Influence of sex and sedentary conditions on sympathetic burst characteristics in prepubertal, postpubertal, and young adult rats.

Recent evidence indicates that sex-based differences in cardiovascular disease (CVD) begin early in life, particularly when associated with risk factors such as a sedentary lifestyle. CVD is associated with elevated sympathetic nerve activity (SNA), quantified as increased SNA burst activity in humans. Whether burst characteristics are influenced by sex or sedentary conditions at younger ages is unknown. The purpose of our study is to compare SNA bursts in active and sedentary female and male rats at ages including prepuberty and young adulthood. We hypothesized that burst characteristics and blood pressure are higher under sedentary conditions and lower in female rats compared with males. We analyzed splanchnic SNA (SpSNA) recordings from Inactin-anesthetized male and female rats at 4-, 8-, and 16-wk of age. Physically active and sedentary rats were each housed in separate, environmentally controlled chambers where physically active rats had free access to an in-cage running wheel. Sympathetic bursts were obtained by rectifying and integrating the raw SpSNA signal. Burst frequency, burst height, and burst width were calculated using the Peak Parameters extension in LabChart. Our results showed that sedentary conditions produced a greater burst width in 8- and 16-wk-old rats compared with 4-wk-old rats in both males and females (P < 0.001 for both). Burst frequency and incidence were both higher in 16-wk-old males compared with 16-wk-old females (P < 0.001 for both). Our results suggest that there are sedentary lifestyle- and sex-related mechanisms that impact sympathetic regulation of blood pressure at ages that range from prepuberty into young adulthood.NEW & NOTEWORTHY The mechanisms of decreased incidence of cardiovascular disease (CVD) in reproductive-age women compared with age-matched men are unknown. The strong association between elevated sympathetic activity and CVD led us to characterize splanchnic sympathetic bursts in female and male rats. Prepubescent males and females exhibited narrower sympathetic bursts, whereas young adult males had higher resting burst frequency compared with age-matched females. Sex-based regulation of sympathetic activity suggests a need for sex-dependent therapeutic strategies to combat CVD.

Online Detection of Catecholamine Release from the Perfused Rat Adrenal Gland.

Retrogradely perfused adrenal glands have historically served for establishing many of our current knowledge on the stimulus-secretion coupling process. Although the use of intact adrenals has largely been switched to isolated chromaffin cells, adrenal glands are still a very valuable tool to characterize physiological and pharmacological questions. Even more, this is an excellent preparation for studying the splanchnic nerve/chromaffin cell interaction. In this chapter, we will provide the ways to (i) perform retrograde perfusion of isolated rat adrenals, (ii) the method to apply electrical splanchnic nerve stimulation, and (iii) the preparation of adrenals to conduct online electrochemical detection of catecholamine release.

Divergent splanchnic sympathetic efferent nerve pathways regulate interleukin-10 and tumour necrosis factor-α responses to endotoxaemia.

