Sympathetic Nerve Activity Responses Research Articles

Central nervous system regulation of brown adipose tissue.

Thermogenesis, the production of heat energy, in brown adipose tissue is a significant component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature in many species from mouse to man and plays a key role in elevating body temperature during the febrile response to infection. The sympathetic neural outflow determining brown adipose tissue (BAT) thermogenesis is regulated by neural networks in the CNS which increase BAT sympathetic nerve activity in response to cutaneous and deep body thermoreceptor signals. Many behavioral states, including wakefulness, immunologic responses, and stress, are characterized by elevations in core body temperature to which central command-driven BAT activation makes a significant contribution. Since energy consumption during BAT thermogenesis involves oxidation of lipid and glucose fuel molecules, the CNS network driving cold-defensive and behavioral state-related BAT activation is strongly influenced by signals reflecting the short- and long-term availability of the fuel molecules essential for BAT metabolism and, in turn, the regulation of BAT thermogenesis in response to metabolic signals can contribute to energy balance, regulation of body adipose stores and glucose utilization. This review summarizes our understanding of the functional organization and neurochemical influences within the CNS networks that modulate the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolic alterations in BAT thermogenesis and BAT energy expenditure that contribute to overall energy homeostasis and the autonomic support of behavior.

Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation.

Energy expenditure is determined by metabolic rate and diet-induced thermogenesis. Normally, energy expenditure increases due to neural mechanisms that sense plasma levels of ingested nutrients/hormones and reflexively increase sympathetic nerve activity (SNA). Here, we investigated neural mechanisms of glucose-driven sympathetic activation by determining contributions of neuronal activity in the hypothalamic paraventricular nucleus (PVN) and activation of corticotropin-releasing factor (CRF) receptors in the rostral ventrolateral medulla (RVLM). Glucose was infused intravenously (150 mg/kg, 10 min) in male rats to raise plasma glucose concentration to a physiological postprandial level. In conscious rats, glucose infusion activated CRF-containing PVN neurons and TH-containing RVLM neurons, as indexed by c-Fos immunofluorescence. In α-chloralose/urethane-anesthetized rats, glucose infusion increased lumbar and splanchnic SNA, which was nearly prevented by prior RVLM injection of the CRF receptor antagonist astressin (10 pmol/50 nl). This cannot be attributed to a nonspecific effect, as sciatic afferent stimulation increased SNA and ABP equivalently in astressin- and aCSF-injected rats. Glucose-stimulated sympathoexcitation was largely reversed during inhibition of PVN neuronal activity with the GABA-A receptor agonist muscimol (100 pmol/50 nl). The effects of astressin to prevent glucose-stimulated sympathetic activation appear to be specific to interruption of PVN drive to RVLM because RVLM injection of astressin prior to glucose infusion effectively prevented SNA from rising and prevented any fall of SNA in response to acute PVN inhibition with muscimol. These findings suggest that activation of SNA, and thus energy expenditure, by glucose is initiated by activation of CRF receptors in RVLM by descending inputs from PVN.

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

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.

Abstract 272: Divergent Neural Control of Blood Pressure vs Resting Metabolic Rate by Angiotensin: The Role of AT 1A Signaling in Leptin-Sensitive Cells

