ABSTRACT
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.
Subject(s)
Paraventricular Hypothalamic Nucleus/metabolism , Receptors, AMPA/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Splanchnic Nerves/metabolism , Tumor Necrosis Factor-alpha/metabolism , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Excitatory Amino Acid Antagonists/pharmacology , GABA-A Receptor Agonists/pharmacology , Male , Muscimol/pharmacology , Paraventricular Hypothalamic Nucleus/physiology , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism , Splanchnic Nerves/drug effects , Splanchnic Nerves/physiologyABSTRACT
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.
Subject(s)
Cancer Pain/therapy , Nerve Block/methods , Pain Management/methods , Pancreatic Neoplasms/therapy , Quality of Life , Splanchnic Nerves/physiology , Aged , Analgesics, Opioid/administration & dosage , Cancer Pain/mortality , Cancer Pain/psychology , Double-Blind Method , Female , Humans , Male , Middle Aged , Nerve Block/mortality , Pain Measurement/drug effects , Pain Measurement/methods , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/psychology , Quality of Life/psychology , Splanchnic Nerves/drug effects , Survival Rate/trendsABSTRACT
Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg-1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.
Subject(s)
Cardiovascular Physiological Phenomena/drug effects , Oxaliplatin/adverse effects , Oxaliplatin/pharmacokinetics , Platinum/metabolism , Respiratory Physiological Phenomena/drug effects , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Baroreflex/drug effects , Blood/drug effects , Chemoreceptor Cells/drug effects , Drug Administration Schedule , Heart Rate , Male , Oxaliplatin/administration & dosage , Random Allocation , Rats , Rats, Sprague-Dawley , Splanchnic Nerves/drug effects , Sympathetic Nervous System/drug effects , Tissue DistributionABSTRACT
El dolor abdominal crónico de origen benigno puede ser incapacitante y disminuye significativamente la calidad de vida de algunos pacientes. Para su tratamiento es usual el uso crónico de opioides que se han asociado a originar otras fuentes de dolor, por lo que deberían sopesar tratamientos farmacológicos alternativos. Sin embargo, cuando estos no son efectivos, insuficientes u ocasionan efectos adversos intolerables, el manejo intervencionista del dolor debería considerarse. En este campo la inhibición de los nervios esplácnicos que es una técnica que puede ser empleada para el control del dolor oncológico, podría jugar un papel importante a pesar de que aún no cuenta con evidencia sólida de su aplicabilidad en tratar el dolor crónico de origen benigno. Hasta donde sabemos, en el Ecuador es la primera vez que se realiza este procedimiento y el presente informe sugiere que puede ofrecer buenos resultados, incluso después de terminado el efecto de los fármacos utilizados
Chronic abdominal pain of benign origin can be disabling and significantly reduces the quality of life of some patients. Common treatment includes the chronic use of opioids that have also been linked with causing different sources of pain, so alternative pharmacological treatments should be considered instead. However, when these are not effective, insufficient, or cause intolerable adverse effects, interventional pain management should be considered. In this field, the inhibition of splanchnic nerves, which is a technique that can be used to control cancer pain, could play an important role in the treatment of chronic pain of benign origin, despite the lack of solid evidence in its applicability. As far as we know, it is the first time that this procedure has been performed in Ecuador and this report suggests that it can offer positive results even after the effect of the drugs used has ended
Subject(s)
Humans , Female , Adult , Nerve Block/methods , Splanchnic Nerves/drug effects , Abdominal Pain/drug therapy , Chronic Pain/drug therapy , Pain Management/methods , Analgesia/methodsABSTRACT
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.
