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Evidence for histamine as a neurotransmitter in the cardiac sympathetic nervous system

【摘要】:正Sympathetic nerve endings are endowed with auto-inhibitory histamine(HA) H_3 receptors.Activation of H_3 receptors inhibits sympathetic neurotransmission.However little is known about the origin of the endogenous HA that activates presynaptic H_3 receptors on sympathetic terminals.The present study provides direct evidence to demonstrate the coexistence of HA and norepinephrine(NE) within sympathetic neurons,and reveals the modulation mechanisms of HA release from sympathetic terminals.The colocalization of HA and NE immunoreactivities was identified within superior cervical ganglia(SCG) neurons,celiac ganglion principal neurons of the mouse,dog and monky as well as in the vas deferens,mesenteric artery axon,and varicosities of the mouse and guinea pig.HA and NE immunoreactivity levels were significantly attenuated after chemical sympathectomy with 6-hydroxydopamine(6-OHDA).Coexistence of NE and HA was also visualized in the cardiac sympathetic axon and varicosities labeled with anterograde tracer biotinylated dextran amine.Using pre-embedding immunoelectron microscopy,HA-like high-density immunoreactive products were seen in the small vesicles(50 nm in diameter) of the guinea pig vas deferens and cultured guinea pig SCG neurons. Depolarization of cardiac sympathetic nerve endings(synaptosomes) with 50 mM potassium stimulated endogenous HA release,which was significantly attenuated by 6-OHDA or a vesicular monoamine transporter 2(VMAT2) inhibitor reserpine pretreatments.Compound 48/80,a mast cell releaser,did not affect cardiac synaptosome HA exocytosis.Furthermore, K~+ evoked HA release was abolished by the N-type Ca~(2+)-channel blocker w-conotoxin,but was not affected by the L-type Ca~(2+)-channel blocker lacidipine.Cardiac synaptosome HA exocytosis was augmented by the enhanced synthesis of HA or the inhibition of HA metabolism.HA H_3-receptor activation by(R)-a-methylhistamine inhibited high K~+-evoked histamine release.The HA H_3 receptor antagonist thioperamide enhanced K~+-evoked HA release and blocked the(R)-α-methylhistamine effect.The K~+-evoked endogenous NE release was attenuated by preloading the cardiac synaptosomes with L-histidine or quinacrine.These inhibitory effects were reversed by thioperamide or antagonized byα-fluoromethylhistidine. By combination of Styryl dye FM1-43 with HA immunofluorescence histochemistry techniques,we further measure the mobility of HA synaptic vesicles in the cultured guinea pig SCG neuron boutons.The results showed that both intensity of HA-like red fluorescence and FM1-43 green fluorescence were simultaneously decreased with extended stimulation period.The results of FRAP measurement and HA immunohistochemistry indicated that the diffusion coefficient of HA vesicles in cultured SCG neuron boutons was 0.09μm~2/s,which was almost similar to diffusion coefficient of other classical vesicles.Our findings indicate that HA widely existed in sympathetic system of different species and was localized in small synaptic vesicles of sympathetic nerve.HA could be released from sympathetic terminals during stimulation.Co-release of NE and HA from sympathetic nerve may be inhibited by endogenous HA via activation of presynaptic HA H_3-receptors.The H_3-receptor may function as an autoreceptor,rather than a heteroreceptor, in the regulation of sympathetic neurotransmission,and HA may be a novel sympathetic neurotransmitter.

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