Site-Specific Formation of Thyrotropin-Releasing Hormone-Induced Gastric Ulcers through the Vagal System

Okumura T, Uehara A, Watanabe Y, Taniguchi Y, Kitamori S, Namiki M. Site-specific formation of thyrotropin-releasing hormone-induced gastric ulcers through the vagal system. Scand J Gastroenterol 1994;29:226-231.

The left and right dorsal motor nuclei (DMN) separately innervate the anterior and posterior gastric walls through the left and right gastric branches of the vagus nerve (GBVN) in rats. The present study was carried out to investigate the effects of selective centrally originated excitation of the unilateral vagal system on the gastric area in which vagus-induced gastric ulcers developed. Since intracisternally injected thyrotropin-releasing hormone (TRH) stimulates neurons in the bilateral DMNs to produce gastric ulcers, selective stimulation of the unilateral vagal system was produced by contralateral gastric branch vagotomy before intracisternal injection of TRH. Intracisternal injection of TRH (2 ng/rat) into left gastric branch-vagotomized rats resulted in lesion formation only on the posterior gastric wall and not on the anterior wall. In contrast, in right gastric branch-vagotomized rats TRH-induced gastric lesions were observed only on the anterior gastric wall and not on the posterior wall. These results suggest that selective stimulation of the left or right DMN induces site-specific ulcer formation through the left or right GBVN. Next, gastric acid secretion was determined in pylorus-ligated rats to examine a role of acid hypersecretion in site-specific ulcer formation caused by TRH. Of interest was that gastric acid secretion in unilaterally vagotomized rats given TRH intracisternally was significantly smaller than that in sham-operated rats given intracisternal saline, although the former rats developed gastric ulcers, whereas the latter did not. It is therefore speculated that gastric hyperacidity plays a less important role in the peripheral mechanisms of TRH-induced site-specific gastric ulceration.     

Use of horseradish peroxidase to identify hindbrain sites that influence gastric motility in the cat

To identify hindbrain sites that influence gastric motility, we administered multiple injections of horseradish peroxidase into the anterior surface of the antrum near the lesser curvature in 3 cats, and used light microscopy to identify horseradish peroxidase-positive neurons in the hindbrain. Retrogradely labeled neurons were found evenly distributed on both sides in the dorsal motor nucleus of the vagus. Labeling extended from 2.5 mm rostral to 2.0 mm caudal to the obex. Labeled neurons were not localized to a specific region of the dorsal motor nucleus of the vagus: no labeling was observed in the nucleus ambiguus or in the nuclei of the solitary tract. Electrical stimulation of the dorsal motor nucleus of the vagus in the area with the greatest number of labeled cell bodies was performed in 4 cats while monitoring antral motility, arterial pressure, and heart rate. Stimulation elicited pronounced antral contractions but no changes in arterial pressure or heart rate. These data demonstrate that the retrograde neuronal tracing technique permits localization of central nervous system sites that specifically influence gastric function.     

Abdominal pathways and central origin of rat vagal fibers that stimulate gastric acid

The brainstem location and peripheral course of the vagal preganglionic fibers that stimulate gastric acid secretion were identified using electrical stimulation combined with retrograde (True Blue; Dr. K. G. Illing, Gross Umstadt, Germany) and anterograde (Dil; Molecular Probes) fluorescent neural tracers in rats with various selective vagotomies. Animals with only one or both gastric branch(es) spared had normal, large gastric acid responses to electrical stimulation of the ipsilateral cervical vagus and showed an abundance of Dil-labeled vagal fibers and terminals in the gastric myenteric plexus. Rats with only the unpaired hepatic branch spared had a much smaller but significant gastric acid response and a few labeled vagal profiles in the antral region of the stomach. In contrast, rats with only one or both celiac branch(es) intact had neither a gastric acid response, nor evidence for Dil transport to the stomach. Retrograde transport of True Blue through the spared vagal axons to the brainstem indicated that the cell bodies of the preganglionics that send their axons through the acid-positive gastric and hepatic branches occupy the medial longitudinal columnar subnuclei of the dorsal motor nucleus. It is concluded that besides the long-recognized gastric branches, which are the major access route to the parietal cells, the hepatic branch contains a small number of fibers that most likely reach the antrum through the right gastroepiploic artery along the greater curvature and/or the right gastric artery.     

