Differential effects of selective vagotomy and tropisetron in aminoprivic feeding

Both total subdiaphragmatic vagotomy (TVAGX) and serotonin(3) receptor blockade with tropisetron or ondansetron attenuate amino acid-imbalanced diet (Imb) anorexia. Total vagotomy is less effective than tropisetron in reducing Imb-induced anorexia and also blunts the tropisetron effect. With the use of electrocautery at the subdiaphragmatic level of the vagus, we severed the ventral and dorsal trunks as well as the hepatic, ventral gastric, dorsal gastric, celiac, and accessory celiac branches separately or in combination to determine which vagal branches or associated structures may be involved in these responses. Rats were prefed a low-protein diet. On the first experimental day, tropisetron or saline was given intraperitoneally 1 h before presentation of Imb. Cuts including the ventral branch, i.e., TVAGX, ventral vagotomy (above the hepatic branch), and hepatic + gastric vagotomies (but not hepatic branch cuts alone) caused the highest (P < 0.05) Imb intake on day 1 with or without tropisetron. The responses to tropisetron were not affected significantly. On days 2-8, groups having vagotomies that included the hepatic branch recovered faster than sham-treated animals. Because the hepatic and gastric branches together account for most of the vagal innervation to the proximal duodenum, this area may be important in the initial responses, whereas structures served by the hepatic branch alone apparently act in the later adaptation to Imb.     

On the vagal cardiac nerves,with special reference to the early evolution of the head–trunk interface

The vagus nerve, or the tenth cranial nerve, innervates the heart in addition to other visceral organs, including the posterior visceral arches. In amniotes, the anterior and posterior cardiac branches arise from the branchial and intestinal portions of the vagus nerve to innervate the arterial and venous poles of the heart, respectively. The evolution of this innervation pattern has yet to be elucidated, due mainly to the lack of morphological data on the vagus in basal vertebrates. To investigate this topic, we observed the vagus nerves of the lamprey (Lethenteron japonicum), elephant shark (Callorhinchus milii), and mouse (Mus musculus), focusing on the embryonic patterns of the vagal branches in the venous pole. In the lamprey, no vagus branch was found in the venous pole throughout development, whereas the arterial pole was innervated by a branch from the branchial portion. In contrast, the vagus innervated the arterial and venous poles in the mouse and elephant shark. Based on the morphological patterns of these branches, the venous vagal branches of the mouse and elephant shark appear to belong to the intestinal part of the vagus, implying that the cardiac nerve pattern is conserved among crown gnathostomes. Furthermore, we found a topographical shift of the structures adjacent to the venous pole (i.e., the hypoglossal nerve and pronephros) between the extant gnathostomes and lamprey. Phylogenetically, the lamprey morphology is likely to be the ancestral condition for vertebrates, suggesting that the evolution of the venous branch occurred early in the gnathostome lineage, in parallel with the remodeling of the head–trunk interfacial domain during the acquisition of the neck. J. Morphol. 277:1146–1158, 2016. © 2016 Wiley Periodicals, Inc.     

Metamorphic changes in the vagal innervation to the alimentary tract in the green frog, Rana clamitans (Ranidae).

The alimentary tract of typical anurans shortens extensively at metamorphosis, when the microphagous tadpole transforms into a macrophagous frog. We used methylene blue vital stain and Sihler stain, in conjunction with microdissection, to map the distribution of the gastric branch of the vagus nerve in green frogs (Rana clamitans) before and after metamorphosis. After metamorphosis, terminal divisions of the gastric branch can be observed on the tunica musculosa extending as far as the pylorus. In the tadpole, the gastric branch ends abruptly on the esophagus. The premetamorphic pattern of innervation is consistent with the absence of digestive activity in the foregut before metamorphosis. Preliminary experiments, involving stimulation of the gastric branch of the vagus in the tadpoles, confirm the anatomical observation of the absence of vagal innervation before metamorphosis.     

