心迷走节前神经元氨基酸能传入的相互影响及P物质和开胃素的调制
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摘要
心率和心功能的调节是由心迷走神经主导的。心迷走节前神经元(CVN)主要位于延髓疑核(NA),少部分位于迷走背核(DMNV)以及疑核与迷走背核之间的中间带。CVN因缺乏“起搏细胞”样特性而不能自主性发放,它们的活动完全依赖其突触传入。CVN接受兴奋性谷氨酸能和胆碱能传入,以及抑制性GABA能和甘氨酸能传入。
研究CVN突触传入的相互作用和调制对理解这些神经元的神经调控是非常重要的。既往的研究发现CVN的兴奋性和抑制性氨基酸能突触传入都可被烟碱受体激活所易化,而且呼吸性窦性心律的产生部分由GABA能突触传递的胆碱能易化所引起。已知,氨基酸能神经是CVN的主要突触传入,然而,它们是否、以及如何在调节这些神经元中相互作用尚不了解。这一问题如果放在癫痫病理背景下考虑,变得尤其重要。癫痫发作与抑制性突触传递下降有关,但癫痫发作时CVN的发放行为模式目前尚不知道。因此,本研究的第一个目的是探讨CVN的兴奋性和抑制性氨基酸能突触传入之间的相互作用,并验证“CVN在癫痫诱导条件下以痫样(seizure-like)模式发放”的假说。
许多神经肽可通过作用于中枢调节心率和心功能。而包括心血管疾病在内的某些疾病,其发生发展与特定神经肽在中枢的释放和结合力改变有关。而有些神经肽已被发现通过调制CVN氨基酸能突触传入影响心迷走活动。
Orexin-A和orexin-B是一族新的神经肽成员,由外侧下丘脑和穹隆周围的神经元产生。有证据表明Orexin参与心率和心功能的中枢迷走控制,但在突触水平其机制尚不清楚。Orexin是否对CVN的GABA能和甘氨酸能突触传入有不同的调制作用,并由此使两种抑制性突触传入对CVN产生不同的调节,也缺乏研究。本研究的第二个目的是研究orexin-A对CVN的GABA能和甘氨酸能突触传入的调制作用。
P物质(SP)早被发现与心率和心功能的中枢迷走调控有关。但在突触水平,对SP如何影响CVN的活动所知甚少。这一问题如果与一些重要心血管疾病如心肌缺血和高血压一起考虑,就显得更为重要。心肌缺血和高血压患者伴有心迷走张力和心率变异性降低,其程度与心性猝死发生率的升高相关。心肌缺血和高血压时内脏传入末梢释放SP增加、与脑干神经核的结合力升高。但是,关于中枢SP浓度和结合力的变化是否与呼吸性心律变异性的降低有关尚无证据。本研究的第三个目的是研究SP是否可通过直接作用于CVN、或作用于CVN的氨基酸能突触传入来影响这些神经元的活动;研究SP是否可影响CVN抑制性突触传入的吸气性增强,并由此改变心律的呼吸性变异。
实验在新生SD幼年大鼠进行。通过在心脏基底部脂肪垫或心包内注射rhodamine逆行标记CVN。在脑片用荧光鉴定CVN,并用膜片钳方法研究。在一些有自主呼吸节律的脑片,还通过抑制性突触传入的吸气性增强这一特征鉴定CVN。
实验结果和结论如下:
1.支配迷走背核内CVN的GABA能神经元接受紧张性谷氨酸能调控,而支配疑核内CVN的GABA能神经元很少或不接受紧张性谷氨酸能调控。这些结果提示迷走背核内CVN的调控与疑核内CVN的调控是不同的。这种差异可能使疑核内CVN和迷走背核内CVN在心率和心功能的迷走调控中起不同的作用。
2.在阻断抑制性突触传递条件下,CVN在电压钳下产生间歇性兴奋性内向电流,或在电流钳下产生间歇性痫样放电。CVN的这种痫样激活与舌下神经运动神经元的痫样放电同步。这些结果提供了新的证据,提示癫痫时CVN可能以痫样模式发放。而这种发放模式可能与癫痫病人发作时的神经源性发作性心动过缓、心跳骤停、甚至猝死有关。
3.Orexin-A剂量依赖性地增加CVN的GABA能和甘氨酸能自发性抑制性突触后电流(sIPSCs)的频率,且甘氨酸能sIPSCs对Orexin-A的反应比GABA能sIPSCs更为敏感,提示这两类突触传入都能抑制CVN,但在心迷走功能的突触调控中可能有不同的作用。
4.P物质增强CVN的GABA能和甘氨酸能突触传入,并减弱这些突触传入的吸气性增强。提示P物质可抑制心迷走活动,并抑制心迷走活动的呼吸性变异。这一机制可能与心肌缺血和高血压时心迷走活动减弱、心率变异性降低有关。
The physiological control of heart rate and cardiac functions is dominated by the activity of the parasympathetic nerves. Preganglionic cardiac vagal neurons (the CVNs) are primarily located in the nucleus ambiguus (NA), although some can also be found in the dorsal motor nucleus of the vagus (DMNV) and in the intermediate zone between the NA and the DMNV. The CVNs are intrinsically silent, and their activity relies completely on their synaptic inputs. The CVNs receive excitatory glutamatergic and cholinergic inputs, and inhibitory GABAergic and glycinergic inputs.
Studying the interaction and modulation of the synaptic inputs of the CVNs are critically important in understanding neural control of these neurons. Previous both excitatory and inhibitory amino acidergic inputs of the CVNs have been proved to be facilitated by nicotinic cholinergic receptors, and the nicotinic facilitation of the GABAergic inputs has been proved to be related to the genesis of respiratory sinus arrhythmia. However the amino acidergic inputs, the major synaptic inputs of the CVNs, have not been