title: Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels.
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.
authors.affiliation: Department of Pharmacology, Cornell University Medical College, New York, New York.
authors.forename: M
authors.initials: M
authors.lastname: Endou
authors.forename: E
authors.initials: E
authors.lastname: Poli
authors.forename: R
authors.initials: R
authors.lastname: Levi
mesh_terms: D000320:Adrenergic Fibers / Q000502:physiology*; D000818:Animals; D016275:Atrial Function; D015220:Calcium Channels / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D019204:GTP-Binding Proteins / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000294:innervation / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D006632:Histamine; D017442:Histamine Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D037342:Pertussis Toxin; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D020866:omega-Conotoxin GVIA
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D017442:Histamine Agonists; D008761:Methylhistamines; D010455:Peptides; D018100:Receptors, Histamine H3; D010566:Virulence Factors, Bordetella; C069357:alpha-methylhistamine; D006632:Histamine; D020866:omega-Conotoxin GVIA; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D009638:Norepinephrine