Inhibition Of Sympathetic Nerve Activity Research Articles

Electroacupuncture Rebalances Autonomic Nervous Activities Decreasing Blood Pressure in Salt-Sensitive Hypertensive Rats

High blood pressure (BP) associated with sympathetic overactivity is observed in hypertensive animals and patients. We have recently reported that electroacupuncture (EA) at two sets of acupoints ST36-37 and SP6-7 attenuates BP in Dahl salt-sensitive hypertensive (DSSH) rats through a positive interaction between sympathetic nerve activity inhibition (sympathoinhibition, SI-EA) and anti-inflammation (AI-EA). Chronic inflammation is not only influenced by sympathetic (SNA) but also by parasympathetic nerve activity (PNA). However, it remains unclear if combined SI-EA + AI-EA (cEA) rebalances autonomic nerve activity by both inhibiting SNA and exciting PNA that alleviate hypertension (HTN). We hypothesized that cEA decreased SNA and increased PNA in DSSH rats. Dahl salt-sensitive (DSS) rats were fed 4% salt diet and randomly allocated into two groups: cEA or Sham-EA (no electrical stimulation). Another group of DSS rats studied as normotensive (NTNive) controls were fed a standard rat chow throughout the experiment. Systolic/diastolic BP (SBP/DBP) were measured with Tail-cuff via CODA system once a week. Once DSSH rats developed moderate HTN (SBP 160±5 mmHg), cEA or Sham-EA was applied twice weekly for five weeks, while the NTNive control groups received five weeks of similar study procedures (restraining) without the intervention. After five weeks of treatments, rats were anesthetized for the neuronal recording of SNA and PNA. Cervical vagal nerve (CVN) or splanchnic sympathetic nerve (SSN) was isolated from surrounding connective tissue under a dissecting microscope. Multiple-unit nerve activities were recorded and analyzed with Spike2 software. We observed that SBP (189.2±3.5 mmHg) and DBP (138.6±2.2 mmHg) in Sham-EA treated DSSH rats were higher than SBP (140.8±1.8 mmHg) by 25.6% and DBP (105.5±1.4 mmHg) by 23.9% in rats treated with repetitive cEA. Throughout the study, SBP (132.7±1.8 to 135.2±2.1 mmHg) and DBP (74.1±1.7 to 82.9±2.6 mmHg) in NTNive rats remained within normal range. Furthermore, activity of SSN was significantly greater in Sham-EA treated DSSH rats (23.1±1.6 imp/s) compared to cEA treated rats (15.2±2.0 imp/s, P=0.043) and NTNive rats (11.5 ±0.8 imp/s, P=0.004). Activity of CVN was higher in DSSH rats treated with cEA (27.8±2.9 imp/s) than Sham-EA (12.5±2.3 imp/s, P=0.016). Relative to Sham-EA, activity of CVN was higher (42.5±2.9 imp/s, P=0.001) in normal rats. In conclusion, cEA treatment effectively alleviates hypertension by restoring the balance of autonomic nervous functions through sympathoinhibition and parasympathoexcitation. Funding: NIH 1RO1AT011306-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of renal denervation on cardiac function after percutaneous coronary intervention in patients with acute myocardial infarction

ObjectiveTo observe the effect of renal artery denervation (RDN) on cardiac function in patients with acute myocardial infarction after percutaneous coronary intervention (AMI-PCI). MethodsThis is a single-centre, prospective randomized controlled study. A total of 108 AMI-PCI patients were randomly assigned to the RDN group or the control group at 1:1 ratio. All patients received standardized drug therapy after PCI, and patients in the RDN group underwent additional RDN at 4 weeks after the PCI. The follow-up period was 6 months after RDN. Echocardiography-derived parameters, cardiopulmonary exercise testing (CPET) data, Holter electrocardiogram, heart rate variability (HRV) at baseline and at the 6 months-follow up were analyzed. ResultsBaseline indexes were similar between the two groups (all P > 0.05). After 6 months of follow-up, the echocardiography-derived left ventricular ejection fraction was significantly higher in the RDN group than those in the control group. Cardiopulmonary exercise test indicators VO2Max, metabolic equivalents were significantly higher in the RDN group than in the control group. HRV analysis showed that standard deviation of the normal-to-normal R–R intervals, levels of square root of the mean squared difference of successive RR intervals were significantly higher in the RDN group than those in the control group. ConclusionsRDN intervention after PCI in AMI patients is associated with improved cardiac function, improved exercise tolerance in AMI patients post PCI. The underlying mechanism of RDN induced beneficial effects may be related to the inhibition of sympathetic nerve activity and restoration of the sympathetic-vagal balance in these patients.

