Baseline Sympathetic Activity Research Articles

Sex differences in sympathetic activity and pulse wave velocity in adults with chronic kidney disease.

Chronic kidney disease (CKD) is characterized by sympathetic nervous system (SNS) overactivity that contributes to increased vascular stiffness and cardiovascular risk. Although it is well established that SNS activity and vascular stiffness are substantially elevated in CKD, whether sex differences in autonomic and vascular function exist in CKD remains unknown. We tested the hypothesis that compared with females, males with CKD have higher baseline sympathetic activity that is related to increased arterial stiffness. One hundred twenty-nine participants (96 males and 33 females) with CKD stages III and IV were recruited and enrolled. During two separate study visits, vascular stiffness was assessed by measuring carotid-to-femoral pulse wave velocity (cfPWV), and resting muscle sympathetic nerve activity (MSNA) was measured by microneurography. Males with CKD had higher resting MSNA compared with females with CKD (68 ± 16 vs. 55 ± 14 bursts/100 heart beats, P = 0.005), whereas there was no difference in cfPWV between the groups (P = 0.248). Resting MSNA was not associated with cfPWV in both males and females. In conclusion, males with CKD have higher resting sympathetic activity compared with females with CKD. However, there was no difference in vascular stiffness between the sexes. There was no correlation between resting MSNA and cfPWV, suggesting that non-neural mechanisms may play a greater role in the progression of vascular stiffness in CKD, particularly in females.NEW & NOTEWORTHY Males with chronic kidney disease (CKD) have higher resting muscle sympathetic nerve activity (MSNA) compared with females. There was no correlation between MSNA and carotid-to-femoral pulse wave velocity (cfPWV), suggesting that non-neural mechanisms may play a greater role in the progression of vascular stiffness in CKD. Sex differences in SNS activity may play a mechanistic role in observations from epidemiological studies suggesting greater cardiovascular risk in males compared with females with CKD.

Sex differences in arterial stiffness and sympathetic activity in older CKD patients

Chronic kidney disease (CKD) is characterized by sympathetic nervous system overactivity that contributes to increased arterial stiffness and cardiovascular risk. While premenopausal females are relatively protected from cardiovascular disease in healthy individuals, older postmenopausal females without kidney disease have similar degrees of sympathetic overactivity, vascular stiffness and cardiovascular risk compared to older age-matched males in the general population. However, in the CKD population, cardiovascular mortality risk remains higher in older males compared to age-matched females and whether sex differences in neural and vascular function exist in older CKD patients is unknown. Therefore, we tested the hypothesis that compared to older females, older males with CKD have higher baseline sympathetic activity that is related to increased arterial stiffness. In 207 CKD patients (N=90 females, 62 ± 9 years; and N=117 males, 60 ± 9 years), we measured resting sympathetic nerve activity directed to muscle (MSNA) by microneurography at the peroneal nerve. At a separate visit, arterial stiffness was determined by carotid-to-femoral pulse wave velocity (PWV) using transcutaneous Doppler flow velocity (SphygmoCor®). Office blood pressure (BP) and 24-hour ambulatory BP monitoring (ABPM; Spacelabs) were performed using standard techniques. Resting MSNA was higher in males versus females with CKD (43 ± 10 vs 31 ± 14 bursts/min; p= 0.039). Both office and 24-hour ambulatory diastolic BP (79 ± 11 vs 67 ± 14 mmHg, p<0.001) and mean arterial pressure (96 ± 10 vs 88 ± 13 mmHg, p<0.001) were also higher in males versus females. PWV was not different between male and female groups (p= 0.157). There was no association between PWV and resting MSNA in males, while in females, there was an inverse relationship between PWV and MSNA burst frequency (r2=0.271; p=0.039) and burst incidence (r2=0.310; p=0.025). Older male CKD patients have higher resting MSNA, office and ambulatory BP compared to older females with CKD. In contrast, there were no differences in arterial stiffness measured as PWV between sexes. In males, increased MSNA was not associated with increased arterial stiffness, while MSNA was negatively correlated with PWV in females. Sex differences in neural and vascular function may impact cardiovascular outcomes in older patients with CKD. Supported by NIH grants R01HL135183, R33AT010457. This is the full abstract presented at the American Physiology Summit 2023 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.

