ascertained because the selective H 3 -receptor agonists ( R )α-methylhistamine and imetit reduced norepinephrine release, and the specific H 3 -receptor antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca 2+ -channel blocker ω-conotoxin and the protein kinase C inhibitor Ro31-8220. Functional relevance of these H 3 -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 )α-methylhistamine. Also, thioperamide antagonized the effect of ( R )α-methylhistamine. Our findings are the first demonstration that H 3 -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, H 3 -receptor–induced attenuation of sympathetic neurotransmission may be clinically relevant.