well understood with regard to whether and how they interact each other in controlling these neurons. This issue becomes particularly significant if considered under the background of epilepsy or seizures, since little is known about the firing behavior of the CVNs during epileptic attacks, which are well known to be related to decreased function of inhibitory neurotransmission. Thus, the first purpose of the present study is to investigate the interaction between the excitatory and the inhibitory amino acidergic inputs of the CVNs, and to test the hypothesis that the CVNs fire in seizure-like pattern under seizure-evoking condition.
Many neuropeptides regulate heart rate and cardiac functions through their central actions; and altered central release and binding of certain neuropeptides are related to some diseases including cardiovascular disorders. Some neuropeptides have been proved to affect cardiac vagal activity by modulating the amino acidergic inputs of the CVNs.
Orexin-A and orexin-B, also known as hypocretin-1 and hypocretin-2, are members of a new family of neuropeptides synthesized in the lateral hypothalamus and perifornical area neurons. Some evidence suggests that orexins might have a role in the parasympathetic control of heart rate and cardiac functions. However, the mechanisms by which orexins affect the CVNs are not clear at the synaptic level, and it is not known whether the GABAergic inputs and the glycinergic inputs are differentially regulated by orexins, and by which to play different roles in the control of the CVNs. The second purpose of the present study is to evaluate the effects of orexin-A on the glycinergic and the GABAergic inputs of the CVNs.
Substance P (SP) has long been indicated to be involved in the vagal control of heart rate and cardiac functions. However, little is known about how SP alters the activity of the CVNs at synaptic level. This issue is more significant if considered with some important cardiovascular diseases such as myocardial ischemia and hypertension. Myocardial ischemia and hypertension are known to have diminished cardiac vagal tone and heart rate variability (including the respiratory-related), which have been well proved to be correlated with increased incidence of sudden cardiac death. It has also been found that these diseases have increased SP release from visceral afferents and enhanced SP binding in brainstem nuclei. However whether the increased central SP concentration and enhanced central SP binding are related to the diminished respiratory-related heart rate variability is not known. The third purpose of the present study is to test whether SP affects the CVNs directly or by acting on their amino acidergic inputs, and whether SP affects the respiratory-related enhancement of the inhibitory amino acidergic inputs, and by which to alter the respiratory-related heart rate variability.