The renin-angiotensin system (RAS) and leptin both contribute to resting metabolic rate (RMR) and blood pressure control, and thus may contribute to obesity-hypertension. Previously we demonstrated a required role for angiotensin AT 1A receptors in the brain in RMR, and renal and sympathetic nerve activity (SNA) responses to leptin. Here we tested the hypothesis that AT 1A receptors, specifically localized to leptin-sensitive cells, are required for the blood pressure and RMR effects of brain ANG. The AT 1A gene was conditionally disrupted in cells that express the long (b) form of the leptin receptor (ObRb-Cre x AT 1A flox mice; “KO”), and blood pressure was assessed by radiotelemetry under baseline and deoxycorticosterone (DOCA)-salt stimulated conditions. While 24-hr blood pressure (MAP; control n=10, 115 ± 4, vs KO n=9, 115 ± 6 mmHg) and heart rate (control n=10, 561 ± 9, vs KO 563 ± 11 BPM) were not different between control and KO mice, baroreflex sensitivity was significantly increased in KO mice at baseline (control n=6, 3.4 ± 0.7, vs KO n=6, 5.6 ± 0.5 msec/mmHg, P<0.05). DOCA-salt significantly increased MAP (control=8, 130 ± 4, vs KO n=7, 129 ± 3) and decreased baroreflex sensitivity (control=6, 3.0 ± 0.5, vs KO n=5, 2.8 ± 0.5, P<0.05 vs baseline) in all mice. In contrast, RMR responses to DOCA-salt were abolished in KO mice (baseline n=2, 0.2 ± 0.01, vs DOCA-salt n=2, 0.2 ± 0.02). We conclude that AT 1A signaling specifically in leptin-sensitive cells is critically involved in RMR control, but is relatively dispensable for cardiovascular control. To further characterize the cells that mediate the leptin-AT 1A interaction critical for RMR control, we performed immunohistochemical staining for adrenocorticotropin (ACTH) in the arcuate nucleus of mice that express GFP via the AT 1A promoter (“NZ44”). Complete lack of colocalization supports the conclusion that AT 1A are not expressed by proopiomelanocortin (POMC) neurons. In contrast, KO mice exhibit a baseline increase in glutamate decarboxylase mRNA in the arcuate nucleus, consistent with a possible localization of AT 1A upon agouti related peptide (AgRP) neurons. AT 1A may therefore suppress AgRP neuron γ-aminobutyric acid production and thus disinhibit POMC neuronal activity, to ultimately stimulate RMR.

Abstract 080: Selective Knockout of the Intracellular Isoform of Renin in the Brain Contributes to Metabolic and Cardiovascular Control

Renin gene expression is regulated by two distinct promoter-first exon combinations that target renin for either secretion (exon 1a initiating secreted renin, sREN) or for cytoplasmic retention (exon 1b initiating intracellular renin, icREN). The icREN isoform is expressed predominantly in the brain and its expression is downregulated whereas sREN expression is upregulated by deoxycorticosterone (DOCA)-salt suggesting each isoform may be differentially regulated. We generated mice that lack icREN, but preserve sREN, by flanking exon-1b and its surrounding sequences (including the promoter) with loxP sites and breeding successively with mice expressing flipase and cre-recombinase. Real time quantitative RT-PCR analysis revealed a loss of icREN mRNA in the brain, but a preservation of sREN mRNA in the kidney. Total body weight was normal in male icREN-KO mice (26.3±0.7 g, n=8, 12 wk) compared to controls (25.3±0.7 g, n=12, 12 wk), but total (2.14±0.09 g vs 2.46±0.11 g) and relative (9.0±0.5 % vs 10.7±0.6%) fat mass as measured by NMR were reduced in 8-week icREN-KO mice (n=14-16, P<0.05). Whereas food intake was normal, there was an increase in resting metabolic rate as measured by respirometry in icREN-KO (0.1484±0.0036 kcal/hr, n=41, P=0.02 by ANCOVA) vs controls (0.1389±0.0038 kcal/hr, n=38). There was also a trend toward decreased digestive efficiency (81.1±1.0%, n=6, P=0.06) vs controls (84.9±1.2%, n=3) at 22 wk of age. Systolic blood pressure was decreased in icREN-KO mice (113±1 mmHg, n=12, 17.0±1.2 wk vs 120±3 mmHg, n=5, 15.9±1.9 wk, P<0.05). We previously reported a functional link between the synthesis and action of angiotensin-II and the action of leptin. We tested if this was impaired in icREN-KO mice by measuring the renal sympathetic nerve activity (RSNA) response to acute intracerebroventricular (ICV) administration of leptin. The decrease in arterial pressure was confirmed in this cohort of icREN-KO mice. Surprisingly, the RSNA response to leptin was greater in icREN-KO mice compared to controls (257.9±16.0%, n=3 vs 157.0±13.9%, n=4, 4 hr after leptin, P=0.01). Captopril attenuated the sympathetic response to ICV leptin. Together these data suggest that this novel icREN isoform contributes to metabolic and cardiovascular control.

Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity.

