Compensatory recovery of vagal control of hemodynamics after unilateral vagotomy

This study investigated whether each part of the heart is evenly innervated by the left or right vagus and observed the mechanism of compensatory recovery after unilateral cervical vagotomy. HR, BP, LVSP and +/-dp/dt max all decreased one week after left vagotomy, whereas only BP and -dp/dt max decreased one week after right vagotomy. Western blot analyses revealed that the expression of M(2) receptors in the left atrium and left ventricle was upregulated after subacute (1 week) left/right vagotomy. However, significantly more cholinesterase-positive nerves in LV and RV were seen one week after unilateral vagotomy compared to the sham-operated group. In addition, baroreflex sensitivity was increased after subacute right vagotomy. The decreasing effects of ACh (0.5 microg/kg) on LVSP and +/-dp/dt max (but not on HR and BP) were facilitated by subacute unilateral vagotomy. Our present experiments indicate that 1) the working myocardium is innervated bilaterally by the vagus, 2) ventricular contractility is influenced more by denervation of the left than the right vagus and 3) up-regulation of M(2) muscarinic receptors in the left heart, increase of cholinergic nerves, and high baroreflex sensitivity could be involved in the mechanism of compensatory hemodynamic recovery via contralateral vagus overactivity, thereby amplifying contralateral vagal activity and decreasing cardiac contractility.     

迷走神经在心率变异性中的作用

采用功率谱和近似熵 (approximateentropy ,ApEn)的方法 ,分析清醒家兔在双侧迷走神经保留 ,右、左侧迷走神经切断以及双侧迷走神经同时切断时心搏间期 (RRI)的变化。结果显示 :双侧迷走神经保留时功率谱中高频功率 (HF)、低频功率 (LF)及ApEn值均高于双侧及单侧迷走神经切断时 (P <0 0 5 ) ,LF/HF比值最小 ;切断单侧迷走神经 ,ApEn变小 ,LF/HF比值在右侧迷走神经切断时增大 ,而切断左侧迷走时LF/HF比值无明显变化 ;双侧迷走神经切断后LF/HF比值最大 ,ApEn最低。结果表明 :心率变异主要由迷走神经调节 ,右侧迷走神经起主要作用 ;传统心率变异性测量方法与非线性方法所得结果一致     

Acetylcholine content in superior cervical ganglion following reinnervation of vagal afferent fibers in cat

The superior cervical ganglion (SCG) was reinnervated by vagal afferent fibers by cross anastomosis between the cranial end of nodose ganglion and the caudal end of SCG in cats. Formation of functional synapses was evidenced by unilateral mydriasis and contraction of the nictitating membrane in response to inflation of the stomach with a balloon or to electrical stimulation of the afferent vagus. The acetylcholine (ACh) content in the cross-anastomosed SCG (reinnervated by vagal afferent fibers) was measured. In anastomosed SCG, the ACh content was about half of normal SCG, but significantly higher than chronically decentralized SCG. Also the ACh content in nodose ganglion (NDG) was investigated in situations in which there was anastomosis, chronic supra, infra, or supra-/infranodose vagotomy. The ACh content of anastomosed NDG was near that of supranosdose vagotomized ganglion. The ACh content of supra-/infranodose vagotomized NDG, which can be considered the NDG itself, was as much as that of normal intact NDG. It was found that the ACh content of infranodose vagotomized NDG was increased, possibly the result of vagal efferent axonal flow or transport. The ACh content of vagal trunk with or without infranodose vagotomy was also measured. The ACh content of vagal trunk with infranodose vagotomy was smaller than that of the normal trunk, but there was still a considerable quantity of ACh. There was no significant change in wet weight of the SCG and NDG before or after the operations. From these results we have concluded that the transmission of the cross-anastomosed SCG (reinnervated with vagal afferent nerve) was cholinergic; and that the vagal afferent nerve have afferent cell bodies not only in NDG but also in peripheral vagal trunks (infranodose portion). These results strongly suggest that vagal afferent fibers are in part cholinergic.     