The CVNs were retrogradedly labeled by injecting rhodamine into the fat pads of the heart or into the cardiac sac of newborn rats. The CVNs were identified by presence of fluorescence in brainstem slices and studied using patch-clamp. In some slices with respiratory-like rhythm the CVNs were functionally identified by presence of inspiratory-related augmentation of their inhibitory inputs.
Following are the results and conclusions:
1. The GABAergic neurons preceding the CVNs in the DMNV are tonically excited by glutamatergic inputs, whereas the GABAergic neurons preceding the CVNs in the NA receive little, if any, glutamatergic control. These findings indicated that the CVNs in the DMNV are differentially regulated from the CVNs in the NA, which may be a possible mechanism that enables the CVNs in the DMNV to play different roles from those in the NA in the parasympathetic control of heart rate and cardiac functions.
2. Blockade of inhibitory neurotransmission evoked intermittent seizure-like activation of the CVNs, as was recorded as intermittent excitatory inward currents (IEICs) under voltage clamp and intermittent seizure-like firing under current clamp. The seizure-like activation of the CVNs was in synchrony with that of the hypoglossal motor neurons. These results have given new evidence that the CVNs might fire in a seizure-like pattern during epileptic attack, which might be responsible for the neurogenic ictal bradyarrhythmia, cardiac asystole, or even the sudden deaths of patients of epilepsy.
3. Orexin-A dose-dependently increased the frequency of both the glycinergic and the GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) of the CVNs; the glycinergic neurons preceding the CVNs were more sensitive to orexin-A than the GABAergic neurons preceding the CVNs, which might indicate that these two kinds of inhibitory neurons play different roles in the synaptic control of the CVNs.
4. SP enhanced the GABAergic and the glycinergic inputs of the CVNs, and diminished the inspiratory-related augmentation of these inputs. These results suggested that SP inhibits cardiac vagal activity and diminishes its respiratory-related variability, which might be related to the weakened cardiac vagal tone and heart rate variability in myocardial ischemia and hypertension.
研究CVN突触传入的相互作用和调制对理解这些神经元的神经调控是非常重要的。既往的研究发现CVN的兴奋性和抑制性氨基酸能突触传入都可被烟碱受体激活所易化,而且呼吸性窦性心律的产生部分由GABA能突触传递的胆碱能易化所引起。已知,氨基酸能神经是CVN的主要突触传入,然而,它们是否、以及如何在调节这些神经元中相互作用尚不了解。这一问题如果放在癫痫病理背景下考虑,变得尤其重要。癫痫发作与抑制性突触传递下降有关,但癫痫发作时CVN的发放行为模式目前尚不知道。因此,本研究的第一个目的是探讨CVN的兴奋性和抑制性氨基酸能突触传入之间的相互作用,并验证“CVN在癫痫诱导条件下以痫样(seizure-like)模式发放”的假说。
许多神经肽可通过作用于中枢调节心率和心功能。而包括心血管疾病在内的某些疾病,其发生发展与特定神经肽在中枢的释放和结合力改变有关。而有些神经肽已被发现通过调制CVN氨基酸能突触传入影响心迷走活动。