Adrenergic innervation of the dorsal vagal motor nucleus: possible involvement in inhibitory control of gastric acid and pancreatic insulin secretion

Summary Morphological and physiological approaches were used to investigate the possible role of an adrenergic innervation of the dorsal vagal complex in the control of basal gastric acid and pancreatic insulin secretion in the rat. The use of retrograde-tracing methods with injections of True Blue or of wheat-germ agglutinin into the stomach or pancreas first confirmed that most vagal preganglionic neurons innervating these two viscera are localized in the dorsal motor nucleus of the vagus, a number of them connected to both viscera. Light- and electron-microscopic investigation of the organization of adrenergic neuronal structures immunoreactive to phenylethanolamine-N-methyltransferase within this medullary nucleus further revealed: (i) that adrenergic axons establish profuse synaptic connections of the symmetrical type with perikarya and dendrites of this nucleus, and (ii) that several of these adrenergic fibers are connected with retrogradely labeled neurons innervating the stomach and/or pancreas. Lastly, measurements of basal gastric acid output and plasma insulin clearly indicated that both visceral secretions are rapidly and conspicuously decreased by local infusion of 2 nM adrenaline within the dorsal vagal complex. Taken together, these data strongly suggest that the adrenergic innervation of the dorsal medulla oblongata is involved in direct synaptic inhibition of the parasympathetic preganglionic neurons of the vagus that control secretion of gastric acid and pancreatic insulin.     

Innervation pattern of the gill arches and gills of the carp (Cyprinus carpio)

The innervation pattern of the respiratory gill arches of the carp (Cyprinus carpio) is described. The gill region is innervated by the branchial branches of the glossopharyngeal and vagal nerves. Each branchial nerve divides at the level of or just distal to the epibranchial ganglion into: 1) a pretrematic branch, 2) a dorsal pharyngeal branch, and 3) a posttrematic branch. The dorsal pharyngeal branch innervates the palatal organ in the roof of the buccal cavity. The pretrematic and posttrematic branches innervate the posterior and anterior halves, respectively, of the gill arches bordering a gill slit. Each branch splits into an internal and an external part. The internal bundle innervates the buccal side of the gill arch, including the gill rakers. The external bundle terminates in the gill filaments. The epibranchial motor branch, a small nerve bundle containing only motor fibers, circumvents the ganglion and anastomoses distally with the posttrematic branch. The detailed course and branching patterns of these branches are described.     

The innervation of the human esophagus

There are usually 3 left and 4 right esophageal branches of the sympathetic chains. Besides a direct approach to the organ, they form a delicate network between aorta and esophagus. This network exchanges fibers with the vagus nerves. The vagal supply of the cranial third is rather poor. It is richest in the middle third. As a rule, the left anterior, left posterior, right anterior and right posterior main branches can be prepared. There are relatively few communications between right and left ramuli. Above the esophageal hiatus, always quite distinct anterior vagal chords are found, while posteriorly there are usually only very thin nerve bundles.     

Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases

Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organ protect the target organ against sustained ischemia–reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning (RRPC) are well established in heart, but their mechanisms still remain to be elucidated. So, the present study was designed to investigate the possible role of oxygen-sensing hypoxia inducible factor-prolyl 4-hydroxylases (HIF-P4Hs) in RRPC-induced cardioprotection in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion and reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Ethyl 3,4-dihydroxybenzoate (EDHB) and α-ketoglutarate (α-KG) were employed as HIF-P4Hs inhibitor and activator, respectively. Diethyldithiocarbamic acid (DDCA) was employed as NFkB inhibitor. Remote renal preconditioning prevented I/R-induced myocardial injury and produced cardioprotective effects. Pharmacological preconditioning with EDHB (100 mg kg⁻¹ i.p.) mimicked the cardioprotective effects of RRPC. However, α-KG (200 mg kg⁻¹ i.p.) and DDCA (150 mg kg⁻¹ i.p.) abolished cardioprotective effects of RRPC and EDHB. So, it may be concluded that inhibition of HIF-P4H has a key role in RRPC-induced cardioprotection. Further, remote preconditioning-induced HIF-P4H inhibition may have triggered a transduction pathway involving activation of NFkB.     

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.     