It has been established that vagal nerve stimulation (VNS) benefits patients and/or animals with heart failure. However, the impact of VNS on sympathetic nerve activity (SNA) remains unknown. In this study, we investigated how vagal afferent stimulation (AVNS) impacts baroreflex control of SNA. In 12 anesthetized Sprague–Dawley rats, we controlled the pressure in isolated bilateral carotid sinuses (CSP), and measured splanchnic SNA and arterial pressure (AP). Under a constant CSP, increasing the voltage of AVNS dose dependently decreased SNA and AP. The averaged maximal inhibition of SNA was ‐28.0 ± 10.3%. To evaluate the dynamic impacts of AVNS on SNA, we performed random AVNS using binary white noise sequences, and identified the transfer function from AVNS to SNA and that from SNA to AP. We also identified transfer functions of the native baroreflex from CSP to SNA (neural arc) and from SNA to AP (peripheral arc). The transfer function from AVNS to SNA strikingly resembled the baroreflex neural arc and the transfer functions of SNA to AP were indistinguishable whether we perturbed ANVS or CSP, indicating that they likely share common central and peripheral neural mechanisms. To examine the impact of AVNS on baroreflex, we changed CSP stepwise and measured SNA and AP responses with or without AVNS. AVNS resets the sigmoidal neural arc downward, but did not affect the linear peripheral arc. In conclusion, AVNS resets the baroreflex neural arc and induces sympathoinhibition in the same manner as the control of SNA and AP by the native baroreflex.

Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct.

Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensinII type1 receptor (AT1R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT1Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β1-adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno-associated virus carrying small interfering RNA against either MR (AAV-MR-siRNA) or AT1R (AAV-AT1R-siRNA), or as control scrambled siRNA. At 4weeks post MI, AT1R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end-diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and dP/dtmax decreased. AAV-MR-siRNA and AAV-AT1R-siRNA both normalized AT1R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and dP/dtmax as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250mgkg(-1)day(-1) in the drinking water for 4weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR-dependent upregulation of AT1Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR-AT1R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β1 blockade.

Acute cyclooxygenase inhibition does not alter muscle sympathetic nerve activity or forearm vasodilator responsiveness in lean and obese adults.

Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation and decreased vasodilator responsiveness. We hypothesized that obese individuals would have greater indices of inflammation compared with lean controls, and that cyclooxygenase inhibition using ibuprofen would reduce muscle sympathetic nerve activity (MSNA) and increase forearm blood flow in these subjects. We measured MSNA, inflammatory biomarkers (C‐reactive protein [CRP] and Interleukin‐6 [IL‐6]), and forearm vasodilator responses to brachial artery acetylcholine and sodium nitroprusside in 13 men and women (7 lean; 6 obese) on two separate study days: control (CON) and after 800 mg ibuprofen (IBU). CRP (1.7 ± 0.4 vs. 0.6 ± 0.3 mg/L; P < 0.05) and IL‐6 (4.1 ± 1.5 vs. 1.0 ± 0.1pg/mL; P < 0.05) were higher in the obese group during CON and tended to decrease with IBU (IL‐6: P < 0.05; CRP: P = 0.14). MSNA was not different between groups during CON (26 ± 4 bursts/100 heart beats (lean) versus 26 ± 4 bursts/100 heart beats (obese); P = 0.50) or IBU (25 ± 4 bursts/100 heart beats (lean) versus 30 ± 5 bursts/100 heart beats (obese); P = 0.25), and was not altered by IBU. Forearm vasodilator responses were unaffected by IBU in both groups. In summary, an acute dose of ibuprofen did not alter sympathetic nerve activity or forearm blood flow responses in healthy obese individuals, suggesting that the cyclooxygenase pathway is not a major contributor to these variables in this group.

Dietary salt intake exaggerates sympathetic reflexes and increases blood pressure variability in normotensive rats.