Neurogenic Background for Emotional Stress-Associated Hypertension.

The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals. The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressureand even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases. The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.

Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

This study aimed to determine how transcutaneous vagus nerve stimulation (tVNS) alters autonomic nervous activity by comparing the effects of different tVNS frequencies and current intensities. We also investigated the sex-dependent autonomic response to tVNS. Thirty-five healthy adult participants were stimulated using a tVNS stimulator at the left cymba conchae while sitting on a reclining chair; tVNS-induced waveform changes were then recorded for different stimulus frequencies (Experiment 1: 3.0 mA at 100 Hz, 25 Hz, 10 Hz, 1 Hz, and 0 Hz (no stimulation)) and current intensities (Experiment 2: 100 Hz at 3.0 mA, 1.0 mA, 0.2 mA (below sensory threshold), and 0 mA (no stimulation)) using an electrocardiogram. Pulse widths were set at 250 µs in both experiment 1 and 2. Changes in heart rate (HR), root-mean-square of the difference between two successive R waves (RMSSD), and the ratio between low-frequency (LF) (0.04–0.15 Hz) and high-frequency (HF) (0.15–0.40 Hz) bands (LF/HF) in spectral analysis, which indicates sympathetic and parasympathetic activity, respectively, in heart rate variability (HRV), were recorded for analysis. Although stimulation at all frequencies significantly reduced HR (p = 0.001), stimulation at 100 Hz had the most pronounced effect (p = 0.001) in Experiment 1 and was revealed to be required to deliver at 3.0 mA in Experiment 2 (p = 0.003). Additionally, participants with higher baseline sympathetic activity experienced higher parasympathetic response during stimulation, and sex differences may exist in the autonomic responses by the application of tVNS. Therefore, our findings suggest that optimal autonomic changes induced by tVNS to the left cymba conchae vary depending on stimulating parameters and sex.

Elevated Activity of the Sympathetic Nervous System Is Related to Diminished Practice Effects in Memory: A Pilot Study.

Background:Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load.Objective:In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects.Methods:Thirty cognitively healthy individuals aged 40–70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance.Results:Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners.Conclusion:These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline.

Relation of interleukin-17 and high-sensitivity C-reactive proteins with sympathetic reactivity in pre-hypertensive young adult

Objectives: Recent studies have shown that both innate and adaptive immunity response contributes to vascular dysfunction by vascular remodelling and later hypertension. Furthermore, the sympathetic activity mediates the vascular dysfunction through pro-inflammatory activity of immune system. In context to insidious onset hypertension, the study was planned to observe the association of immunity with the increased sympathetic activity in pre-hypertensive adults. Materials and Methods: Thirty healthy pre-hypertensive (as per JNC VII) non-smokers, non-alcoholic and non-obese male adults volunteers were recruited from the study area. Equal numbers of normotensive controls were taken for comparison. On reporting day, they were subjected to the recording of demographic and anthropometric measurements, hand grip dynamometry and later investigated for serum levels of interleukin-17 (IL-17) and high-sensitivity C-reactive proteins (hsCRP) after written informed consent. The data collected were analysed for differences in mean and association of immune and inflammatory markers with sympathetic activity by statistical tests. Results: Significantly higher values of weight, BMI, % BF, visceral fat, resting heart rate and IL-17 and a lower sympathetic reactivity was observed in pre-hypertensive subjects. Values of hsCRP was higher in prehypertensive but was not statistically significant.. IL-17 was a positive significant predictor with 4.7 times (P = 0.02) increase in odds of being pre-hypertensive, whereas sympathetic reactivity was a significant negative predictor (OR = 0.75; P = 0.001). SBP and DBP are both related negatively and significantly (P < 0.05) to the sympathetic reactivity suggesting that blood pressure is related to sympathetic nervous system. Furthermore, the hsCRP is observed to be related positively to the % BF and to only SBP and RHR, complimenting link of adiposity as an inflammatory process to blood pressure. IL-17 levels in blood are observed to be positively and significantly related to DBP. Conclusion: Elevated IL-17 levels are significant predictor of pre-hypertension along with lower sympathetic reactivity. No direct association was observed between IL-17 and sympathetic system except with raised DBP. Immune mechanism is part of pathogenesis of increased blood pressure in pre-hypertensive with enhanced baseline sympathetic activity.