Subject(s)
Galanin/drug effects , Neurons, Afferent/physiology , Splanchnic Nerves/drug effects , Visceral Pain/physiopathology , Animals , Colon/innervation , Female , Male , Mice , Mice, Inbred C57BL , Neurons, Afferent/drug effects , Nociception , Receptors, Galanin/agonists , Splanchnic Nerves/physiology , Stress, MechanicalABSTRACT
El cáncer de páncreas produce dolor en más del 80 % de los pacientes, con un manejo analgésico en ocasiones insatisfactorio debido a las opciones terapéuticas limitadas y a la variación de la práctica clínica, siendo necesario un manejo multidisciplinar. El desarrollo de este artículo ha consistido en revisar la literatura y resumir la evidencia actual de los procedimientos intervencionistas neurolíticos para manejar el dolor visceral asociado al cáncer de páncreas. La fuente de artículos de esta revisión se ha obtenido a través de PubMed y Medline, limitando la búsqueda a ensayos controlados y aleatorizados, revisiones sistematizadas, estudios prospectivos y retrospectivos y presentaciones de series de casos. Se muestra la evidencia actual de los diferentes abordajes para la neurólisis del plexo celiaco y de los nervios esplácnicos, describiendo su eficacia, riesgos, complicaciones y limitaciones. El objetivo final ha sido establecer una propuesta de algoritmo intervencionista que pueda mejorar el manejo del dolor en los pacientes que sufren dolor visceral debido al cáncer de páncreas
Pancreatic cancer provokes pain in more than 80 % of patients, resulting in a management of pain that is often unsatisfactory due to the limited treatment options and the significant variation in clinical practice, emphasizing the need for a multidisciplinary approach. This article has been redacted to review the literature and summarize the actual evidence of neurolytic procedures to treat pain caused by pancreatic cancer. The sources of these of articles have been obtained by using PubMed and Medline, restricting the search to randomized control comparative studies, systematic reviews, prospective and retrospective studies, and case series presentations. This article shows the actual evidence of the different approaches for the celiac plexus and splanchnic nerve neurolysis, regarding its efficacy, risks, adverse effects, and limitations. The final objective has been to propose an interventional algorithm that might help to improve pain management in patients suffering from pancreatic cancer
Subject(s)
Humans , Chronic Pain/therapy , Pain Management/methods , Cancer Pain/therapy , Nerve Block/methods , Pancreatic Neoplasms/complications , Celiac Plexus/drug effects , Splanchnic Nerves/drug effects , Endosonography/methods , Patient SelectionABSTRACT
No disponible
Subject(s)
Humans , Splanchnic Nerves/drug effects , Nerve Block/methods , Radiofrequency Therapy/methods , Cancer Pain/therapy , Pain Management/methodsABSTRACT
BACKGROUND: Little information is available about the clinical history of patients with incidentally detected splanchnic vein thrombosis and its therapeutic management remains controversial. The aim of this study was to assess the risk factors, therapeutic strategies, and long-term outcomes of incidentally detected splanchnic vein thrombosis. METHODS: We analysed data from patients with incidentally detected splanchnic vein thrombosis who were enrolled in an international, multicentre, prospective cohort study of splanchnic vein thrombosis between 2008 and 2012. The study was done at 31 centres in 11 countries (Italy, South Korea, Germany, Canada, Belgium, the Netherlands, Brazil, USA, France, Israel, UK). Information about demographic characteristics, risk factors, and treatment was collected. The study outcomes during the 2-year follow-up were major bleeding (International Society on Thrombosis and Haemostasis definition plus the need for hospital admission), thrombotic events (venous or arterial thromboses), and mortality. The primary analysis period was from the diagnosis of incidentally detected splanchnic vein thrombosis until the first adjudicated clinical outcome or the end of follow-up. FINDINGS: Between May 2, 2008, and Jan 30, 2012, we enrolled 177 patients with incidentally detected splanchnic vein thrombosis (median age 57 years [IQR 49-66], 118 [67%] men, 138 [78%] patients with portal vein thrombosis). The most common underlying diseases were liver cirrhosis (82 [46%] patients) and solid cancer (62 [35%] patients). Anticoagulant treatment was prescribed to 109 (62%) patients. Median duration of anticoagulation was 6 months (IQR 5-12) for patients who received parenteral anticoagulants alone and 24 months (IQR 12-24) for patients treated with vitamin K antagonists. During a median follow-up of 2 years (IQR 1-2), the incidence of major bleeding was 3·3 events (95% CI 1·7-6·3) per 100 patient-years and the incidence of thrombotic events was 8·0 events (95% CI 5·2-12·1) per 100 patient-years. On-treatment incidence was 3·2 events (95% CI 1·2-8·4) per 100 patient-years for major bleeding and 3·9 events (95% CI 1·6-9·5) per 100 patient-years for thrombotic events. In multivariate analysis, anticoagulant treatment as a time-dependent variable reduced the incidence of thrombotic events (hazard ratio 0·85, 95% CI 0·76-0·96) without increasing the risk of major bleeding (p>0·05). In patients with clinically suspected splanchnic vein thrombosis, the incidence of major bleeding was 3·9 events (95% CI 2·6-5·7) per 100 patient-years and the incidence of thrombotic events was 7·0 events (95% CI 5·2-9·3) per 100 patient-years. INTERPRETATION: Our results show that the prognosis of incidentally detected splanchnic vein thrombosis is similar to that of clinically suspected splanchnic vein thrombosis and suggest that similar treatment strategies should be applied. FUNDING: Pfizer Canada research grant.