Cardiorespiratory responses to chemical activation of right ventricular receptors

Previous reports have shown that activation of left ventricular receptors with sympathetic afferents elicits increases in respiratory output and arterial pressure. The purpose of the present study was to determine whether similar responses are produced by chemical activation of epicardial receptors in the right ventricle. Receptors were stimulated by applying either capsaicin (10 micrograms) or bradykinin (500 ng) to the epicardial surface of the right ventricle in anesthetized cats. Application of either chemical evoked an increase in respiratory output (phrenic nerve activity), a decrease in heart rate, and a nonsignificant increase in arterial pressure in intact cats. However, capsaicin and bradykinin produced significant increases in arterial pressure, heart rate, and respiratory output after bilateral cervical vagotomy. In contrast, a fall in both heart rate and arterial pressure with only small increases in respiratory output were evoked after bilateral removal of the stellate ganglia in cats with intact vagi. Only small responses to the chemical stimulation of right ventricular receptors persisted after combined vagotomy and stellate ganglionectomy. These findings suggest that 1) activation of epicardial receptors with sympathetic afferents originating in the right ventricle causes an increase in cardiorespiratory function, and 2) activation of right ventricular receptors with vagal afferents produces decreases in heart rate and arterial pressure.     

Vagotomy enhances experimental metastases of 4THMpc breast cancer cells and alters substance P level

We have previously demonstrated that inactivation of capsaicin-sensitive sensory neurons enhances lung and heart metastases of breast carcinoma. Because a significant part of sensory innervation of lung tissue is supplied by the vagus nerve, we here examined the effects of unilateral mid-cervical vagotomy in the metastases of 4THMpc breast carcinoma and tissue Substance P (SP) levels. Balb-c mice were injected orthotopically with 4THMpc cells 1 week after vagotomy. Animals were sacrificed 27-30 days after injection of 4THMpc cells and the extent of metastases was determined. Unilateral vagotomy, right or left significantly increased the lung, liver and kidney metastases without altering the growth rate of the primary tumor. Heart metastases were increased only following left vagotomy. The changes in SP levels were somewhat surprising such that vagotomy actually increased while sham-operation decreased SP levels in lung. The effect of sham-operation was reversed by unilateral vagotomy demonstrating that vagal activity decreases total SP levels in the lung. Increased SP levels might be due to decreased degradation of the peptide. Presence of the tumor markedly increased SP level in the lung, which was more prominent in vagotomized animals. These results provide evidence that vagal activity may protect against metastatic disease.     

Changes in intestinal endocrine cells in the mouse after unilateral cervical vagotomy

The effect of right or left unilateral cervical vagotomy on the intestinal endocrine cells was studied in 23 mice at 2 and 8 weeks after operation, respectively. The results were compared with that from 10 sham operated mice. Various types of endocrine cells in duodenum and proximal colon were detected by immunohistochemistry and quantified by computerized image analysis. In mouse duodenum, chromogranin-, CCK/gastrin-, GIP- and somatostatin-cells were significantly decreased at 2 weeks after right vagotomy, but returned to the control levels at 8 weeks. Serotonin-cells were reduced at both 2 and 8 weeks after right vagotomy. The amount of the duodenal endocrine cells did not change after left vagotomy with the exception of secretin-cells, which were diminished at 8 weeks after both right and left vagotomy. In the proximal colon, chromogranin-cells were also decreased at 2 weeks after right vagotomy. Serotonin-cells were reduced at 8 weeks after left vagotomy but not right vagotomy. There was no significant difference between the unilaterally vagotomized and the sham operated mice with regard to PYY- and glucagon-cells. It was concluded that vagotomy affected the intestinal endocrine cells in mouse. The influence was more pronounced in the small intestine than the proximal colon. The right vagus nerves seemed to exert more effect on the intestinal endocrine cells than the left ones.     