The efferent branches of the splanchnic sympathetic nerves that enhance interleukin-10 (IL-10) and suppress tumour necrosis factor-α (TNF) levels in the reflex response to systemic immune challenge were investigated in anaesthetized, ventilated rats. Plasma levels of TNF and IL-10 were measured 90 min after intravenous lipopolysaccharide (LPS, 60 µg/kg). Splanchnic nerve section, ganglionic blockade with pentolinium tartrate or ß2 adrenoreceptor antagonism with ICI 118551 all blocked IL-10 responses. Restoring plasma adrenaline after splanchnic denervation rescued IL-10 responses. TNF responses were disinhibited by splanchnic denervation or pentolinium treatment, but not by ICI 118551. Splanchnic nerve branches were cut individually or in combination in vagotomized rats, ruling out any vagal influence on results. Distal splanchnic denervation, sparing the adrenal nerves, disinhibited TNF but did not reduce IL-10 responses. Selective adrenal denervation depressed IL-10 but did not disinhibit TNF responses. Selective denervation of either spleen or liver did not affect IL-10 or TNF responses, but combined splenic and adrenal denervation did so. Finally, combined section of the cervical and lumbar sympathetic nerves did not affect cytokine responses to LPS. Together, these results show that the endogenous anti-inflammatory reflex is mediated by sympathetic efferent fibres that run in the splanchnic, but not other sympathetic nerves, nor the vagus. Within the splanchnic nerves, divergent pathways control these two cytokine responses: neurally driven adrenaline, acting via ß2 adrenoreceptors, regulates IL-10, while TNF is restrained by sympathetic nerves to abdominal organs including the spleen, where non-ß2 adrenoreceptor mechanisms are dominant. KEY POINTS: An endogenous neural reflex, mediated by the splanchnic, but not other sympathetic nerves, moderates the cytokine response to systemic inflammatory challenge. This reflex suppresses the pro-inflammatory cytokine tumour necrosis factor-α (TNF), while enhancing levels of the anti-inflammatory cytokine interleukin-10 (IL-10). The reflex enhancement of IL-10 depends on the splanchnic nerve supply to the adrenal gland and on ß2 adrenoreceptors, consistent with mediation by circulating adrenaline. After splanchnic nerve section it can be rescued by restoring circulating adrenaline. The reflex suppression of TNF depends on splanchnic nerve branches that innervate abdominal tissues including, but not restricted to, spleen: it is not blocked by adrenal denervation or ß2 adrenoreceptor antagonism. Distinct sympathetic efferent pathways are thus responsible for pro- and anti-inflammatory cytokine components of the reflex regulating inflammation.

Local ionotropic glutamate receptors are required to trigger and sustain ramping of sympathetic nerve activity by hypothalamic paraventricular nucleus TNFα.

Tumor necrosis factor-α (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFα (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P < 0.0001, n = 10). Given that TNFα can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. When compared with that of vehicle (n = 5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), 2.48 nmol; D-(-)-2-amino-5-phosphonopentanoic acid (APV), 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%), attenuated TNFα-induced SSNA ramping (n = 5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P < 0.0001, n = 5). Whereas separate blockade of PVN AMPA or NMDA receptors (n = 5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n = 5) or PVN inhibition with the GABA-A receptor agonist muscimol (n = 5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.NEW & NOTEWORTHY The proinflammatory cytokine TNFα contributes to heightened SNA in cardiovascular disease models, but mechanisms remain obscure. Here, we demonstrate that TNFα injection into the hypothalamic PVN triggers SNA ramping by mechanisms dependent on local ionotropic glutamate receptor availability, but largely independent of TNFα autoinduction. Continued SNA ramping depends on ionotropic glutamate receptor and neuronal activity in PVN, indicating that strengthening and/or increased efficacy of glutamatergic transmission is necessary for acute sympathoexcitation by PVN TNFα.

Neurolytic Splanchnic Nerve Block and Pain Relief, Survival, and Quality of Life in Unresectable Pancreatic Cancer: A Randomized Controlled Trial.

BACKGROUND: Neurolytic splanchnic nerve block is used to manage pancreatic cancer pain. However, its impact on survival and quality of life remains controversial. The authors' primary hypothesis was that pain relief would be better with a nerve block. Secondarily, they hypothesized that analgesic use, survival, and quality of life might be affected. METHODS: This randomized, double-blind, parallel-armed trial was conducted in five Chinese centers. Eligible patients suffering from moderate to severe pain conditions were randomly assigned to receive splanchnic nerve block with either absolute alcohol (neurolysis) or normal saline (control). The primary outcome was pain relief measured on a visual analogue scale. Opioid consumption, survival, quality of life, and adverse effects were also documented. Analgesics were managed using a protocol common to all centers. Patients were followed up for 8 months or until death. RESULTS: Ninety-six patients (48 for each group) were included in the analysis. Pain relief with neurolysis was greater for the first 3 months (largest at the first month; mean difference, 0.7 [95% CI, 0.3 to 1.0]; adjusted P < 0.001) compared with placebo injection. Opioid consumption with neurolysis was lower for the first 5 months (largest at the first month; mean difference, 95.8 [95% CI, 67.4 to 124.1]; adjusted P < 0.001) compared with placebo injection. There was a significant difference in survival (hazard ratio, 1.56 [95% CI, 1.03 to 2.35]; P = 0.036) between groups. A significant reduction in survival in neurolysis was found for stage IV patients (hazard ratio, 1.94 [95% CI, 1.29 to 2.93]; P = 0.001), but not for stage III patients (hazard ratio, 1.08 [95% CI, 0.59 to 1.97]; P = 0.809). No differences in quality of life were observed. CONCLUSIONS: Neurolytic splanchnic nerve block appears to be an effective option for controlling pain and reducing opioid requirements in patients with unresectable pancreatic cancer.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Sympathetic nerves control bacterial clearance.