电刺激下丘脑外侧区对大鼠胃缺血-再灌注损伤的影响

采用夹闭大鼠腹腔动脉30min,松开动脉夹血流复灌60min的胃缺血－再灌注损伤(gastric ischemia reperfusion injury,GI-RI)模型,用电和化学刺激,电损毁的方法观察了下丘脑外侧区（lateral hypothalamic area,LHA)对GI－RI的影响,并对其机制进行了初步分析,结果表明：（1）以0．2,0．4,0．6mA的电流强度刺激LHA,GI－RI均显著加重,且有强度－效应依赖关系,LHA内注射L－谷氨酸（L－Glu)后,对LI－RI的效应与电刺激相似,电损毁双侧LHA,GI－RI面积较电刺激组明显减小;（2）损毁双侧背侧迷走复合体（dorsal vagal complex,DVC)或切损毁是LHA,GI－RI面积较电刺激组明显减小;（2）损 侧背侧迷走复合体（dorsal vagal complex,DVC)或切断膈下迷走神经均能取消电刺激LHA加重GI－RI的作用。（3）电刺激LHA使缺血－再灌注（ischemia-reperfusion,I-R)的胃粘膜丙二醛（MDA）含量升高,超氧化物歧化酶（SOD）活性降低;（4）电刺激LHA使I－R的胃液量和总酸排出量增多,而酸度,胃蛋白酶活性和胃壁结合粘液量等无明显改变,结果提示;LHA是对GI－RI具有加重作用的中枢部位,其作用是通过DVC及迷走神经下传的,电刺激LHA加重GI－RI的作用与胃粘膜MDA含量增加,SOD活性降低,胃液量和总酸排出量增加等因素有关,而似与酸度,胃蛋白酶活性,胃壁结合粘液量等因素无关。     

Subdiaphragmatic vagal afferent nerves modulate visceral pain

Activation of the vagal afferents by noxious gastrointestinal stimuli suggests that vagal afferents may play a complex role in visceral pain processes. The contribution of the vagus nerve to visceral pain remains unresolved. Previous studies reported that patients following chronic vagotomy have lower pain thresholds. The patient with irritable bowel syndrome has been shown alteration of vagal function. We hypothesize that vagal afferent nerves modulate visceral pain. Visceromotor responses (VMR) to graded colorectal distension (CRD) were recorded from the abdominal muscles in conscious rats. Chronic subdiaphragmatic vagus nerve sections induced 470, 106, 51, and 54% increases in VMR to CRD at 20, 40, 60 and 80 mmHg, respectively. Similarly, at light level of anesthesia, topical application of lidocaine to the subdiaphragmatic vagus nerve in rats increased VMR to CRD. Vagal afferent neuronal responses to low or high-intensity electrical vagal stimulation (EVS) of vagal afferent Adelta or C fibers were distinguished by calculating their conduction velocity. Low-intensity EVS of Adelta fibers (40 microA, 20 Hz, 0.5 ms for 30 s) reduced VMR to CRD at 40, 60, and 80 mmHg by 41, 52, and 58%, respectively. In contrast, high-intensity EVS of C fibers (400 microA, 1 Hz, 0.5 ms for 30 s) had no effect on VMR to CRD. In conclusion, we demonstrated that vagal afferent nerves modulate visceral pain. Low-intensity EVS that activates vagal afferent Adelta fibers reduced visceral pain. Thus EVS may potentially have a role in the treatment of chronic visceral pain.     

Neuropeptides as central integrators of autonomic nerve activity: effects of TRH, SRIF, VIP and bombesin on gastric and adrenal nerves

The nerve activity of the gastric ramus of the splanchnic (sympathetic) nerve, gastric ramus of the vagus, adrenal ramus of the splanchnic nerve and the superior laryngeal nerve (laryngeal ramus of vagus) were assessed before and after i.c.v. injection of neuropeptides in the rat. TRH stimulated the vagal branch but attenuated the sympathetic outflow to the stomach. In contrast, the sympathetic outflow to the adrenal was enhanced by TRH. SRIF suppressed the activity of all the nerves studied. VIP did not affect the sympathetic outflow to the stomach while suppressing the gastric branch of the vagus. The adrenal sympathetic branch as well as the superior laryngeal nerve was stimulated by VIP. Bombesin suppressed both vagal and sympathetic outflow to the stomach but markedly stimulated the laryngeal branch of the vagus. The adrenal sympathetic nerve was either stimulated or attenuated slightly by bombesin. These results indicate that centrally administered neuropeptides produce reactions specific for each nerve.     

