Thoracic Vagus Research Articles

Stellate ganglia stimulation counteracts vagal stimulation by significantly increasing heart rate and blood pressure.

Vasovagal syncope (VVS) is the leading cause of syncope. The most frequent mechanism is that of a cardioinhibitory response, vasodepressor response, or mixture of both. Neural stimulation that negates or overcomes the effects of vagal tone may be used as a treatment strategy for VVS. Six male canines were studied. Stimulation (10-Hz, 2ms pulse duration, 2min duration) of the cervical vagus (CV), thoracic vagus (TV), and stellate ganglia (SG) was performed using needle electrodes at 3V, 5V, and 10V output. SG stimulation at an output of 10V overlaying TV stimulation at the same output was performed. Heart rate (HR), blood pressure (BP), and cardiac output (CO) were measured before, during, and after stimulation. Right cervical vagal stimulation was associated with significant hemodynamic changes. HR, SBP, and DBP were reduced (107±16 vs. 78±15bpm [P<0.0001], 116±24 vs. 107±28mmHg [P=0.002] and 71±18 vs. 58±20mmHg [P<0.0001]), respectively, while left cervical vagal stimulation had minimal changes. CV stimulation was associated with greater hemodynamic changes than TV stimulation. Left and right SG stimulation significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR at 5V and 10V, which could be observed within 30s after stimulation. An output-dependent increase in hemodynamic parameters was seen with both left and right SG stimulation. No difference between left and right SG stimulation was seen. SG stimulation overlay significantly increased HR, BP, and CO from baseline vagal stimulation bilaterally. Stellate ganglia stimulation leads to increased HR and BP despite significant vagal stimulation. This may be exploited therapeutically in the management of vasovagal syncope.

Cardiovascular Response to Intraneural Right Vagus Nerve Stimulation in Adult Minipig

ObjectiveThis study explored intraneural stimulation of the right thoracic vagus nerve (VN) in sexually mature male minipigs to modulate safe heart rate and blood pressure response. Material and MethodsWe employed an intraneural electrode designed for the VN of pigs to perform VN stimulation (VNS). This was delivered using different numbers of contacts on the electrode and different stimulation parameters (amplitude, frequency, and pulse width), identifying the most suitable stimulation configuration. All the parameter ranges had been selected from a computational cardiovascular system model. ResultsClinically relevant responses were observed when stimulating with low current intensities and relatively low frequencies delivered with a single contact. Selecting a biphasic, charge-balanced square wave for VNS with a current amplitude of 500 μA, frequency of 10 Hz, and pulse width of 200 μs, we obtained heart rate reduction of 7.67 ± 5.19 beats per minute, systolic pressure reduction of 5.75 ± 2.59 mmHg, and diastolic pressure reduction of 3.39 ± 1.44 mmHg. ConclusionHeart rate modulation was obtained without inducing any observable adverse effects, underlining the high selectivity of the intraneural approach.

Spontaneous Ventilation Video-Assisted Thoracoscopic Surgery for Geriatric Patients With Non-Small-Cell Lung Cancer

