迷走神经对心室功能的调控机制研究进展

自主神经系统由交感神经系统和副交感神经系统（迷走神经）组成,二者相互拮抗,对哺乳动物心脏的功能调控具有重要的作用。副交感（迷走）神经对心房可产生变时、变传导和变力作用,但是对心室的支配及对心室的调控作用还不清楚。一直以来都存在一个误解,认为交感神经支配心脏的各个部位而副交感神经仅支配心脏的室上性组织,对心室没有支配。近年来的研究显示在一些哺乳动物的心脏上,胆碱能神经在心室也有分布,且对左心室的功能有重要的调控作用。本文从解剖及组织化学、分子生物学和功能学三个方面阐述迷走神经对心室的支配及调控证据,并对心章收缩功能的迷走神经（毒蕈碱）调控及其信号转导途径进行综述。     

蓝斑核、中缝大核和迷走神经背核在胃运动调节中的关系

目的：探讨蓝斑（LC）、中缝大核（NRM）和迷走神经背核（DMV）,及其相关递质和受体对胃运动的调节途径及机制,阐明它们在调节胃运动中的相互关系。方法：实验采用了核团定位电刺激、损毁和核团微量注射等实验方法,以记录胃内压,统计胃收缩幅度作为胃运动变化的指标。结果：①刺激LC显著降低胃收缩幅度（P〈0.01）,损毁DMV可以减弱此效应,而阻断DMV上的肾上腺素能α受体,可以反转此抑胃效应。②刺激NRM显著降低胃收缩幅度（P〈0.01）,损毁DMV后此效应被消除;阻断DMV上的5-HT2A受体使胃收缩幅度大幅度降低（P〈0.01）,此时再刺激NRM不能进一步的抑制胃运动;而损毁LC后刺激NRM,可消除NRM的抑胃效应,在LC注射5-HT2A受体阻断剂也可以消除该效应。结论：①LC可能通过DMV的5-HT2A受体和α受体对生理条件下正常胃的运动起着重要的双向调节作用;②NRM通过LC上的5-HT2A受体而发挥其对胃运动的抑制效应。     

胃壁肾上腺素能受体作用的分析

选用46只 Wistar 大鼠,分别观察了酚妥拉明和心得安对迷走神经完整和切断迷走神经大鼠胃内压的影响。结果为:酚妥拉明对迷走神经完整大鼠的胃内压没有影响,但能使切断迷走神经大鼠的胃内压明显下降,心得安可使去迷走神经和迷走神经完整大鼠的胃内压均升高,且两者无明显差异。结果表明:(1)支配胃的肾上腺素能神经紧张性作用主要表现为抑制;(2)β-受体可能仅位于胃平滑肌上,且介导抑制作用;(3)依赖迷走神经发挥作用的 α-受体介导抑制作用,而胃壁平滑肌上的 α 受体介导兴奋作用。     

电刺激弓状核对胃内压的影响及其外周途径分析

选用 Wistar,大鼠68只,乌拉坦麻醉下观察了电刺激弓状核对胃内压的影响。结果为:电刺激弓状核,胃内压显著降低;这一作用被迷走神经切断或腹腔神经丛摘除而减弱;酚妥拉明也能减弱电刺激弓状核的这一作用,但阿托品和心得安对此均无影响;同时去除交感神经和迷走神经时,刺激弓状核的这一作用虽被减弱,但仍然存在。上述结果表明:(1)刺激弓状核降低胃内压的外周神经途径同时涉及交感神经和迷走神经;前者由α-受体介导,后者可能由其中的非胆碱能、非肾上腺素能纤维发挥作用;(2)体液因素可能参与刺激弓状核的这一作用。     

交感神经对去迷走神经大鼠胃泌素释放的刺激作用

为了探讨迷走神经切除后血清胃泌素浓度增加的机制,本实验用放射免疫法系统观察了大鼠双侧膈下迷走神经切除后三个月血清胃泌素浓度的变化和交感神经在这种变化中的作用。结果发现,迷走神经切除后,血清胃泌素浓度增加6倍以上,而且这种增加不是继发于胃内pH和胃内压的改变;迷走神经和交感神经都切除的动物,血清胃泌素浓度也有增加,但明显低于单纯迷走神经切除组;迷走神经切除后两个月再切除交感神经可使已升高的胃泌素下降42％。实验说明,迷走神经切除后,交感神经可刺激胃泌素释放,这一作用是去迷走神经后血清胃泌素水平增加的原因之一。     