Subject(s)
Anticoagulants/therapeutic use , Registries , Splanchnic Nerves/drug effects , Venous Thrombosis/drug therapy , Venous Thrombosis/epidemiology , Adult , Aged , Female , Follow-Up Studies , Humans , Incidence , International Agencies , Male , Middle Aged , Prognosis , Prospective Studies , Splanchnic Nerves/pathology , Survival Rate , Venous Thrombosis/pathologyABSTRACT
UNLABELLED: Pancreatic and other upper abdominal organ malignancies can produce intense visceral pain syndromes that are frequently treated with splanchnic nerve neurolysis (SNN) or celiac plexus neurolysis (CPN). Although commonly performed with either alcohol or phenol, there is scant literature on the comparative effectiveness, duration of benefit, and complication profile comparing the 2 agents. This study presents a retrospective chart review of 93 patients who underwent SNN for cancer-related abdominal pain in order to describe patient characteristics, examine comparative efficacy, duration of benefit, and incidence of complications with alcohol vs. those of phenol. Consistent with previous studies, SNN reduced reported pain scores while not significantly reducing opioid consumption. No difference in pain outcomes was found comparing alcohol versus phenol based neurolytic techniques. Celiac axis tumor infiltration and pre-procedural local radiation therapy did not change the effectiveness of the procedure. Our data demonstrated that 44.57% of patients had = 30% pain reduction while 43.54% did not have pain reduction. Interestingly, the procedure produced significant improvements in anxiety, depression, difficulty thinking clearly, and feeling of well-being. In addition, no difference in complications was seen between the agents either. SNN was an effective and relatively safe procedure for the treatment of pain associated with pancreatic and other upper abdominal organ malignancies in our sample of patients. Choice of neurolytic agent can appropriately be left to the clinical judgment and local availability of the treating physician. The change in ancillary symptoms has a theoretical basis that supports a biopsychosocial model of pain since changes in one target area (pain) impact other related ones (depression and anxiety). KEY WORDS: Celiac plexus, splanchnic nerves, neurolysis, nerve block, alcohol, ethanol, phenol, pain, cancer pain, abdominal pain, visceral pain, symptom assessment.
Subject(s)
Abdominal Pain/drug therapy , Autonomic Nerve Block/methods , Cancer Pain/drug therapy , Celiac Plexus/drug effects , Ethanol/pharmacology , Outcome Assessment, Health Care , Phenol/pharmacology , Splanchnic Nerves/drug effects , Abdominal Pain/etiology , Cancer Pain/etiology , Ethanol/administration & dosage , Female , Humans , Male , Phenol/administration & dosage , Retrospective StudiesABSTRACT
We hypothesized that blockade of angiotensin II type 2 receptors (AT2Rs) in the rostral ventrolateral medullary pressor area (RVLM) may elicit sympathoexcitatory responses which are smaller in hypertensive rats compared to normotensive rats. This hypothesis was tested in urethane-anesthetized, artificially ventilated male 14-week-old spontaneously hypertensive rats (SHR). Age-matched male Wistar-Kyoto rats (WKY) and Wistar rats were used as controls. PD123319 (AT2R antagonist) was microinjected into the RVLM and mean arterial pressure (MAP), heart rate (HR) and greater splanchnic nerve activity (GSNA) were recorded. Increases in MAP, HR and GSNA elicited by unilateral microinjections of PD123319 into the RVLM were significantly smaller in SHR when compared with those in WKY and Wistar rats. Unilateral microinjections of l-glutamate (l-Glu) into the RVLM elicited greater increases in MAP and GSNA in SHR compared to those in WKY. AT2R immunoreactivity was demonstrated in the RVLM neurons which were retrogradely labeled from the intermediolateral cell column (IML) of the spinal cord. These results indicate that AT2Rs are present on the RVLM neurons projecting to the IML and their blockade results in sympathoexcitatory responses. Activation of AT2Rs has an inhibitory influence in the RVLM and these receptors are tonically active. Attenuation of the function of AT2Rs in the RVLM may play a role in genesis and/or maintenance of hypertension in SHR.
