Functional identification of histamine H3-receptors in the human heart.
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.
Imamura
M
M
Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
Seyedi
N
N
Lander
H M
HM
Levi
R
R
D002469:Cell Separation; D004558:Electric Stimulation; D005089:Exocytosis; D006321:Heart / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008761:Methylhistamines / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000503:physiopathology; D009206:Myocardium / Q000737:chemistry*; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D018100:Receptors, Histamine H3 / Q000032:analysis* / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D007211:Indoles; D008761:Methylhistamines; D010880:Piperidines; D018100:Receptors, Histamine H3; C077430:imetit; C069357:alpha-methylhistamine; D011493:Protein Kinase C; D013890:Thiourea; C052075:thioperamide; C064758:Ro 31-8220; D009638:Norepinephrine