The aim of the present study was to compare the short-term outcomes between spontaneous ventilation video-assisted thoracic surgery (SV-VATS) and mechanical ventilation video-assisted thoracic surgery (MV-VATS) in the elderly. All patients included in the present study underwent lobectomy, segmentectomy, or wedge resection and lymph node dissection. A retrospective cohor. The first affiliated hospital of Guangzhou Medical University, Guangzhou, China. The present study included 799 elderly patients diagnosed with non-small-cell lung cancer undergoing SV-VATS or MV-VATS. After propensity score matching, 80 patients in the SV-VATS group and 80 patients in the MV-VATS group were analyzed. Patients in the SV-VATS group received spontaneous-ventilation anesthesia, which was administered as follows: intravenous anesthesia+laryngeal mask airway+thoracic paravertebral block+visceral pleural surface anesthesia+thoracic vagus nerve block. Patients in the MV-VATS group received general endotracheal anesthesia. SV-VATS or MV-VATS was performed according to the preference of the patients. There were no significant differences in anesthesia time (226.3 ± 79.8 v 238.5 ± 66.2 min; p=0.44), surgery time (166.2 ± 102.6 v 170.1 ± 83.4 min; p=0.66), and number of dissected lymph nodes (5.3 ± 7.5 v 4.4 ± 7.4; p=0.23) between the two groups. There were significant differences in intraoperative bleeding (61.5 ± 165.1 v 82.2 ± 116.9 mL; p < 0.001). After surgery, the two groups were statistically comparable in terms of hospitalization (17.6 ± 7.6 v 17.2 ± 6.9 days; p=0.95) and incidence of complications (7.5% v 13.8%; p=0.20), while there were significant differences in chest tube duration (6.1 ± 3.3 v 4.5 ± 1.2 days; p < 0.001). SV-VATS is feasible and as safe as MV-VATS, and it could be considered as an alternative treatment for the elderly.

Fetal topography of branches of the cervical and thoracic divisions of the vagus nerves

The study of age and individual anatomical variability of vagus nerves and their branches in different age periods of human ontogenesis causes interest among both morphologists and doctors of different specialties.The aim of the study. To find out the topography of the cervical and thoracic divisions of the vagus nerves in human fetuses aged from 4th to 10th gestational months.Materials and methods. The research was conducted on 75 preparations of human fetuses ranging from 81.0 to375.0 mm in parietal-coccygeal length (PCL) using methods of macro-microscopic dissection and morphometry.Results. In human fetuses, the left vagus nerve is placed anteriorly to the left subclavian artery, then on the lateral surface of the Botallo’s arterial duct and the aortic arch. In the neck region, the superior cardiac branch departs from the left vagus nerve and goes to the anterior surface of the left common carotid artery.In the inferior part of the left common carotid artery, the superior cardiac branch gives off two branches: the middle one reaches the aortic arch wall, and the lateral one runs along the anterior surface of the left common carotid artery. The left recurrent laryngeal nerve departs from the left vagus nerve at the level of the inferior border of the aortic arch. The right vagus nerve passes from the right subclavian artery anteriorly and gives rise to the right recurrent laryngeal nerve, which continues inferiorly and posteriorly around the subclavian artery. The superior cardiac branch originates from the right vagus nerve at the level of the inferior border of the thyroid gland. The inferior cardiac branch departs inferiorly and medially from the right laryngeal nerve and is located on the right anterolateral surface of the trachea.Conclusions. During the fetal period of human ontogenesis, age and individual anatomical variations of the branches of the cervical and thoracic vagus nerves is observed, which is manifested by the variability of the structure, asymmetry of the topography of the recurrent laryngeal nerves, bronchial, esophageal and cardiac branches. The left recurrent laryngeal nerve departs from the left vagus nerve at the level of the inferior border of the aortic arch, the right recurrent laryngeal nerve departs from the right vagus nerve at the level of the right subclavian artery. The esophageal nervous plexus is formed by esophageal branches of the vagus nerves, which then forms mainly the posterior vagal trunk. The anterior vagal trunk is a direct continuation of the left vagus nerve branches. The innervation of the aortic arch involves the common cardiac trunk, which is formed by the superior cardiac branch and the superior cardiac nerve and also anastomoses both with vagus nerve and with recurrent laryngeal nerves.

Transcutaneous Auricular Vagus Nerve Stimulation.

