Changes In Sympathetic Nerve Activity Research Articles

Acute hypernatremia increases functional connectivity of NaCl sensing regions in the human brain: An fMRI pilot study

Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies.

Vagal nerve and sympathetic nerve activity in response to glucagon-like peptide-1 (GLP-1) receptor stimulation in conscious rats

GLP-1 (Glucagon-Like Peptide-1) is a type of gastrointestinal hormone that plays an integral role in regulating glucose homeostasis and appetite control. GLP-1 receptors are expressed throughout the body, and it has been suggested that GLP-1 can be detected by vagal afferent nerve activity, leading to changes in sympathetic nerve activity. However, the details of the effects of GLP-1 receptor stimulation on autonomic nerve activity have not been reported. Therefore, this study investigated the effects of different sites of GLP-1 receptor stimulation on autonomic nerve activity by administering GLP-1 receptor agonists via three routes: intravenous (IV), intraportal vein (iport), and intraperitoneal (iperi). Male Wistar rats were chronically implanted with electrodes, catheters for measuring cervical vagal activity, renal and lumbar sympathetic nerve activity, electroencephalogram, electromyogram, electrocardiogram, arterial pressure, sensors for tissue fluid glucose concentration, and catheters for drug administration in the vein, portal vein, and abdominal cavity. Exendin-4, a GLP-1 receptor agonist, was administered to conscious rats via one of the following routes: intravenous, intra-portal vein, or intra-abdominal. Cervical vagal activity was increased in all routes of Exendin-4 administration. Renal sympathetic nerve activity was rapidly decreased by Exendin-4 administration and gradually recovered to pre-administration levels. There were no significant differences in renal sympathetic nerve activity among the different routes of Exendin-4 administration. On the other hand, lumbar sympathetic nerve activity increased slowly after Exendin-4 administration through the iperi and iport routes, while it decreased initially, then gradually increased following administration through the IV route. These results demonstrate that stimulation of GLP-1 receptors by Exendin-4 increases vagal nerve activity, decreases renal sympathetic nerve activity, and produces regionally different responses in lumbar sympathetic nerve activity depending on the site of stimulation. JST (JPMJMS2023). 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.

Impact of vericiguat on baroreflex-mediated sympathetic circulatory regulation: An open-loop analysis.

To quantify in vivo the effects of the soluble guanylate cyclase (sGC) stimulator, vericiguat, on autonomic cardiovascular regulation in comparison with the nitric oxide (NO) donor, sodium nitroprusside. In anesthetized Wistar-Kyoto rats, baroreflex-mediated changes in sympathetic nerve activity (SNA), arterial pressure (AP), central venous pressure (CVP), and aortic flow (AoF) were examined before and during the intravenous continuous administration (10 μg·kg-1·min-1) of vericiguat or sodium nitroprusside (n = 8 each). Systemic vascular resistance (SVR) was calculated as SVR = (AP-CVP) / AoF. Neither vericiguat nor sodium nitroprusside affected fitted parameters of the baroreflex-mediated SNA response. Both vericiguat and sodium nitroprusside decreased the AP mainly through their peripheral effects. Vericiguat halved the slope of the SNA-SVR relationship from 0.012 ± 0.002 to 0.006 ± 0.002 mmHg·min·mL-1·%-1 (P = 0.008), whereas sodium nitroprusside caused a near parallel downward shift in the SNA-SVR relationship with a reduction of the SVR intercept from 1.235 ± 0.187 to 0.851 ± 0.123 mmHg·min/mL (P = 0.008). Neither vericiguat nor sodium nitroprusside significantly affected the baroreflex-mediated SNA response. The vasodilative effect of vericiguat became greater toward high levels of SNA and AP, possibly reflecting the increased sGC sensitivity to endogenous NO. By contrast, the effect of sodium nitroprusside was more uniform over the range of SNA. These results help better understand cardiovascular effects of vericiguat.

Exaggerated renal sympathetic nerve and pressor responses during spontaneously occurring motor activity in hypertensive rats.

Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

Impact of neurally mediated antidiuretic effect relative to pressure diuresis during acute changes in sympathetic nerve activity.

