Evidence For Histamine As A New Neurotransmitter In Cardiac Sympathetic Nerve System

Our previous study and others demonstrated that histamine H3 receptor represented an inhibitory presynaptic receptor localized on cardiac sympathetic nerve terminals of guinea pig, once activated by selective ligands, histamine H3 receptor inhibited norepinephrine release by sympathetic nerve stimulation and the associated inotropic responses. But litter is known about the source of endogenous histamine that activates modulatory histamine H3 receptor on the adrenergic nerve terminals in cardiovascular tissues.We further found the expression of histidine decarboxylase (HDC) mRNA in the superior cervical ganglia of guinea pig, and the co-localization of histamine and tyrosine hydroxylase (TH) in the superior cervical ganglia of guinea pig and release of histamine from cardiac sympathetic terminals in guinea pig isolated atrium. The potential role of cardiac sympathetic histamine might be able to modulate sympathetic transmission via histamine H3 receptors.Therefore, the aim of the present study is to directly demonstrate that histamine can be biosynthesized and stored in the cardiac sympathetic nerve system, released from the sympathetic nerve terminal and to determine whether endogenous histamine can modulate the release of endogenous histamine and norepinephrine from adrenergic nerve terminals through the presynaptic histamine H3 receptor.1 The exist of histamine in the superior cervical ganglia of guinea pig and macaca mulatto monkeyThe co-localization of histamine and dopamine- P -hydroxylase(D 3 H) or norepinephrine was examined by a double immunofluerescence. Staining for histamine was localized to the neuronal soma of principal neurons within superior cervical ganglia of guinea pig and macaca mulatto monkey. The coexistence of histamine and dopamine- P -hydroxylase, norepinephrine was identified in the same neuronal cell. The immunoreactivities of both histamine and norepinephrine were significantly attenuated after chemical sympathetic nerve axotomy with administration of 6-hydroxydopamine.2 The distribution of histamine in the fibers from superior cervical ganglia to heart of guinea pigUsing fluorescent antegrade labeling technology, we detected the distribution of fibers from the superior cervical ganglia to the sino-atrial node atrium and ventricle of guinea pig, and we further detected the localization of histamine in the fibers from the superior cervical ganglia to the left and right atrium. It indicated that once synthesized in the superior cervical ganglia, histamine could be transmitted from the superior cervical ganglia to the heart and released from the terminal.3 Bioynthesis, storage, release and metabolism of histamine in the cardiac synaptosomesFunctional evidence evaluated that histamine was released from the cardiac sympathetic nerve terminals isolated from the guinea pig and mucaca mulatto monkey heart, and the high K+-induced release of cardiac sympathetic histamine was depended on the extracellular Ca2+ via the N-type Ca2+-channel. It was not compound 48/80 but 6-OHDA could affect release of histamine from the cardiac synaptosomes; it suggested that the endogenous histamine was not from mast cells, but from cardiac sympathetic nerve system. Pre-incubation with L-histidine (precursor of histamine) or inhibition of the activity of histamine N-methyltransferase using quinacrine could increase the release of histamine from cardiac sympathetic nerve terminals, and inhibition of the HDC activity using a -FMH could decrease the release of histamine from L-histidine preload synaptosomes, it suggested that cardiac sympathetic histamine was decarboxylased by histidine.decarboxylase from L-histidine, released from the terminal and inactived by histamine N-methyltransferase. 4 Histamine H3 receptor activation and modulation of histamine and norepinephrine release from cardiac synaptosomesWe next assessed whether activation of histamine H3 receptors modulates release of histamine from cardiac sympathetic nerve terminals. The histamine H3 receptor agonist (R)- a -methylhistamirie (a -MH, 0.3 umol/L) attenuated the high K+-evoked histamine release from the cardiac synaptosomes. While pre-incubated with 0.3 umol/L thioperamide (the histamine H3 receptor antagonist), it reversed the effect of not only a -MH, but also of the endogenous histamine which could activate the histamine H3 receptor and...