5-Aminolevulinic acid hydrochloride enhances bupivacaine-induced hypotension in spontaneously hypertensive rats

PurposeOral administration of 5-aminolevulinic acid hydrochloride (5-ALA-HCl) has been reported to enhance the hypotensive effects associated with anesthetics, especially in elderly hypertensive patients treated with antihypertensive agents. The present study aimed to clarify the effects of antihypertensive-agent- and anesthesia-induced hypotension by 5-ALA-HCl in spontaneously hypertensive rats (SHRs). MethodsWe measured blood pressure (BP) of SHRs and normotensive Wistar Kyoto (WKY) rats treated with amlodipine or candesartan before and after administration of 5-ALA-HCl. We also investigated the change in BP following intravenous infusion of propofol and intrathecal injection of bupivacaine in relation to 5-ALA-HCl administration. FindingsOral administration of 5-ALA-HCl significantly reduced BP in SHRs and WKY rats with amlodipine and candesartan. Infusion of propofol significantly reduced BP in SHRs treated with 5-ALA-HCl. Intrathecal injection of bupivacaine significantly declined SBP and DBP in both SHRs and WKY rats treated with 5-ALA-HCl. The bupivacaine-induced decline in SBP was significantly larger in SHRs compared with WKY rats. ConclusionThese findings suggest that 5-ALA-HCl does not affect the antihypertensive agents-induced hypotensive effect, but enhances the bupivacaine-induced hypotensive effect, especially in SHRs, indicating that 5-ALA may contribute to anesthesia-induced hypotension via suppression of sympathetic nerve activity in patients with hypertension.

Ganglion stellate blockade in the treatment algorithm of the malignant electric storm: one center, five years and 72 procedures in 59 patients

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Malignant electric storm (ES) is a life-threatening condition with a high mortality rate. With years of increasing numbers of implanted ICDs, we witness increasing numbers of patients treated for ES. The role of local suppression of sympathetic nerve activity using ultrasound-guided anesthetic ganglion stellate blockade (GSB) is still under investigation with the first favorable published data from prospective cohorts. Objective To present data from a cohort of consecutive patients treated for ES at our cardiac center using a two-stage algorithm including GSB. Method and Cohort Between 2017 and 2021, 59 patients were treated using the two-stage algorithm ( when the first stage of standard procedures failed - ions, antiarrhythmic drugs, ischemia correction, heart rate modification, sedation, and GSB was performed as the second stage of the algorithm when ventricular arrhythmia recurred) in 72 GSB procedures. 57 GSB in men (79.2%)/15 GSB (20.8%) in women. Mean age 68.1 +/- 12.1 years. Mean LV EF 29.6 +/- 8.9%. 22 GSB in diabetic patients (30.6%). Ischemic etiology of ES in 41 cases (56.9%). Monomorphic ventricular tachycardia dominated among arrhythmias with 53 cases ( 73.6%). Betablocker and amiodarone were administered in 67 and 56 cases, respectively ( 93.1 and 77.8%). A statistically significant decrease of 87.7% in ventricular arrhythmias treated with shock ICD or ATP was seen ( decrease from 57.2 to 1.43 episodes 48 hours before vs. 48 hours after GSB, p<.0001) (Table 1). Hemodynamically unstable patients on continuous catecholamines responded significantly less to the two-step algorithm, including GSB. Horner’s syndrome and other demographic and medication parameters did not appear to predict a better response to GSB (Table 2 ). No serious adverse events were observed. In one case, intermittent ( couple hours) vocal chord paresis after bilateral GSB has been observed. Conclusion The two-stage algorithm for the treatment of ES, including ganglion stellate blockade, has shown stable high efficacy over the years with exceptional safety. However, the actual efficacy must be proven in a double-blinded study to allow the widespread method to the clinical practice.