GAS CHROMATOGRAPHIC ESTIMATION OF ACETYLCHOLINE IN THE RABBIT HEART USING A NITROGEN SELECTIVE DETECTOR

The distribution of ACh in the rabbit heart was investigated by a modified gas chromatographic estimation method. ACh was extracted with perchloric acid, precipitated as reineckate and demethylated with sodium benzenethiolate. The tertiary amines derived from ACh and other choline esters were concentrated by a microdistillation procedure. Gas chromatography was performed using a nitrogen selective detector. In the range of concentrations between 0.4 and 2.5 nmol ACh per tissue sample the coefficient of variation was 5.2 per cent. The recovery of ACh added to heart extracts was 101 per cent. Evidence for the identity of the choline ester isolated from rabbit hearts and authentic ACh was obtained by equal retention times and by correspondence of the ratio N/C of the respective tertiary amines. Parallel measurements using gas chromatography and bioassay on the rat blood pressure yielded closely corresponding values of ACh levels in the rabbit heart. The concentration of ACh was much higher in the atria than in the ventricles. In both atria, and ventricles the ACh concentration was higher in the right than in the left part of the rabbit heart. Endogenous propionylcholine or butyrylcholine were not detected.     

Participation of the Breuer-Hering inflation reflex in regulation of respiration frequency in anaesthetized rats.

The respiration frequency and Breuer-Hering inflation reflex (BHIR) values were compared in anaesthetized rats after unilateral vagotomy. Nos significant differences were found in the decrease in respiration frequency after transection of the right of left vagus and there were no differences in BHIR values in correlation to conduction by the right or left vagus. With unilateral vagotomy and an inflation pressure of 20 cm H20 the BHIR values fell to about one fourth of the control values. Progressive cooling of the contralateral vagus led at 8-10 degrees C to a non-significant decrease in respiration frequency to 87% of the initial value; in this state the BHIR could not be elicited. Further cooling of the vagus to 0 degrees C reduced respiration frequency to the same values as in bilateral vagotomy. The discrepancy between the mild decrease in respiration frequency and simultaneous disappearance of the BHIR shows that changes in respiration frequency in anaesthetized rats are not directly correlated to the presence of the BHIR.     

Effects of unilateral cervical vagotomy on antral endocrine cells in mouse.

The present study was carried out to investigate the effect of unilateral cervical vagotomy on the antral endocrine cells in mouse. Fifty-four mice were randomly divided into three groups, 18 in each, for left or right cervical vagotomy, or sham operation as controls. The animals were sacrificed 2, 4, and 8 weeks after the operation, respectively. Chromogranin-, gastrin/CCK-, serotonin-, and somatostatin-cells were detected by immunohistochemistry and quantitated by computerised image analysis. The results showed that the number of chromogranin-cells was decreased in both left and right vagotomized mice after 4 weeks and remained at the same level after 8 weeks. The numbers of gastrin-, serotonin- and somatostatin-cells did not change after right vagotomy. However, the numbers of gastrin- and somatostatin-cells were decreased after left vagotomy, whereas no change was found in serotonin-cells. Endocrine cells with vacuolated cytoplasm and pyknotic nuclei were also observed during the course of time. The alteration in the antral endocrine cells observed in this study seemed to be dynamic and depended on the observation time after the operation as well as the denervated branches of the vagus nerve. This may explain, at least partially the contradictory results obtained earlier by different investigators.     

Localization of the reflex pathway responsible for the vasodepressor reaction induced by inferior vena caval occlusion and isoproterenol.

Vasodepressor reactions were induced in 27 rats by a combination of inferior vena caval occlusion and an infusion of isoproterenol. A vasodepressor reaction was defined as paradoxical heart rate slowing during inferior vena caval occlusion. The R-R intervals were measured at 5-s intervals before, during, and after 60 s of inferior vena caval occlusion. The purpose of this study was to examine the role of the right and left vagus nerve and the right and left stellate ganglia in this reflex. Under control conditions inferior vena caval occlusion accelerated the rate (R-R, -15.9 +/- 0.9 ms). During an infusion of isoproterenol (0.5-1.0 micrograms.min-1), inferior vena caval occlusion produced paradoxical rate slowing, i.e., a vasodepressor reaction (R-R, +75.0 +/- 2.2 ms). The vasodepressor reaction was examined during inferior vena caval occlusion and isoproterenol under the following additional states: atropine methyl bromide or right vagotomy did not alter the reaction; left vagotomy eliminated the reaction; and right or left stellectomy greatly reduced the vasodepressor reaction. We conclude the following: (1) left vagal afferents mediate the vasodepressor reaction; (2) cardiac sympathetic fibers participate in the vasodepressor reaction by withdrawing efferent tone through the right stellate ganglion, and by generating the afferent signal, which triggers the vasodepressor reaction through the left stellate ganglion.     