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection.

Anatomical and clinical implications of vagal modulation of the spleen.

The vagus nerve coordinates most physiologic functions including the cardiovascular and immune systems. This mechanism has significant clinical implications because electrical stimulation of the vagus nerve can control inflammation and organ injury in infectious and inflammatory disorders. The complex mechanisms that mediate vagal modulation of systemic inflammation are mainly regulated via the spleen. More specifically, vagal stimulation prevents organ injury and systemic inflammation by inhibiting the production of cytokines in the spleen. However, the neuronal regulation of the spleen is controversial suggesting that it can be mediated by either monosynaptic innervation of the splenic parenchyma or secondary neurons from the celiac ganglion depending on the experimental conditions. Recent physiologic and anatomic studies suggest that inflammation is regulated by neuro-immune multi-synaptic interactions between the vagus and the splanchnic nerves to modulate the spleen. Here, we review the current knowledge on these interactions, and discuss their experimental and clinical implications in infectious and inflammatory disorders.

Galanin suppresses visceral afferent responses to noxious mechanical and inflammatory stimuli.

Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signaling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose-dependent suppression of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, suppresses mechanosensitivity. The effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulfate-induced colitis. We conclude that galanin has a marked suppressive effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediators, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception in the bowel and the therapeutic potential of targeting galaninergic signaling to treat visceral hypersensitivity.

Bowel Motility After Injury to the Superior Mesenteric Plexus During D3 Extended Mesenterectomy.

BACKGROUND: Improvement of lymphadenectomy in right colectomy requires removal of all tissue surrounding the superior mesenteric vessels beneath the pancreatic notch. Short- and long-term bowel motility disorders after D3 extended mesenterectomy with consecutive superior mesenteric plexus transection are studied. METHODS: Patients without pre-existing motility disorders undergoing D3 extended mesenterectomy were examined 3 times using the wireless motility capsule: before, at 3 wk, and 6 mo after surgery. Segmental transit times and contractility were analyzed using mixed effect modeling. Correlation between contractility and transit time was assessed by the Pearson correlation coefficient. RESULTS: Fifteen patients (4 men), with median age 62 y, were included. Mean values for the three consecutive examinations are as follows. Gastric transit time increased from 237 to 402 and 403 min, respectively. Small bowel transit time decreased from 246 to 158 (P < 0.01) and 199 (P = 0.03) min, respectively. Colonic transit time decreased from 1742 to 1450 and 1110 (P = 0.02) min, respectively. Gastric contractions per minute (CPM) varied from 1.73 to 1.05 (P = 0.01) and 2.47 (P < 0.01), respectively. Small bowel CPM decreased from 3.43 to 2.68 and 3.34, respectively. Colonic CPM ranged from 1.59 to 1.45 and 1.91 (P = 0.08), respectively. Correlation between small bowel (SB) transit time and CPM was -0.45 (P = 0.09) preoperatively, and -0.03 (P = 0.91) 6 mo postoperatively. CONCLUSIONS: Extrinsic SB denervation leads to significantly accelerated SB transit, reduced contractility, and disturbed correlation between transit time and contractility early after denervation. Both number of contractions and transit time in the denervated SB show a clear tendency toward normalization at 6 mo.

Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway.