Effects of nuclei ambiguus and dorsal motor nuclei of vagus on gastric H+ and HCO3- secretion in rats

AIM: To determine the effects of electrical stimulation of nucleus ambiguus (NA) and dorsal motor nuclei of vagus (DMV) on gastric acid and bicarbonate secretion in rats. METHODS: NA and DMV in rats were electrically stimulated. Pylorus ligation or esophagus perfusion was used to collect the gastric secretion. The titratable H quantum, H concentration, HCO3- secretion quantum were measured. RESULTS: Electrical stimulation of NA had no effects on the volume of gastric juice, titratable acidity and acid concentration, but elicited a pronounced increase in the total bicarbonate. However, electrical stimulation of DMV significantly increased the titratable acidity, the volume of gastric juice and the acid concentration. Similarly, electrical stimulation of either NA or DMV decreased the respiratory frequency and sinus bradycardia. CONCLUSION: NA in rats can not control the secretion of gastric acid but the secretion of bicarbonate in gastric juice, while DMV controls the secretion of gastric acid.     

Effects of nuclei ambiguus and dorsal motor nuclei of vagus on gastric H^＋ and HCO3 secretion in rats

AIM: To determine the effects of electrical stimulation of nucleus ambiguus (NA) and dorsal motor nuclei of vagus (DMV) on gastric acid and bicarbonate secretion in rats. METHODS: NA and DMV in rats were electrically stimulated. Pylorus ligation or esophagus perfusion was used to collect the gastric secretion. The titratable H(+) quantum, H(+) concentration, HCO(3)(-) secretion quantum were measured. RESULTS: Electrical stimulation of NA had no effects on the volume of gastric juice, titratable acidity and acid concentration, but elicited a pronounced increase in the total bicarbonate. However, electrical stimulation of DMV significantly increased the titratable acidity, the volume of gastric juice and the acid concentration. Similarly, electrical stimulation of either NA or DMV decreased the respiratory frequency and sinus bradycardia. CONCLUSION: NA in rats can not control the secretion of gastric acid but the secretion of bicarbonate in gastric juice, while DMV controls the secretion of gastric acid.     

Modulation of hypothalamic arcuate nucleus on gastric motility in rats

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Chronic effects of nicotine on gastric secretion in rats with hypothalamic lesions

The gastric secretory response to chronic injections of nicotine (2000 µg base /kg/day for 14 days) was studied in 2-hour pylorus-ligated male Sprague-Dawley rats (256.8±1.3 g). In sham anterior hypothalamic-lesioned animals, nicotine produced an increase in gastric juice volume and in acid and pepsin outputs. After bilateral electrolytic destruction of the anterior hypothalamic area or the rostral portion of the ventromedial nucleus, the response to chronic nicotine administration was abolished. Bilateral electrolytic lesions in the posterior hypothalamus did not block the gastric secretory stimulation produced by nicotine, whereas bilateral abdominal vagotomy did. It is concluded that the gastric secretory stimulation produced by the chronic administration of nicotine is mediated via the anterior hypothalamic area, the ventromedial nucleus in the anterior hypothalamus and the vagus nerves.Supported in part by a grant from the American Medical Association Education and Research Foundation.     

Preganglionic vagus nerve fibers also enter the greater curvature of the stomach in rats and ferrets

The efferent gastric vagus nerve fibers appear to enter the stomach by several routes. For example, the rate of gastric acid secretion is directly affected by the nerves of the greater curvature of the stomach. Specifically, acid secretion decreases abruptly after division of the gastroepiploic nerve(s). To determine whether efferent vagus nerve fibers are contained in the gastroepiploic nerve(s), horseradish peroxidase, a protein that undergoes retrograde axonal transport, was applied to these nerves; the brainstem locus of the nuclei of the vagus nerves was examined 2 days later. Typical peroxidase labeling was observed in the dorsal motor nucleus of the vagus nerve in 5 of 6 rats and 3 of 3 ferrets; the hypothesis that efferent vagus nerves enter the greater curvature of the stomach was thus supported in two vertebrate species. These previously unrecognized nerves should be considered in the interpretation of experimental and clinical phenomena.     