迷走神经运动背核内心迷走神经元的GABA能突触前支配受谷氨酸能紧张性调控

谷氨酸能和GABA能支配是心迷走节前神经元(cardiac vagal neuron,CVN)的主要兴奋性和抑制性突触传入.在CVN的活动调节中,这两种支配是否有相互作用、以及如何相互作用目前尚不清楚.本研究用神经元逆行荧光染料标记法和电压膜片钳方法证明,谷氨酸NMDA型和非NMDA型受体拮抗剂AP5和CNQX在全脑片应用条件下,对疑核(nucleus ambiguus,NA)内CVN的GABA能突触前活动无明显影响,而对迷走神经运动背核(dorsal motor nucleus ofthe vagus,DMNX)内CVN的GABA能突触前活动有显著的抑制作用.这些观察结果提示支配迷走神经运动背核内CVN的GABA能神经元可能接受紧张性谷氨酸能支配,而支配疑核内CVN的GABA能神经元则没有这种紧张性谷氨酸能支配.疑核内和迷走神经运动背核内CVN的这种调节差异,是两个核团的CVN在心率和心功能调节中功能分工的可能机制之一.     

呼吸道神经与炎症及癌变的关系(英文)

肺癌是主要医学难题之一,尽管分子生物学和药理学技术在进步,肺癌的治疗结果却不尽人意。临床上,炎症与肿瘤密切相关,炎症能够促进肿瘤的形成。从遗传角度讲,这两个过程受到同一个基因座的调控。越来越多的证据表明,神经和免疫两个系统存在交互作用,其中迷走神经起着重要作用。在临床及动物实验中分别观察到:切除迷走神经后肺部的肿瘤发生率增高,转移增加。表明迷走神经具有保护作用,能抑制肿瘤生长。气道感受器是生物感应器,能感受肺部炎症及肿瘤生长过程中的多种介质和细胞因子。这些信号通过迷走神经传递给脑,提供肿瘤生长的信息,随后产生一系列的反应调节炎症的广度和强度以及肿瘤生长速度。肿瘤细胞表达神经递质的受体,能提供底物与神经元直接相互作用。因此,免疫反应的神经调节既可以靶向炎症又可以靶向肿瘤。认识肺部神经如何监控肿瘤的生长并且产生神经免疫相互作用以调节肿瘤的进展及转移,将提高肺癌的治疗水平。     

Orexin-A对大鼠胃功能的影响

目的:探讨Orexin-A对大鼠胃功能的影响。方法:通过大鼠迷走神经复合体微量注射Orexin-A后,观察大鼠胃运动、胃液和胃酸分泌的变化。结果:DVC微量注射Orexin-A后,大鼠胃收缩幅度以及收缩频率明显升高,且呈明显剂量依赖关系(P0.05),SB334867可显著阻断Orexin-A对促胃运动效应(P0.05)。DVC微量注射orexin-A后,大鼠胃液及胃酸分泌且呈剂量依赖性增加(P0.05)。结论:迷走神经复合体微量注射Orexin-A能影响胃的运动以及胃内体液的分泌。     

大鼠灰翼区微量注射6-羟多巴胺对迷走-迷走抑胃反射的影响

本文用乌拉坦麻醉的大鼠,观察了灰翼区微量注射6-羟多巴胺(6-OHDA)对迷走-迷走抑胃反射的影响。实验动物分三组:空白对照组、溶媒组和6-OHDA 组。实验结果表明,在溶媒组刺激迷走神经中枢端使胃电慢波的振幅和胃内压分别下降到刺激前对照值的36.87±22.07%和32.52±25.41%,与空白对照组相比无显著的差异(P>0.05)。但是,在6-OHDA组,刺激迷走神经中枢端对胃电和胃运动的抑制效应明显减弱,慢波的振幅与胃内压分别下降到刺激前对照值的67.48±13.21%和50.88±21.40%,同溶媒组相比有非常显著的差异(P<0.01)。结果提示,延髓灰翼区的儿茶酚胺能神经参与迷走-迷走抑胃反射的中枢机制。     

大鼠孤束核神经降压素在迷走—加压反应中的作用

采放放射免疫、核团微量注射及组织荧光分光测定等实验方法,研究了大量孤束核神经降压素对迷走－加压反应的影响,结果表明,１．不走神经向中端,孤束核神经降压素免疫活性物的含量明显增高;２．孤束核内注入抗神经降压素血清后,刺激颈迷走神经向中端,迷走－加压反应明显;３．孤束核内注入神经降压素后,刺激颈迷走神经向中端,迷走－加压反应明显减弱,４．孤束核注入神经降压素后,刺激颈迷走神经向中端,孤束核去甲腺素含量     

Spatial organization of neurons in the dorsal motor nucleus of the vagus synapsing with intragastric cholinergic and nitric oxide/VIP neurons in the rat