The organ-specific nitric oxide synthase activity in the interaction with sympathetic nerve activity: a hypothesis.

The sympathetic nerve activity (SNA) is augmented in hypertension. SNA is regulated by neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide synthase (eNOS) activity in hypothalamic paraventricular nuclei (PVN) and/or brainstem rostral ventrolateral medulla. High nNOS or eNOS activity within these brain regions lowers the SNA, whereas low cerebral nNOS and/or eNOS activity causes SNA augmentation. We hypothesize that the decreased cerebral nNOS/eNOS activity, which allows the enhancement of SNA, leads to the augmentation of renal eNOS/nNOS activity. Similarly, when the cerebral nNOS/eNOS activity is increased and SNA is suppressed, the renal eNOS/nNOS activity is suppressed as well. The activation of endothelial alpha(2)-adrenoceptors, may be a possible mechanism involved in the proposed regulation. Another possible mechanism might be based on nitric oxide, which acts as a neurotransmitter that tonically activates afferent renal nerves, leading to a decreased nNOS activity in PVN. Furthermore, the importance of the renal nNOS/eNOSactivity during renal denervation is discussed. In conclusion, the presented hypothesis describes the dual organ-specific role of eNOS/nNOS activity in blood pressure regulation and suggests possible connection between cerebral NOS and renal NOS via activation or inhibition of SNA, which is an innovative idea in the concept of pathophysiology of hypertension.

Effects of an SGLT2 inhibitor on the salt sensitivity of blood pressure and sympathetic nerve activity in a nondiabetic rat model of chronic kidney disease.

The glucose-lowering effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors is reduced in patients with diabetes who have chronic kidney disease (CKD). In the present study, we examined the effect of an SGLT2 inhibitor on the salt sensitivity of blood pressure (BP), circadian rhythm of BP, and sympathetic nerve activity (SNA) in nondiabetic CKD rats. Uninephrectomized Wistar rats were treated with adenine (200 mg/kg/day) for 14 days. After stabilization with a normal-salt diet (NSD, 0.3% NaCl), a high-salt diet (HSD, 8% NaCl) was administered. Mean arterial pressure (MAP) was continuously monitored using a telemetry system. We also analyzed the low frequency (LF) of systolic arterial pressure (SAP), which reflects SNA. In adenine-induced CKD rats, HSD consumption for 5 days significantly increased the mean MAP from 106 ± 2 to 148 ± 3 mmHg. However, MAP was decreased to 96 ± 3 mmHg within 24 h after switching back to a NSD (n = 7). Treatment with an SGLT2 inhibitor, luseogliflozin (10 mg/kg/day, p.o., n = 7), significantly attenuated the HSD-induced elevation of MAP, which was associated with a reduction in LF of SAP. These data suggest that treatment with an SGLT2 inhibitor attenuates the salt sensitivity of BP, which is associated with SNA inhibition in nondiabetic CKD rats.

Sympathetic Enhancement of Memory T-Cell Homing and Hypertension Sensitization.

Effector memory T lymphocytes (TEM cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated on reexposure to the hypertensive stimulus. Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow-residing hypertension-specific TEM cells. Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8+ T cells. These cells, defined by their proliferative response on coculture with dendritic cells from Ang (angiotensin) II-infused mice, were reduced in denervated compared with innervated bone of Ang II-infused mice. Adoptively transferred CD8+ T cells from Ang II-infused mice preferentially homed to innervated compared with denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled designer receptor exclusively activated by designer drug augmented CD8+ TEM bone marrow accumulation. Adoptive transfer studies using mice lacking β2AR (β2 adrenergic receptors) indicate that β2AR in the bone marrow niche, rather than T-cell β2AR is critical for TEM cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD (designer receptor exclusively activated by designer drug) injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension-specific CD8+ TEM cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose Ang II. Sympathetic nerves contribute to the homing and survival of hypertension-specific TEM cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation on reexposure to hypertension stimuli.