Leptin-induced satiation mediated by abdominal vagal afferents

Leptin is a hormone secreted into the systemic blood primarily by white adipose tissue. However, leptin also is synthesized and stored by cells in the gastric mucosa. Because gastric mucosal leptin is secreted in response to ingestion of a meal, we hypothesized that it might contribute to satiation (meal termination) by acting on gastrointestinal vagal afferent neurons. To test whether leptin is capable of acutely reducing short-term food intake, we measured consumption of a liquid meal (15% sucrose) following low-dose leptin administration via the celiac artery, which perfuses the upper gastrointestinal tract. Leptin (1, 3, 10 mug) was infused via a chronically implanted, nonocclusive celiac arterial catheter or via a jugular vein catheter with its tip in the right cardiac atrium. Fifteen percent sucrose intake was then measured for 30 min. We found that leptin dose dependently inhibited sucrose intake when infused through the celiac catheter but not when infused into the general circulation via a jugular catheter. Plasma leptin concentrations in the general circulation following celiac arterial or jugular leptin infusions were not significantly different. Celiac arterial leptin infusion did not reduce meal size in vagotomized or capsaicin-treated rats. Finally, we also found that reduction of meal size by celiac leptin infusion was markedly enhanced when coinfused with cholecystokinin, a gastrointestinal satiety peptide whose action depends on vagal afferent neurons. Our results support the hypothesis that leptin contributes to satiation by a mechanism dependent on gastrointestinal vagal afferent innervation of the upper gastrointestinal tract.     

Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection

It has been recently reported that release of erythropoietin could mediate the cardioprotective effects of remote renal preconditioning. However, the mechanism of erythropoietin-mediated cardioprotection in remote preconditioning is still unexplored. Therefore, the present study was designed to investigate the possible signal transduction pathway of erythropoietin-mediated cardioprotection in remote preconditioning in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Remote renal preconditioning and erythropoietin preconditioning (5,000 IUkg(-1), i.p.) attenuated ischemia-reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of diethyldithiocarbamic acid (150 mg kg(-1) i.p.), a selective NFkB inhibitor, and glibenclamide (5 mg kg(-1) i.p.), a selective K(ATP) channel blocker, attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning. However, administration of minoxidil (1 mg kg(-1) i.v.), a selective K(ATP) channel opener, restored the attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning in diethyldithiocarbamic acid pretreated rats. These results suggest that K(ATP) channel is a downstream mediator of NFkB activation in remote preconditioning and erythropoietin preconditioning. Therefore, it may be concluded that erythropoietin preconditioning and remote renal preconditioning trigger similar signaling mechanisms for cardioprotection, i.e., NFkB activation followed by opening of K(ATP) channels.     

Desheathing the nodose ganglion is not a reliable method of de-efferentation in the ferret

The present study reports the results of physiological and anatomical experiments in which the purpose was to determine whether desheathing the nodose ganglion is a reliable method of vagal de-efferentation in the ferret. In physiological studies, the effects of electrically stimulating the treated and untreated vagal nerves on cardiovascular and intestinal responses were examined and compared with previously obtained data after left supranodose vagotomy. The anatomical studies illustrated the effects of desheathing the left nodose ganglion on the transport of horseradish peroxidase (HRP) within a thoracic vagal communicating branch. These data were compared to data from control animals and animals that had undergone left supranodose vagotomy. The results demonstrated that severing the fascicles overlying the left nodose ganglion and allowing the nerve fibers to degenerate, caused no reduction in labeled efferent cell bodies in the left dorsal motor nucleus of the vagus as compared to controls. However, after left supranodose vagotomy there were no efferent cell bodies labeled in the left dorsal motor nucleus of the vagus. Following degeneration of the fascicles, electrical stimulation of the peripheral cut end of this nerve did not abolish the efferent responses in 7 out of 9 animals studied, whereas supranodose vagotomy abolished the responses in all animals. These findings demonstrate that desheathing the nodose ganglion and thereby removing the nerve bundles overlying the nodose ganglion is not a guaranteed method of destroying the efferent fibers in the vagus nerve of the ferret. Supranodose vagotomy, therefore, is a more reliable method of de-efferentation in this species.     

Comparative study of the cardioprotective effects of local and remote preconditioning in ischemia/reperfusion injury

