交感神经组胺的突触效应及其在急性缺血性心律失常中的病理生理功能的研究
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摘要
我们实验室前期研究发现,在交感神经元内存在有合成组胺的关键酶---组氨酸脱羧酶;组胺与去甲肾上腺素广泛共存于不同种属的交感神经元胞体、轴突以及末梢内;且亚细胞定位也显示,交感神经突触囊泡之中含有大量组胺。同时,适当的神经刺激条件下还能引发组胺自交感神经末梢释放,而释放的组胺则受到交感神经突触前组胺H3受体和α2肾上腺素受体的共同调控。基于这一系列研究发现,我们实验室率先提出了组胺是交感神经递质,且交感神经末梢组胺H3受体是一种自身受体的学术观点。但是,我们的前期研究所主要关注的是组胺在交感神经中的存在、定位以及其释放调控,而对其释放后的突触效应和生理或病理生理功能则知之甚少:交感神经组胺究竟有着怎样的突触前、后效应?其效应与交感神经的兴奋性有着怎样的关系?外源性的组胺是否能够模拟交感组胺的这些效应?此外,交感组胺又介导了怎样的病理生理作用呢?这些问题的回答将能够更为全面的定义组胺的交感神经递质身份。
1豚鼠输精管交感神经源性组胺的释放及突触效应的研究
为探讨交感神经源性组胺的突触前、后作用以及与交感神经兴奋性的关系,本研究运用电场刺激豚鼠离体输精管模型观察了不同频率电场刺激交感神经末梢所引发释放的组胺对标本收缩功能的影响。发现交感神经刺激能够诱发组胺释放,这种释放不受肥大细胞脱颗粒剂化合物48/80以及肥大细胞稳定剂色甘酸钠的影响,但对钠通道阻断剂河豚毒素以及交感神经化学损毁剂6-羟多巴胺高度敏感。当刺激频率为12.5 Hz时,释放的神经源性组胺只能够激活交感神经突触前H3受体而起到突触前抑制作用;而当刺激频率增至25或50 Hz条件时,组胺则可同时激活交感神经突触前H3受体以及突触后H1受体。但是,只有刺激频率高于50 Hz时才能观察到组胺的直接突触后收缩效应。组氨酸脱羧酶抑制剂α-fluoromethylhistidine能够显著抑制交感神经刺激所导致的组胺释放以及组胺介导的效应。提示经由组氨酸脱羧酶合成的交感神经源性组胺具有特定的突触效应,并与交感神经兴奋性密切相关。随着电场刺激频率的不同,其效应分别表现为突触前抑制、突触后易化以及直接的突触后收缩效应。
2外源性组胺对交感神经源性组胺突触效应模拟的研究
为进一步研究交感神经源性组胺的功能,本研究使用了不同浓度的外源性组胺,以观察其对内源性组胺突触作用的模拟效应。我们发现只有在浓度高于10μM时,外源性施加的组胺才能够引发直接的标本收缩效应。而尽管浓度为10 nM–1μM的外源性组胺不能够引发豚鼠输精管的直接收缩效应,但在12.5 Hz电场刺激时,浓度为10 nM和1μM的外源性组胺对于标本收缩效应分别具有抑制或者易化的作用。10 nM外源性组胺的抑制作用可被组胺H3受体阻断剂thioperamide所阻断,而1μM的外源性组胺的易化作用则可被组胺H1受体阻断剂氯苯那敏取消。这进一步提示,外源性组胺能够模拟不同神经兴奋状态下交感神经源性组胺的突触前、后作用。
3交感神经源性组胺在小鼠急性缺血性心律失常中的病理生理作用的研究
基于上述发现,为探讨交感神经源性组胺在急性缺血时交感神经过度兴奋所致的心律失常中的病理生理作用,本研究观察了其在肥大细胞缺失小鼠、组氨酸脱羧酶敲除小鼠以及野生型对照小鼠离体心脏中的分布和释放情况,并分析了对于室性心动过速和室颤等严重室性心律失常发生的影响。
结果发现组胺在肥大细胞缺失小鼠的颈上神经节神经元中仍有分布;而在组氨酸脱羧酶敲除小鼠颈上神经节中则没有。电场刺激心脏交感神经或短时程停灌模拟急性缺血刺激均可促发野生型和肥大细胞缺失小鼠离体灌流心脏标本中释放对6-羟多巴胺预处理敏感的组胺,同时短时程停灌还能诱发明显的室性心动过速和室颤。但上述刺激因素对组氨酸脱羧酶缺失小鼠心脏标本组胺释放以及室性心律失常的发生却没有显著影响。小鼠离体灌流心脏标本复灌后室性心动过速和室颤的持续时间与其释放的组胺呈正相关。此外,α-fluoromethylhistidine预处理可以抑制肥大细胞缺失小鼠离体心脏标本短时程停灌后室性心动过速和室颤的发生率和持续时间;而组胺H2受体阻断剂法莫替丁和β1肾上腺素受体阻断剂阿替洛尔预处理同样可以显著减轻野生型和肥大细胞缺失小鼠离体心脏室性心律失常的持续时间,且二者具有协同作用。法莫替丁还能够显著抑制野生型和肥大细胞缺失小鼠心脏标本停灌复灌所致的心肌cAMP含量的上升,但对于组氨酸脱羧酶缺失小鼠心脏标本则无显著影响。提示交感神经源性组胺对于急性缺血性心律失常的发生有着显著的促进作用,其通过激动突触后组胺H2受体一方面产生直接的正性变时作用,另一方面易化β1肾上腺素受体从而增强去甲肾上腺素的致心律失常效应。
综上,本研究得出以下结论:(1)交感神经源性组胺释放后可通过激活交感神经突触前组胺H3受体产生突触前抑制,并通过激活突触后H1或H2受体产生相应的突触后作用;(2)交感神经源性组胺的突触后作用与交感神经兴奋程度密切相关;(3)外源性组胺可以模拟交感神经源性组胺在不同神经兴奋状态下的突触作用;(4)交感神经源性组胺在急性缺血性心律失常的发生发展中具有重要的病理生理作用,组胺及其H2受体可能是今后治疗急性缺血性心律失常的新靶点。
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 deferens
In 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 deferens
In 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 hearts
Based 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.