Simulation of the diffusion of acetylcholine in the neuroeffector junctions of the sinus node

Traditionally, the diffusion of acetylcholine (ACh) from a neuron to cardiac muscle in a neuroeffector junction has been modeled as radial diffusion from a nerve ending into a spherical homogeneous medium. Various microscopic structures in the heart may or may not influence the spatial distribution of ACh within neuroeffector junctions. To determine the effect of microscopic anatomy on the diffusion of ACh in neuroeffector junctions, we simulated the diffusion of ACh in a two-dimensional inhomogeneous geometry that was based on micrographs of neuroeffector junctions in the sinus node. ACh was released at sites adjacent to a neuron. Simulations showed that the times of peak concentration after release and the peak concentrations per se were distributed symmetrically above and below and to the right and left of the neuron, but not radially about the neuron. We conclude that the diffusion of ACh in the neuroeffector junctions of the sinus node cannot be predicted well by a mathematical model that assumes radial diffusion in a spherical and homogeneous medium.     

Vagosympathetic interactions in ischemia-induced myocardial norepinephrine and acetylcholine release

To elucidate the pathophysiological roles of vagosympathetic interactions in ischemia-induced myocardial norepinephrine (NE) and acetylcholine (ACh) release, we measured myocardial interstitial NE and ACh levels in response to a left anterior descending coronary occlusion in the following groups of anesthetized cats: intact autonomic innervation (INT, n = 7); vagotomy (VX, n = 6); local administration of atropine (Atro, n = 6); transection of the stellate ganglia (TSG, n = 5); local administration of phentolamine (Phen, n = 6); and combined vagotomy and transection of the stellate ganglia (VX+TSG, n = 5). The maximum NE release was enhanced in the VX group (141 +/- 30 nmol/l, means +/- SE, P < 0.05) compared with the INT group (61 +/- 12 nmol/l). Neither the Atro (50 +/- 24 nmol/l) nor VX+TSG groups (84 +/- 25 nmol/l) showed enhanced NE release. The maximum ACh release was unaltered in the TSG and Phen groups compared with the INT group (19 +/- 4, 18 +/- 4, and 13 +/- 3 nmol/l, respectively). These findings indicate that the cardiac vagal afferent but not efferent activity reduced the ischemia-induced myocardial NE release. In contrast, the cardiac sympathetic afferent and efferent activities played little role in the ischemia-induced myocardial ACh release.     

Ipsilateral vagotomy to unilaterally ovariectomized pre-pubertal rats modifies compensatory ovarian responses

The present study evaluates the participation of the vagus nerve in pre-pubertal rats with unilateral ovariectomy on puberty onset, and on progesterone, testosterone and estradiol serum levels, and the compensatory responses of the ovary. Unilateral vagotomy did not modify the onset of puberty in unilaterally ovariectomized rats. Ovulation rates of animals with the left vagus nerve sectioned and the left ovary in-situ was lower than in rats with only unilateral ovariectomy. Sectioning the left vagus to 32-day old rats with the left ovary in-situ resulted in lower compensatory ovarian hypertrophy than in rats with right unilateral ovariectomy. Twenty-eight or 32-day old animals with sectioning of the right vagus nerve and the right ovary in situ showed higher compensatory ovulation. Twenty-eight -day old rats with the right ovary in situ had higher progesterone and testosterone levels than animals of the same age with the left ovary in-situ. Compared to animals with the right ovary in situ, animals treated at 32-days of age, sectioning the ipsi-lateral vagus nerve resulted in higher progesterone levels. Higher progesterone levels were observed in 28- and 32 days old rats with the left ovary in situ and left vagus nerve sectioned. Thirty-two day old animals with the right ovary in situ and right vagus nerve sectioned had higher progesterone levels than rats of the same age with the left ovary in situ and left vagus nerve sectioned. Left vagotomy to 28-day old rats with the left ovary in situ resulted in higher testosterone levels, a reverse response to that observed in animals with sectioning of the right vagus and the right ovary in situ. Thirty-two day old rats with the left ovary in situ and left vagus nerve sectioned showed lower testosterone levels than animals without vagotomy and with the left ovary in situ.     