Invasive vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. Besides recognized clinical efficacy in about 60% of patients, there are major drawbacks such as invasiveness and common side effects including hoarseness, sore throat, shortness of breath, and coughing. Invasive VNS applies electrical stimulation to the left cervical branch of the vagus nerve and excites thick-myelinated afferent nerve fibers. Peripheral vagus nerve afferent volley initiates brainstem activity in the nucleus of the solitary tract and provokes typical brainstem and cerebral activation patterns that mediate the anticonvulsive mode of action. Whereas invasive VNS is an established neuromodulatory treatment in drug-resistant epilepsy, transcutaneous VNS (tVNS) of the auricular branch of the vagus nerve is suggested to be an alternative access path to the same neuronal network without invasiveness. Preclinical and clinical studies indicate that especially the cymba conchae of the auricle is selectively supplied by the auricular branch of the vagus nerve. Recent anatomical data demonstrate existence and quantity of thick-myelinated afferent nerve fibers of the left auricular branch of the vagus nerve that carries 21% of thick-myelinated afferent nerve fibers counted in the left thoracic vagus nerve in humans. Projection of auricular branch of the vagus nerve afferents from the auricle to the nucleus of the solitary tract is known from histochemical and electrophysiological experiments in rodents and confirmed in humans by functional imaging. Cerebral activation patterns triggered by invasive and tVNS resemble each other in appearance. Clinical trials in patients address safety and performance of tVNS and provide evidence for application in drug-resistant epilepsy.

Vagus nerve and phrenic nerve guided systematic nodal dissection for lung cancer.

Systematic nodal dissection (SND), which is defined as “all the mediastinal tissues containing the lymph nodes are dissected and removed systematically within anatomical landmarks”, is vital in surgical treatment for patients with non-small cell lung cancer (NSCLC) with curative intent (1). However, for avoiding surgical complications or other reasons, a variation of SND affects the thoroughness of lymph node dissection and the accuracy of pathologic nodal (pN) staging, which are the most significant prognostic factors in resectable NSCLC (2,3). Also, reduction in the severity and incidence of postoperative complications, such as nerve injury, is of utmost importance and remains challenging (4). Although some studies reported the experience and skills in mediastinal lymph node dissection (4,5), a standard and systematic procedure for nerve protection are still lacking. Therefore, an easy-to-follow standardized approach of SND, which can not only achieve regional en bloc lymph node resection but also effectively protect the nerves, is critically needed. Based on clinical practice experience, we discovered that the hilar and mediastinal lymph nodes are distributed along with the courses of these two nerves and connected in some anatomical regions (Figure 1). Thus, we first divided the lymph nodes into three areas of each side and developed an improved approach named “duo-nerve-guided SND” for resectable lung cancer, aiming to easily achieve complete resection of hilar and mediastinal lymph nodes as well as adipose tissue without increasing the nerve-related complications. Open in a separate window Figure 1 The anatomy of the thoracic vagus nerve and phrenic nerve and the distribution of lymph nodes. (A,C) The hilar and mediastinal lymph nodes were distributed along the vagus and phrenic nerves as well as their anatomical thoracic branches (pulmonary plexus, cardiac plexus, and esophageal plexus); (B,D) the regional lymph nodes distribution. Area A (green), the posterior area of the hilum; area B (blue), the anterior area of the hilum; area C (red), the anterior mediastinal area for the left side, the superior mediastinal area for the right side. (E) The subcarinal lymph nodes in left side (station 7); (F) the station 4L lymph nodes. RVN, right vagus nerve; LVN, left vagus nerve; LRLN, left recurrent laryngeal nerve.

Myelinated Axons in the Auricular Branch of the Human Vagus Nerve.

Transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN) resulted in deactivation of temporal lobe structures, similar to invasive cervical vagus nerve (CVN) stimulation. Presumably, both methods stimulated myelinated afferent beta axons mediating anti-convulsive effects. How numbers of A beta axons in the human ABVN compare to those of the CVN is unknown. The ABVN, CVN, recurrent laryngeal nerve (RLN) and thoracic vagus nerve (TVN) were dissected from embalmed bodies. Numbers and calibers of myelinated axons were analyzed in semithin sections. Myelinated axons in the left and right ABVN averaged to 385 and 363, respectively. Numbers of A beta axons measuring ≥7 µm averaged to 64 and 78 on the left and right, respectively. Numbers of A beta axons in CVN were estimated by subtracting myelinated presumed motor axons in RLN from the total count of CVN. This resulted in 280 and 504 A beta axons on the left and right, respectively, concurring well with the thick myelinated axon count of the ipsilateral TVN (255 and 466, respectively). Thus, the ratio of A beta axons in the ABVN and CVN was ∼1:5 and 1:6 on the left and right side, respectively. These results indicate that transcutaneous ABVN stimulation might be a promising alternative to invasive CVN stimulation. Anat Rec, 299:1184-1191, 2016. © 2016 Wiley Periodicals, Inc.

