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 n orepinephrine release, we searched for the presence of H-3-receptors d irectly in sympathetic nerve endings (cardiac synaptosomes) isolated f rom 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 a nd imetit reduced norepinephrine release, and the specific H-3-recepto r antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca2+-channel bloc ker omega-conotoxin and the protein kinase C inhibitor Ro31-8220. Func tional relevance of these H-3-receptors was obtained by showing that t ransmural electrical stimulation of sympathetic nerve endings in human atrial tissue increased contractility, an effect blocked by propranol ol and attenuated in a concentration-dependent manner by (R)alpha-meth ylhistamine. Also. thioperamide antagonized the effect of (R)alpha-met hylhistamine. Our findings are the first demonstration that H-3-recept ors are present in sympathetic nerve endings in the human heart, where they modulate adrenergic responses by inhibiting norepinephrine relea se. Since myocardial ischemia causes intracardiac histamine release. H -3-receptor-induced attenuation of sympathetic neurotransmission may h e clinically relevant.