Renal Sympathetic Denervation Improves Outcomes in a Canine Myocardial Infarction Model.

BackgroundMyocardial infarction (MI) is the main cause of heart failure (HF), and sympathetic nerve activity is associated with prognosis chronic heart failure. Renal sympathetic denervation (RDN) is noted for its powerful effect on the inhibition of sympathetic nerve activity. This study investigated the effect of RDN on heart failure in dogs after myocardial infarction.Material/MethodsThe experimental animals were randomized into 2 groups: the MI group (n=12) and the sham operation group (n=6). In the MI group we established an MI model by permanently ligating the left anterior descending branch. After 4 weeks, the MI dogs were randomly divided into 2 groups: the MI+RDN group (MI+renal sympathetic denervation, n=6) and the simple MI group (n=6). Animals in the MI+RDN group underwent both surgical and chemical renal denervation.ResultsCompared with sham operation group, left ventricular fraction shortening (LVFS) and left ventricular ejection fraction (LVEF) were significantly reduced in the simple MI group, while the reduction was partly reversed in the MI+RDN group. RDN reduced sympathetic nerve activity and release of B-type natriuretic peptide (BNP) and Angiotensin II (AngII) in the MI+ RDN group but not in the simple MI group.ConclusionsCanine renal sympathetic denervation prevents myocardial malignant remodeling by lowering the activity of the systemic sympathetic nerve and inhibiting renin-angiotensin-aldosterone system (RASS) activation, providing a new target and method for the treatment of heart failure.

The pivotal role of melatonin in ameliorating chronic kidney disease by suppression of the renin–angiotensin system in the kidney

Melatonin is a hormone produced by the pineal gland, predominantly at night, and plays a pivotal role in regulating the circadian rhythm as well as a variety of biological functions, including anti-inflammation, anti-oxidation, inhibition of sympathetic nerve activity, and preservation of endothelial cell function. The intrarenal renin-angiotensin system (RAS) is one of the most important contributors in the pathophysiology of chronic kidney disease (CKD) and hypertension, independent of the circulating RAS, due to sodium reabsorption and inflammation and fibrosis in the kidney. However, the relationship between melatonin secretion and intrarenal RAS activation has remained unknown. It has been recently shown that impaired nighttime melatonin secretion is associated with nighttime urinary angiotensinogen excretion, a surrogate marker of intrarenal RAS activation and renal damage in patients with CKD. Moreover, it has also been indicated that melatonin administered exogenously exercises antioxidant effects that ameliorate intrarenal RAS activation and renal injury in chronic progressive CKD animal models. As a result, the new roles of melatonin in suppressing RAS in the kidney via amelioration of reactive oxygen species have been clarified. Therefore, we review the relationship between melatonin and intrarenal RAS activation and indicate the possibility of a new strategy to suppress CKD, which is a risk factor for cardiovascular and end-stage renal diseases.

Improvement of glycemic control by treatment for insomnia with suvorexant in type 2 diabetes mellitus

IntroductionAcute and chronic insomnia can exacerbate type 2 diabetes mellitus (T2DM). We investigated suvorexant (an anti-insomnia drug that targets the orexin system) effects on sleep architecture and glucose metabolism in T2DM patients with insomnia. Materials and methodsThis 7 day open-label, single-arm, intervention trial included 18 subjects with T2DM and insomnia. After 1 day acclimatization, daily glucose levels, sleep architecture, and autonomic nervous function were evaluated by continuous glucose monitoring (CGM), single-channel electroencephalography, and accelerometry, respectively. ResultsSuvorexant treatment for 3 days significantly increased total sleep time and sleep efficiency, with partial suppression of sympathetic nerve activity. CGM-measured 24 h mean glucose level decreased significantly from 157.7 ± 22.9 to 152.3 ± 17.8 mg/dL, especially in the early glucose surge after the midnight nadir (from 28.3 ± 15.0 to 18.2 ± 9.9 mg/dL), and until supper with a significant improvement in homeostasis model assessment of insulin resistance from 4.0 ± 2.8 to 2.9 ± 1.6, respectively. ConclusionsSuvorexant treatment for insomnia of subjects with T2DM significantly improved CGM-measured daily glycemic control, which was associated with changes in sympathomimetic tone and/or improved insulin sensitivity. The amelioration of insomnia may therefore be a target for improving glycemic control in T2DM patients with insomnia.