Thyrotropin-releasing hormone in the dorsal vagal complex stimulates hepatic blood flow in rats

Central administration of thyrotropin-releasing hormone (TRH) enhances hepatic blood flow in animal models. TRH nerve fibers and receptors are localized in the dorsal vagal complex (DVC), and retrograde tracing techniques have shown that hepatic vagal nerves arise mainly from the left DVC. However, nothing is known about the central sites of action for TRH to elicit the stimulation of hepatic blood flow. The effect of microinjection of a TRH analogue into the DVC on hepatic blood flow was investigated in urethane-anesthetized rats. After measuring basal flow, a stable TRH analogue (RX-77368) was microinjected into the DVC and hepatic blood flow response was observed for 120 minutes by laser Doppler flowmetry. Either left or right cervical vagotomy or hepatic branch vagotomy was performed 2 hours before the peptide. Microinjection of RX-77368 (0.5-5 ng) into the left DVC dose-dependently increased hepatic blood flow. The stimulation of hepatic blood flow by RX-77368 microinjection into the left DVC was eliminated by left cervical and hepatic branch vagotomy but not by right cervical vagotomy. By contrast, microinjection of RX-77368 into the right DVC did not significantly alter hepatic blood flow. These results suggest that TRH acts in the left DVC to stimulate hepatic blood flow through the left cervical and hepatic vagus, indicating that neuropeptides may act in the specific brain nuclei to regulate hepatic function.     

An experimental study of gastric mucosal blood flow in endotoxemia of the rat,with special reference to the vagus nerve and EDRF

Gastric mucosal lesions are an important complication in endotoxemia. In order to define the role played by the vagus nerve and endothelial-derived relaxing factor (EDRF) in gastric mucosal blood flow, an investigation was carried out on four groups of rats: a control group; a group given lipopolysaccharide (LPS, 5 mg/kg); a group given gossypol-acetic acid (gossypol), which has an injurious effect on the vascular endothelial cell; and a group given L-NG-monomethyl arginine (LNMMA). Following the administration of acetylcholine and papaverine hydrochloride (via the splenic artery) and vagus nerve stimulation in all four groups of rats, the effects of vagus nerve stimulation and EDRF on the gastric mucosal blood flow were determined with a laser Doppler rheometer. In the LPS group, the gastric mucosal blood flow was decreased after acetylcholine administration and vagus nerve stimulation. This was also the case in the gossypol group. These findings suggest that inhibition of EDRF release may be responsible for the reduced gastric mucosal blood flow observed in endotoxemia.     

睡眠剥夺对大鼠胃运动及其神经中枢的影响

目的观察急性睡眠剥夺对胃排空及支配胃运动的神经中枢电生理活动的影响,为防治因睡眠剥夺对胃排空引起的胃动力障碍提供理论依据。方法采用同步实验,应用电生理学的方法,观察延髓中与胃运动密切相关的孤束核(nucleustractussolitary ,NTS)及迷走神经背运动核(Dorsalmotornucleusofthevagusnerve ,DMV)中神经元细胞放电的变化情况,同时采用浆膜法检测胃电的变化。结果随着睡眠剥夺时间的不断延长,延髓中与胃运动密切相关的孤束核(NTS)及迷走神经背运动核(DMV)中神经元细胞放电产生了不同的变化情况。在睡眠剥夺的第一周,迷走神经复合体的放电明显增加,胃电活动却呈现初始增加,逐渐减低状态,但无明显规律;而在睡眠剥夺的第二周,迷走神经复合体的放电呈现抑制状态,胃电活动呈现紊乱状态。结论急性睡眠剥夺对大鼠的胃运动影响明显,同时对支配胃运动的神经中枢亦有显著影响。     

Peripheral functional organisation of vagally evoked gastric motor responses in the ferret.

The aims of the present study were to determine the relative amplitudes of intragastric motor responses evoked by different vagal branches and to establish whether the effects of acute or chronic vagotomy could be predicted from these data. Intragastric pressure responses to electrical stimulation of the vagus were measured in urethane-anaesthetised ferrets and acute or chronic vagotomies were performed. The results show that the left and right cervical vagi were equipotential and fully overlaped each other. Their contributions to the dorsal trunk were equipotential and fully overlapping and so were their contributions to the ventral trunk. The dorsal trunk was more effective than the ventral trunk and there was total functional overlap between these two trunks. Vagal evoked gastric motor responses of the ferret are apparently organised in a different way from vagally induced acid secretion or hormone release in the cat. Acute removal of a trunk led to a reduction in evoked responses that was not linear function of the effect of stimulation of that trunk. In contrast, chronic removal caused a relative increase in evoked responses that ws inversely related to the decrease caused by acute removal. The implications of total functional overlap and neuromuscular reorganisation after chronic vagotomy are discussed.     