Sympathetic nerve fibers in human cervical and thoracic vagus nerves.

Vagus nerve stimulation (VNS) therapy has been used for chronic heart failure and is believed to improve imbalance of autonomic control by increasing parasympathetic activity. Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the vagus nerve (VN). To examine the sympathetic components within the human VN and correlate them with the presence of cardiac and neurologic diseases. We performed immunohistochemistry on 31 human cervical and thoracic VNs (total 104 VNs) from autopsies and reviewed the patients' records. We correlated the quantity of sympathetic nerve fibers within the VNs with cardiovascular and neurologic disease states. All 104 VNs contain tyrosine hydroxylase (TH)-positive (sympathetic) nerve fibers; the mean TH-positive areas were 5.47% in the right cervical VN, 3.97% in the left cervical VN, 5.11% in the right thoracic VN, and 4.20% in the left thoracic VN. The distribution of TH-positive nerve fibers varied from case to case: central, peripheral, or scattered throughout nerve bundles. No statistically significant differences in nerve morphology were seen between diseases in which VNS is considered effective (depression and chronic heart failure) and other cardiovascular diseases or neurodegenerative disease. Human VNs contain sympathetic nerve fibers. The sympathetic component within the VN could play a role in physiologic effects reported with VNS. The recognition of sympathetic nerve fibers in the VNs may lead to better understanding of the therapeutic mechanisms of VNS.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Phenotypic characterization of gastric sensory neurons in mice

Recent studies suggest that the capsaicin receptor [transient receptor potential vanilloid (TRPV)1] may play a role in visceral mechanosensation. To address the potential role of TRPV1 in vagal sensory neurons, we developed a new in vitro technique allowing us to determine TRPV1 expression directly in physiologically characterized gastric sensory neurons. Stomach, esophagus, and intact vagus nerve up to the central terminations were carefully dissected and placed in a perfusion chamber. Intracellular recordings were made from the soma of nodose neurons during mechanical stimulation of the stomach. Physiologically characterized neurons were labeled iontophoretically with neurobiotin and processed for immunohistochemical experiments. As shown by action potential responses triggered by stimulation of the upper thoracic vagus with a suction electrode, essentially all abdominal vagal afferents in mice conduct in the C-fiber range. Mechanosensitive gastric afferents encode stimulus intensities over a wide range without apparent saturation when punctate stimuli are used. Nine of 37 mechanosensitive vagal afferents expressed TRPV1 immunoreactivity, with 8 of the TRPV1-positive cells responding to stretch. A small number of mechanosensitive gastric vagal afferents express neurofilament heavy chains and did not respond to stretch. By maintaining the structural and functional integrity of vagal afferents up to the nodose ganglion, physiological and immunohistochemical properties of mechanosensory gastric sensory neurons can be studied in vitro. Using this novel technique, we identified TRPV1 immunoreactivity in only one-fourth of gastric mechanosensitive neurons, arguing against a major role of this ion channel in sensation of mechanical stimuli under physiological conditions.

Thoracic Vagal Efferent Nerve Stimulation Evokes Substance P-Induced Early Airway Bronchonstriction and Late Proinflammatory and Oxidative Injury in the Rat Respiratory Tract

Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation via action of nuclear factor-kappaB (NF-kappaB) activation and reactive oxygen species (ROS) production. Our results showed that increased frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O (2)(-) and H(2)O(2) ROS amount. L-732138 (NK(1) receptor antagonist), SR-48968 (NK(2) receptor antagonist), dimethylthiourea (H(2)O(2) scavenger) or catechins (O (2)(-) and H(2)O(2) scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation. Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-kappaB (NF-kappaB) in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of NF-kappaB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases substance P release to trigger NF-kappaB mediated ICAM-1 expression and O (2)(-) and H(2)O(2) ROS production in the respiratory tract.