We examined urine excretion during primary acute sympathetic activation (PASA) in anesthetized Wistar-Kyoto rats. Since arterial pressure (AP) changes with sympathetic nerve activity (SNA) during PASA, urine excretion reflects a neurally mediated antidiuretic effect combined with an effect of pressure diuresis. We hypothesized that preventing AP changes under PASA would enable the direct estimation of the neurally mediated antidiuretic effect alone. We changed the isolated carotid sinus pressure stepwise from 60 to 180 mmHg and compared the relationship of normalized urine flow (nUF, urine flow normalized by body weight) versus SNA between conditions allowing and preventing baroreflex-mediated changes in the mean AP. The slope of the SNA-nUF relationship was [Formula: see text]nUFvar = 0.444 ± 0.074 μL·min-1·kg-1·%-1 when the mean AP was variable, whereas it was [Formula: see text]nUFfix = -0.143 ± 0.032 μL·min-1·kg-1·%-1 when the mean AP was fixed at 100 mmHg (n = 7 rats). The slope associated with the effect of pressure diuresis alone, calculated as [Formula: see text]nUFvar - [Formula: see text]nUFfix, was 0.586 ± 0.105 μL·min-1·kg-1·%-1. Hence, the potency of the neurally mediated antidiuretic effect |[Formula: see text]nUFfix|/([Formula: see text]nUFvar - [Formula: see text]nUFfix) was 0.235 ± 0.014 relative to the effect of pressure diuresis under PASA. Our findings would aid an integrative understanding of the effects of renal hemodynamic and sympathetic modulations on urine output function.

Simultaneous measurement of central amygdala neuronal activity and sympathetic nerve activity during daily activities in rats.

What is the central question of this study? The functional relationships between central amygdala neuronal activity (CeANA) and sympathetic nerve activity in daily activities remain unclear. We aimed to measure CeANA, renal and lumbar sympathetic nerve activity (RSNA and LSNA, respectively), heart rate (HR) and arterial pressure simultaneously in freely moving rats. What is the main finding and its importance? The CeANA was significantly related to RSNA and LSNA and HR in a behavioural state-dependent and regionally different manner; meanwhile, CeANA was tightly associated with RSNA and HR across all behavioural states. Thus, it is likely that the amygdala is a component of neural networks generating regional differences in RSNA and LSNA. The central amygdala (CeA) is involved in generating diverse changes in sympathetic nerve activity (SNA) in response to changes in daily behavioural states. However, the functional relationships between CeA neuronal activity (CeANA) and SNA in daily activities are still unclear. In the present study, we developed a method for simultaneous and continuous measurement of CeANA and SNA in freely moving rats. Wistar rats were chronically instrumented with multiple electrodes (100-μm-thick stainless-steel wire) for the measurement of CeANA, renal SNA (RSNA) and lumbar SNA (LSNA), and electroencephalogram, EMG and ECG electrodes, in addition to catheters for measurement of arterial pressure (AP). During the transition from non-rapid eye movement sleep to quiet wakefulness, moving and grooming states, a significant linear relationship was observed between CeANA and RSNA (P<0.0001), between CeANA and LSNA (P =0.0309), between CeANA and heart rate (HR) (P=0.0123) and between CeANA and EMG (P =0.0089), but no significant correlation was observed between CeANA and AP (P =0.5139). During rapid eye movement sleep, the relationships between CeANA and RSNA, LSNA, HR, AP and EMG deviated from the previously observed linear relationships, but the time course of RSNA and HR changes was the mirror image of that of CeANA, whereas the time course of changes in LSNA and AP was not related to that of CeANA. In conclusion, CeANA was related to RSNA, LSNA and HR in a behavioural state-dependent and regionally different manner, and CeANA was tightly associated with RSNA and HR across all behavioural states.

The activation of C1 neurons during REM sleep is dependent on the arterial baroreflex