Previous studies have reported that chronic increases in dietary salt intake enhance sympathetic nerve activity and arterial blood pressure (ABP) responses evoked from brain stem nuclei of normotensive, salt-resistant rats. The purpose of the present study was to determine whether this sensitization results in exaggerated sympathetic nerve activity and ABP responses during activation of various cardiovascular reflexes and also increases ABP variability. Male Sprague-Dawley rats were fed 0.1% NaCl chow (low), 0.5% NaCl chow (medium), 4.0% NaCl chow (high) for 14 to 17 days. Then, the animals were prepared for recordings of lumbar, renal, and splanchnic sympathetic nerve activity and ABP. The level of dietary salt intake directly correlated with the magnitude of sympathetic nerve activity and ABP responses to electrical stimulation of sciatic afferents or intracerebroventricular infusion of 0.6 mol/L or 1.0 mol/L NaCl. Similarly, there was a direct correlation between the level of dietary salt intake and the sympathoinhibitory responses produced by acute volume expansion and stimulation of the aortic depressor nerve or cervical vagal afferents. In contrast, dietary salt intake did not affect the sympathetic and ABP responses to chemoreflex activation produced by hypoxia or hypercapnia. Chronic lesion of the anteroventral third ventricle region eliminated the ability of dietary salt intake to modulate these cardiovascular reflexes. Finally, rats chronically instrumented with telemetry units indicate that increased dietary salt intake elevated blood pressure variability but not mean ABP. These findings indicate that dietary salt intake works through the forebrain hypothalamus to modulate various centrally mediated cardiovascular reflexes and increase blood pressure variability.

Cardiac sympathetic afferent reflex response to intermedin microinjection into paraventricular nucleus is mediated by nitric oxide and γ-amino butyric acid in hypertensive rats.

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) and involves in the regulation of cardiovascular function in both peripheral tissues and central nervous system (CNS). Paraventricular nucleus (PVN) of hypothalamus is an important site in the control of cardiac sympathetic afferent reflex (CSAR) which participates in sympathetic over-excitation of hypertension. The aim of this study is to investigate whether IMD in the PVN is involved in the inhibition of CSAR and its related mechanism in hypertension. Rats were subjected to two-kidney one-clip (2K1C) surgery to induce renovascular hypertension or sham-operation (Sham). Acute experiments were carried out four weeks later under anesthesia. The CSAR was evaluated with the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to the epicardial application of capsaicin. The RSNA and MAP were recorded in sinoaortic-denervated, cervical-vagotomized and anesthetized rats. Bilateral PVN microinjection of IMD (25 pmol) caused greater decrease in the CSAR in 2K1C rats than in Sham rats, which was prevented by pretreatment with adrenomedullin (AM) receptor antagonist AM22-52, non-selective nitric oxide (NO) synthase (NOS) inhibitor L-NAME or γ-amino butyric acid (GABA)B receptor blocker CGP-35348. PVN pretreatment with CGRP receptor antagonist CGRP8-37 or GABA(A) receptor blocker gabazine had no significant effect on the CSAR response to IMD. AM22-52, L-NAME and CGP-35348 in the PVN could increase CSAR in Sham and 2K1C rats. These data indicate that IMD in the PVN inhibits CSAR via AM receptor, and both NO and GABA in the PVN involve in the effect of IMD on CSAR in Sham and renovascular hypertensive rats.

The role of TNF‐α in femoral artery occlusion‐augmented autonomic responsiveness (1132.6)

Prior studies demonstrated that metabolically sensitive receptors in thin‐fiber muscle afferents contribute to the amplified responses of sympathetic nerve activity and arterial blood pressure observed in rats with femoral artery occlusion (24‐72 hrs). The purpose of this study was to examine the role played by TNF‐α in augmented sympathetic responsiveness induced by stimulation of muscle metabolic receptors following 72 hrs of femoral artery occlusion. First, the results of this study show that the levels of TNF‐α are increased in dorsal root ganglion (DRG) neurons of limbs with 72 hrs of femoral artery occlusion. Second, protein expression of TNF‐α is dominantly observed within DRG neuron supply C‐fiber muscle afferent nerves and TNF‐α receptor type 1 (TNFR1) is largely identified in DRG compared with TNFR2. Third, TNF‐α synthesis suppressor pentoxifylline (PTX) administered previously into the hindlimb muscles significantly attenuates sympathetic and blood pressure responses induced by arterial injection of capsaicin into the hindlimb muscles. Capsaicin was applied to stimulate metabolically sensitive receptors in thin‐fiber muscle afferents nerves. Overall, our data suggest that TNF‐α plays a role in modulating augmented sympathetic responsiveness via metabolic receptors of thin fiber muscle afferent nerves when arterial blood supply to the hindlimb is deficient under ischemic conditions.Grant Funding Source: NIH P01 HL096570 and AHA EIA 0840130N

Chronic effects of obstructive apnea on renal and lumbar sympathetic nerve activity in conscious rats (857.3)