Choline acetyltransferase activity and distribution in rat hearts after bilateral cervical vagotomy

The activity of choline acetyltransferase (ChAt; E.C. 2.3.1.6) measured as the bromoacetylcholine-sensitive portion of the maximal rate of acetylcholine synthesis has been determined in homogenates of nine regions of the heart of control rats and rats sacrificed 72-74 h after bilateral cervical vagotomy. When related to the content of protein, the activity of ChAT was lowered by 30% in the atria and unchanged in the ventricles of vagotomized rats. The highest absolute decline caused by vagotomy was observed in the sinoatrial region; it was somewhat less in the rest of the right atrium and in the interatrial septum and considerably less in the left atrium. It is concluded that preganglionic parasympathetic fibres supply mainly the sinoatrial region and the right atrium, and that they do not branch to the ventricles. Preganglionic ChAT nts about 30% of total ChAT activity in the atria. The sinoatrio-ventricular gradient in the distribution of ChAT in the heart is due to uneven distribution of both the pre- and postganglionic ChAT pools (i.e., of both the pre- and postganglionic cholinergic nerve fibres and nerve cell bodies).     

Cardiac acetylcholine concentration in the rat

Varying values for the acetylcholine (ACh) concentration in the rat heart have been reported. The possibility that the method of sampling may influence prompted a comparison of heart levels of ACh obtained by two different procedures for sacrificing animals. One method was by microwave irradiation in vivo and the others being in vitro on the irradiated heart removed after decapitation. There were significant differences found in cardiac ACh concentration between the in vivo irradiated group and the decapitation groups. In decapitated animals, the cardiac ACh concentration became increasingly lower on standing. We also measured the ACh concentration of right atrium, left atrium, right ventricle and left ventricle. They were 4.62 +/- 1.57 nmol/g (mean +/- SD), 2.58 +/- 1.01, 2.76 +/- 1.00 and 2.12 +/- 0.70, respectively. We conclude the microwave irradiation in vivo is a more appropriate method for determining the cardiac ACh concentration.     

The role of vagus nerves in different changes of the right atrial pressure following intravenous injection of pressor vasoactive drugs

In acute experiments on anesthetized cats, intravenous injection of the norepinephrine and angiotensin caused different changes of right atrial pressure in intact animals (decreasing--I group, of animals, and increasing--II group). After right and left vagus nerves had been cut, the right atrial pressure in the I group of animals decreased, but its changes were lesser than in intact animals due to slowing down of the increase of the right ventricular myocardial contractility and venous return. The latter was the result of severe diminution of the increase of the superior vena cava flow compared with the intact animals, meanwhile the value of the inferior vena cava flow did not change. In the II group animals after vagotomy and intravenous injection of the noripinephrine and angiotensin the sign of the right atrial pressure became negative, i. e. the direction of its shifts changed to the opposite, compared with intact animals. In this case, the changes of the sign of the right atrial pressure was caused by the removal of the reflectory inhibitory vagal influences on the heart, because the values of the right ventricular myocardial contractility and venous return were the same as in intact animals of the group, due to decreasing of the value of the superior vena cava flow and increasing of the shifts of the inferior vena cava flow. The vagotomy alone caused also different changes (decreasing or increasing) of right atrial pressure following increasing of the right ventricular myocardial contractility, meanwhile the changes of the venous return were insignificant. Direct electrical stimulation of both the right and the left vagus nerves caused the increasing of the right atrial pressure and decreasing of the right ventricular myocardial contractility and venous return. Thus we concluded, that different changes of the right atrial pressure in animals following intravenous injection of the pressor vasoactive drugs could be the result of different manifestations of the vagal afferent impulsation, which has influence on the sympathetic tonic discharges on the vessels of the regions of the superior and inferior vena cava, and the vagal reflectory inhibitory influences on the heart.     