IntroductionNatural sleep‐wake patterns are associated with changes in sympathetic nerve activity (SNA) controlling cardiovascular function. The mechanisms underlying the effects of sleep‐wake state on SNA are not well understood. C1 neurons in the rostral ventrolateral medulla regulate cardiovascular function through SNA and mediate the sympathetic arterial baroreflex. In this study we determine the effect of sleep‐wake transitions on the activity of C1 neurons and investigate the contribution of the arterial baroreflex to these effects.MethodsThe activity of C1 neurons was measured using fiber photometry (calcium imaging) in freely behaving adult rats while monitoring the vigilance states. C1 neurons were targeted with GCaMP7s by microinjection of AAV1‐syn‐FLEX‐jGCaMP7s in the RVLM of Tyrosine Hydroxylase‐Cre transgenic rats, an optical fiber was implanted above the injection site, rats were fitted with a EEG/EMG head stage to monitor sleep‐wake state, and a radio telemetry probe to record BP. One month after the surgery, C1 neuron activity was recorded before and 7 days after sino‐aortic denervation to eliminate inputs from arterial baroreflex. Normalized fluorescence changes are expressed as Z‐score (mean ± SD) and t‐test was used to determine statistically significant differences.ResultsC1 activity was increased by acute hypotension induced by sodium nitroprusside (2.1 ± 0.5 vs. ‐0.92 ± 0.4, p&lt;0.0001, n=5), indicating the barosensitive nature of the recorded cells. C1 activity increased during transitions from NREM to wake (‐0.60 ± 0.1 vs. 0.59 ± 0.2, p&lt;0.0001, n=6) and decreased during transitions from wake to NREM (0.34 ± 0.2 vs. ‐0.32 ± 0.2, p&lt;0.0001, n=6). C1 activity increased during transitions from NREM to REM sleep (‐0.74 ± 0.1 vs. 0.77 ± 0.1, p&lt;0.0001, n=6) and decreased in transitions from REM to wake (0.58 ± 0.2 vs. ‐0.59 ± 0.2, p&lt;0.0001, n=5). Baroreceptor denervation attenuates the increase in C1 neuron activity during REM sleep (0.4 ± 0.7 vs1.8 ± 0.4 Δ Z‐score, p=0.0054, n=4) and during wakefulness (0.59 ±0.6 vs 1.6 ± 0.4, p=0.0210, n=4) when compared to the increase before sino‐aortic denervation.ConclusionC1 neuron activity during sleep‐wake transitions mirrors the pattern of SNA. This observation indicates that C1 neurons contribute to changes in SNA associated with natural sleep‐wake patterns. Baroreceptor denervation attenuates the change in C1 activity observed during transitions to REM, indicating that the feedback from the arterial baroreflex contributes to the elevation in C1 activity in this sleep state.

Acute Hypernatremia Increases Functional Connectivity of Sodium Sensing Regions in the Brain

Rodent studies have identified specialized sodium chloride (NaCl)‐sensing neurons in the circumventricular organs (CVOs), which mediate NaCl‐induced changes in sympathetic nerve activity, arginine vasopressin (AVP), thirst, and blood pressure (BP). In humans, acute hypernatremia has been shown to increase sympathetic nerve activity, AVP, thirst and BP. However, few human studies have investigated the network of NaCl sensing regions of the brain using functional magnetic resonance imaging (fMRI).ObjectiveTo determine how the functional connectivity of sodium sensing regions of the brain change during an acute hypernatremic perturbation.MethodsResting‐state fMRI was performed on 9 healthy young adults (29±4 yrs, 5M) at baseline and during a 30 min 3% NaCl intravenous infusion at a rate of 0.15 ml/kg/min. Venous blood samples and perceived thirst (Likert scale, cm) were obtained before and immediately following the infusion. Serum electrolytes, plasma osmolality, hematocrit, and hemoglobin were assessed. Beat‐to‐beat blood pressure was measured continuously. Seed‐based voxel‐wise functional connectivity analysis was performed in AFNI using spherical seeds placed bilaterally in the subfornical organ (SFO), the organum vasculosum lamina terminalis (OVLT) as well as cortical sensory regions such as the insula. Functional connectivity was compared at baseline vs. early infusion (min 0‐15) and baseline vs. late infusion (min 16‐30) at p &lt; 0.01, corrected for multiple comparisons with 3dClustSim.ResultsThirst (∆1.9±2.0 cm), serum sodium (∆3.2±2.1 mmol/L), and plasma osmolality (∆6.9±4.7 mOsm/kg H2O) all increased from baseline to post‐infusion (p&lt;0.05). Head motion was minimal and did not change throughout the stages of the infusion (mean motion = 0.11±0.10 mm, p&gt;0.80). Hypertonic saline infusion increased local functional connectivity between the SFO and OVLT (Z score baseline=0.07±0.01, Z score late phase=0.17+0.01, p&lt;0.01). A similar increase in functional connectivity was seen between the insula and somatosensory cortex.ConclusionAcute hypernatremia increases local functional connectivity within the CVOs and between cortical sensory regions of the brain.

Involvement of Neuropeptide Y within Paraventricular Nucleus in Electroacupuncture Inhibiting Sympathetic Activities in Hypertensive Rats.