Electrical stimulation of the vagus nerve (VNS) is a novel strategy used to treat inflammatory conditions. Therapeutic VNS activates both efferent and afferent fibers; however, the effects attributable to vagal afferent stimulation are unclear. Here, we tested if selective activation of afferent fibers in the abdominal vagus suppresses systemic inflammation. In urethane-anesthetized rats challenged with lipopolysaccharide (LPS, 60 µg/kg, i.v.), abdominal afferent VNS (2 Hz for 20 min) reduced plasma tumor necrosis factor alpha (TNF) levels 90 min later by 88% compared with unmanipulated animals. Pre-cutting the cervical vagi blocked this anti-inflammatory action. Interestingly, the surgical procedure to expose and prepare the abdominal vagus for afferent stimulation ('vagal manipulation') also had an anti-inflammatory action. Levels of the anti-inflammatory cytokine IL-10 were inversely related to those of TNF. Prior bilateral section of the splanchnic sympathetic nerves reversed the anti-inflammatory actions of afferent VNS and vagal manipulation. Sympathetic efferent activity in the splanchnic nerve was shown to respond reflexly to abdominal vagal afferent stimulation. These data demonstrate that experimentally activating abdominal vagal afferent fibers suppresses systemic inflammation, and that the efferent neural pathway for this action is in the splanchnic sympathetic nerves.

Differences in sympathetic nervous system activity and NMDA receptor levels within the hypothalamic paraventricular nucleus in rats with differential ejaculatory behavior.

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.

Angiotensin 1-7 in the rostro-ventrolateral medulla increases blood pressure and splanchnic sympathetic nerve activity in anesthetized rats.

Angiotensin 1-7 (ANG-(1-7)), a derivative of angiotensin I or II, is involved in the propagation of sympathetic output to the heart and vasculature, and the receptor for ANG-(1-7), the Mas receptor, is expressed on astrocytes in the rostral ventrolateral medulla (RVLM). We recorded blood pressure (BP) and splanchnic sympathetic nerve activity (SSNA) before and after focal injection of ANG-(1-7) into the RVLM of rats. Unilateral injection of ANG-(1-7) into the RVLM, acting through the Mas receptor, increased SSNA and BP, and glutamate receptor antagonists, CNQX and D-AP5, partially reduced the ANG-(1-7) effect. ATP is often co-released with glutamate, and blocking ATP with PPADS also reduced the pressor response to microinjection of ANG-(1-7) within the RVLM. The effects of ANG-(1-7) were blocked by the MAS receptor antagonist, A-779 (which had no consistent effect on blood pressure or sympathetic nerve activity when injected on its own). We conclude that astrocytes in the RVLM participate in central, angiotensin-dependent regulation of blood pressure and sympathetic nerve activity, and the Mas receptor, when activated by ANG-(1-7), elicits the release of the gliotransmitters, glutamate and ATP. These gliotransmitters then cause an increase in sympathetic nerve activity and blood pressure by interacting with AMPA/kainate and P2X receptors in the RVLM.

Differences in sympathetic nervous system activity and NMDA receptor levels within the hypothalamic paraventricular nucleus in rats with differential ejaculatory behavior / 亚洲男科学杂志(英文版)

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.

Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease.

Inflammatory bowel disease (IBD), that is Crohn's disease (CD) and ulcerative colitis, affects about 1.5 million persons in the USA and 2.2 million in Europe. The pathophysiology of IBD involves immunological, genetic and environmental factors. The treatment is medico-surgical but suspensive. Anti-TNFα agents have revolutionized the treatment of IBD but have side effects. In addition, a non-negligible percentage of patients with IBD stop or take episodically their treatment. Consequently, a nondrug therapy targeting TNFα through a physiological pathway, devoid of major side effects and with a good cost-effectiveness ratio, would be of interest. The vagus nerve has dual anti-inflammatory properties through its afferent (i.e. hypothalamic-pituitary-adrenal axis) and efferent (i.e. the anti-TNFα effect of the cholinergic anti-inflammatory pathway) fibres. We have shown that there is an inverse relationship between vagal tone and plasma TNFα level in patients with CD, and have reported, for the first time, that chronic vagus nerve stimulation has anti-inflammatory properties in a rat model of colitis and in a pilot study performed in seven patients with moderate CD. Two of these patients failed to improve after 3 months of vagus nerve stimulation but five were in deep remission (clinical, biological and endoscopic) at 6 months of follow-up and vagal tone was restored. No major side effects were observed. Thus, vagus nerve stimulation provides a new therapeutic option in the treatment of CD.