Cortical representation of the heart sinus node zone

Evoked potentials (EP) arising in response to electrical stimulation of the heart sinus node zone (SNZ) were registered in the cortex of the large hemispheres (LHS) of cats. EP with the shortest latent period (LP) of 18-19 months were recorded both in the left and right hemispheres in the area of a cross-shaped cleft (associative field PCA, partially the I motorsensor zone and the I sensorimotor zone). Besides, EP with a more durable LP (20-21 months) were registered in the 2nd sensorimotor zone. EP remained unchanged after bilateral vagotomy and disappeared after spinal cord cutting at C-2 level. The presence of the functional centre regulating cardiac activity in the branch sections of LHS is suggested.     

IN VIVO SYNTHESIS OF RAPIDLY-LABELLED RNA WITHIN THE RAT NODOSE GANGLIA FOLLOWING VAGOTOMY

Abstract— The synthesis of rapidly-labelled RNA was studied in the nodose ganglia following unilateral vagotomy. Early changes were detected in the electrophoretic patterns of RNA from both ganglia following a crush of the right vagus. The right ganglionic response is characterized by two phases, the first involving rapid processing of rRNA with associated changes in 'message-like' RNA (mlRNA). A second change, detected by 14 days, appears to involve an increase in the heterodispersity of mlRNA and decreased processing of rRNA. The left ganglion follows a very similar response to that of the right with the exception of the changes in rRNA. However, the left response lags behind that of the right by at least 1 day. We conclude that extensive changes in gene expression are occurring in both ganglia. The similarity of the responses of both ganglia suggests that axon regeneration (in the right) and collateral sprouting (in the left) may produce analogous changes in gene expression, but not in rRNA synthesis.     

Laterality of human primary gustatory cortex studied by MEG

We examined the laterality of the human gustatory neural pathway by measuring gustatory-evoked magnetic fields (GEMfs) and demonstrating the activation of the human primary gustatory cortex (PGC). In patients whose chorda tympani nerve had been severed unilaterally on the right side, we stimulated the normal side (i.e., left side) of the chorda tympani nerve with NaCl solution using a device developed for measuring GEMfs. We used the whole-head magnetoencephalography system for recording GEMfs and analyzed the frequency and latency of PGC activation in each hemisphere. "The transitional cortex between the insula and the parietal operculum" was identified as PGC with the base of the central sulcus in this experiment. Significant difference was found in frequencies among bilateral, only-ipsilateral, and only-contralateral responses by the Friedman test (P < 0.05), and more frequent bilateral responses were observed than only-ipsilateral (P < 0.05) or only-contralateral responses (P < 0.01) by the multiple comparison tests. In the bilateral responses, the averaged activation latencies of the transitional cortex between the insula and the parietal operculum were not significantly different in both hemispheres. These results suggest that unilateral gustatory stimulation will activate the transitional cortex between the insula and the parietal operculum bilaterally in humans.     

Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy

The effects of left and right unilateral cervical vagotomy on the content of several neuroendocrine peptides were studied in different parts of the murine gastrointestinal tract, known to receive vagal innervation. The neuroendocrine peptides investigated were secretin, gastric inhibitory peptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, substance P, VIP, neurotensin, neuropeptide Y (NPY), and galanin. The neuroendocrine peptide concentration was affected after both left and right vagotomy, and that the changes in the concentrations of the neuroendocrine peptide levels occurred in all the gastrointestinal segments investigated, namely antrum, small and large intestine. However, these changes varied, depending on which side was vagotomized and the interval after vagotomy. It is concluded that the vagus nerve had an important impact on the neuroendocrine system in the murine gut. It is suggested, furthermore that the contradictory results obtained earlier on the effect of vagotomy on the gastrointestinal peptides may depend on differences in the vagotomy methods used and on differences in observation time after vagotomy.