Organization of the newborn piglets vagal motor complex: insights into integrated autonomic control mechanisms

Pediatric disorders frequently exhibit dysregulation of sympatho-vagal activity, and impaired control of cardiovascular vagal networks. Factors influencing the maturation of vagal networks are of special interest because they normally protect the heart and circulation, facilitate digestion, and preserve visceral metabolism. At present, scant literature exists regarding the development of vagal innervation of the heart. This study in neonatal swine, Sus scrofa, mapped the normal anatomy of vagal motor cell groups, with special focus on the origins of cardiomotor neurons. Right cardiac nerve branches, or the right thoracic vagal trunk were resected, inserted into capillary glass vials filled with 2% FluoroGold (FG) tracer solutions, and sealed to prevent leakage (false positives). Dorsal and ventral vagal complexes were identified on cross-sectioned tissues incubated in a well-characterized specific FG antibody. Thoracic and abdominal vagal motoneurons were cytologically heterogeneous, and predominantly medium-sized, polygonal cell bodies. Discrete longitudinal cell columns were observed, as well as organized arrays of elongate spindle-shaped cells in formation. Long axes and dendrites appeared to orient toward incoming peripheral sensory and central afferents, and were juxtaposed to cerebral microvasculature. The piglets' dorsal vagal complex is: (i) thick and long, comparable to ruminants, in contrast to much shorter lengths in non-ruminants, and (ii) the chief source of vagal motoneurons, forming discrete, topographically organized parasympathetic cell groups with distinct dendritic arbors. The cardiac motor subnucleus is localized to a highly restricted areal subunit of nucleus ambiguus' external formation in the vicinity of the obex. On the other hand, dorsal cardiac vagal motoneurons were few in number and diffusely distributed. Dorsal vagal motoneurons of neonatal swine likely projected primarily to the enteric nervous system, exerting excitatory influence over gastrointestinal activity.

Left vagal stimulation induces dynorphin release and suppresses substance P release from the rat thoracic spinal cord during cardiac ischemia.

Electrostimulatory forms of therapy can reduce angina that arises from activation of cardiac nociceptive afferent fibers during transient ischemia. This study sought to determine the effects of electrical stimulation of left thoracic vagal afferents (C(8)-T(1) level) on the release of putative nociceptive [substance P (SP)] and analgesic [dynorphin (Dyn)] peptides in the dorsal horn at the T(4) spinal level during coronary artery occlusion in urethane-anesthetized Sprague-Dawley rats. Release of Dyn and SP was measured by using antibody-coated microprobes. While Dyn and SP had a basal release, occlusion of the left anterior descending coronary artery only affected SP release, causing an increase from lamina I-VII. Left vagal stimulation increased Dyn release, inhibited basal SP release, and blunted the coronary artery occlusion-induced release of SP. Dyn release reflected activation of descending pathways in the thoracic spinal cord, because vagal afferent stimulation still increased the release of Dyn after bilateral dorsal rhizotomy of T(2)-T(5). These results indicate that electrostimulatory therapy, using vagal afferent excitation, may induce analgesia, in part, via inhibition of the release of SP in the spinal cord, possibly through a Dyn-mediated neuronal interaction.

C-Fos expression in rat brain stem and spinal cord in response to activation of cardiac ischemia-sensitive afferent neurons and electrostimulatory modulation.