Orexin-A和orexin-B是一族新的神经肽成员,由外侧下丘脑和穹隆周围的神经元产生。有证据表明Orexin参与心率和心功能的中枢迷走控制,但在突触水平其机制尚不清楚。Orexin是否对CVN的GABA能和甘氨酸能突触传入有不同的调制作用,并由此使两种抑制性突触传入对CVN产生不同的调节,也缺乏研究。本研究的第二个目的是研究orexin-A对CVN的GABA能和甘氨酸能突触传入的调制作用。
P物质(SP)早被发现与心率和心功能的中枢迷走调控有关。但在突触水平,对SP如何影响CVN的活动所知甚少。这一问题如果与一些重要心血管疾病如心肌缺血和高血压一起考虑,就显得更为重要。心肌缺血和高血压患者伴有心迷走张力和心率变异性降低,其程度与心性猝死发生率的升高相关。心肌缺血和高血压时内脏传入末梢释放SP增加、与脑干神经核的结合力升高。但是,关于中枢SP浓度和结合力的变化是否与呼吸性心律变异性的降低有关尚无证据。本研究的第三个目的是研究SP是否可通过直接作用于CVN、或作用于CVN的氨基酸能突触传入来影响这些神经元的活动;研究SP是否可影响CVN抑制性突触传入的吸气性增强,并由此改变心律的呼吸性变异。
实验在新生SD幼年大鼠进行。通过在心脏基底部脂肪垫或心包内注射rhodamine逆行标记CVN。在脑片用荧光鉴定CVN,并用膜片钳方法研究。在一些有自主呼吸节律的脑片,还通过抑制性突触传入的吸气性增强这一特征鉴定CVN。
实验结果和结论如下:
1.支配迷走背核内CVN的GABA能神经元接受紧张性谷氨酸能调控,而支配疑核内CVN的GABA能神经元很少或不接受紧张性谷氨酸能调控。这些结果提示迷走背核内CVN的调控与疑核内CVN的调控是不同的。这种差异可能使疑核内CVN和迷走背核内CVN在心率和心功能的迷走调控中起不同的作用。
2.在阻断抑制性突触传递条件下,CVN在电压钳下产生间歇性兴奋性内向电流,或在电流钳下产生间歇性痫样放电。CVN的这种痫样激活与舌下神经运动神经元的痫样放电同步。这些结果提供了新的证据,提示癫痫时CVN可能以痫样模式发放。而这种发放模式可能与癫痫病人发作时的神经源性发作性心动过缓、心跳骤停、甚至猝死有关。
3.Orexin-A剂量依赖性地增加CVN的GABA能和甘氨酸能自发性抑制性突触后电流(sIPSCs)的频率,且甘氨酸能sIPSCs对Orexin-A的反应比GABA能sIPSCs更为敏感,提示这两类突触传入都能抑制CVN,但在心迷走功能的突触调控中可能有不同的作用。
4.P物质增强CVN的GABA能和甘氨酸能突触传入,并减弱这些突触传入的吸气性增强。提示P物质可抑制心迷走活动,并抑制心迷走活动的呼吸性变异。这一机制可能与心肌缺血和高血压时心迷走活动减弱、心率变异性降低有关。
The physiological control of heart rate and cardiac functions is dominated by the activity of the parasympathetic nerves. Preganglionic cardiac vagal neurons (the CVNs) are primarily located in the nucleus ambiguus (NA), although some can also be found in the dorsal motor nucleus of the vagus (DMNV) and in the intermediate zone between the NA and the DMNV. The CVNs are intrinsically silent, and their activity relies completely on their synaptic inputs. The CVNs receive excitatory glutamatergic and cholinergic inputs, and inhibitory GABAergic and glycinergic inputs.
Studying the interaction and modulation of the synaptic inputs of the CVNs are critically important in understanding neural control of these neurons. Previous both excitatory and inhibitory amino acidergic inputs of the CVNs have been proved to be facilitated by nicotinic cholinergic receptors, and the nicotinic facilitation of the GABAergic inputs has been proved to be related to the genesis of respiratory sinus arrhythmia. However the amino acidergic inputs, the major synaptic inputs of the CVNs, have not been well understood with regard to whether and how they interact each other in controlling these neurons. This issue becomes particularly significant if considered under the background of epilepsy or seizures, since little is known about the firing behavior of the CVNs during epileptic attacks, which are well known to be related to decreased function of inhibitory neurotransmission. Thus, the first purpose of the present study is to investigate the interaction between the excitatory and the inhibitory amino acidergic inputs of the CVNs, and to test the hypothesis that the CVNs fire in seizure-like pattern under seizure-evoking condition.