Theory and history of the study of muscle sympathetic nerve activity

Heart failure is a rapidly growing epidemic in developed countries. It has been well documented that heart failure is associated with abnormal neurohumoral activation. The autonomic regulation is characterized by decreased parasympathetic and elevated sympathetic activity. While the cardiovagal activity could be easily assessed by various heart rate variability parameters, markers of the sympathetic activity are not readily available. Percutaneous insertion of microelectrodes in a peripheral nerve allows recording of the muscle sympathetic vasomotor nerve activity (MSNA). MSNA shows good correlation with the cardiac sympathetic activity, and also with the levels of circulating catecholamines. Besides determination of the baseline sympathetic activity, rapid sympathetic responses to various stimuli can be also described by changes of MSNA. Elevated MSNA has been documented in several diseases, including hypertension, obesity, myocardial ischemia and renal failure. In heart failure, the elevated MSNA is well correlated to the clinical severity of the patient's conditions, and serves as a prognostic marker of mortality. In our paper, we give a short account of the history of MSNA studies, describe its physiological background and clinical relevance with special regard to heart failure. Orv Hetil. 2020; 161(29): 1190-1199.

Centrally acting adrenomedullin in the long-term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats.

What is the central question of this study? Adrenomedullin in the rostral ventrolateral medulla (RVLM) increases sympathetic activity; given that adrenomedullin is released during hypoxia, what are the effects of its agonism and antagonism in the RVLM after chronic intermitent hypoxia (CIH) exposure? What is the main finding and its importance? CIH exposure sensitizes adrenomedullin-dependent mechanisms in the RVLM, supporting its role as a sympathoexcitatory neuromodulator. A novel mechanism was identified for the generation of sympathetic overdrive and hypertension associated with hypoxia, providing potential guidance on new therapeutic approaches for controlling sympathetic hyperactivity in diseases such as sleep apnoea and neurogenic hypertension. Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50-55g) submitted to CIH (6% oxygen every 9min, 8hday-1 for 10 days) were studied in an arterially perfused in situ preparation where sympathetic activity was recorded. In control rats (n=6), exogenously applied adrenomedullin in the RVLM raised baseline sympathetic activity when combined with episodic activation of peripheral chemoreceptors (KCN 0.05%, 5 times every 5min). This sympathoexcitatory response was markedly amplified in rats previously exposed to CIH (n=6). The antagonism of adrenomedullin receptors in the RVLM caused a significant reduction in sympathetic activity in the CIH group (n=7), but not in controls (n=8). The transient reflex-evoked sympathoexcitatory response to peripheral chemoreceptor stimulation was not affected by either adrenomedullin or adrenomedullin receptor antagonism in the RVLM of control and CIH rats. Our findings indicate that CIH sensitizes the sympathoexcitatory networks within the RVLM to adrenomedullin, supporting its role as an excitatory neuromodulator when intermittent hypoxia is present. These data reveal novel state-dependent mechanistic insights into the generation of sympathetic overdrive and provide potential guidance on possible unique approaches for controlling sympathetic discharge in diseases such as sleep apnoea and neurogenic hypertension.

Sympathetic activation in chronic anxiety: not just at the "height" of stress. Editorial Focus on "Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety".

Sympathetic activation in chronic anxiety: not just at the "height" of stress. Editorial Focus on "Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety".