The purpose of this study was to identify central neuronal sites activated by stimulation of cardiac ischemia-sensitive afferent neurons and determine whether electrical stimulation of left vagal afferent fibers modified the pattern of neuronal activation. Fos-like immunoreactivity (Fos-LI) was used as an index of neuronal activation in selected levels of cervical and thoracic spinal cord and brain stem. Adult Sprague-Dawley rats were anesthetized with urethane and underwent intrapericardial infusion of an "inflammatory exudate solution" (IES) containing algogenic substances that are released during ischemia (10 mM adenosine, bradykinin, prostaglandin E2, and 5-hydroxytryptamine) or occlusion of the left anterior descending coronary artery (CoAO) to activate cardiac ischemia-sensitive (nociceptive) afferent fibers. IES and CoAO increased Fos-LI above resting levels in dorsal horns in laminae I-V at C2 and T4 and in the caudal nucleus tractus solitarius. Dorsal rhizotomy virtually eliminated Fos-LI in the spinal cord as well as the brain stem. Neuromodulation of the ischemic signal by electrical stimulation of the central end of the left thoracic vagus excited neurons at the cervical and brain stem level but inhibited neurons at the thoracic spinal cord during IES or CoAO. These results suggest that stimulation of the left thoracic vagus excites descending inhibitory pathways. Inhibition at the thoracic spinal level that suppresses the ischemic (nociceptive) input signal may occur by a short-loop descending pathway via signals from cervical propriospinal circuits and/or a longer-loop descending pathway via signals from the nucleus tractus solitarius.

Central vagal sensory and motor connections: human embryonic and fetal development

The embryonic and fetal development of the nuclear components and pathways of vagal sensorimotor circuits in the human has been studied using Nissl staining and carbocyanine dye tracing techniques. Eight fetal brains ranging from 8 to 28 weeks of development had DiI (1,1′-dioctadecyl-3,3,3′,3′ tetramethylindocarbocyanine perchlorate) inserted into either the thoracic vagus nerve at the level of the sternal angle (two specimens of 8 and 9 weeks of gestation) or into vagal rootlets at the surface of the medulla (at all other ages), while a further five were used for study of cytoarchitectural development. The first central labeling resulting from peripheral application of DiI to the thoracic vagus nerve was seen at 8 weeks. By 9 weeks, labeled bipolar cells at the ventricular surface around the sulcus limitans (sl) were seen after DiI application to the thoracic vagus nerve. Subnuclear organization as revealed by both Nissl staining and carbocyanine dye tracing was found to be advanced at a relatively early fetal age, with afferent segregation in the medial Sol apparent at 13 weeks and subnuclear organization of efferent magnocellular divisions of dorsal motor nucleus of vagus nerve noticeable at the same stage. The results of the present study also confirm that vagal afferents are distributed to the dorsomedial subnuclei of the human nucleus of the solitary tract, with particular concentrations of afferent axons in the gelatinosus subnucleus. These vagal afferents appeared to have a restricted zone of termination from quite early in development (13 weeks) suggesting that there is no initial exuberance in the termination field of vagal afferents in the developing human nucleus of the solitary tract. On the other hand, the first suggestion of afferents invading 10N from the medial Sol was not seen until 20 weeks and was not well developed until 24 weeks, suggesting that direct monosynaptic connections between the sensory and effector components of the vagal sensorimotor complex do not develop until this age.

The role of neuronal nitric oxide in the vagal control of cardiac interval of the rat heart in vitro

The aim of this study was to examine the role of neuronal nitric oxide (NO) on vagal regulation of the rat heart in vitro using the neuronal nitric oxide synthase (nNOS) inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM). All experiments were carried out in the presence of the β-adrenoreceptor antagonist atenolol (4 μM). Right thoracic vagus, or its cardiac branch, was stimulated at frequencies of 2, 4, 8, 16 and 32 Hz (pulse duration 1 ms, 20 V, for 20 s) before and after addition of TRIM (0.14 mM) and cardiac interval (ms) assessed. There was a significant positive linear correlation between cardiac interval and vagal frequency giving a slope of 2.76±0.8 ms/Hz (slope±S.E. slope; data pooled from eight rats) which was significantly attenuated following TRIM to 0.4±0.6 ms/Hz ( P<0.05 ANOVA; n=8 rats). Nicotine applied in cumulative concentrations (0.03, 0.1, 0.3, 0.5, 1 mM) caused a linear concentration-dependent increase in cardiac interval, with a slope of 403±72 ms/mM ( n=10 rats) which was significantly attenuated after treatment with hexamethonium (28 μM), to 190±36 ms/mM ( n=10 rats, P<0.05 ANOVA), and atropine (3 μM) 100±31 ms/mM ( n=9 rats, P<0.05 ANOVA) but not following TRIM (0.14 mM) 262±48 ms/mM ( n=9 rats, P<0.05 ANOVA). These results suggest that NO facilitates vagal effects on the rat heart in vitro by an action at the pre-ganglionic/post-ganglionic synapse.