This study investigated responses of renal (RSNA) and lumbar sympathetic nerve activity (LSNA) of rats to repeated obstructive apnea over 4 days. Wistar male rats were chronically instrumented for measurements of RSNA, LSNA, and oxygen saturation of the brain tissue, and a tracheal balloon for induction of apnea was implanted. At least 3 days after the surgery, the rats were subjected to obstructive apnea by inflating the tracheal balloon for 40 seconds. This process was repeated 6 times/hour for 5 hours/day over a 4‐day period. The basal level of RSNA increased gradually and significantly throughout the 4‐day experimental period. The magnitude of the LSNA increase was less than that of RSNA. The basal levels of arterial pressure and heart rate remained within the normal ranges throughout the experimental period. These data suggest that repeated obstructive apnea activates RSNA in a cumulative manner, which may in part explain the underlying mechanism for development of hypertension in sleep apnea syndrome. JSPS Grant.

Salt loading increases the muscle sympathetic nerve activity response to upright tilt: a pilot study (1170.3)

Increased sodium intake reduces resting muscle sympathetic nerve activity (MSNA). We hypothesized that the increase in MSNA during upright tilt would be greater following a high sodium (HS) diet compared to a low sodium (LS) diet. Six healthy women (40±6[SD]yrs) were tested following a 7 day HS (5750mgNa+/day) and 7 day LS diet (1150mgNa+/day) in randomized order during the mid‐luteal phase. Blood pressures (BP, SunTech), heart rate (HR, ECG), cardiac output (Qc, C2H2 rebreathing) and MSNA (microneurography) were measured at rest, 30o and 60o head‐up tilt. Stroke volume (SV) and total peripheral resistance (TPR) were calculated. BP was similar at supine and 30o but higher at 60o following the HS when compared to LS diet. HR, Qc, SV and TPR were similar following each diet. Supine MSNA burst frequency and burst incidence (BI) respectively were lower following the HS (13±8 bursts.min‐1, 22±13 bursts.100beats‐1) than the LS diet (22±10 bursts.min‐1, 36±18 bursts.100beats‐1). The increase in BI from baseline to 60o was greater after the HS (28±4 bursts.100beats‐1) than the LS diet (22±11 bursts.100beats‐1). These preliminary results suggest a HS diet may enhance the MSNA response and increase BP during orthostasis in healthy women. This could be due to greater sympathetic vasoconstrictor reserve and/or alteration of the sympathetic baroreflex following the HS diet.

Reflex control of renal sympathetic nerve activity in heart failure is preserved in ovary intact female rats (1171.3)

Following myocardial infarction (MI), pathological increases in sympathetic nerve activity (SNA) drive the development and progression of heart failure. The current study investigated the effects of female sex and ovarian hormones on arterial baroreflex and cardiac sympathetic afferent reflex (CSAR) control over renal SNA in MI‐induced heart failure. 6 weeks post MI or sham surgery , arterial pressure and renal SNA responses were recorded in chloralose‐urethane anesthetized male, female and ovariectomized female (OVX) rats. In male and OVX MI groups, arterial baroreflex control of renal SNA was significantly impaired compared to shams, due mostly to an impaired ability to inhibit SNA. In ovary‐intact females, arterial baroreflex control of renal SNA was unaltered in MI animals compared to sham. CSAR mediated increases in renal SNA were significantly augmented in male and OVX MI groups when compared to ovary‐intact female MI group. The current study is the first to describe a protective effect of ovarian hormones on reflex control of SNA in MI‐induced heart failure.Grant Funding Source: Lottery Health New Zealand and University of Auckland Faculty Research Development Fund

Cardiovascular responses to disinhibition of rostral ventrolateral medulla (RVLM) following unilateral RVLM blockade in sedentary or physically active, sinoaortic denervated rats (875.13)

