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


LUQ Xiao-Xing,LI Ming-Kai,HU Jing,HE Gong-Hao Department of Pharmacology,the Fourth Military Medical University,Xi'an 710032,China


<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 neurons,celiac ganglion principal neurons of the mouse,dog and monkey as well as in the vas deferens,mesenteric artery axon,and varicosities of the mouse and guinea pig. Coexistence of NE and HA was also visualized in the cardiac sympathetic axon and varicosities labeled with anterograde tracer biotinylated dextran amine.HA-like high-density immunoreactive products were seen in the small vesicles(50nm in diameter).Depolarization of cardiac sympathetic nerve endings with 50 mmol/L potassium stimulated endogenous HA release.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 blockerω-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.High K~+-evoked histamine release was inhibited by (R)-α-methylhistamine,an H_3 receptor agonist.The K~+-evoked endogenous NE release was attenuated by preloading the cardiac synaptosomes with L-histidine or quinacrine.By combination of Styryl dye FM1-43 with HA immunofluorescence histochemistry techniques,we that both intensity of HA-like red fluorescence and FM1-43 green fluorescence were simultaneously decreased with extended stimulation period.Additionally,the neurogenically released histamine evoked by 12.5 Hz of nerve stimulation on isolated guinea pig vas deferens only activated presynaptic H_3 receptors and mediate presynaptic inhibitory effects,while under 25 or 50 Hz stimulation condition, histamine simultaneously activated both presynaptic H_3 receptors and postsynaptic H_1 receptors.The application of exogenous histamine could mimic these pre-and postsynaptic effects.Our findings indicate that HA may be a newly identified sympathetic neurotransmitter and the H_3-receptor may function as an autoreceptor,rather than a heteroreceptor,in the regulation of sympathetic neurotransmission.The functions of sympathetic histamine varied according to the frequencies of sympathetic nerve stimulation.


sympathetic nerve;;superior cervical ganglia;;histamine;;histamine H_3 receptor


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