Insignificant bilateral convergence of preganglionic vagal fibers on postganglionic neurons to the canine heart

We determined the extent of convergence of preganglionic fibers from the right and left vagus nerves on postganglionic neurons that supply the sinoatrial node in chloralose-anesthetized dogs. We administered hemicholinium-3 and stimulated the right vagus nerve at a high frequency to deplete acetylcholine from the postganglionic parasympathetic neurons supplied by that nerve. We compared the effects of this "depletion regimen" with the responses in two control groups: a stimulation control group, which was subjected to high-frequency right vagus stimulation only, and a drug control group, which received a hemicholinium-3 infusion only. The effects of right vagus stimulation did not differ from those of left vagus stimulation in either of the control groups. In the animals subjected to the depletion regimen, the responses to right vagus stimulation were almost abolished. However, the left vagus nerve retained its ability to prolong cardiac cycle length in these animals. Thus, our experiments indicate that left vagus preganglionic fibers do not converge with right vagus preganglionic fibers on a substantial pool of postganglionic neurons that innervate the canine sinoatrial node.     

胃电刺激诱导大鼠延髓孤束核和迷走神经运动背核c-fos蛋白表达

背景：胃电刺激（GES）可以调控胃慢波，但其作用机制尚不完全清楚。原癌基因蛋白c—fos的表达可作为神经元功能活动的标志物。目的：以c-fos蛋白的表达为观察指标，探讨GES调控胃肌电慢波的神经机制。方法：将雌性Wistar大鼠随机分为对照组和GES组。GES以控制胃慢波为准，持续1h。分别于刺激后0．5、1、2和5h处死大鼠，以免疫组化方法观察c—fos蛋白在延髓孤束核和迷走神经运动背核中的表达。结果：对照组延髓孤束核和迷走神经运动背核仅见微量c—fos蛋白表达，GES后0．5h其表达开始增强，1h时达高峰，以后逐渐减弱。结论：GES可以调控胃肌电慢波，GES后延髓孤束核和迷走神经运动背核神经元c-fos蛋白表达阳性提示迷走神经可能参与了该调控作用。     

辣椒素对电针调控胃运动的影响作用及意义

目的探讨辣椒素毁损感觉神经生长的情况下,对电针调控胃运动的影响作用及意义。方法电针刺激经辣椒素干预大鼠足三里穴,采用免疫组织化学方法及电生理的方法,检测原癌基因c fos在中枢延髓的孤束核(NTS)及迷走神经背运动核(DMV)中的表达以及中枢延髓的孤束核及迷走神经背运动核中神经元细胞放电频率的变化情况,同时采用浆膜法观察胃电的变化情况。结果辣椒素针刺组胃电的波幅和频率与生理盐水针刺组存在显著性差异(P <0 .0 1) ,生理盐水针刺组胃电的波幅和频率与单纯生理盐水组胃电的波幅和频率存在显著性差异(P <0 .0 1)。原癌基因c fos在孤束核及迷走神经背运动核中的表达,辣椒素针刺组阳性率与生理盐水针刺组存在显著性差异(P <0 .0 1) ,生理盐水针刺组阳性率与单纯生理盐水组存在显著性差异(P <0 .0 1)。辣椒素针刺组NTS与DMV内神经元细胞放电频率的变化与生理盐水针刺组存在显著性差异(P <0 .0 1)。而与辣椒素非针刺组及单纯生理盐水组未见有明显差异(P >0 .0 5 ) ;同时,生理盐水针刺组NTS与DMV内神经元细胞放电频率与单纯生理盐水组存在显著性差异(P <0 .0 1)。结论电针对胃运动具有调控作用,且电针对穴位的作用性质可能是一种伤害性刺激。     

Inhibitory influence of the nuclei of the posterior hypothalamus on the pro-oestrous surge of LH

The effect of transecting caudal afferents to the medial basal hypothalamus on the pro-oestrous surge of LH was studied in cyclic female rats. Rats with transverse cuts placed just in front of the mammillary bodies and caudal to the ventromedial hypothalamic nucleus showed an earlier time of onset of pro-oestrous surge of LH. Conversely, rats with transverse cuts placed 2 mm more caudally or with cuts along the lateral edges of the hypothalamus showed no altered release of LH. Advanced release of LH occurred also in rats in which the ventral premammillary nuclei or the posterior hypothalamic nuclei were bilaterally destroyed but not in those sham operated or with lesions in the dorsal premammillary nuclei. The number of ova ovulated was higher in rats bearing lesions of any of these nuclei but enhanced LH release was seen only in animals with lesions of the posterior hypothalamic nuclei. Electrochemical stimulation (anodic d.c., 100 microA, 15 s) applied at noon of pro-oestrus to the ventral premammillary nucleus, dorsal premammillary nucleus or posterior hypothalamic nucleus prevented ovulation and the preovulatory discharge of LH. It is concluded that inputs from nuclei of the posterior hypothalamus are inhibitory for LH release and could participate in determining the timing and magnitude of the pro-oestrous surge of the hormone.     