Renal Denervation Reduced Ventricular Arrhythmia After Myocardial Infarction by Inhibiting Sympathetic Activity and Remodeling.

BackgroundVentricular arrhythmia after myocardial infarction is the most important risk factor for sudden cardiac death, which poses a serious threat to human health. As the correlation between autonomic nervous systemic dysfunction and heart rhythm abnormality has been gradually revealed, remedies targeting autonomic nervous system dysfunction, especially the sympathetic nerve, have emerged. Among them, renal denervation is noted for its powerful effect on the inhibition of sympathetic nerve activity. We aim to investigate whether renal denervation can reduce ventricular arrhythmia after myocardial infarction and thus decrease the risk of sudden cardiac death. In addition, we explore the potential mechanism with respect to nerve activity and remodeling.Methods and ResultsTwenty‐four beagles were randomized into the control (n=4), renal denervation (n=10), and sham (n=10) groups. Permanent left anterior descending artery ligation was performed to establish myocardial infarction in the latter 2 groups. Animals in the renal denervation group underwent both surgical and chemical renal denervation. Compared with dogs in the sham group, dogs in the renal denervation group demonstrated attenuated effective refractory period shortening and inhomogeneity, flattened restitution curve, increased ventricular threshold, and decreased ventricular arrhythmia. Heart rate variability assessment, catecholamine measurement, and nerve discharge recordings all indicated that renal denervation could reduce whole‐body and local tissue sympathetic tone. Tissue analysis revealed a significant decrease in neural remodeling in both the heart and stellate ganglion.ConclusionsSurgical and chemical renal denervation decreased whole‐body and local tissue sympathetic activity and reversed neural remodeling in the heart and stellate ganglion. Consequently, renal denervation led to beneficial remodeling of the electrophysiological characteristics in the infarction border zone, translating to a decrease in ventricular arrhythmia after myocardial infarction.

Antioxidant Melatonin: Potential Functions in Improving Cerebral Autoregulation After Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a subtype of stroke with high mortality and morbidity. Impaired cerebral autoregulation following SAH has been reported owing to effects on sympathetic control, endothelial function, myogenic response, and cerebral metabolism. Impaired cerebral autoregulation is associated with early brain injury, cerebral vasospasm/delayed cerebral ischemia, and SAH prognosis. However, few drugs have been reported to improve cerebral autoregulation after SAH. Melatonin is a powerful antioxidant that is effective (easily crosses the blood brain barrier) and safe (tolerated in large doses without toxicity). Theoretically, melatonin may impact the control mechanisms of cerebral autoregulation via antioxidative effects, protection of endothelial cell integrity, suppression of sympathetic nerve activity, increase in nitric oxide bioavailability, mediation of the myogenic response, and amelioration of hypoxemia. Furthermore, melatonin may have a comprehensive effect on cerebral autoregulation. This review discusses the potential effects of melatonin on cerebral autoregulation following SAH, in terms of the association between pharmacological activities and the mechanisms of cerebral autoregulation.

Targeted regulation of sympathetic activity in paraventricular nucleus reduces inducible ventricular arrhythmias in rats after myocardial infarction