1豚鼠输精管交感神经源性组胺的释放及突触效应的研究
为探讨交感神经源性组胺的突触前、后作用以及与交感神经兴奋性的关系,本研究运用电场刺激豚鼠离体输精管模型观察了不同频率电场刺激交感神经末梢所引发释放的组胺对标本收缩功能的影响。发现交感神经刺激能够诱发组胺释放,这种释放不受肥大细胞脱颗粒剂化合物48/80以及肥大细胞稳定剂色甘酸钠的影响,但对钠通道阻断剂河豚毒素以及交感神经化学损毁剂6-羟多巴胺高度敏感。当刺激频率为12.5 Hz时,释放的神经源性组胺只能够激活交感神经突触前H3受体而起到突触前抑制作用;而当刺激频率增至25或50 Hz条件时,组胺则可同时激活交感神经突触前H3受体以及突触后H1受体。但是,只有刺激频率高于50 Hz时才能观察到组胺的直接突触后收缩效应。组氨酸脱羧酶抑制剂α-fluoromethylhistidine能够显著抑制交感神经刺激所导致的组胺释放以及组胺介导的效应。提示经由组氨酸脱羧酶合成的交感神经源性组胺具有特定的突触效应,并与交感神经兴奋性密切相关。随着电场刺激频率的不同,其效应分别表现为突触前抑制、突触后易化以及直接的突触后收缩效应。
2外源性组胺对交感神经源性组胺突触效应模拟的研究
为进一步研究交感神经源性组胺的功能,本研究使用了不同浓度的外源性组胺,以观察其对内源性组胺突触作用的模拟效应。我们发现只有在浓度高于10μM时,外源性施加的组胺才能够引发直接的标本收缩效应。而尽管浓度为10 nM–1μM的外源性组胺不能够引发豚鼠输精管的直接收缩效应,但在12.5 Hz电场刺激时,浓度为10 nM和1μM的外源性组胺对于标本收缩效应分别具有抑制或者易化的作用。10 nM外源性组胺的抑制作用可被组胺H3受体阻断剂thioperamide所阻断,而1μM的外源性组胺的易化作用则可被组胺H1受体阻断剂氯苯那敏取消。这进一步提示,外源性组胺能够模拟不同神经兴奋状态下交感神经源性组胺的突触前、后作用。
3交感神经源性组胺在小鼠急性缺血性心律失常中的病理生理作用的研究
基于上述发现,为探讨交感神经源性组胺在急性缺血时交感神经过度兴奋所致的心律失常中的病理生理作用,本研究观察了其在肥大细胞缺失小鼠、组氨酸脱羧酶敲除小鼠以及野生型对照小鼠离体心脏中的分布和释放情况,并分析了对于室性心动过速和室颤等严重室性心律失常发生的影响。
结果发现组胺在肥大细胞缺失小鼠的颈上神经节神经元中仍有分布;而在组氨酸脱羧酶敲除小鼠颈上神经节中则没有。电场刺激心脏交感神经或短时程停灌模拟急性缺血刺激均可促发野生型和肥大细胞缺失小鼠离体灌流心脏标本中释放对6-羟多巴胺预处理敏感的组胺,同时短时程停灌还能诱发明显的室性心动过速和室颤。但上述刺激因素对组氨酸脱羧酶缺失小鼠心脏标本组胺释放以及室性心律失常的发生却没有显著影响。小鼠离体灌流心脏标本复灌后室性心动过速和室颤的持续时间与其释放的组胺呈正相关。此外,α-fluoromethylhistidine预处理可以抑制肥大细胞缺失小鼠离体心脏标本短时程停灌后室性心动过速和室颤的发生率和持续时间;而组胺H2受体阻断剂法莫替丁和β1肾上腺素受体阻断剂阿替洛尔预处理同样可以显著减轻野生型和肥大细胞缺失小鼠离体心脏室性心律失常的持续时间,且二者具有协同作用。法莫替丁还能够显著抑制野生型和肥大细胞缺失小鼠心脏标本停灌复灌所致的心肌cAMP含量的上升,但对于组氨酸脱羧酶缺失小鼠心脏标本则无显著影响。提示交感神经源性组胺对于急性缺血性心律失常的发生有着显著的促进作用,其通过激动突触后组胺H2受体一方面产生直接的正性变时作用,另一方面易化β1肾上腺素受体从而增强去甲肾上腺素的致心律失常效应。
综上,本研究得出以下结论:(1)交感神经源性组胺释放后可通过激活交感神经突触前组胺H3受体产生突触前抑制,并通过激活突触后H1或H2受体产生相应的突触后作用;(2)交感神经源性组胺的突触后作用与交感神经兴奋程度密切相关;(3)外源性组胺可以模拟交感神经源性组胺在不同神经兴奋状态下的突触作用;(4)交感神经源性组胺在急性缺血性心律失常的发生发展中具有重要的病理生理作用,组胺及其H2受体可能是今后治疗急性缺血性心律失常的新靶点。
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 deferens
In 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 deferens
In 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 hearts
Based 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.
引文
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