The dorsal motor nucleus of the vagus (DMV) contains preganglionic neurons that control gastric motility and secretion. Stimulation of different parts of the DMV results in a decrease or an increase in gastric motor activities, suggesting a spatial organization of vagal preganglionic neurons in the DMV. Little is known about how these preganglionic neurons in the DMV synapse with different groups of intragastric motor neurons to mediate contraction or relaxation of the stomach. We used pharmacological and immunohistochemical methods to characterize intragastric neural pathways involved in mediating gastric contraction and relaxation in rats. Microinjections of L-glutamate (L-Glu) into the rostral or caudal DMV produced gastric contraction and relaxation, respectively, in a dose-related manner. Intravenous infusion of hexamethonium blocked these actions, suggesting mediation via preganglionic cholinergic pathways. Atropine inhibited gastric contraction by 85.5 +/- 4.5%. Gastric relaxation was reduced by intravenous administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 52.5 +/- 11.9%) or VIP antagonist (56.3 +/- 14.9%). Combined administration of L-NAME and VIP antagonist inhibited gastric relaxation evoked by L-Glu (87.8 +/- 4.3%). Immunohistochemical studies demonstrated choline acetyltransferase immunoreactivity in response to L-Glu microinjection into the rostral DMV in 88% of c-Fos-positive intragastric myenteric neurons. Microinjection of L-Glu into the caudal DMV evoked expression of nitric oxide (NO) synthase and VIP immunoreactivity in 81 and 39%, respectively, of all c-Fos-positive intragastric myenteric neurons. These data indicate spatial organization of the DMV. Depending on the location, microinjection of L-Glu into the DMV may stimulate intragastric myenteric cholinergic neurons or NO/VIP neurons to mediate gastric contraction and relaxation.     

Suppression of vagal motor activities evokes laryngeal afferent-mediated inhibition of gastric motility

We previously reported that the activation of water-responsive afferents in the superior laryngeal nerve was responsible for the inhibition of gastric motility. The present study was undertaken to clarify the roles of the vagal preganglionic neurons responsible for laryngeal afferent-mediated inhibition of gastric motility. Intravenous injection of atropine abolished the inhibition of motility in both the distal and the proximal stomach induced by water administration into the larynx. The neurons in the dorsal motor nucleus of the vagus (DMV), which project to the abdominal viscera, were exclusively inhibited by water administration. Taken together, inhibition of neurons in the DMV induces inhibition of gastric motility evoked by laryngeal water-responsive afferents via a cholinergic pathway. Because chemical lesions of the intermediate DMV, but not the caudal DMV, abolished the inhibition of the distal stomach motility induced by water administration, the intermediate DMV is responsible for the inhibition shown in the distal stomach.     

Gastric effects of thyrotropin-releasing hormone microinjected into the dorsal vagal nucleus in cats

We investigated the gastric acid secretory and motility responses to microinjection of thyrotropin-releasing hormone (TRH) into the dorsal motor nucleus of the vagus (DMV) in anesthetized cats. Gastric acid output was collected every 15 min through a gastric cannula after saline flush and titrated to pH 7.0. Antral and corpus contractions were continuously recorded by extraluminal force transducers. TRH dissolved in 200 nl of saline and microinjected unilaterally into the DMV induced a dose-dependent (50-200 ng) increase in gastric acid secretion. The acid secretory response began in the first 15 min collection and lasted 45 min. TRH frequently increased the force of contractions of the antrum and corpus within one minute of microinjection. The minimal effective dose for eliciting increased motility was lower than for inducing acid secretion. These results demonstrate that TRH acts in the DMV of cats to stimulate gastric acid secretion and contractions.     

Glucose does not activate nonadrenergic, noncholinergic inhibitory neurons in the rat stomach

We reported previously that intravenously administered d-glucose acts in the central nervous system to inhibit gastric motility induced by hypoglycemia in anesthetized rats. The purpose of this study was to determine whether this effect is due to inhibition of dorsal motor nucleus of the vagus (DMV) cholinergic motoneurons, which synapse with postganglionic cholinergic neurons, or to excitation of DMV cholinergic neurons, which synapse with postganglionic nonadrenergic, noncholinergic (NANC) neurons, particularly nitrergic neurons. Three approaches were employed: 1) assessment of the efficacy of d-glucose-induced inhibition of gastric motility in hypoglycemic rats with and without inhibition of nitric oxide synthase [10 mg/kg iv nitro-l-arginine methyl ester (l-NAME)], 2) assessment of the efficacy of intravenous bethanechol (30 mug.kg(-1).min(-1)) to stimulate gastric motility in hypoglycemic rats during the time of d-glucose-induced inhibition of gastric motility, and 3) determination of c-Fos expression in DMV neurons after intravenous d-glucose was administered to normoglycemic rats. Results obtained demonstrated that l-NAME treatment had no effect on d-glucose-induced inhibition of gastric motility; there was no reduction in the efficacy of intravenous bethanechol to increase gastric motility, and c-Fos expression was not induced by d-glucose in DMV neurons that project to the stomach. These findings indicate that excitation of DMV cholinergic motoneurons that synapse with postganglionic NANC neurons is not a significant contributing component of d-glucose-induced inhibition of gastric motility.     

