scholarly journals A Hypothalamic Leptin-Glutamate Interaction in the Regulation of Sympathetic Nerve Activity

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Hong Zheng ◽  
Xuefei Liu ◽  
Yulong Li ◽  
Kaushik P. Patel
Keyword(s):  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Leptin Receptor ◽  
Nmda Receptor Antagonist ◽  
Sympathetic Activation ◽  
Nerve Activity ◽  
Glutamate Signaling ◽  
Hypothalamic Nuclei ◽  
Confocal Calcium Imaging

Accumulated evidence indicates that obesity-induced type 2 diabetes (T2D) is associated with enhanced sympathetic activation. The present study was conducted to investigate the role for leptin-glutamate signaling within the hypothalamus in regulating sympathetic nerve activity. In anesthetized rats, microinjections of leptin (5 ng ~ 100 ng) into the arcuate nucleus (ARCN) and paraventricular nucleus (PVN) induced increases in renal sympathetic nerve activity (RSNA), blood pressure (BP), and heart rate (HR). Prior microinjections of NMDA receptor antagonist AP5 (16 pmol) into the ARCN or PVN reduced leptin-induced increases in RSNA, BP, and HR in both ARCN and PVN. Knockdown of a leptin receptor with siRNA inhibited NMDA-induced increases in RSNA, BP, and HR in the ARCN but not in the PVN. Confocal calcium imaging in the neuronal NG108 and astrocytic C6 cells demonstrated that preincubation with leptin induced an increase in intracellular calcium green fluorescence when the cells were challenged with glutamate. In high-fat diet and low-dose streptozotocin-induced T2D rats, we found that leptin receptor and NMDA NR1receptor expressions in the ARCN and PVN were significantly increased. In conclusion, these studies provide evidence that within the hypothalamic nuclei, leptin-glutamate signaling regulates the sympathetic activation. This may contribute to the sympathoexcitation commonly observed in obesity-related T2D.

Abstract 036: Pomc Neurons, But Not Agrp Neurons, Are Required For Leptin-induced Sympathetic Activation

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Balyssa B Bell ◽  
Shannon M Harlan ◽  
Donald A Morgan ◽  
Kamal Rahmouni
Keyword(s):  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Neuronal Population ◽  
Sympathetic Activation ◽  
Nerve Activity ◽  
Brown Adipose ◽  
Induced Hypertension ◽  
The Brain

Leptin acts in the brain to decrease food intake and promote energy expenditure by increasing sympathetic nerve activity (SNA) to thermogenic brown adipose tissue. Leptin also increases SNA to other beds including kidney with implications for obesity-induced hypertension. We previously demonstrated the importance the arcuate nucleus (Arc) of the hypothalamus in mediating leptin-induced increases in regional SNA, but the specific neuronal population within the Arc that mediates these responses is unknown. We hypothesized that agouti-related peptide (AgRP) and/or proopiomelanocortin (POMC) neurons of the Arc are critical for the increases in SNA in response to leptin. To test this, we generated mice lacking the leptin receptor specifically in AgRP or POMC neurons by crossing the LepR flox/flox mice with AgRP Cre or POMC Cre mice. Consistent with previous reports, both AgRP Cre/ LepR flox/flox mice and POMC Cre /LepR flox/flox mice have a slightly elevated body weight relative to littermate controls. Next, we used multifiber sympathetic nerve recording to assess the SNA effects of leptin. Intracerebroventricular (ICV) injection of leptin (2 μg) led to a comparable increase in renal SNA in control mice (210±93%) and AgRP Cre /LepR flox/flox mice (191±53%). AgRP Cre/ LepR flox/flox mice also displayed a normal lumbar SNA response to ICV leptin (384±86%) relative to controls (325±46%). In contrast, POMC Cre /LepR flox/flox mice exhibited a significantly reduced renal SNA response to ICV leptin (5±17%) as compared to controls (174±45%). Lumbar SNA response to leptin was also blunted in POMC Cre /LepR flox/flox mice (24±21%) as compared to controls (358±53%). Thus, deletion of the leptin receptor from POMC neurons, but not AgRP neurons, interferes with the ability of leptin to increase sympathetic traffic. These results demonstrate that the sympathetic nerve responses evoked by leptin emanate from leptin action on POMC neurons.

scholarly journals Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity

2010 ◽  
Vol 299 (3) ◽  
pp. H925-H931 ◽  
Author(s):  
G. S. Gilmartin ◽  
M. Lynch ◽  
R. Tamisier ◽  
J. W. Weiss
Keyword(s):  
Blood Pressure ◽  
Sympathetic Nerve ◽  
Intermittent Hypoxia ◽  
Sympathetic Nerve Activity ◽  
Muscle Sympathetic Nerve Activity ◽  
Chronic Intermittent Hypoxia ◽  
Sympathetic Activation ◽  
Nerve Activity ◽  
Blood Pressure Elevation ◽  
Healthy Humans