Relation between localization of gastric mucosal lesions and microvascular disturbance

Acute gastric mucosal lesions in the rats were produced by intermittent electrical stimuli to a main trunk of the left gastric artery (LGA), right gastroepiploic artery (RGEA) or a posterior branch of the left gastric artery (PLGA). The image processing analysis was applied to determine the relation between distribution of the lesions and perfusion area of the supplying artery to which electrical stimuli were given. Electrical stimuli of 50 Hz, 5 msec, 100 microA was supplied to the artery for 30 sc three times with 10 sec interval. A series of these stimuli was repeated three times. The mucosal blood flow measured with the laser doppler method in each perfusion area was reduced to less than 35% of the control value during the electrical stimuli for 30 sec. After the repeated electrical stimuli to LGA, 85.8 and 95.4% of the mucosal lesions were found in the mean and maximum perfusion area of LGA, respectively. Electrical stimuli to PLGA caused 84.5% and 95.3 of the lesions in the mean and maximum area of PLGA, respectively. Stimuli to RGEA caused 53.4% and 74.1% of the lesions in the mean and maximum perfusion area of RGEA. In the antrum, electrical stimuli to LGA, PLGA or RGEA produced 0%, 5.4% or 5.0% of the mucosal lesions. It is concluded that the corpus mucosal lesions induced by regional ischemia are distributed in the ischemic area.     

Medullary parasympathetic projections innervate specific sites in the feline stomach

The purpose of our study was to determine the site of origin of vagal neurons that innervate specific parts of the stomach (the fundus, corpus, and antrum/pylorus). This was done by injecting the retrograde fluorescent tracer Fast Blue into these parts of the cat stomach and examining the hindbrain for cells labeled with retrograde tracer. We found that vagal preganglionic innervation to the stomach originates from two medullary nuclei, namely, the dorsal motor nucleus of the vagus (bilateral) and the nucleus retroambiguus (left). All parts of the stomach receive innervation from the dorsal motor nucleus of the vagus (primarily from the area ranging from 0.5 to 1.8 mm rostral to the obex), but only the fundus and corpus receive innervation from the nucleus retroambiguus. Injection of tracer into the fundus labeled cells within the lateral half of the dorsal motor nucleus of the vagus and injection of tracer into the antrum/pylorus labeled cells within the medial portion. Finally, injection of tracer into the corpus labeled cells throughout the mediolateral axis of the dorsal motor nucleus of the vagus. The finding of a columnar organization of the dorsal motor nucleus of the vagus implies some type of functional organization of gastrointestinal control. The fact that vagal inputs to the stomach arise from the dorsal motor nucleus of the vagus and nucleus retroambiguus suggests a separation of vagal pathways controlling different gastric functions (e.g., pacemaker activity, motility, and secretion).     

Differences in the ovulation rate of the right or left ovary in unilaterally ovariectomized rats: effect of ipsi- and contralateral vagus nerves on the remaining ovary

The possible existence of peripheral asymmetry in the neuroendocrine mechanisms participating in the response of the ovary to gonadotrophins, and the participation of the vagus nerve, was investigated. At oestrus, the ovulation rate (number of ovulating/number of treated rats) of the left ovary in right unilaterally ovariectomized rats was lower than that in the right ovary in left unilaterally ovariectomized rats (42 vs 84%). No differences in the number of ova shed per ovulating animal nor in compensatory ovarian hypertrophy (COH) were observed. Bilateral section of the vagus nerve resulted in reduced COH only in those animals with the left ovary in situ (right unilaterally ovariectomized). Section of the left vagus nerve induced different effects depending upon which ovary was left in situ. When the left ovary was in situ an increase in ovulation rate, COH and number of ova shed was observed; however, when the right ovary was left in place the above three parameters decreased. Section of the right vagus nerve produced a decrease only in COH in both right and left unilaterally ovariectomized animals. It is concluded that in the unilaterally ovariectomized rat the right ovary seems more able to react to compensatory regulatory systems than does the left. The character of the information carried by the left and right vagus nerve is different.