Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels

J Pharmacol Exp Ther. 1994 Apr;269(1):221-9.

Abstract

Discovered as inhibitory autoreceptors in central histaminergic pathways, histamine H3-receptors may also modulate peripheral cholinergic and central adrenergic function. Recently, H3-receptors were reported to inhibit adrenergic inotropic responses in guinea pig atria, possibly at prejunctional sites. We have assessed whether the H3-mediated modulation of cardiac adrenergic activities results from a reduction in norepinephrine release. We have found that (R) alpha-methylhistamine, the selective histamine H3-receptor agonist, attenuates the inotropic and chronotropic response of isolated guinea pig atria to transmural stimulation of adrenergic nerve endings. This attenuation was associated with a marked reduction in endogenous norepinephrine release. In contrast (R) alpha-methylhistamine did not modify the chronotropic effect of exogenous norepinephrine. The attenuation of adrenergic responses by (R) alpha-methylhistamine was 1) prevented by thioperamide, the selective H3-receptor antagonist; 2) attenuated by pertussis-toxin pretreatment and 3) potentiated by the N-type Ca(++)-channel blocker omega-conotoxin, which also potentiated the sympathetic modulatory effects of adrenergic-alpha 2 and adenosine-A1 receptor agonists. Our findings indicate that prejunctional histamine H3-receptors modulate the depolarization-dependent norepinephrine release from sympathetic nerve endings in the guinea pig myocardium. These receptors are probably coupled to a pertussis-toxin-sensitive Gi/Go protein and probably effect a reduction in Ca++ current. We have previously reported that sympathetic stimulation elicits a frequency-dependent release of cardiac histamine, whereas others had found that adrenergic activity regulates histamine's rapid turnover pool. Accordingly, presynaptic H3-receptors are likely to serve a modulatory role in cardiac adrenergic function.

Publication types

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

MeSH terms

  • Adrenergic Fibers / physiology*
  • Animals
  • Atrial Function
  • Calcium Channels / physiology*
  • Cardiotonic Agents / pharmacology
  • Drug Synergism
  • Electric Stimulation
  • GTP-Binding Proteins / physiology*
  • Guinea Pigs
  • Heart / drug effects*
  • Heart / innervation
  • Heart / physiology*
  • Heart Atria / drug effects
  • Histamine
  • Histamine Agonists / pharmacology
  • In Vitro Techniques
  • Male
  • Methylhistamines / pharmacology
  • Myocardial Contraction / drug effects
  • Norepinephrine / metabolism
  • Norepinephrine / pharmacology
  • Peptides / pharmacology*
  • Pertussis Toxin*
  • Receptors, Histamine H3 / drug effects*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / physiology
  • Virulence Factors, Bordetella / pharmacology*
  • omega-Conotoxin GVIA

Substances

  • Calcium Channels
  • Cardiotonic Agents
  • Histamine Agonists
  • Methylhistamines
  • Peptides
  • Receptors, Histamine H3
  • Virulence Factors, Bordetella
  • alpha-methylhistamine
  • Histamine
  • omega-Conotoxin GVIA
  • Pertussis Toxin
  • GTP-Binding Proteins
  • Norepinephrine