Subject(s)
Angiotensin II Type 2 Receptor Blockers/pharmacology , Arterial Pressure/drug effects , Glutamic Acid/pharmacology , Heart Rate/drug effects , Imidazoles/pharmacology , Medulla Oblongata/drug effects , Pyridines/pharmacology , Splanchnic Nerves/drug effects , Animals , Blood Pressure/drug effects , Hypertension , Immunohistochemistry , Male , Medulla Oblongata/metabolism , Microinjections , Neurons/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Receptor, Angiotensin, Type 2/metabolism , Spinal Cord Lateral Horn/metabolismABSTRACT
Cardiovascular autonomic dysfunction in seizure is a major cause of sudden unexpected death in epilepsy. The catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) maintain sympathetic vasomotor tone and blood pressure through their direct excitatory projections to the intermediolateral (IML) cell column. Glutamate, the principal excitatory neurotransmitter in brain, is increased in seizures. Pituitary adenylate cyclase activating polypeptide (PACAP) is an excitatory neuropeptide with neuroprotective properties, whereas microglia are key players in inflammatory responses in CNS. We investigated the roles of glutamate, PACAP, and microglia on RVLM catecholaminergic neurons during the cardiovascular responses to 2 mg/kg kainic acid (KA)-induced seizures in urethane anesthetized, male Sprague Dawley rats. Microinjection of the glutamate antagonist, kynurenic acid (50 nl; 100 mM) into RVLM, blocked the seizure-induced 43.2 ± 12.6% sympathoexcitation (p ≤ 0.05), and abolished the pressor responses, tachycardia, and QT interval prolongation. PACAP or microglia antagonists (50 nl) (PACAP(6-38), 15 pmol; minocycline 10 mg/ml) microinjected bilaterally into RVLM had no effect on seizure-induced sympathoexcitation, pressor responses, or tachycardia but abolished the prolongation of QT interval. The actions of PACAP or microglia on RVLM neurons do not cause sympathoexcitation, but they do elicit proarrhythmogenic changes. An immunohistochemical analysis in 2 and 10 mg/kg KA-induced seizure rats revealed that microglia surrounding catecholaminergic neurons are in a "surveillance" state with no change in the number of M2 microglia (anti-inflammatory). In conclusion, seizure-induced sympathoexcitation is caused by activation of glutamatergic receptors in RVLM that also cause proarrhythmogenic changes mediated by PACAP and microglia. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy is a major cause of death in epilepsy. Generally, seizures are accompanied by changes in brain function leading to uncontrolled nerve activity causing high blood pressure, rapid heart rate, and abnormal heart rhythm. Nevertheless, the brain chemicals causing these cardiovascular changes are unknown. Chemicals, such as glutamate and pituitary adenylate cyclase activating polypeptide, whose expression is increased after seizures, act on specific cardiovascular nuclei in the brain and influence the activity of the heart, and blood vessels. Microglia, which manage excitation in the brain, are commonly activated after seizure and produce pro- and/or anti-inflammatory factors. Hence, we aimed to determine the effects of blocking glutamate, pituitary adenylate cyclase activating polypeptide, and microglia in the RVLM and their contribution to cardiovascular autonomic dysfunction in seizure.