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17–24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr ( n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 ± 1.3 vs. 74 ± 1.7 mmHg, P < 0.01), MSNA [9.94 ± 2.0 to 14.63 ± 1.5 bursts/min ( P < 0.05); 16.89 ± 3.2 to 26.97 ± 3.3 bursts/100 heartbeats (hb) ( P = 0.01)], and forearm vascular resistance (FVR) (35.3 ± 5.8 vs. 55.3 ± 6.5 mmHg·ml−1·min·100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

scholarly journals Exacerbated pressor and sympathoexcitatory effects of central Elabela in spontaneously hypertensive rats

2020 ◽  
Vol 318 (1) ◽  
pp. H124-H134 ◽  
Author(s):  
Zhi Geng ◽  
Chao Ye ◽  
Ying Tong ◽  
Feng Zhang ◽  
Ye-Bo Zhou ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sympathetic Nerve ◽  
Spontaneously Hypertensive Rats ◽  
Sympathetic Nerve Activity ◽  
Akt Pathway ◽  
Sympathetic Activation ◽  
Hypertensive Rats ◽  
Nerve Activity ◽  
Vasopressin Release ◽  
Spontaneously Hypertensive

Elabela (ELA) is a newly discovered peptide that acts as a novel endogenous ligand of angiotensin receptor-like 1 (APJ) receptor. This study was designed to evaluate the effects of ELA-21 in paraventricular nucleus (PVN) on blood pressure and sympathetic nerve activity in spontaneously hypertensive rats (SHR). Experiments were performed in male Wistar-Kyoto rats (WKY) and SHR. ELA expression was upregulated in PVN of SHR. PVN microinjection of ELA-21 increased renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine, and arginine vasopressin (AVP) levels in SHR. Intravenous injection of ELA-21 significantly decreased MAP and HR in both WKY and SHR, but only induced a slight decrease in RSNA. APJ antagonist F13A in PVN abolished the effects of ELA-21 on RSNA, MAP and HR. Intravenous infusion of both ganglionic blocker hexamethonium and AVP V1a receptor antagonist SR49059 caused significant reduction in the effects of ELA-21 on RSNA, MAP and HR in SHR, while combined administration of hexamethonium and SR49059 abolished the effects of ELA-21. ELA-21 microinjection stimulated Akt and p85α subunit of phosphatidylinositol 3-kinase (PI3K) phosphorylation in PVN, whereas PI3K inhibitor LY294002 or Akt inhibitor MK-2206 almost abolished the effects of ELA-21 on RSNA, MAP, and HR. Chronic PVN infusion of ELA-21 induced sympathetic activation, hypertension, and AVP release accompanied with cardiovascular remodeling in normotensive WKY. In conclusion, ELA-21 in PVN induces exacerbated pressor and sympathoexcitatory effects in hypertensive rats via PI3K-Akt pathway. NEW & NOTEWORTHY We demonstrated that PVN microinjection of ELA-21 increases sympathetic nerve activity and blood pressure, which can be abolished by pretreatment of APJ antagonist. This is the first demonstration that central ELA can induce hypertension. The pressor effects in PVN are mediated by both sympathetic activation and vasopressin release via PI3K-Akt pathway. Our data confirm that ELA is upregulated in the PVN of SHR and so may be involved in the pressor and sympathoexcitatory effects in hypertension.

Slow head-up tilt causes lower activation of muscle sympathetic nerve activity: loading speed dependence of orthostatic sympathetic activation in humans

2009 ◽  
Vol 297 (1) ◽  
pp. H53-H58 ◽  
Author(s):  
Atsunori Kamiya ◽  
Toru Kawada ◽  
Shuji Shimizu ◽  
Satoshi Iwase ◽  
Masaru Sugimachi ◽  
...  
Keyword(s):  
Tilt Angle ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Muscle Sympathetic Nerve Activity ◽  
Amplitude Dependence ◽  
Sympathetic Activation ◽  
Control Test ◽  
Nerve Activity ◽  
Lower Activation ◽  
Head Up Tilt

Many earlier human studies have reported that increasing the tilt angle of head-up tilt (HUT) results in greater muscle sympathetic nerve activity (MSNA) response, indicating the amplitude dependence of sympathetic activation in response to orthostatic stress. However, little is known about whether and how the inclining speed of HUT influences the MSNA response to HUT, independent of the magnitude of HUT. Twelve healthy subjects participated in passive 30° HUT tests at inclining speeds of 1° (control), 0.1° (slow), and 0.0167° (very slow) per second. We recorded MSNA (tibial nerve) by microneurography and assessed nonstationary time-dependent changes of R-R interval variability using a complex demodulation technique. MSNA averaged over every 10° tilt angle increased during inclination from 0° to 30°, with smaller increases in the slow and very slow tests than in the control test. Although a 3-min MSNA overshoot after reaching 30° HUT was observed in the control test, no overshoot was detected in the slow and very slow tests. In contrast with MSNA, increases in heart rate during the inclination and after reaching 30° were similar in these tests, probably because when compared with the control test, greater increases in plasma epinephrine counteracted smaller autonomic responses in the very slow test. These results indicate that slower HUT results in lower activation of MSNA, suggesting that HUT-induced sympathetic activation depends partially on the speed of inclination during HUT in humans.