Although electroacupuncture (EA) has been used to decrease the blood pressure (BP) clinically, the underlying mechanisms are not clearly clarified. This study aimed to assess the hypothesis that EA treatment exerts a hypotensive action via suppressing sympathetic activities and modulating neuropeptide Y (NPY) function within the paraventricular nucleus (PVN) of hypertensive rats. Male Sprague-Dawley rats were selected for the experiment, and the hypertensive models were established by the two-kidney, one-clip (2K1C) method. Then, the rats were randomly assigned to the sham group, 2K1C group, 2K1C plus EA group, and 2K1C plus sham EA group. EA treatment at the acupoints ST36 and ST40 overlying the peroneal nerves was given once a day for 30 days. The radiotelemetry system was applied to collect the arterial BP recordings. Power spectral analyses of BP variability, BP responses to ganglionic blockade, and plasma levels of norepinephrine and epinephrine were performed to assess the changes in sympathetic nerve activity. Real-time PCR and Western blots were carried out to examine the expression of NPY system in the PVN. The responses of PVN microinjection with NPY Y1R antagonist BIBO3304 were detected to check the endogenous NPY tone. The results showed that the enhanced arterial BP and sympathetic activities were effectively reduced by 30 days of EA treatment, and baroreflex sensitivity was improved in 2K1C hypertensive rats. The level of NPY mRNA and protein expression in the PVN was markedly upregulated by EA treatment in 2K1C rats. In addition, the pressor responses of PVN microinjection with NPY Y1R antagonist BIBO3304 in 2K1C models were remarkably augmented by the EA stimulation. Our results indicate that the increased NPY expression and function in the PVN induced by EA treatment contribute to antihypertensive and sympathetic suppression on hypertensive rats. The findings may elucidate the underlying mechanisms of the acupuncture to be a potential therapeutic strategy against hypertension.

Changes in sympathetic nerve activity and arterial pressure regulation induced by exercise

Changes in sympathetic nerve activity and arterial pressure regulation induced by exercise

Sympathetic nerve activity changes following acute exposures to electronic and tobacco cigarette smoking in humans

Abstract Background/Introduction Tobacco cigarette (TC) smoking acutely increases blood pressure and sympathetic nerve activity, whereas there are scarce data on the impact of electronic cigarette (EC). Purpose The aim of the study was to assess the acute effects of TC, EC and sham smoking on blood pressure, heart rate and sympathetic nervous system in healthy subjects. Methods We studied 12 normotensive male habitual smokers (mean age 33 years) free of cardiovascular disease. The study design was randomized and placebo controlled with 3 experimental sessions (sham smoking, tobacco cigarette smoking, and e-cigarette smoking) in random order, each session on a separate day. Subjects smoked 2 tobacco cigarettes containing 1.1 mg nicotine or simulate smoking (sham smoking) with the 2 cigarettes separated by 5 minutes. Additionally, participants smoked e-cigarettes for a period of 5 and 30 minutes. In all occasions, sympathetic drive was assessed by muscle sympathetic nerve activity (MSNA) (baroreflex-dependent) and skin sympathetic nerve activity (SSNA) (baroreflex-independent) based on established methodology (microneurography). Results After the first and second TC smoking, there was significant increase in mean arterial pressure (MAP) (by 6 and 8 mmHg, respectively, overall p&amp;lt;0.001) and heart rate (by 8 and 12 beats/minute, respectively, overall p&amp;lt;0.001) compared to baseline. Similarly, EC smoking at 5 and 30 minutes compared to baseline was accompanied by augmentation of MAP (by 6 and 10 mmHg, respectively, overall p&amp;lt;0.001) and heart rate (by 5 and 9 beats/minute, respectively, overall p&amp;lt;0.001). Sham smoking was accompanied by a reduction in MAP after the first and second cigarette compared to baseline (by 2 and 4 mmHg, respectively, p=0.001), whereas there was no significant difference in heart rate (p=NS). The first and second TC smoking was characterized by lower muscle MSNA (by 6 and 6 bursts/minute, respectively, overall p&amp;lt;0.001) compared to baseline, whereas SSNA was increased (by 9 and 10 bursts/minute respectively, overall p&amp;lt;0.001). Additionally, EC smoking at 5 and 30 minutes caused a decrease in MSNA (by 8 and 8 bursts/minute, respectively, overall p&amp;lt;0.00) and an augmentation in SSNA (by 7 and 9 bursts per minute, respectively, overall p&amp;lt;0.001) compared to baseline. Sham smoking had no significant effect on MSNA and SSNA (p=NS for both). Conclusions Sympathetic, pressor and heart rate unfavorable responses to EC smoking are similar to those elicited by TC in healthy subjects. Our findings provide novel insights into the negative impact of EC on cardiovascular system and support opinions recommending great caution concerning EC use. Funding Acknowledgement Type of funding sources: None.