BackgroundThe hypothalamic paraventricular nucleus (PVN) is the center of the regulation of autonomic nervous system functions and cardiovascular activity. Phosphoinositide-3 kinase (PI3K)-AKT pathway in PVN contributes to mediate sympathetic nerve activity and is activated in spontaneously hypertensive rats. Overactivation of the sympathetic output was considered as an important mechanism of the arrhythmias. In the present study, we aimed to explore whether targeted regulation of sympathetic activity in PVN could reduce the peripheral sympathoexcitatory and attenuate the ventricular arrhythmias (VAs) in myocardial infarction (MI) rats via PI3K-AKT pathway. MethodsA stainless steel gauge guide cannula was stereotaxically implanted into the PVN, and 7 days later, rats were randomly divided into the following 4 groups: group A, control+dimethyl sulfoxide (DMSO); group B, control+LY294002; group C, MI surgery+DMSO; and group D, MI surgery+LY294002. Studies were conducted seven days post-MI. Myocardial function, infarct size, inducible VAs by programmed electrical stimulation, renal sympathetic nerve activity (RSNA), and protein level of PI3K and AKT were measured. ResultsMI increased the protein ratios of p-PI3K-to-total-PI3K and p-AKT-to-total-AKT in PVN but can be reduced by LY294002 treatment. Inhibition of sympathetic nerve activity in PVN led to a reversion in plasma norepinephrine, RSNA and inducible VAs in MI rats. ConclusionsPI3K-AKT pathway in the PVN was a main mechanism in regulating sympathetic activity and arrhythmias in MI rats. Targeted inhibition of sympathetic activity in PVN may be a potential treatment for the VAs via PI3K-AKT pathway.

Inhibitory Effects of Intranasal Insulin Administration on Fat Oxidation during Exercise Are Diminished in Overweight Young Individuals

Endurance training at a level (FATmax) that raises the maximal fat oxidation rate (max FOR) may contribute to body weight loss in obese individuals. However, max FOR and FATmax are reduced in subjects with obesity and/or with insulin resistance compared with those without. On the other hand, in humans, intranasal insulin administration increases the concentration of insulin in cerebrospinal fluid when peripheral effects are absent, resulting in reduced food intake and body weight. However, it remains unclear whether insulin delivery to the brain affects fat oxidation during exercise. In this study, we examined the effects of nasal insulin administration on max FOR during exercise in 11 normal-weight (N group) and seven overweight (O group) young individuals. On two separate days, either 40 IU regular insulin (INS) or normal saline, as placebo (PL), was randomly administered intranasally after overnight fasting, and then each participant underwent a graded exercise test. Indirect calorimetry was used to assess max FOR during exercise and FATmax. Blood insulin and glucose levels did not change after insulin administration. In the N group, max FOR tended to decrease in the INS trial (p = 0.050); FATmax and the total amount of fat oxidation during exercise were significantly smaller in the INS trial than in the PL trial. Max FOR was significantly smaller in the O group than in the N group (p = 0.021) and was not influenced by insulin administration. Blood adrenaline levels increased by exercise tended to be reduced by insulin administration in the N group only. In conclusion, intranasal insulin administration reduces fat oxidation during exercise without increasing peripheral insulin levels, possibly via the suppression of sympathetic nerve activity. The inhibitory effects of intranasal insulin administration on fat oxidation during exercise are diminished in overweight subjects, suggesting cerebral insulin effects are attenuated in this population. Disclosure H. Yokoyama: None. R. Takeda: None. E. Kawai: None. A. Ota: None. E. Morita: None. D. Imai: None. Y. Suzuki: None. T. Morioka: Consultant; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., MSD K.K., Eli Lilly and Company, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Takeda Pharmaceuticals U.S.A., Inc., Novo Nordisk Inc., Kowa Pharmaceuticals America, Inc., Astellas Pharma US, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd. M. Emoto: Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Astellas Pharma Inc, Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Company Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. M. Inaba: None. K. Okazaki: None.

Neurons in the Ventral Lateral Preoptic (vLPO) Area Inhibit Brown Adipose Tissue (BAT) Thermogenesis