Raising the pressure: Hemodynamic effects of splanchnic nerve stimulation.

A number of cardiovascular and neurological diseases are characterized by a dysregulation of intravascular volume distribution. The veins and arteries of the visceral organs form the so-called splanchnic vascular compartment and are the largest reservoir for intravascular blood. The blood localized in the splanchnic compartment can be mobilized in and out of the compartment via passive compression or active neurohormonal recruitment. We studied the hemodynamic effects of splanchnic nerve stimulation during five cases of irreversible electroporation (IRE) in patients with pancreatic cancer. In IRE, repeated bursts of high-voltage electrical fields are applied to visceral beds for >1 min, which induces rapid increase in blood pressure, heart rate, and cardiac output. We present the first analysis into the hemodynamic changes with splanchnic nerve stimulation and explore potential mechanisms of the hyperdynamic state. Our analysis presents the first human report of splanchnic nerve stimulation to induce hypertension and volume redistribution, introducing the splanchnic nerves as a key component of cardiovascular regulation.NEW & NOTEWORTHY Our case series provides the first detailed description of human hemodynamic effects with splanchnic nerve stimulation. Splanchnic nerve stimulation results in profound hemodynamic alteration with rapid onset of hypertension and blood mobilization.

Gastric distension causes changes in heart rate and arterial blood pressure by affecting the crosstalk between vagal and splanchnic systems in anesthetised rats.

Various hindbrain nuclei have been demonstrated to be involved in the control of the cardiovascular reflexes elicited by both non-noxious and noxious gastric distension, through parasympathetic and sympathetic activation. The different role played by the branches of autonomic nervous system in exerting these effects and their crosstalk in relation to low-/high-pressure distension rate has not been examined yet. Therefore, in the present work, monolateral and bilateral vagotomy and splanchnicotomy were performed in anesthetised rats to analyse the involvement of hindbrain nuclei in haemodynamic changes caused by gastric distension at high (80 mmHg) and low (15 mmHg) pressure. The analysis of c-Fos expression in neuronal areas involved in cardiovascular control allowed us to examine their recruitment in response to various patterns of gastric distension and the crosstalk between vagal and splanchnic systems. The results obtained show that the low-pressure (non-noxious) gastric distension increases both heart rate and arterial blood pressure. In addition, the vagus nerve and hindbrain nuclei, such as nucleus ambiguous, ventrolateral medulla and lateral reticular nucleus, appear to be primarily involved in observed responses. In particular, we have found that although vagus nerve plays a central role in exerting those cardiovascular reflex changes at low gastric distension, for its functional expression an intact splanchnic system is mandatory. Hence, the absence of splanchnic input attenuates pressor responses or turns them into depressor responses. Instead at high-pressure (noxious) gastric distension, the splanchnic nerve represents the primary component in regulating the reflex cardiovascular effects.

Immunohistochemical characteristics of neurons in the ganglia of the greater splanchnic nerve of the pig.