The RVLM is a bilateral region in the brainstem important for sympathetic control of arterial pressure (AP). Although tonically active, both RVLMs receive strong γ‐amino‐butyric acid (GABA)‐mediated inhibition, due in part to tonic arterial baroreceptor input. Previous studies report that unilateral inhibition of the RVLM in sinoaortic denervated (SAD) rabbits leads to dramatic decreases in AP and sympathetic nerve activity (SNA), demonstrating the importance of the baroreflex to resting AP. Following SAD, a strong GABAergic input to RVLM persists and likely suppresses the activity of the RVLM in the absence of baroreceptor input. However, whether this inhibition is altered in sedentary (SED) and active conditions is unknown. The current study was aimed at testing the hypothesis that inhibition of one RVLM in SAD rats would result in enhanced non‐barosensitive GABAergic input in the remaining intact RVLM, and this input would be greater in the SEDs compared to the active rats (i.e., 12 weeks of chronic wheel running on average =WR ). In Inactin‐anesthetized SEDs (n=4) and WRs (n=4), AP and splanchnic SNA were recorded following surgical SAD. Following inhibition of one RVLM (muscimol 2mM, 90nl), bicuculline (5mM, 90nl) was microinjected into the contralateral RVLM. Preliminary data indicate that changes in mean AP appeared to be higher in the SEDs (∆60±12mmHg) compared to the WRs (∆44±15mmHg). Due to small sample size, however, we were unable to support our finding statistically. Splanchnic SNA responses between SEDs (∆52%±16) and WRs (∆49%±23) did not appear to differ. These preliminary data suggest that in the absence of baroreceptor input, MAP and SNA are significantly reduced due to strong non‐barosensitive GABAergic input to the intact RVLM. However, non‐barosensitive GABAergic input may be altered in response to sedentary and active conditions.Grant Funding Source: Supported by R01‐HL096787; R01‐ HL096787‐S1

Chronic vagal nerve stimulation improves baroreflex neural arc function in heart failure rats

We tested whether 6-wk vagal stimulation (VS) treatment improved open-loop baroreflex function in rats after myocardial infarction (MI). The following three groups of Sprague-Dawley rats were examined: normal control (NC, n = 9), MI with no treatment (MI-NT, n = 8), and MI treated with VS (MI-VS, n = 7). Under anesthesia, a stepwise input ranging from 60 to 180 mmHg was imposed on isolated carotid sinus baroreceptor regions, while the responses in splanchnic sympathetic nerve activity (SNA) and arterial pressure (AP) were measured. The response range of percent SNA was greater in the MI-VS than in the MI-NT group (63.8 ± 4.9% vs. 33.1 ± 3.8%, P < 0.01). The slope of the AP response to percent SNA was not different between the MI-VS and MI-NT groups (0.611 ± 0.076 vs. 0.781 ± 0.057 mmHg/%). The difference in the response range of AP between the MI-VS and MI-NT groups did not reach statistical significance (40.7 ± 6.2 vs. 26.4 ± 3.5 mmHg). In conclusion, the 6-wk VS treatment significantly improved the baroreflex control of SNA, but the effect was limited for the baroreflex total-loop function due to the lack of significant improvement in the AP response to percent SNA.

Coping with dehydration: sympathetic activation and regulation of glutamatergic transmission in the hypothalamic PVN

Autonomic and endocrine profiles of chronic hypertension and heart failure resemble those of acute dehydration. Importantly, all of these conditions are associated with exaggerated sympathetic nerve activity (SNA) driven by glutamatergic activation of the hypothalamic paraventricular nucleus (PVN). Here, studies sought to gain insight into mechanisms of disease by determining the role of PVN ionotropic glutamate receptors in supporting SNA and mean arterial pressure (MAP) during dehydration and by elucidating mechanisms regulating receptor activity. Blockade of PVN N-methyl-D-aspartate (NMDA) receptors reduced (P < 0.01) renal SNA and MAP in urethane-chloralose-anesthetized dehydrated (DH) (48 h water deprivation) rats, but had no effect in euhydrated (EH) controls. Blockade of PVN α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors had no effect in either group. NMDA in PVN caused dose-dependent increases of renal SNA and MAP in both groups, but the maximum agonist evoked response (Emax) of the renal SNA response was greater (P < 0.05) in DH rats. The latter was not explained by increased PVN expression of NMDA receptor NR1 subunit protein, increased PVN neuronal excitability, or decreased brain water content. Interestingly, PVN injection of the pan-specific excitatory amino acid transporter (EAAT) inhibitor DL-threo-β-benzyloxyaspartic acid produced smaller sympathoexcitatory and pressor responses in DH rats, which was associated with reduced glial expression of EAAT2 in PVN. Like chronic hypertension and heart failure, dehydration increases excitatory NMDA receptor tone in PVN. Reduced glial-mediated glutamate uptake was identified as a key contributing factor. Defective glutamate uptake in PVN could therefore be an important, but as yet unexplored, mechanism driving sympathetic hyperactivity in chronic cardiovascular diseases.