Neurons in the preoptic area of the hypothalamus play important roles in thermoregulation. However, the subregions of the preoptic hypothalamus are heterogeneous, such that neuronal activation at some sites elicits hyperthermia, while others evoke hypothermia. Here we show that in urethane/chloralose‐anesthetized, artificially‐ventilated rats, neurons in the vLPO (0.0 to −1.44 mm caudal to bregma, 0.8 to 1.5 mm lateral to the midline, and −8.0 to 9.8 mm below the dura surface, incisor bar in flat skull position) have a hypothermic effect mediated by inhibition of sympathetic nerve activity (SNA) and BAT thermogenesis. The activation of cvLPO neurons with nanoinjections of NMDA (0.2 mM, 60 nl) evoked a complete inhibition of cold‐evoked BAT thermogenesis: BAT SNA (−97 %, p = 0.01), BAT temperature (TBAT, −0.4 °C, p = 0.01), expired CO2, (Exp CO2, −0.4 %, p = 0.0004), mean arterial pressure (MAP, −9 mmHg, p = 0.01) and heart rate (HR, −53 bpm, p = 0.0005). Similar BAT sympathoinhibitory responses were obtained with nanoinjections of bicuculline (BIC, 1.0 mM, 60 nl) in the vLPO. Under thermoneutral conditions, the inhibition of cvLPO neurons by activation of local GABAA receptors (muscimol, 1.2 mM, 60 nl) increased BAT SNA (+99 % p = 0.0001), TBAT (+2.2 °C, p = 0.0001), Exp CO2 (+1.0 %, p = 0.00003), and HR (+58 bpm, p = 0.007), with no change in MAP (p = 0.5). Nanoinjections of muscimol, or the glutamate receptor antagonists, AP5/CNQX, in the dorsomedial hypothalamus (DMH), or in the rostral raphe pallidus (rRPa), reversed the activation of BAT thermogenesis evoked by inhibition of vLPO neurons. Activation of neurons in vLPO inhibited the BAT thermogenesis evoked by BIC nanoinjections in the DMH, but not the increase in BAT SNA evoked by BIC nanoinjections in the rRPa. We conclude that vLPO contains BAT sympathoinhibitory neurons that mediate the warm ambient‐evoked inhibition of BAT thermogenesis through a direct or indirect GABAergic input to rRPa. Similarly to the cold‐evoked activation of BAT thermogenesis, that following inhibition of vLPO neurons requires the glutamatergic, BAT sympathoexcitatory pathway from DMH to BAT sympathetic premotor neurons in rRPa. These novel findings a key population of BAT sympathoinhibitory neurons in the central pathway mediating the skin warming‐evoked inhibition of BAT thermogenesis, requiring the addition of a BAT sympathoinhibitory pathway between vLPO and rRPa to the current model of central autonomic thermoregulation.Support or Funding InformationThis work was supported by NIH R01‐NS091066 (S.F.M.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CLOSED-LOOP BAROREFLEX NEUROMODULATION MARKEDLY AUGMENTS VOLUME TOLERANCE AND INSTANTLY RESOLVES PULMONARY CONGESTION IN ACUTE HEART FAILURE

Suppression of sympathetic nerve activity (SNA) is a reasonable therapeutic target in the management of acute heart failure (AHF). However, practical interventions to manipulate SNA without compromising hemodynamics remain unestablished. In this study, we developed a closed-loop pressure controller

Glucose Metabolic Changes in the Brain and Muscles of Patients with Nonspecific Neck Pain Treated by Spinal Manipulation Therapy: A [18F]FDG PET Study.

Objective. The aim of this study was to investigate changes in brain and muscle glucose metabolism that are not yet known, using positron emission tomography with [18F]fluorodeoxyglucose ([18F]FDG PET). Methods. Twenty-one male volunteers were recruited for the present study. [18F]FDG PET scanning was performed twice on each subject: once after the spinal manipulation therapy (SMT) intervention (treatment condition) and once after resting (control condition). We performed the SMT intervention using an adjustment device. Glucose metabolism of the brain and skeletal muscles was measured and compared between the two conditions. In addition, we measured salivary amylase level as an index of autonomic nervous system (ANS) activity, as well as muscle tension and subjective pain intensity in each subject. Results. Changes in brain activity after SMT included activation of the dorsal anterior cingulate cortex, cerebellar vermis, and somatosensory association cortex and deactivation of the prefrontal cortex and temporal sites. Glucose uptake in skeletal muscles showed a trend toward decreased metabolism after SMT, although the difference was not significant. Other measurements indicated relaxation of cervical muscle tension, decrease in salivary amylase level (suppression of sympathetic nerve activity), and pain relief after SMT. Conclusion. Brain processing after SMT may lead to physiological relaxation via a decrease in sympathetic nerve activity.