Abstract 3559: β2-adrenoceptor Protein Expression Is Different Between Buffy Coat And Adipose Tissue

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kazuko Masuo ◽  
Tomohiro Katsuya ◽  
Hiromi Rakugi ◽  
Ken Sugimoto ◽  
Toshio Ogihara ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Expression ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Leptin Receptor ◽  
Whole Body ◽  
Receptor Protein ◽  
Nerve Activity ◽  
Caucasian Men ◽  
Obese Subjects

Background: Obesity and hypertension are associated with β2-adrenoceptor polymorphisms accompanying with heightened sympathetic nerve activity. In the present study we compared β2-adrenoceptor protein expression between buffy coats (white blood cells as a representive for whole-body) and abdominal subcutaneous fat to further evaluate the contributions of sympathetic nerve activity and β2-adrenoceptor to obesity and hypertension. Methods: In 17 obese normotensive Caucasian men (BMI≥30.0 kg/m2) and 8 age-matched lean Caucasian men (BMI<25 kg/m2), we measured BMI, blood pressure (BP), whole-body plasma norepinephrine (NE) spillover, NE clearance, plasma leptin, and β2-adrenoceptor protein concentration and leptin receptor protein concentration in buffy coats and in abdominal subcutaneous adipose tissue. The β2-adrenoceptor protein expression and leptin receptor protein expression were analysed by Western blotting. Results: Obese subjects had significantly higher whole-body NE spillover (673±245 ng/mL vs. 431±156, P<0.05), plasma leptin (15.2±4.3 ng/mL vs. 4.8±2.4, P<0.01), and BP levels (P<0.05) compared to lean subjects, but the whole-body NE clearance rate was similar. Obese subjects had significantly greater expression of β2-adrenoceptor protein in buffy coats (P<0.05) compared to lean subjects, while they had significantly less β2-adrenoceptor protein expression in abdominal fat (P<0.05). Leptin receptor protein expression in both buffy coats and abdominal fat were greater in obese subjects compared to lean subjects. Conclusions: Obese subjects had greater β2-adrenoceptor protein expression in buffy coats, but less β2-adrenoceptor protein expression in fat. This may suggest that blunted sympathetic nerve activity in adipose tissue (observed by less β2-adrenoceptor protein expression in fat) might relate to obesity and heightened sympathetic nerve activity in whole-body (observed by greater β2-adrenoceptor protein expression in buffy coats and higher NE spillover) may be linked to hypertension. The findings support the concept of selective leptin resistance. Sympathetic nerve activity and β2-adrenoceptor, not leptin, plays an important role is mechanisms of obesity and obesity-related hypertension.

Neurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea

1993 ◽  
Vol 74 (6) ◽  
pp. 2969-2975 ◽  
Author(s):  
B. J. Morgan ◽  
T. Denahan ◽  
T. J. Ebert
Keyword(s):  
Arterial Pressure ◽  
Sympathetic Nerve ◽  
Sleep Disordered Breathing ◽  
Sympathetic Nerve Activity ◽  
Intrathoracic Pressure ◽  
Sympathetic Activation ◽  
Nerve Activity ◽  
Primary Mechanism ◽  
Obstructive Sleep ◽  
Voluntary Apnea

To investigate the mechanisms responsible for fluctuations in arterial pressure and sympathetic nerve activity that occur during obstructive sleep apnea, we studied neurocirculatory responses to Mueller maneuvers and breath holds in conscious humans. During 20-s Mueller maneuvers at -40 mmHg, mean arterial pressure fell initially (-11 +/- 3 mmHg) and then rose above baseline (+8 +/- 3 mmHg) on release of the inspiratory strain. Sympathetic outflow to skeletal muscle was almost completely suppressed during the initial moments of the maneuver and rose to more than three times the baseline level at the termination of the maneuver. Simple 20-s breath holds were accompanied by time-dependent increases in both arterial pressure (+11 +/- 3 mmHg) and sympathetic nerve activity (> 3 times baseline). The administration of supplemental O2 greatly attenuated the increases in arterial pressure and sympathetic nerve activity during Mueller maneuvers and breath holds. We conclude that carotid chemoreflex stimulation is the primary mechanism responsible for apnea-induced sympathetic activation during wakefulness and that it may contribute importantly to the sympathetic activation that accompanies sleep-disordered breathing.