AimsThough the cardioprotective effects of local or remote preconditioning have been estimated, it is still unclear which of them is more reliable and provides more cardioprotection. The present investigation was directed to compare, in one study, the cardioprotective effects of different cycles of local or remote preconditioning in ischemia/reperfusion (I/R)-induced electrophysiological, biochemical and histological changes in rats.Main methodsRats were randomly assigned into 10 groups. Groups 1 and 2 were normal and I/R groups, respectively. Other groups were subjected to 1, 2, 3, 4 cycles of local or remote preconditioning before myocardial I/R (40 min/10 min). Heart rate and ventricular arrhythmias were recorded during I/R progress. At the end of reperfusion, plasma creatine kinase-MB (CK-MB) activity and total nitrate/nitrite (NO_x) were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and myeloperoxidase (MPO) activity were estimated in the heart left ventricle. Histological examination was also performed to visualize the protective cellular effects of the effective cycle of local or remote preconditioning.Key findingsIn general, local preconditioning was more effective than remote preconditioning in reducing ventricular arrhythmias, CK-MB release, lactate accumulation and elevated MPO activity as well as preserving adenine nucleotides. Concerning the most effective group in each therapy, 3 cycles of local preconditioning provided more cardioprotection than that of remote preconditioning in the histological examination.SignificanceDespite being invasive, local preconditioning provided more effective cardioprotection than remote preconditioning in ameliorating the overall electrophysiological, biochemical and histological changes.     

Chemotherapy-induced pica and anorexia are reduced by common hepatic branch vagotomy in the rat

Anticancer agents, such as cisplatin, induce vomiting, nausea, and anorexia. Cisplatin primarily acts on vagal afferents to produce emesis, but little is known about how this drug generates nausea and anorexia. Electrophysiology indicates that cisplatin activates vagal afferents of the common hepatic branch (CHB). Rats lack an emetic response but do ingest kaolin clay (a pica response) when made sick by toxins, and this behavior can be inhibited by antiemetic drugs. It has been postulated that pica may serve as a proxy for emesis in the rat. The goal of this study was to assess the effect of CHB or ventral gastric (Gas) or celiac (Cel) branch vagotomies on pica and anorexia produced by cisplatin in the rat. The effects of apomorphine, a dopamine receptor agonist, which induces emesis via a central mechanism, were also assessed. Cisplatin-induced pica was suppressed by CHB vagotomy (a 61% reduction) but not by Gas and Cel vagotomy. Suppression of daily food intake and body weight following cisplatin treatment was also blunted by CHB ablation but not by Gas or Cel vagotomy. No vagotomy condition exhibited altered apomorphine-induced pica. The results indicate that the CHB, which innervates primarily the duodenum, plays an important role in cisplatin-induced malaise. These data suggest that pica has sensory pathways similar to emetic systems, since a vagotomy condition inhibited cisplatin-induced pica but had no effect on apomorphine-induced pica. This investigation contributes to the delineation of the physiology of pica and neural systems involved in malaise in the nonvomiting rat.     

迷走神经功能调节与心肌缺血保护

心血管系统的生理活动受自主神经系统(autonomic nervous system,ANS)调节.已有研究表明,自主神经功能紊乱,尤其是迷走神经功能低下,与心血管疾病(cardiovascular disease,CVD)的发生、发展及预后密切相关.本文结合国内外研究现状,就本研究室在迷走神经对心脏不同部位的调控及其对心肌的保护作用机制方面的研究成果进行阐述.通过收缩功能检测及标准玻璃微电极细胞内记录技术,发现迷走神经递质--乙酰胆碱对哺乳动物心室肌有直接作用,可抑制细胞收缩力及动作电位时程;通过组织化学染色及分子生物学方法进一步证明心室有毒蕈碱受体分布;通过膜片钳技术显示在部分动物心室肌上存在乙酰胆碱激活的内向整流钾通道(acetylcholine-activated potassium channel,KACh),并且其电流(IK·ACh)和心房肌一样具有衰减现象.前期研究证明心房肌IK·ACh的衰减与毒蕈碱受体、G蛋白或钾通道磷酸化有关;而心室肌的IK·ACh还有待于进一步研究.我们建立了相关动物模型,结合心率变异性分析等自主神经评价方法,探讨ANS在健康和疾病状态下的变化情况,证明了迷走神经对心脏调节的增龄性改变及代偿效应.通过提高迷走张力(乙酰胆碱缺血预/后适应、有氧运动、β受体阻断剂),研究改善自主神经平衡对缺血心肌的保护作用以及胆碱能抗炎通路防御缺血,再灌注诱导的炎症损伤机制.综合评价心脏自主神经调节,改善交感和迷走张力平衡,将为CVD防治的基础研究提供重要的理论依据.     

Selective ablation of spinal afferent neurons containing CGRP attenuates gastric hyperemic response to acid.

