FUNCTIONAL IDENTIFICATION OF HISTAMINE H-3 RECEPTORS IN THE HUMAN HEART

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)alpha-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 Ca2+-channel blocker omega-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)alpha-methylhistamine. Also. thioperamide antagonized the effect of (R)alpha-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 he clinically relevant.