Short-Term Sustained Hypoxia Elevates Basal and Hypoxia-Induced Ventilation but Not the Carotid Body Chemoreceptor Activity in Rats.

Exposure to chronic sustained hypoxia (SH), as experienced in high altitudes, elicits an increase in ventilation, named ventilatory acclimatization to hypoxia (VAH). We previously showed that rats exposed to short-term (24 h) SH exhibit enhanced abdominal expiratory motor activity at rest, accompanied by augmented baseline sympathetic vasoconstrictor activity. In the present study, we investigated whether the respiratory and sympathetic changes elicited by short-term SH are accompanied by carotid body chemoreceptor sensitization. Juvenile male Holtzman rats (60–80 g) were exposed to SH (10% O2 for 24 h) or normoxia (control) to examine basal and hypoxic-induced ventilatory parameters in unanesthetized conditions, as well as the sensory response of carotid body chemoreceptors in artificially perfused in situ preparations. Under resting conditions (normoxia/normocapnia), SH rats (n = 12) exhibited higher baseline respiratory frequency, tidal volume, and minute ventilation compared to controls (n = 11, P < 0.05). SH group also showed greater hypoxia ventilatory response than control group (P < 0.05). The in situ preparations of SH rats (n = 8) exhibited augmented baseline expiratory and sympathetic activities under normocapnia, with additional bursts in abdominal and thoracic sympathetic nerves during late expiratory phase that were not seen in controls (n = 8, P < 0.05). Interestingly, basal and potassium cyanide-induced afferent activity of carotid sinus nerve (CSN) was similar between SH and control rats. Our findings indicate that the maintenance of elevated resting ventilation, baseline sympathetic overactivity, and enhanced ventilatory responses to hypoxia in rats exposed to 24 h of SH are not dependent on increased basal and sensorial activity of carotid body chemoreceptors.

Study of the effect of 61-point relaxation therapy in premenstrual syndrome

Background: Premenstrual syndrome (PMS) in a constellation of physical and emotional symptoms during a women’s menstrual cycle. PMS is most common in women between the age group of 25 and 45 years. The estimate is that 80% of women experience some type of premenstrual change during their reproductive period. The definite cause of PMS is still not identified, but several studies have proved that PMS is a stress-induced psychophysiological disorder and stress is a cause of the symptoms of PMS. Some simple stress-relieving exercises perform on a regular basis can bring a feeling of peace and calm. Aims and Objectives: This study aims to study the effect of 61-point relaxation (61-PR) therapy in PMS. Materials and Methods: The protocol was approved by the institutional ethical committee before starting the study. The study group consisted of 40 females suffering from PMS in the age group of 18–40 years, having regular menstrual cycles of 28–34 days. The study group was divided into two groups - Group A consisting of 20 subjects having no intervention and Group B also consists of 20 subjects performing 61-PR. Control group consisted of 30 healthy female subjects. An automated sphygmomanometer was used to record a baseline diastolic (DBP) and systolic blood pressure (SBP) from the right arm. An automated biofeedback apparatus Relax 701 was used to record heart rate (HR/min), galvanic skin response (GSR; kΏ), electromyogram (EMG; mV), respiratory rate (RR/min), and peripheral temperature (T;°F) simultaneously. The subjects in Group B performed 61-PR exercises. It was started 7 days before the due date of menstruation for 3 successive menstrual cycles. On the past day, the parameters were again recorded. Results: We observed SBP, DBP, HR, EMG, GSR, and RR in Group B showed a very significant reduction (P < 0.001) while T increased significantly (P < 0.001) in the 3rd menstrual cycle, on comparing with the baseline levels. In our study, the females with PMS showed decrease in the high baseline sympathetic activity. On comparing Group B with Group A, we found an increased relaxation response in Group B. Conclusion: In this study, the females with PMS showed a decrease in the high basal sympathetic activity and an increased relaxation response in Group B.