The gastric mucosa, in particular submucosal blood vessels, are innervated by afferent neurons containing neuropeptides such as calcitonin gene-related peptide. Stimulation of sensory neurons innervating the gastric mucosa increases submucosal blood flow. Since sensory neurons supplying the stomach are of dual origin from nodose and dorsal root ganglia, we examined the effect of selective ablation of either the vagal or spinal sensory innervation to the upper gastrointestinal tract on the increase in gastric mucosal blood flow in response to acid back diffusion into the gastric mucosa. Perineural application of capsaicin to the celiac/superior mesenteric ganglia, but not to the vagus nerves, significantly inhibited by 53% the hyperemic response to acid back diffusion. Tissue levels of immunoreactive calcitonin gene-related peptide in the gastric corpus were significantly reduced (by 73%) by periceliac capsaicin treatment, but unaffected by perivagal capsaicin treatment. These data suggest that spinal capsaicin-sensitive afferents containing calcitonin gene-related peptide immunoreactivity are involved in mediating increases in gastric mucosal blood flow. This increase in gastric mucosal blood flow mediated by sensory neurons may act as a protective mechanism against mucosal injury, similar to responses seen in other tissues such as skin.     

Functional anatomy of the vagal innervation of the cervical trachea of the dog.

The canine cervical trachea has been used for numerous studies regarding the neural control of tracheal smooth muscle. The purpose of the present study was to determine whether there is lateral dominance by either the left or right vagal innervation of the canine cervical trachea. In anesthetized dogs, pressure in the cuff of the endotracheal tube was used as an index of smooth muscle tone in the trachea. After establishment of tracheal tone, as indicated by increased cuff pressure, either the right or left vagus nerve was sectioned followed by section of the contralateral vagus. Sectioning the right vagus first resulted in total loss of tone in the cervical trachea, whereas sectioning the left vagus first produced either a partial or no decrease in tracheal tone. After bilateral section of the vagi, cuff pressure was recorded during electrical stimulation of the rostral end of the right or left vagus. At the maximum current strength used, stimulation of the left vagus produced tracheal constriction that averaged 28.5% of the response to stimulation of the right vagus (9.0 +/- 1.8 and 31.6 +/- 2.5 mmHg, respectively). In conclusion, the musculature of cervical trachea in the dog appears to be predominantly controlled by vagal efferents in the right vagus nerve.     

Heterozygous disruption of Flk-1 receptor leads to myocardial ischaemia reperfusion injury in mice: application of affymetrix gene chip analysis

This study addresses an important clinical issue by identifying potential candidates of vascular endothelial growth factor (VEGF) signalling through the Flk-1 receptor that trigger cardioprotective signals under ischaemic stress. Isolated working mouse hearts of both wild-type (WT) and Flk-1(+/-) were subjected to global ischaemia (I) for 30 min. followed by 2 hrs of reperfusion (R). Flk-1(+/-) myocardium displayed almost 50% reduction in Flk-1 mRNA as examined by quantitative real-time RT-PCR at the baseline level. Flk-1(+/-) mouse hearts displayed reduction in left ventricular functional recovery throughout reperfusion (dp/dt 605 versus 884), after 2 hrs (P<0.05). Coronary (1.9 versus 2.4 ml) and aortic flow (AF) (0.16 versus 1.2 ml) were reduced in Flk-1(+/-) after 2 hrs of reperfusion. In addition, increased infarct size (38.4%versus 28.41%, P<0.05) and apoptotic cardiomyocytes (495 versus 213) were observed in Flk-1(+/-) knockout (KO) mice. We also examined whether ischaemic preconditioning (PC), a novel method to induce cardioprotection against ischaemia reperfusion injury, through stimulating the VEGF signalling pathway might function in Flk-1(+/-) mice. We found that knocking down Flk-1 resulted in significant reduction in the cardioprotective effect by PC compared to WT. Affymetrix gene chip analysis demonstrated down-regulation of important genes after IR and preconditioning followed by ischaemia reperfusion in Flk-1(+/-) mice compared to WT. To get insight into the underlying molecular pathways involved in ischaemic PC, we determined the distinct and overlapping biological processes using Ingenuity pathway analysis tool. Independent evidence at the mRNA level supporting the Affymetrix results were validated using real-time RT-PCR for selected down-regulated genes, which are thought to play important roles in cardioprotection after ischaemic insult. In summary, our data indicated for the first time that ischaemic PC modifies genomic responses in heterozygous VEGFR-2/Flk-1 KO mice and abolishes its cardioprotective effect on ischaemic myocardium.