scholarly journals Different Responses of Muscle Sympathetic Nerve Activity to Dapagliflozin Between Patients With Type 2 Diabetes With and Without Heart Failure

2021 ◽  
Author(s):  
Takuto Hamaoka ◽  
Hisayoshi Murai ◽  
Tadayuki Hirai ◽  
Hiroyuki Sugimoto ◽  
Yusuke Mukai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Brain Natriuretic Peptide ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Nerve Activity ◽  
Sodium Glucose Cotransporter

Background Sodium‐glucose cotransporter 2 inhibitors improve cardiovascular outcomes in patients with diabetes with and without heart failure (HF). However, their influence on sympathetic nerve activity (SNA) remains unclear. The purpose of this study was to evaluate the effect of sodium‐glucose cotransporter 2 inhibitors on SNA and compare the responses of SNA to sodium‐glucose cotransporter 2 inhibitors in patients with type 2 diabetes with and without HF. Methods and Results Eighteen patients with type 2 diabetes, 10 with HF (65.4±3.68 years) and 8 without HF (63.3±3.62 years), were included. Muscle SNA (MSNA), heart rate, and blood pressure were recorded before and 12 weeks after administration of dapagliflozin (5 mg/day). Sympathetic and cardiovagal baroreflex sensitivity were simultaneously calculated. Brain natriuretic peptide level increased significantly at baseline in patients with HF than those without HF, while MSNA, blood pressure, and hemoglobin A1c did not differ between the 2 groups. Fasting blood glucose and homeostatic model assessment of insulin resistance did not change in either group after administering dapagliflozin. MSNA decreased significantly in both groups. However, the reduction in MSNA was significantly higher in patients with HF than patients with non‐HF (−20.2±3.46 versus −9.38±3.65 bursts/100 heartbeats; P =0.049), which was concordant with the decrease in brain natriuretic peptide. Conclusions Dapagliflozin significantly decreased MSNA in patients with type 2 diabetes regardless of its blood glucose‐lowering effect. Moreover, the reduction in MSNA was more prominent in patients with HF than in patients with non‐HF. These results indicate that the cardioprotective effects of sodium‐glucose cotransporter 2 inhibitors may, in part, be attributed to improved SNA.

scholarly journals Modulation of Sirt1 and FoxO1 on Hypothalamic Leptin‐Mediated Sympathetic Activation and Inflammation in Diet‐Induced Obese Rats

2021 ◽  
Author(s):  
Xuefei Liu ◽  
Hong Zheng
Keyword(s):  
Blood Pressure ◽  
Protein Kinase ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Immune Cell ◽  
Microglial Cells ◽  
Sympathetic Activation ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Blood Pressure Responses

Background Hypothalamic leptin‐mediated signaling contributes to the exaggerated sympatho‐excitation and increased blood pressure in obesity‐associated hypertension. The aim of the study was to investigate the roles of energy‐sensing enzyme sirtuin1 (Sirt1) and forkhead box protein O1 (FoxO1) on the hypothalamic leptin‐mediated high sympathetic nerve activity and inflammation in obesity. Methods and Results Sprague Dawley rats were fed with high‐fat diet (HFD) for 12 weeks. In vivo, the potential of Srit1 and FoxO1 in the sympathetic effects of leptin was investigated via siRNA injection to knockdown Sirt1 or FoxO1 gene in the arcuate nucleus (ARCN) of hypothalamus in rats. In vitro, the effects of Sirt1 or FoxO1 on leptin‐mediated inflammation were observed in proopiomelanocortin (POMC) and microglial cells. Knockdown Sirt1 by siRNA significantly reduced the renal sympathetic nerve activity (RSNA) and blood pressure responses to leptin injection in the ARCN in the HFD rats. Conversely, knockdown FoxO1 significantly enhanced the RSNA and blood pressure responses to leptin injection in the HFD rats. Knockdown Sirt1 reduced the levels of pro‐inflammatory cytokines interleukin 6 (IL‐6), tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β), C1q/TNF‐related protein‐1 (CTRP1), and immune cell infiltration in the ARCN in the HFD rats. Knockdown FoxO1 significantly increased the level of IL‐6 in the ARCN of HFD rats. In cultured hypothalamic POMC and microglial cells, knockdown Sirt1 significantly reduced leptin‐induced IL‐6 expression, affected the levels of AMP‐activated protein kinase (AMPK) and serine/threonine‐specific protein kinase (Akt). Knockdown FoxO1 significantly increased leptin‐induced IL‐6 in both POMC cells and microglial cells. Conclusions These data suggest that both Sirt1 and FoxO1 are the key modulators of leptin signaling in the hypothalamus contributed to the over sympathetic activation and inflammation in obesity.

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