Potent central nervous system action of p-Glu-His-(3,3'-dimethyl)-Pro NH2, a stabilized analog of TRH, to stimulate gastric secretion in rats

Intracisternal injection of the TRH analog RX 77368 (p-Glu-His-(3,3'-dimethyl)-Pro NH2) increased gastric acid and pepsin output in conscious pylorus-ligated rats. In urethane-anesthetized, gastric fistula rats, intracisternal RX 77368 or TRH induced stimulation of gastric acid output which was rapid in onset, long lasting, and dose-dependent, in doses ranging from 3 to 100 ng/rat for RX 77368, and 0.1 to 1 micrograms/rat for TRH. Vagotomy or atropine pretreatment reversed RX 77368 gastric secretory response. The analog was less effective when infused intravenously (1-10 micrograms X kg-1 X h-1) and 22 times more potent than TRH when given intracisternally. These results demonstrated the ability of RX 77368 to act within the rat brain to enhance gastric secretion (acid and pepsin) through vagus cholinergic dependent mechanisms. The enhanced potency and extended duration of action of RX 77368 over TRH, could make intracisternal injection of this peptide a useful test to induce centrally mediated vagal dependent stimulation of gastric secretion in rats.     

尾核P物质对胃运动的抑制效应系通过黑质,迷走背核经迷走神经所介导

本工作观察损毁下丘脑外侧区,黑质,迷走背核及其传出神经对尾核微量注射Ｐ物质引起的胃肌电快波和胃运动抑制效应的影响。实验结果：该抑制效应不依赖于下丘脑外侧区的完整但可被损毁黑质,迷走背核或迷走上所消除。用利血平耗竭交感神经递质则不影响该效应。这些结果表明：尾核ＳＰ的抑胃效应系通过黑质、迷走背核经迷走神经所传出。     

Catecholaminergic neurons in rat dorsal motor nucleus of vagus project selectively to gastric corpus

Nitric oxide synthase-immunoreactive (NOS-IR) neurons in the rat caudal dorsal motor nucleus of the vagus (DMV) project selectively to the gastric fundus and may be involved in vagal reflexes controlling gastric distension. This study aimed to identify the gastric projections of tyrosine hydroxylase-immunoreactive (TH-IR) DMV neurons, whether such neurons colocalize NOS-IR, and if they are activated after esophageal distension. Gastric-projecting neurons were identified after injection of retrograde tracers into the muscle wall of the gastric fundus, corpus, or antrum/pylorus before removal and processing of the brain stems for TH- and NOS-IR. A significantly higher proportion of corpus- compared with fundus- and antrum/pylorus-projecting neurons were TH-IR (14% compared with 4% and 2%, respectively, P < 0.05). Colocalization of NOS- and TH-IR was never observed in gastric-projecting neurons. In rats tested for c-Fos activation after intermittent esophageal balloon distension, no colocalization with TH-IR was observed in DMV neurons. These findings suggest that TH-IR neurons in the caudal DMV project mainly to the gastric corpus, constitute a subpopulation distinct from that of nitrergic vagal neurons, and are not activated on esophageal distension.     

Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex

The dorsal motor nucleus of the vagus (DMV) is pivotal in the regulation of upper gastrointestinal functions, including motility and both gastric and pancreatic secretion. DMV neurons receive robust GABA- and glutamatergic inputs. Microinjection of the GABA(A) antagonist bicuculline (BIC) into the DMV increases pancreatic secretion and gastric motility, whereas the glutamatergic antagonist kynurenic acid (KYN) is ineffective unless preceded by microinjection of BIC. We used whole cell patch-clamp recordings with the aim of unveiling the brain stem neurocircuitry that uses tonic GABA- and glutamatergic synapses to control the activity of DMV neurons in a brain stem slice preparation. Perfusion with BIC altered the firing frequency of 71% of DMV neurons, increasing firing frequency in 80% of the responsive neurons and decreasing firing frequency in 20%. Addition of KYN to the perfusate either decreased (52%) or increased (25%) the firing frequency of BIC-sensitive neurons. When KYN was applied first, the firing rate was decreased in 43% and increased in 21% of the neurons; further perfusion with BIC had no additional effect in the majority of neurons. Our results indicate that there are several permutations in the arrangements of GABA- and glutamatergic inputs controlling the activity of DMV neurons. Our data support the concept of brain stem neuronal circuitry that may be wired in a finely tuned organ- or function-specific manner that permits precise and discrete modulation of the vagal motor output to the gastrointestinal tract.