Arrhythmogenic effect of sympathetic histamine in mouse hearts subjected to acute ischemia

Mol Med. 2012 Feb 10;18(1):1-9. doi: 10.2119/molmed.2011.00225.


The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout (HDC(-/-)) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC(-/-) mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H(2) receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H(2) receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Arrhythmias, Cardiac / metabolism*
  • Atenolol / pharmacology
  • Famotidine / pharmacology
  • Heart / drug effects*
  • Heart Rate / drug effects
  • Histamine / metabolism*
  • Histamine H2 Antagonists / pharmacology
  • Histamine Release / physiology
  • Histidine Decarboxylase / genetics
  • Mice
  • Mice, Knockout
  • Myocardial Ischemia / metabolism*
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / physiopathology*
  • Myocardium
  • Norepinephrine / pharmacology
  • Sympathetic Nervous System
  • Tachycardia, Ventricular / metabolism
  • Ventricular Fibrillation / metabolism


  • Anti-Arrhythmia Agents
  • Histamine H2 Antagonists
  • Atenolol
  • Famotidine
  • Histamine
  • Histidine Decarboxylase
  • Norepinephrine