Neural-humoral responses during head-up tilt in healthy young white and black women

Young black women have higher prevalence of hypertension during pregnancy compared to white women, which may be attributable to differences in blood pressure (BP) regulation. We hypothesized that young normotensive black women would demonstrate augmented muscle sympathetic nerve activity (MSNA) and renal-adrenal responses to orthostasis. Fifteen white and ten black women (30 ± 4 vs. 32 ± 6 years; means ± SD) had haemodynamics and MSNA measured during baseline (BL), 30 and 60° head-up tilt (HUT), and recovery. Blood was drawn for catecholamines, direct renin, vasopressin, and aldosterone. BL brachial systolic BP (SBP: 107 ± 6 vs. 101 ± 9 mmHg) and diastolic BP (DBP: 62 ± 4 vs. 56 ± 7 mmHg) were higher in white women (both p < 0.05). Δ DBP (60° HUT-BL) was greater in black women compared to white (p < 0.05). Cardiac output and total peripheral resistance were similar between groups. MSNA burst frequency was higher in whites (BL: 16 ± 10 vs. 14 ± 9 bursts/min, main effect p < 0.05) and increased in both groups during HUT (60°: 39 ± 8 vs. 34 ± 13 bursts/min, p < 0.05 from BL). Noradrenaline was higher in white women during 60° HUT (60° HUT: 364 ± 102 vs. 267 ± 89 pg/ml, p < 0.05). Direct renin was higher and vasopressin and Δ aldosterone tended to be higher in blacks (BL, direct renin: 12.1 ± 5.0 vs. 14.4 ± 3.7 pg/ml, p < 0.05; BL, vasopressin: 0.4 ± 0.0 vs. 1.6 ± 3.6 pg/ml, p = 0.065; Δ aldosterone: −0.9 ± 5.1 vs. 3.8 ± 7.5 ng/ml; p = 0.069). These results suggest that young normotensive white women may rely on sympathetic neural activity more so than black women who have a tendency to rely on the renal-adrenal system to regulate BP during an orthostatic stress.

Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney

Hypertonic NaCl infused into the carotid arteries increases mean arterial pressure (MAP) and changes sympathetic nerve activity (SNA) via cerebral mechanisms. We hypothesized that elevated sodium levels in the blood supply to the brain would induce differential responses in renal and cardiac SNA via sensors located outside the blood-brain barrier. To investigate this hypothesis, we measured renal and cardiac SNA simultaneously in conscious sheep during intracarotid infusions of NaCl (1.2 M), sorbitol (2.4 M), or urea (2.4 M) at 1 ml/min for 4 min into each carotid. Intracarotid NaCl significantly increased MAP (91 ± 2 to 97 ± 3 mmHg, P < 0.05) without changing heart rate (HR). Intracarotid NaCl was associated with no change in cardiac SNA (11 ± 5.0%), but a significant inhibition of renal SNA (-32.5 ± 6.4%, P < 0.05). Neither intracarotid sorbitol nor urea changed MAP, HR, central venous pressure, cardiac SNA, and renal SNA. The changes in MAP and renal SNA were completely abolished by microinjection of the GABA agonist muscimol (5 mM, 500 nl each side) into the paraventricular nucleus of the hypothalamus (PVN). Infusion of intracarotid NaCl for 20 min stimulated a larger increase in water intake (1,100 ± 75 ml) than intracarotid sorbitol (683 ± 125 ml) or intracarotid urea (0 ml). These results demonstrate that acute increases in blood sodium levels cause a decrease in renal SNA, but no change in cardiac SNA in conscious sheep. These effects are mediated by cerebral sensors located outside the blood-brain barrier that are more responsive to changes in sodium concentration than osmolality. The renal sympathoinhibitory effects of sodium are mediated via a pathway that synapses in the PVN.

Sympathetic nerve activity and peripheral vasodilator capacity in young and older men

Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 μg·100 ml(-1)·min(-1); Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men (P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP (r = -0.83 and r = -0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.