Many neuropeptides regulate heart rate and cardiac functions through their central actions; and altered central release and binding of certain neuropeptides are related to some diseases including cardiovascular disorders. Some neuropeptides have been proved to affect cardiac vagal activity by modulating the amino acidergic inputs of the CVNs.
Orexin-A and orexin-B, also known as hypocretin-1 and hypocretin-2, are members of a new family of neuropeptides synthesized in the lateral hypothalamus and perifornical area neurons. Some evidence suggests that orexins might have a role in the parasympathetic control of heart rate and cardiac functions. However, the mechanisms by which orexins affect the CVNs are not clear at the synaptic level, and it is not known whether the GABAergic inputs and the glycinergic inputs are differentially regulated by orexins, and by which to play different roles in the control of the CVNs. The second purpose of the present study is to evaluate the effects of orexin-A on the glycinergic and the GABAergic inputs of the CVNs.
Substance P (SP) has long been indicated to be involved in the vagal control of heart rate and cardiac functions. However, little is known about how SP alters the activity of the CVNs at synaptic level. This issue is more significant if considered with some important cardiovascular diseases such as myocardial ischemia and hypertension. Myocardial ischemia and hypertension are known to have diminished cardiac vagal tone and heart rate variability (including the respiratory-related), which have been well proved to be correlated with increased incidence of sudden cardiac death. It has also been found that these diseases have increased SP release from visceral afferents and enhanced SP binding in brainstem nuclei. However whether the increased central SP concentration and enhanced central SP binding are related to the diminished respiratory-related heart rate variability is not known. The third purpose of the present study is to test whether SP affects the CVNs directly or by acting on their amino acidergic inputs, and whether SP affects the respiratory-related enhancement of the inhibitory amino acidergic inputs, and by which to alter the respiratory-related heart rate variability.
The CVNs were retrogradedly labeled by injecting rhodamine into the fat pads of the heart or into the cardiac sac of newborn rats. The CVNs were identified by presence of fluorescence in brainstem slices and studied using patch-clamp. In some slices with respiratory-like rhythm the CVNs were functionally identified by presence of inspiratory-related augmentation of their inhibitory inputs.
Following are the results and conclusions:
1. The GABAergic neurons preceding the CVNs in the DMNV are tonically excited by glutamatergic inputs, whereas the GABAergic neurons preceding the CVNs in the NA receive little, if any, glutamatergic control. These findings indicated that the CVNs in the DMNV are differentially regulated from the CVNs in the NA, which may be a possible mechanism that enables the CVNs in the DMNV to play different roles from those in the NA in the parasympathetic control of heart rate and cardiac functions.
2. Blockade of inhibitory neurotransmission evoked intermittent seizure-like activation of the CVNs, as was recorded as intermittent excitatory inward currents (IEICs) under voltage clamp and intermittent seizure-like firing under current clamp. The seizure-like activation of the CVNs was in synchrony with that of the hypoglossal motor neurons. These results have given new evidence that the CVNs might fire in a seizure-like pattern during epileptic attack, which might be responsible for the neurogenic ictal bradyarrhythmia, cardiac asystole, or even the sudden deaths of patients of epilepsy.
3. Orexin-A dose-dependently increased the frequency of both the glycinergic and the GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) of the CVNs; the glycinergic neurons preceding the CVNs were more sensitive to orexin-A than the GABAergic neurons preceding the CVNs, which might indicate that these two kinds of inhibitory neurons play different roles in the synaptic control of the CVNs.
4. SP enhanced the GABAergic and the glycinergic inputs of the CVNs, and diminished the inspiratory-related augmentation of these inputs. These results suggested that SP inhibits cardiac vagal activity and diminishes its respiratory-related variability, which might be related to the weakened cardiac vagal tone and heart rate variability in myocardial ischemia and hypertension.
引文
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