The Role of Social Context in Physiological and Psychological Restoration in a Forest: Case Study of a Guided Forest Therapy Program in Taiwan.

Existing studies have demonstrated the restorative benefits of being in forests. However, most studies have designed participants to engage individually in forest walking and viewing, which neglects the social aspect of conversation. Researchers suggested that social context should be studied in order to have a better understanding how forests foster human health. To this end, we examined the role of social context using three types of forest therapy programs: a guided program, a self-guided program, and a walk alone program. A between-subject, pretest–posttest field experimental design was employed to evaluate restorative effects by measuring the physiological responses and mood states incurred in different forest therapy programs. Our findings showed, that the walk alone group exhibited a significant systolic blood pressure decrease and a significant increase in sympathetic nervous activity; the self-guided group showed a significant increase in heart rate values and significant decreases in systolic blood pressure and diastolic blood pressure; and the guided group revealed a significant decrease in systolic blood pressure. Further, the three forest therapy programs had positive effects on improving mood states, except a nonsignificant vigor–activity increase in the walk alone group. The three programs did not exhibit significant differences in changes of restorative benefits in physiological and psychological measures except for a significant difference in changes in sympathetic nervous activity between the walk alone group and guided group. The results showed the restorative benefits of forest therapy are apparent regardless of the program type. The management team should continue promoting forest therapy for public health by providing different types of forest therapy programs and experiences.

Differential shifts in baroreflex control of renal and lumbar sympathetic nerve activity induced by freezing behaviour in rats.

What is the central question of this study? Is the arterial baroreflex involved in causing patterned, region-specific changes in sympathetic nerve activity during freezing behaviour in conscious rats? What is the main finding and its importance? Freezing behaviour is accompanied by differential shifts in the baroreflex control of renal and lumbar sympathetic nerve activity and heart rate. It is noteworthy that baroreflex pathways may be discretely separated, allowing differential modification of baroreflex curves that may generate differential changes in sympathetic nerve activity during freezing behaviour. The present study was designed to test whether the baroreflex stimulus-response curves for renal sympathetic nerve activity (RSNA), lumbar sympathetic nerve activity (LSNA) and heart rate (HR) were shifted in a regionally specific manner during freezing behaviour in conscious rats. Male Wistar rats were chronically instrumented with electrodes and arterial and venous catheters for measurement of RSNA, LSNA and electrocardiogram. After a 60-min control period, freezing behaviour in conscious rats was induced by exposure to loud white noise (90dB) for 10 min. The baroreflex curves for RSNA, LSNA and HR were generated by changing systemic arterial pressure using rapid intravenous infusions of vasoactive drugs and then fitted to an inverse sigmoid function curve. During the freezing behaviour, the baroreflex curve for RSNA was expanded upward with a significant (P<0.001) increase (by 153% compared with the control level) in the upper plateau (maximum capacity of RSNA drive), whereas the baroreflex curve for LSNA remained unchanged. Conversely, the baroreflex curve for HR was shifted leftward with a significant (P=0.004) decrease (by 11mmHg relative to the control level) in the midpoint pressure. Our results indicate that baroreflex curve shifts for RSNA, LSNA and HR occur in a regionally specific manner during freezing behaviour. This indicates that baroreflex pathways may be discretely separated, allowing differential modification of baroreflex curves that may generate differential changes in sympathetic nerve activity during freezing behaviour.

The inflammatory cytokine, interleukin‐1‐beta, drives central immune cell infiltration, changes in sympathetic nerve activity and blood pressure