Abstract P153: Downregulation of Neuronal Nitric Oxide Synthase Within the Paraventricular Nucleus in Insulin Dependent Diabetic Akita Mice

Activation of both renin-angiotensin- system (RAS) and sympathetic system are the primary etiologic events in the development of hypertension in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Our previous studies have demonstrated that neuronal nitric oxide (nNOS) expression and nitric oxide (NO) mediated inhibition of sympathetic nerve activity (SNA) is markedly reduced in the paraventricular nucleus (PVN) of streptozotocin-induced diabetic rats. We have further demonstrated that Angiotensin II (Ang II) via Ang II type 1 receptors (AT 1 R) modulates the expression of nNOS in the PVN, which augments sympathetic outflow. Here we hypothesized that DM-linked hypertension and cardiovascular dysregulation is due to the reduction in nNOS with the PVN. To test the hypothesis, we used Ins2 +/- Akita (a spontaneous, insulin dependent genetic diabetic murine model) which showed an increase in systolic blood pressure at the age of 14 weeks compared to corresponding C57BL/6J (WT) mice with concomitant decreased expression of nNOS (0.75±0.05 WT vs. 0.43±0.11* Akita) in the PVN. Further, Akita mice had increased expression of ACE (angiotensin converting enzyme) (WT 0.34±0.04 vs. Akita 0.58±0.05*) and AT 1 R (WT 0.29±0.09 vs. Akita 0.49±0.03*) and decreased expression of ACE2 (0.27±0.03 WT vs. 0.17±0.05* Akita) and Mas receptor (WT 0.77±0.07 vs. Akita 0.46±0.02*), suggesting an imbalance in the excitatory and protective arms of RAS. Moreover, we found increased protein levels of PIN (a protein inhibitor of nNOS, known to dissociate catalytically active nNOS dimers to monomers) (WT 0.71±0.09 vs. Akita 1.75±0.08) with 72 percent decrease in dimer/monomer ratio of nNOS (WT 0.19±0.0 vs. Akita 0.11±0.04) in the PVN of Akita mice. Taken together, our studies suggest that accumulation of PIN, mediated by activation of the excitatory arm of RAS, leads to a decrease in the active dimeric form of nNOS resulting in reduced NO causing an over-activation of the sympathetic drive, leading to hypertension in DM. 1

The anti-hypertensive effect of a P2X3 receptor antagonist in the spontaneously hypertensive rat is due to inhibition of sympathetic nerve activity

The anti-hypertensive effect of a P2X3 receptor antagonist in the spontaneously hypertensive rat is due to inhibition of sympathetic nerve activity

Sympathetic Nerve Activity Maintains an Anti-Inflammatory State in Adipose Tissue in Male Mice by Inhibiting TNF-α Gene Expression in Macrophages

Adipose tissue macrophages (ATMs) play an important role in the inflammatory response in obese animals. How ATMs are regulated in lean animals has remained elusive, however. We now show that the sympathetic nervous system (SNS) is necessary to maintain the abundance of the mRNA for the proinflammatory cytokine TNF-α at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti-related neuropeptide increased the amount of TNF-α mRNA in epididymal (epi) white adipose tissue (WAT), but not in interscapular brown adipose tissue (BAT), through inhibition of sympathetic nerve activity in epiWAT. The surgical denervation and β-adrenergic antagonist propranolol up-regulated TNF-α mRNA in both epiWAT and BAT in vivo. Signaling by the β2-adrenergic receptor (AR) and protein kinase A down-regulated TNF-α mRNA in epiWAT explants and suppressed lipopolysaccharide-induced up-regulation of TNF-α mRNA in the stromal vascular fraction of this tissue. β-AR-deficient (β-less) mice manifested an increased plasma TNF-α concentration and increased TNF-α mRNA abundance in epiWAT and BAT. TNF-α mRNA abundance was greater in ATMs (CD11b(+) cells of the stromal vascular fraction) from epiWAT or BAT of wild-type mice than in corresponding CD11b(-) cells, and β2-AR mRNA abundance was greater in ATMs than in CD11b(-) cells of epiWAT. Our results show that the SNS and β2-AR-protein kinase A pathway maintain an anti-inflammatory state in ATMs of lean mice in vivo, and that the brain melanocortin pathway plays a role in maintaining this state in WAT of lean mice via the SNS.