Functional identification of histamine H3-receptors in the human heart

Circ Res. 1995 Jul;77(1):206-10. doi: 10.1161/01.res.77.1.206.

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Separation
  • Electric Stimulation
  • Exocytosis
  • Heart / physiology*
  • Histamine Agonists / pharmacology
  • Histamine Antagonists
  • Humans
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Indoles / pharmacology
  • Methylhistamines / pharmacology
  • Myocardial Ischemia / physiopathology
  • Myocardium / chemistry*
  • Norepinephrine / metabolism
  • Piperidines / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Receptors, Histamine H3 / analysis*
  • Receptors, Histamine H3 / drug effects
  • Receptors, Histamine H3 / physiology*
  • Synaptosomes / chemistry*
  • Synaptosomes / metabolism
  • Synaptosomes / physiology*
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology

Substances

  • Histamine Agonists
  • Histamine Antagonists
  • Imidazoles
  • Indoles
  • Methylhistamines
  • Piperidines
  • Receptors, Histamine H3
  • imetit
  • alpha-methylhistamine
  • Protein Kinase C
  • Thiourea
  • thioperamide
  • Ro 31-8220
  • Norepinephrine