IntroductionThe area postrema (AP) is a brain region that lacks a blood brain barrier allowing blood‐borne factors to access the brain. Since the AP is connected to numerous brain regions that play a key role blood pressure regulation, we hypothesised that blood‐borne inflammatory factors such as interleukin‐1 beta (IL‐1β) might play a role in the development of hypertension. In support of this hypothesis, plasma Interleukin‐1 beta is increased in hypertensive patients (Dalekos et al., 1997, J Lab Clin Med,129: 300–8). Furthermore, the receptors for IL‐1β are abundantly expressed in the AP. Here we test whether IL‐1β can act on the AP to cause an increase in blood pressure and renal sympathetic nerve activity (RSNA) in rats.MethodsBlood pressure and renal sympathetic nerve activity (RSNA) were recorded and analyzed after microinjection of different doses of IL‐1β into the AP (10ng and 25ng) of anaesthetised rats. In order to show that IL‐1β, specifically causes an increase in blood pressure, specific IL‐1 receptor blocking antibodies (IL‐1Ra) were injected into the AP prior to a 25ng IL‐1β injection. The AP was extracted for fluorescent activated cell sorting (FACS).ResultsExperiments showed that microinjection of 25ng IL‐1β caused a significant (p&lt;0.01; Mann‐Whitney test) increase in both systolic blood pressure (19.6 ± 3.6 mmHg) and heart rate (55 ±10 bpm) compared with control injections of saline (SBP: 5.47 ± 1.58; HR 12 ± 6). Pre‐treatment with IL‐1Ra attenuated the response to IL‐1β, and was comparable with saline controls. IL‐1β also caused an increase in RSNA (137% ± 43%) and FACS revealed an increase in immune cell infiltration. Immunohistochemistry also revealed that IL‐1β injection results in Fos activation in the AP.ConclusionsIL‐1β injection appears to activate neurons in the area postrema which leads to an increase in blood pressure. By providing new insight into the actions of IL‐1β in the brain, we show that IL‐1β might be a potential target for future treatments for hypertension.Support or Funding InformationAustralian Research Council (FT170100363)National Health and Medical Research Council (GNT 1079680)Rebecca L Cooper Medical Research Foundation

P4388Acute detrimental effects of e-cigarette and tobacco cigarette smoking on blood pressure and sympathetic nerve activity in healthy subjects

Abstract Background/Introduction Tobacco cigarette smoking is related with atherosclerosis progression, blood pressure increase and changes in sympathetic nerve activity. However, there are scarce data on the impact of e-cigarettes that have been proposed as less harmful alternatives on the cardiovascular system and sympathetic drive. Purpose This study aimed to assess the acute effects of tobacco cigarettes, e-cigarettes and sham smoking on blood pressure and sympathetic nervous system in healthy subjects. Methods We studied 10 normotensive male habitual smokers (mean age 33 years, body mass index: 24.1 kg/m2, office blood pressure=117/72 mmHg) free of cardiovascular disease. The study design was randomized and placebo controlled with 3 experimental sessions (sham smoking, tobacco cigarette smoking, and e-cigarette smoking) in random order, each session on a separate day. Subjects smoked 2 tobacco cigarettes containing 1.1 mg nicotine or simulate smoking (sham smoking) with the 2 cigarettes separated by 5 minutes, while 45 minutes after finishing the second cigarette, subjects smoked a third cigarette or sham cigarette. Additionally, participants smoked e-cigarettes for a period of 5 and 30 minutes. In all occasions, sympathetic drive was assessed by muscle sympathetic nerve activity (MSNA) (baroreflex-dependent) and skin sympathetic nerve activity (SSNA) (baroreflex-independent) based on established methodology (microneurography). Results After the first, second and third tobacco cigarette smoking there was markedly and significantly increase in mean arterial pressure (by 11.2±1.4%, 12.3±1.3% and 13.1±1.4%, respectively, p&lt;0.05 for all) and heart rate (by 25.1±3.7%, 26.3±2.7% and 25.9±3.7%, respectively, p&lt;0.05 for all). Similarly e-cigarette smoking at 5 and 30 minutes was accompanied by augmentation of mean arterial pressure (by 10.9±1.2% and 12.8±1.4%, respectively, p&lt;0.05 for both) and heart rate (by 22.5±3.3% and 23.9±3.8%, respectively, p&lt;0.05 for both). Regarding the effect on sympathetic nervous system, the first, second and third tobacco cigarette smoking was accompanied by lower MSNA (by 28.1±4.4%, 29.6±5.3% and 30.1±5.2%, respectively, p&lt;0.05 for all), whereas SSNA was increased (by 98.2±19.4%, 100.2±22.7% and 101.5±21.6%, respectively, p&lt;0.05 for all). Additionally, e-cigarette smoking at 5 and 30 minutes caused a decrease in MSNA (by 26.9±3.6%, and 28.3±5.1%, respectively, p&lt;0.05 for both), and an augmentation in SSNA (by 97.9±20.1% and 100.9±20.6%, respectively, p&lt;0.05 for both). Sham smoking was devoid of any effects on blood pressure, MSNA and SSNA. Conclusions E-cigarette smoking acutely increases blood pressure and has a detrimental effect on sympathetic nerve activity regulation similar to tobacco smoking in healthy subjects. Our findings underscore the negative impact of e-cigarettes on cardiovascular and autonomic nervous system and could aid further recommendation in their use.