Subject(s)
Cardiovascular Abnormalities/etiology , Medulla Oblongata/drug effects , Microglia/drug effects , Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology , Receptors, Glutamate/metabolism , Seizures/complications , Animals , Calcium-Binding Proteins/metabolism , Disease Models, Animal , Excitatory Amino Acid Antagonists/pharmacology , Gamma Rhythm/drug effects , Gamma Rhythm/physiology , Kainic Acid/toxicity , Male , Medulla Oblongata/metabolism , Microfilament Proteins/metabolism , Minocycline/pharmacology , Peptide Fragments/pharmacology , Rats , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/pathology , Splanchnic Nerves/drug effects , Splanchnic Nerves/physiology , Tyrosine 3-Monooxygenase/metabolism , VagotomyABSTRACT
Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30-40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100-200 nm) than in WT mice (200-350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an ~47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell.
Subject(s)
Catecholamines/metabolism , Chromaffin Granules/metabolism , Chromogranin A/deficiency , Energy Metabolism , Adrenal Glands/drug effects , Adrenal Glands/metabolism , Animals , Blotting, Western , Chromaffin Granules/drug effects , Chromaffin Granules/ultrastructure , Chromogranin A/metabolism , Dopamine/metabolism , Endocytosis/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Energy Metabolism/drug effects , Epinephrine/metabolism , Exocytosis/drug effects , Glucose/metabolism , Glycogen/metabolism , Golgi Apparatus/drug effects , Golgi Apparatus/metabolism , Humans , Insulin/pharmacology , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/drug effects , Mitochondria/metabolism , Norepinephrine/metabolism , Splanchnic Nerves/drug effects , Splanchnic Nerves/metabolism , Synaptic Vesicles/drug effects , Synaptic Vesicles/metabolismABSTRACT
The antihypertensive drugs moxonidine and clonidine are α2-adrenoceptor and imidazoline (I1) agonists. Previous results from our laboratory have shown that moxonidine can act in the commissural nucleus of the solitary tract (commNTS). In addition, some studies have shown that GABA or glutamate receptor blockade in the RVLM blunted the hypotension produced by these antihypertensive agents in spontaneously hypertensive rats. Therefore, in the present study we verify whether the cardiovascular and sympathetic effects produced by moxonidine in the commNTS are dependent on GABAergic or glutamatergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethane-anesthetized, and artificially-ventilated male Wistar rats (250-350 g). Injection of the GABAA antagonist bicuculline (25 pmol/50 nL) into the commNTS reduced the hypotension as well as the sympathoinhibition elicited by moxonidine. Prior injection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/50 nL) into the commNTS was not effective in reducing the hypotension and sympathoinhibition elicited by moxonidine. Therefore, we conclude that the hypotensive and sympathoinhibitory effects elicited by microinjection of moxonidine into the commNTS are dependent on GABA receptors, but not ionotropic glutamate receptors.
Subject(s)
Antihypertensive Agents/pharmacology , Cardiovascular Physiological Phenomena/drug effects , Imidazoles/pharmacology , Solitary Nucleus/drug effects , gamma-Aminobutyric Acid/metabolism , Analysis of Variance , Animals , Bicuculline/pharmacology , Blood Pressure/drug effects , Excitatory Amino Acid Antagonists/pharmacology , GABA-A Receptor Antagonists/pharmacology , Heart Rate/drug effects , Kynurenic Acid/pharmacology , Male , Rats , Rats, Wistar , Splanchnic Nerves/drug effects , Splanchnic Nerves/physiology , Time FactorsABSTRACT
Infusion of 5-hydroxytryptamine (5-HT) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaesthetized Sprague-Dawley rats, mean blood pressure was reduced from 101±4 to 63±3mm Hg during slow infusion of 5-HT (25µg/kg/min, i.v.). Pre- and postganglionic splanchnic sympathetic nerve activity were unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5-HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure.