INTRODUCTION: Greater splanchnic nerve (GSN) is by far the largest of the splanchnic nerves and connects the paravertebral and prevertebral ganglia to transmit the majority of nociceptive information from the viscera. Despite its importance, the immunohistochemical features of the porcine GSN neurons have not yet been examined. Therefore, the aim of the study was to investigate the neurochemistry of the porcine GSN neurons and to compare their neurochemical coding with those of the paravertebral and prevertebral ganglia. MATERIAL AND METHODS: Four gilts of Large White Polish breed were examined in this study. Antibodies to tyrosine hydroxylase (TH), dopamine b-hydroxylase (DBH), choline acetyltransferase (ChAT), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), galanin (GAL), methionine-enkephalin (MET), calcitonin gene-related peptide (CGRP), and substance P (SP) were used for immunohistochemical detection of classical neurotransmitters marker enzymes and neuropeptides in neuronal cell bodies of the GSN. RESULTS: Double-labeling immunofluorescence revealed that virtually all GSN neurons exhibited the presence of catecholamine-synthesizing enzymes (TH/DBH-positive) and subpopulations of neurons contained immunoreactivity to NPY, VIP, SOM, GAL and MET. However, CGRP and SP-immunoreactivity were not observed in neuronal somata. CONCLUSIONS: Our data strongly suggest that the general immunohistochemical characterization of ganglion cells in the porcine greater splanchnic nerve is similar to that of the prevertebral ganglia (e.g. celiacomesenteric ganglion).

Spatial and activity-dependent catecholamine release in rat adrenal medulla under native neuronal stimulation.

Neuroendocrine chromaffin cells of the adrenal medulla in rat receive excitatory synaptic input through anterior and posterior divisions of the sympathetic splanchnic nerve. Upon synaptic stimulation, the adrenal medulla releases the catecholamines, epinephrine, and norepinephrine into the suprarenal vein for circulation throughout the body. Under sympathetic tone, catecholamine release is modest. However, upon activation of the sympathoadrenal stress reflex, and increased splanchnic firing, adrenal catecholamine output increases dramatically. Moreover, specific stressors can preferentially increase release of either epinephrine (i.e., hypoglycemia) or norepinephrine (i.e., cold stress). The mechanism for this stressor-dependent segregated release of catecholamine species is not yet fully understood. We tested the hypothesis that stimulation of either division of the splanchnic selects for epinephrine over norepinephrine release. We introduce an ex vivo rat preparation that maintains native splanchnic innervation of the adrenal gland and we document experimental advantages and limitations of this preparation. We utilize fast scanning cyclic voltammetry to detect release of both epinephrine and norepinephrine from the adrenal medulla, and report that epinephrine and norepinephrine release are regulated spatially and in a frequency-dependent manner. We provide data to show that epinephrine is secreted preferentially from the periphery of the medulla and exhibits a higher threshold and steeper stimulus-secretion function than norepinephrine. Elevated stimulation of the whole nerve specifically enhances epinephrine release from the peripheral medulla. Our data further show that elimination of either division from stimulation greatly attenuated epinephrine release under elevated stimulation, while either division alone can largely support norepinephrine release.

The splanchnic anti-inflammatory pathway: could it be the efferent arm of the inflammatory reflex?

What is the topic of this review? We review the current literature on the neural reflex termed the 'inflammatory reflex' that inhibits an excessive release of inflammatory mediators in response to an immune challenge. What advances does it highlight? The original model proposed that the inflammatory reflex is a vago-vagal reflex that controls immune function. We posit that, in the endotoxaemic animal model, the vagus nerves do not appear to play a role. The evidence suggests that the efferent motor pathway, termed here the 'splanchnic anti-inflammatory pathway', is purely sympathetic, travelling via the greater splanchnic nerves to regulate the ensuing inflammatory response to immune challenges. Exposure to immune challenges results in the development of inflammation. An insufficient inflammatory response can be life-threatening, whereas an exaggerated response is also detrimental because it causes tissue damage and, in extreme cases, septic shock that can lead to death. Hence, inflammation must be finely regulated. It is generally accepted that the brain inhibits inflammation induced by an immune challenge in two main ways: humorally, by activating the hypothalamic-pituitary-adrenal axis to release glucocorticoids; and neurally, via a mechanism that has been termed the 'inflammatory reflex'. The efferent arm of this reflex (the neural-to-immune link) was thought to be the 'cholinergic anti-inflammatory pathway'. Here, we discuss data that support the hypothesis that the vagus nerves play no role in the control of inflammation in the endotoxaemic animal model. We have shown and posit that it is the greater splanchnic nerves that are activated in response to the immune challenge and that, in turn, drive postganglionic sympathetic neurons to inhibit inflammation.