Effects of the Trier Social Stress Test on the distributions of IL-6 and MAP levels

Trier Social Stress Test (TSST) is an experimental psychological test that induces changes in autonomic, endocrinological and immunological activity. Two measures used to evaluate the inflammatory activity induced by this test are the interleukin 6 (IL-6), a cytokine sensitive to changes in sympathetic nervous activity, and the mean arterial pressure (MAP), a measure sensitive to changes in autonomic activity. This study had two goals: first, the study examined whether TSST increases IL-6 and MAP levels; second, pre- and post-TSST IL-6 levels were compared for participants whose IL-6 levels increased or decreased due to the TSST. Saliva samples of IL-6 and MAP were taken from 42 participants clinically healthy, without psychiatric history, and data were analysed via quantile comparisons. The results showed that TSST did not lead to an increase in sympathetic activity as indexed by IL-6. Instead, TSST led to increases in MAP. Also, there were significant differences between the IL-6 distributions of people whose IL-6 levels changed from low to high (63%) and from high to low (37%) before and after the TSST. These findings suggest that the TSST will not have the same effect on all participants; that is, individual differences can be assessed using a biomarker to identify people with specialized psychological care needs.

Unaltered neurocardiovascular reactions to mental stress after renal sympathetic denervation

ABSTRACTBackground: The impact of renal denervation (RDN) on muscle sympathetic nerve activity (MSNA) at rest remains controversial. Mental stress (MS) induces transient changes in sympathetic nerve activity, heart rate (HR) and blood pressure (BP). It is not known whether RDN modifies these changes.Purpose: The main objective was to assess the effect of RDN on MSNA and BP alterations during MS.Methods: In 14 patients (11 included in analysis) with resistant hypertension multi-unit MSNA, BP (Finometer ®) and HR were assessed at rest and during forced arithmetics at baseline and 6 months after RDN.Results: Systolic office BP decreased significantly 6 months after RDN (185 ± 29 vs.175 ± 33 mmHG; p = 0.04). No significant changes in MSNA at rest (68 ± 5 vs 73 ± 5 bursts/100hb; p = 0.43) were noted and no significant stress-induced change in group averaged sympathetic activity was found pre- (101 ± 24%; p = 0.9) or post-intervention (108 ± 26%; p = 0.37). Stress was associated with significant increases in mean arterial BP (p < 0.01) and HR (p < 0.01) at baseline, reactions which remained unaltered after intervention. We did not note any correlation between sympathetic nerve activity and BP changes after RDN.Conclusion: Thus, in our group of resistant hypertensives we find no support for the hypothesis that the BP-lowering effect of RDN depends on altered neurovascular responses to stress.

Acute effects of intravenous carvedilol versus metoprolol on baroreflex-mediated sympathetic circulatory regulation in rats

AimsTo compare the effects of metoprolol and carvedilol on baroreflex-mediated sympathetic circulatory regulation. MethodsIn anesthetized Wistar–Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in sympathetic nerve activity (SNA), arterial pressure (AP), heart rate (HR), and aortic flow (AoF) in response to a staircase-wise pressure input were examined before (control) and after intravenous injection of low-dose metoprolol (2 mg/kg), high-dose metoprolol (10 mg/kg), or carvedilol (0.67 mg/kg) (n = 6 each). Peripheral vascular resistance (PVR) was calculated from mean AP divided by mean AoF. ResultsLow-dose metoprolol had limited effect on sympathetic AP regulation compared to control [operating-point AP (drug vs. control): 88.7 ± 7.1 vs. 98.3 ± 3.3 mm Hg, not significant] despite a significant bradycardic effect. Although high-dose metoprolol showed central sympathoinhibition, it increased PVR at a given SNA as a peripheral effect. Consequently, high-dose metoprolol decreased the operating-point AP slightly (96.1 ± 2.7 vs. 101.9 ± 2.7 mm Hg, P < 0.01). Carvedilol showed no significant central sympathoinhibition at the dose examined in this study, but significantly reduced PVR at a given SNA, leading to a marked reduction in the operating-point AP (71.9 ± 8.2 vs. 112.6 ± 7.6 mm Hg, P < 0.05). ConclusionLow-dose metoprolol has limited hypotensive effect despite blockade of sympathetic HR regulation. Although high-dose metoprolol induces central sympathoinhibition, it also induces peripheral vasoconstriction that antagonizes the hypotensive effect. In contrast, carvedilol exhibits hypotensive effect mainly through peripheral vasodilation. Although carvedilol is frequently classified as a β-blocker, its vasodilatory effect via α1-adrenergic blockade plays an important role in AP reduction or heart failure treatment.