Subject(s)
Blood Pressure/physiology , Serotonin/physiology , Splanchnic Circulation/physiology , Splanchnic Nerves/physiology , Sympathetic Nervous System/physiology , Animals , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Electric Stimulation , Ganglia, Sympathetic/surgery , Male , Mesenteric Artery, Superior/drug effects , Mesenteric Artery, Superior/physiology , Pyridines/pharmacology , Pyrroles/pharmacology , Rats , Serotonin/analogs & derivatives , Serotonin/pharmacology , Serotonin Receptor Agonists/pharmacology , Splanchnic Circulation/drug effects , Splanchnic Nerves/drug effects , Sympathetic Nervous System/drug effects , Vasoconstriction/drug effects , Vasoconstriction/physiologyABSTRACT
Obesity and hypertension are commonly associated, and activation of the sympathetic nervous system is considered to be a major contributor, at least in part due to the central actions of leptin. However, while leptin increases sympathetic nerve activity (SNA) in males, whether leptin is equally effective in females is unknown. Here, we show that intracerebroventricular (i.c.v.) leptin increases lumbar (LSNA) and renal (RSNA) SNA and baroreflex control of LSNA and RSNA in α-chloralose anaesthetized female rats, but only during pro-oestrus. In contrast, i.c.v. leptin increased basal and baroreflex control of splanchnic SNA (SSNA) and heart rate (HR) in rats in both the pro-oestrus and dioestrus states. The effects of leptin on basal LSNA, RSNA, SSNA and HR were similar in males and pro-oestrus females; however, i.c.v. leptin increased mean arterial pressure (MAP) only in males. Leptin did not alter LSNA or HR in ovariectomized rats, but its effects were normalized with 4 days of oestrogen treatment. Bilateral nanoinjection of SHU9119 into the paraventricular nucleus of the hypothalamus (PVN), to block α-melanocyte-stimulating hormone (α-MSH) type 3 and 4 receptors, decreased LSNA in leptin-treated pro-oestrus but not dioestrus rats. Unlike leptin, i.c.v. insulin infusion increased basal and baroreflex control of LSNA and HR similarly in pro-oestrus and dioestrus rats; these responses did not differ from those in male rats. We conclude that, in female rats, leptin's stimulatory effects on SNA are differentially enhanced by oestrogen, at least in part via an increase in α-MSH activity in the PVN. These data further suggest that the actions of leptin and insulin to increase the activity of various sympathetic nerves occur via different neuronal pathways or cellular mechanisms. These results may explain the poor correlation in females of SNA with adiposity, or of MAP with leptin.
Subject(s)
Baroreflex/drug effects , Estrogens/pharmacology , Kidney/innervation , Leptin/pharmacology , Lumbosacral Region/innervation , Splanchnic Nerves/drug effects , Animals , Baroreflex/physiology , Estradiol/blood , Estradiol/pharmacology , Estrogens/blood , Estrous Cycle/drug effects , Estrous Cycle/physiology , Female , Insulin/pharmacology , Male , Melanocyte-Stimulating Hormones/pharmacology , Ovariectomy , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/physiology , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 3/antagonists & inhibitors , Receptor, Melanocortin, Type 3/physiology , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Receptor, Melanocortin, Type 4/physiology , Splanchnic Nerves/physiologyABSTRACT
Arterial pressure (AP) elevates as a logarithmic function of exogenously administered dose of norepinephrine (NE). In contrast, AP is nearly linearly correlated with efferent sympathetic nerve activity (SNA) during acute baroreflex intervention. The present study aimed at quantifying the relationship between SNA and plasma NE concentration during acute baroreflex intervention. Carotid sinus regions were isolated from systemic circulation in five Wistar Kyoto rats, and carotid sinus pressure was changed among 60, 100, 120, 140, and 180 mm Hg every 2 min. Arterial blood (0.2 ml) was obtained at each pressure level for plasma NE measurement. Maximum AP and minimum AP were 153.34 ± 6.28 and 67.31 ± 4.92 mm Hg, respectively, in response to pressure perturbation. Plasma NE correlated linearly with SNA for individual animal data (slope: 0.957 ± 0.090 pg · ml(-1) · %(-1), intercept: 46.57 ± 7.22 pg/ml, r(2): ranged from 0.923 to 0.992) and also for group averaged data (NE = 0.956 × SNA + 47.97, r(2 )= 0.982). Blockade of neuronal NE uptake by intravenous desipramine (1 mg/kg) administration increased the slope (2.966 ± 0.686 pg · ml(-1) · %(-1), P < 0.05) and the intercept (168.73 ± 28.53 pg/ml, P < 0.01) of the plasma NE-SNA relationship. These results indicate that the relationship between SNA and plasma NE concentration was nearly linear within the normal physiological range of acute baroreflex control of AP. While plasma NE concentration can reflect changes in SNA, it may also overestimate the sympathetic outflow from the central nervous system when neuronal NE uptake is impaired systemically.