Spinal inhibitory effects of cardiopulmonary afferent inputs in monkeys: neuronal processing in high cervical segments.

Noxious stimulation of spinal afferents inhibits primate spinothalamic tract (STT) neurons in segments distant from the region of afferent entry. Inhibitory effects of cardiopulmonary sympathetic afferent (CPSA) stimulation remain after C(1) transection but disappear with spinal transection between C(3) and C(7). We hypothesized that spinal inhibitory effects produced by CPSA stimulation are processed by neurons in C(1)-C(3) segments. One purpose of this study in anesthetized monkeys was to determine whether chemical activation of high cervical neurons reduced sacral STT cell responses to colorectal distension (CRD) and urinary bladder distension (UBD). First, effects and interactions of pelvic and cardiopulmonary visceral afferent inputs were determined in 10 monkeys on extracellular activity of sacral STT neurons recorded in deep dorsal horn. CRD and UBD increased activity in 95 and 91% of sacral STT neurons, respectively. CPSA and cardiopulmonary vagal stimulation decreased activity in 84 and 56% of STT neurons, respectively. CPSA stimulation decreased CRD-evoked activity in six of eight sacral STT neurons and decreased UBD-evoked activity in five of eight STT neurons tested. Excitatory amino acid application at C2 segment decreased CRD-evoked responses in 7 of 10 sacral STT neurons and decreased UBD-evoked responses in 9 of 12 STT neurons. The second purpose of this study was to examine responses of C(1)-C(3) descending propriospinal neurons to stimulation of cardiopulmonary afferent fibers. If C(1)-C(3) neurons process CPSA input to suppress STT transmission, then CPSA stimulation should excite C(1)-C(3) neurons with descending projections. Effects of thoracic vagus nerve stimulation also were examined. Vagal stimulation inhibits STT neurons in segments below C(3) but excites C(1)-C(3) STT neurons; we theorized that vagal inhibition of sensory transmission might relay in high cervical segments and, therefore, excite C(1)-C(3) descending propriospinal neurons. Extracellular discharge rate was recorded for C(1)-C(3) neurons antidromically activated from thoracic or lumbar spinal cord in 24 monkeys. CPSA stimulation increased activity of 16 of 45 neurons and inhibited one cell. Thoracic vagus stimulation increased activity of 20 of 43 neurons and inhibited one cell; stimulation of abdominal vagus fibers did not affect activity of six of six cells that were excited by thoracic vagal input. Mechanical stimulation of somatic fields excited 30 of 41 neurons tested. All neurons activated by visceral input received convergent somatic input from noxious pinch of somatic receptive fields that generally included the neck and upper body; 11 C(1)-C(3) propriospinal neurons did not respond to any afferent input examined. Results of these studies were consistent with the idea that modulation of spinal nociceptive transmission might involve neuronal connections in high cervical segments.

