The Synaptic Effects Of Sympathetic Histamine And Its Pathophysiological Roles In Acute Ischemia Induced Arrhythmia

Our previous study has found that histidine decarboxylase (HDC), the key enzyme that catalyzes the formation of histamine, was expressed in sympathetic neurons, and that histamine per se coexisted widely with norepinephrine in the bodies, axons and terminals of sympathetic neurons of different species. Moreover, histamine will release from sympathetic nerve endings upon appropriate nerve stimulation, which can be modulated by both presynaptic histamine H3 receptors andα2 adrenoceptors. Based on these points, we have proposed the viewpoints for the first time that histamine is a sympathetic neurotransmitter and that the sympathetic presynaptic histamine H3 receptor is an autoreceptor. However, what our previous study mainly focused on is the existence, the subcelluar location and the release modulation of sympathetic histamine; but some of its aspects still need to be further clarified. Specifically, it is not yet fully understood whether released HA from sympathetic nerves can activate the corresponding receptors located on the pre- or postsynaptic membrane and therefore mediate certain pre- or postsynaptic effects, what is the relationship between the synaptic effects of sympathetic histamine and sympathetic nerve activity, whether exogenous HA can mimic such effects, and what are the physiological or pathophysiological roles of sympathetic histamine. The answers of these questions comprise the key elements necessary for histamine to be defined as a sympathetic neurotransmitter.1 The release and the synaptic effects of sympathetic histamine in guinea pig vas deferensIn order to explore the pre and post synaptic effects of sympathetic histamine and the relationship between the synaptic effects and sympathetic nerve activity, the present study used guinea pig vasa deferentia as a model to observe histamine release and the contractile responses induced by different frequencies of electrical field stimulation. We found that sympathetic nerve stimulation could evoke histamine release, which was independent to mast cell degranulator compound 48/80 and mast cell stabilizer cromolyn, but was highly sensitive to Na+ channel blocker tetrodotoxin and chemical sympathectomy with 6-hydroxydopamine. The neurogenically released histamine evoked by 12.5 Hz of nerve stimulation activated only presynaptic H3 receptors and mediated presynaptic inhibitory effects, while under 25 or 50 Hz stimulation condition, histamine simultaneously activated both presynaptic H3 receptors and postsynaptic H1 receptors. However, the direct contractile responses evoked by sympathetic histamine via H1 receptors were observed at 50 Hz. Histamine release and histamine mediated contractile responses upon sympathetic nerve stimulation were significantly inhibited by pretreatment of histidine decarboxylase inhibitorα-fluoromethylhistidine. These results suggest that histamine, synthesized by histidine decarboxylase, in sympathetic neurons exerts certain synaptic effects, which may vary from presynaptic inhibition, to postsynaptic facilitation, to direct postsynaptic contractile responses according to sympathetic nerve activity.2 The mimic effects of exogenous histamine in guinea pig vas deferensIn order to further explore the function of sympathetic histamine, different concentrations of exogenous histamine were used to see whether they could mimic the effects mediated by endogenous histamine. We found that histamine evoked direct contractile responses only at concentrations over 10μM. Although exogenous histamine (10 nM - 1μM) did not induce any direct contractile responses of guinea pig vasa deferentia, it could either inhibit (10 nM) or facilitate (1μM) the contractile responses evoked by EFS at 12.5 Hz. The inhibitory effect of 10 nM of histamine was blocked by selective H3 receptor antagonist thioperamide, while the facilitory effect of 1μM of histamine was blocked by selective H3 receptor antagonist chlorpheniramine. These results further suggest that the synaptic effects of sympathetic histamine under different states of sympathetic nerve activity could be mimicked by exogenous application of histamine in both presynaptic and postsynaptic ways.3 The pathophysiological effects of sympathetic histamine in acute ischemia induced arrhythmia in mice heartsBased on the above findings, we further explored the pathophysiological effects of sympathetic histamine in acute ischemia induced arrhythmia, in which condition the heart sympathetic nerves are in an overactive state. We have observed the heart sympathetic histamine release and its relationship to arrhythmogenesis in isolated hearts of mast cell deficient mice, histidine decarboxylase knockout mice and their wild type control.We found that histamine was present in the superior cervical ganglion of mast cell deficient mice, but not in that of histidine decarboxylase knockout mice. Both electrical field stimulation and short time stop-flow (acute ischemia) induced 6-hydroxydopamine sensitive histamine release from isolated hearts of wild type mice and mast cell deficient mice. Acute ischemia also induced ventricular tachycardia and ventricular fibrillation in these two strains of mice. But in isolated hearts of histidine decarboxylase knockout mice, electrical field stimulation and acute ischemia did not show significant effects on either histamine release or arrhythmogenesis. Regression analysis revealed positive correlation between heart sympathetic histamine release and arrhythmogenesis. Furthermore, pretreatment withα-fluoromethylhistidine had inhibitory effects on the incidence and duration of acute ischemia induced ventricular tachycardia and ventricular fibrillation. Pretreatment with either selective H2 receptor antagonist famotidine orβ1 aderoceptor antagonist atenolol also significantly reduced the duration of ventricular tachycardia and ventricular fibrillation; and these two drugs showed synergistic effect when used in combination. In addition, famotidine inhibited the increase of myocardial cAMP induced by acute ischemia reperfusion in hearts of wild type mice and mast cell deficient mice but not in that of histidine decarboxylase knockout mice. These results indicate that sympathetic histamine exhibits significant promoting effects on acute ischemia induced arrhythmogenesis via postsynaptic histamine H2 receptors. The activation of heart histamine H2 receptors will exert direct positive chronotropic effects and will also facilitate the arrhythmogenic effects mediated byβ1 aderoceptors via post synaptic synergistic mechanism.In conclusion, 1) As a neurotransmitter, the released sympathetic histamine exerts the presynaptic inhibitory effect via histamine H3 receptors, and exerts corresponding postsynaptic effects via H1 or H2 receptors. 2) The postsynaptic effects of sympathetic histamine depend greatly on the activity of sympathetic nerves. 3) The exogenous histamine can mimic the synaptic effects of sympathetic histamine under different states of sympathetic nerve activity. 4) Sympathetic histamine plays important roles in acute ischemia induced arrhythmogenesis, and histamine and H2 receptors may be potential therapeutic targets in the future.