Subject(s)
Arterial Pressure/physiology , Baroreflex/physiology , Carotid Sinus/physiology , Norepinephrine/blood , Splanchnic Nerves/physiology , Animals , Arterial Pressure/drug effects , Baroreflex/drug effects , Cardiovascular Agents/pharmacology , Carotid Sinus/drug effects , Desipramine/pharmacology , Linear Models , Male , Rats, Inbred WKY , Splanchnic Nerves/drug effectsABSTRACT
The central nervous system plays an important role in regulating sympathetic outflow and arterial pressure in response to ethanol exposure. However, the underlying neural mechanisms have not been fully understood. In the present study, we tested the hypothesis that injection of ethanol in the central nucleus of the amygdala (CeA) increases sympathetic outflow, which may require the activation of local ionotropic excitatory amino acid receptors. In anesthetized rats, CeA injection of ethanol (0, 0.17, and 1.7 µmol) increased splanchnic sympathetic nerve activity (SSNA), lumbar sympathetic nerve activity (LSNA), and mean arterial pressure (MAP) in a dose-dependent manner. A cocktail containing ethanol (1.7 µmol) and kynurenate (KYN), an ionotropic excitatory amino acid receptor blocker, showed significantly blunted sympathoexcitatory and pressor responses compared with those elicited by CeA-injected ethanol alone (P < 0.01). A cocktail containing ethanol and d-2-amino-5-phosphonovalerate, an N-methyl-d-aspartate (NMDA) receptor antagonist, elicited attenuated sympathoexcitatory and pressor responses that were significantly less than ethanol alone (P < 0.01). In addition, CeA injection of acetate (0.20 µmol, n = 7), an ethanol metabolite, consistently elicited sympathoexcitatory and pressor responses, which were effectively blocked by d-2-amino-5-phosphonovalerate (n = 9, P < 0.05). Inhibition of neuronal activity of the rostral ventrolateral medulla (RVLM) with KYN significantly (P < 0.01) attenuated sympathoexcitatory responses elicited by CeA-injected ethanol. Double labeling of immune fluorescence showed NMDA NR1 receptor expression in CeA neurons projecting to the RVLM. We conclude that ethanol and acetate increase sympathetic outflow and arterial pressure, which may involve the activation of NMDA receptors in CeA neurons projecting to the RVLM.
Subject(s)
Amygdala/physiology , Ethanol/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Splanchnic Nerves/physiology , 2-Amino-5-phosphonovalerate/pharmacology , Action Potentials , Amygdala/drug effects , Amygdala/metabolism , Animals , Blood Pressure , Excitatory Amino Acid Antagonists/pharmacology , Kynurenic Acid/pharmacology , Male , Medulla Oblongata/drug effects , Medulla Oblongata/physiology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Splanchnic Nerves/drug effects , Splanchnic Nerves/metabolismABSTRACT
The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known about whether this region influences respiratory or metabolic outflows. The aim of this study was to describe simultaneous changes in respiratory, metabolic and cardiovascular functions evoked by disinhibition of the medial PFC (mPFC) and adjacent lateral septal nucleus (LSN). In urethane-anaesthetized rats, bicuculline methiodide was microinjected (2 mm; GABA-A receptor antagonist) into 90 sites in the mPFC at 0.72-4.00 mm from bregma. Phrenic nerve amplitude and frequency, arterial pressure, heart rate, splanchnic and lumbar sympathetic nerve activities (SNA), expired CO2, and core and brown adipose tissue temperatures were measured. Novel findings included disturbances to respiratory rhythm evoked from all subregions of the mPFC. Injections into the cingulate cortex evoked reductions in central respiratory function exclusively, whereas in ventral sites, particularly the infralimbic region, increases in respiratory drive and frequency, and metabolic and cardiac outflows were evoked. Disinhibition of sites in surrounding regions revealed that the LSN could evoke cardiovascular changes accompanied by distinct oscillations in SNA, as well as increases in respiratory amplitude. We show that activation of neurons within the mPFC and LSN influence respiratory, metabolic and cardiac outflows in a site-dependent manner. This study has implications with respect to the altered PFC neuronal activity seen in stress-related and mental health disorders, and suggests how basic physiological systems may be affected.