Effects of Feeding-Related Peptides on Neuronal Oscillation in the Ventromedial Hypothalamus.

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic nervous system. The VMH also expresses various receptors of the peptides related to feeding. However, it is not well-understood whether the action of feeding-related peptides mediates the activity of glucose-sensing neurons in the VMH. In the present study, we examined the effects of feeding-related peptides on the burst-generating property of the VMH. Superfusion with insulin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, and orexin increased the frequency of the VMH oscillation. In contrast, superfusion with leptin, cholecystokinin, cocaine- and amphetamine-regulated transcript, galanin, ghrelin, and neuropeptide Y decreased the frequency of the oscillation. Our findings indicated that the frequency changes of VMH oscillation in response to the application of feeding-related peptides showed a tendency similar to changes of sympathetic nerve activity in response to the application of these substances to the brain.

Hypertensive Young Adult Female Obese Zucker Rats (OZR) Do not Develop the Impaired Baroreflexes or Reduced Activation of the NTS Observed in Male OZR

Obese Zucker rats (OZR) have dysfunctional leptin receptors, which fosters excess food intake and the development of metabolic syndrome in comparison to lean Zucker rats (LZR) with functional leptin receptors. Adult male OZR and female OZR have excess weight gain, hyperinsulinemia, and hypertension compared to same sex, age‐matched LZR. Adult male OZR have also have blunted baroreflexes that emerge with the development of impaired activation the nucleus tractus solitarius (NTS). In contrast, female OZR do not have blunted baroreflexes at this age (12–14 weeks). This study determined whether fully functional baroreflexes in female OZR corresponded with a sustained ability to activate the NTS in comparison to age‐matched female LZR. Rats were instrumented with indwelling catheters run through a tether and swivel to measure mean arterial pressure (MAP) and heart rate (HR) through a femoral artery and infusion of drugs through a femoral vein while the rats were conscious and undisturbed. As expected, female OZR had elevated MAP compared to female LZR (135 ± 2 vs. 121 ± 2 mmHg in 9 OZR and 7 LZR, P&lt;0.05), as observed in male rats (127± 2 vs. 115 ± 3 mmHg in 13 OZR and 10 LZR, P&lt;0.05). Infusion of phenylephrine (PE) to raise MAP by 40 mmHg evoked the expected blunted bradycardia in male OZR (−52 ± 9 vs. −101 ± 9 bpm in 11 OZR and 10 LZR, P&lt;0.05), whereas responses in female rats were comparable (−111 ± 13 vs. −129 ± 20 bpm in 9 OZR and 7 LZR). Likewise, PE‐induced c‐Fos expression in NTS was reduced in these male OZR compared to LZR (121 ± 18 and 199 ± 21 counts in P&lt;0.05; bilateral counts of NTS at bregma levels −14.2, −13.8, −13.2, and −13.0 mm), but PE‐induced c‐Fos expression in NTS was comparable in female OZR and LZR (311 ± 38 and 390 ± 32 counts). At the age when impaired baroreflex‐mediated changes in sympathetic nerve activity begin to emerge in male OZR (in gain, but not yet in range), the NTS appeared to undergo dramatic neuroplasticity. Male OZR displayed a surge of ΔFosB expression in the NTS at 7–8 weeks of age (375 ± 59 vs. 146 ± 13 counts 4 OZR and 5 LZR, P&lt;0.05), and this difference persisted into adulthood (132 ± 12 vs. 64 ± 10 counts in 6 OZR and 7 LZR, P&lt;0.05). In 7–8 week old female OZR, this surge in ΔFosB expression in the NTS is absent (82 ± 13 and 56 ± 14 counts in 5 OZR and 4 LZR), with little change at 11–12 weeks of age (102 ± 8 and 68 ± 14 counts 5 OZR and 5 LZR). These data suggest that the preservation of NTS function in hypertensive, young adult female OZR with metabolic syndrome may underlie their sustained ability to respond to acute changes in MAP. The surge of ΔFosB expression in NTS of juvenile male OZR but not female OZR may provide important clues for mechanisms underlying the vulnerability of male OZR to the development of impaired NTS function and baroreflexes. These data also highlight the likelihood of differing mechanisms for the development of hypertension and impaired control of MAP by baroreflexes in the setting of metabolic syndrome. Further study is needed determine phenotypes of these NTS neurons, which attributes of metabolic syndrome alter NTS neuronal function and baroreflexes, and how female OZR are protected from these changes despite the development of other attributes of metabolic syndrome.Support or Funding InformationAHA GRNT18880005 to AMS, PRE27260088 to PC