Local capsaicin application to the stellate ganglion and stellatectomy attenuate neurogenic inflammation in rat bronchi

The present study investigated the contributions of vagal and nonvagal sensory nerve fibers on neurogenic inflammation in rat bronchial airways. A surgical procedure was developed via the rat mediastinum ventral intercostal space to prepare an intercostal opening without causing pneumothorax for performing stellate ganglionectomy alone, thoracic vagus nerve section alone, and stellatectomy plus thoracic vagotomy, and for injecting capsaicin (2 μl, 10 mg/ml) and 6-hydroxydopamine (2 μl, 50 mg/ml) into the ganglion. One week later in our procedure, we investigated if neurogenic inflammation induced by an intravenous injection of capsaicin (300 nmol/ml/kg) and innervation density of substance P-immunoreactive sensory axons could be decreased after chronic denervation in the rat lower airways. The major findings were that surgical removal of the right stellate ganglion and local capsaicin application resulted in a significant attenuation of neurogenic plasma extravasation in the right bronchial tree evoked by systemic capsaicin application. Reduction of neurogenic plasma extravasation was totally abolished by combined stellatectomy and thoracic vagotomy. The number of substance P-containing axons was also greatly decreased following these surgical and capsaicin treatments. It is concluded that sensory nerve fibers from both vagal source and nonvagal (spinal) source, which associated with the stellate ganglion, contributed significantly to neurogenic inflammation in the bronchial airways with a slightly higher contribution from the vagus nerve.

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.

1. Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2. The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3. Contractility of the left ventricle was determined from a series of pressure-volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end-systolic pressure-volume relationship was determined to give end-systolic elastance (Ees), a load-independent measure of contractility. 4. In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 +/- 14 %. 5. In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 +/- 16 %. 6. The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg(-1)). 7. Administration of the beta-adrenoreceptor antagonist esmolol (1 mg kg(-1)) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8. These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.

Neurophysiological effects of recurrent laryngeal and thoracic vagus nerves on mediating the neurogenic inflammation of the trachea, bronchi, and esophagus of rats

The present study aims to investigate the neurophysiological effects of recurrent laryngeal nerve and thoracic vagus nerve on the non-cholinergic regulation of neurogenic plasma extravasation of the rat trachea, bronchi, and esophagus. Through thoracotomy, three nerve components, the right thoracic vagal trunk, thoracic vagus nerve, and recurrent laryngeal nerve, were identified. The experiment was sequentially conducted in four steps. First, the individual nerve component was electrically stimulated and the induced inflammatory responses, as quantified by the area density of India ink-labelled blood vessels in the trachea, bronchial trees and esophagus, were compared. Second, we assessed the relative importance of medial and lateral side of the right thoracic vagus nerve in inducing the inflammatory responses by alternative stimulation of one side with simultaneous severance of the other side of this nerve. Third, we examined the effects of transection of the lateral half of the right thoracic vagus nerve on the degeneration of axon fibers located at the following three sites: the nerve segment proximal to cutting site, bronchial and esophageal nerve branches. Finally, we directly observed the inflammatory histopathology of the right lower trachea after stimulation of the medial half of the right thoracic vagus nerve with transection of its lateral half. In this study, we found that the right recurrent laryngeal nerve was predominant in mediating the neurogenic inflammatory responses of upper and dorsal portions of trachea, whereas the right thoracic vagus nerve was predominant in mediating those of the right lower ventral wall of trachea, right main bronchus, and right lobar bronchial trees. The axon fibers of the right thoracic vagus nerve responsible for mediating the neurogenic inflammatory responses of the right lower ventral trachea were mainly accumulated in the medial half, whereas those innervating the right main bronchus, right lobar bronchial trees, and lower esophagus were largely in the lateral half of this nerve. Transection of the lateral half of the right thoracic vagus nerve resulted in significant degeneration of myelinated fibers in its bronchial and esophageal nerve branches. Histopathological examination of the right lower trachea after electrical stimulation of the medial half of thoracic vagus nerve demonstrated the silver-stained leaky venules with accumulations of inflammatory cells. We thus concluded that afferent C-fibers to upper and dorsal portions of trachea were mainly from recurrent laryngeal nerve. In contrast, the neurogenic inflammatory responses of the right lower trachea were predominantly mediated by the medial half of the right thoracic vagus nerve, and those of the right main bronchus, bronchial trees and lower esophagus were largely by the lateral half of this nerve.