Altered cardiac gene expression of noradrenaline enzymes, transporter and β-adrenoceptors in rat model of rheumatoid arthritis.

Baseline sympathetic activity was found to be elevated in rheumatoid arthritis (RA) patients and it is related to increased cardiovascular risk in these patients. Although many studies have highlighted the association between RA and increased cardiac sympathetic activity, the underlying mechanistic links remain unclear. The aim of the present study was to understand how diseases-triggered changes in gene expression may result in maladaptive physiological changes. Our results suggest that the equilibrium between noradrenaline synthesis, release and reuptake was disrupted in the ventricles of arthritic rats. In the acute phase of the arthritic process, decreased gene expression of MAO-A might lead to accumulation of noradrenaline in myocardial interstitial space, whereas increased gene expression of NET protected cardiomyocytes from the deleterious effects of enhanced noradrenaline. During the chronic phase, reduced expression of β1-adrenoceptor and decreased efficiency of noradrenaline reuptake contribute to progressive damage of the myocardium and limits heart efficiency.

Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.

Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β‐adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β‐adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β‐blockade (AUCP ropranolol–AUCS aline, β‐REE) and as a percent (%) of control (AUCP ropranolol÷AUCS aline × 100). β‐REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β‐REE R = −0.58, P = 0.03; %REE R = −0.56, P = 0.04; NE: β‐REE R = −0.55, P = 0.0535; %REE R = −0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity.

Changes in the inspiratory pattern contribute to modulate the sympathetic activity in sino-aortic denervated rats.

What is the central question of this study? Sino-aortic denervated (SAD) rats present normal levels of sympathetic activity and mean arterial pressure. However, neural mechanisms regulating the sympathetic activity in the absence of arterial baroreceptors remain unclear. Considering that respiration modulates the sympathetic activity, we hypothesize that changes in the respiratory network contribute to keep the sympathetic outflow in the normal range after removal of arterial baroreceptors. What is the main finding and its importance? Despite longer inspiration observed in SAD rats, the respiratory-sympathetic coupling is working within a normal range of variation. These findings suggest that in the absence of arterial baroreceptors the respiratory modulation of sympathetic activity is maintained within the normal range. The activity of presympathetic neurons is under respiratory modulation, and changes in the central respiratory network may impact on the baseline sympathetic activity and mean arterial pressure. It is well known that after removal of baroreceptor afferents [sino-aortic denervation (SAD)], rats present an unexpected normal level of mean arterial pressure. We hypothesized that changes in the respiratory pattern and in the respiratory modulation of the sympathetic activity contribute to keep the sympathetic outflow within a normal range of variation in the absence of arterial baroreceptors in rats. To study these mechanisms, we recorded perfusion pressure and the activities of phrenic and thoracic sympathetic nerves in male juvenile rats using the working heart-brainstem preparation. The time of inspiration significantly increased in SAD rats, and this change was not dependent on the carotid bodies or on the vagal afferents. However, no changes were observed in the perfusion pressure or in the baseline thoracic sympathetic nerves in all phases of the respiratory cycle in SAD rats. Our data show that despite longer inspiratory activity, the baseline sympathetic activity is maintained at a normal level in SAD rats. These findings indicate that the respiratory-sympathetic coupling is normal after SAD and suggest that the respiratory modulation of sympathetic activity is maintained within the normal range after the removal of arterial baroreceptors.

Differential effects of renal denervation on arterial baroreceptor function in Goldblatt hypertension model.

Sympathetic vasomotor activity is significantly increased in renovascular hypertension. Renal denervation (DnX) has emerged as a novel therapy for resistant hypertension to drug therapy. However, the underlying mechanisms regarding the reduction in blood pressure (BP) after DnX remain unclear. Thus, the aim of this study was to evaluate the effects of DnX of a clipped kidney on the baseline and baroreceptor reflex control of post-ganglionic sympathetic activity to the contralateral kidney (rSNA) and lumbar (lSNA) nerves in Goldblatt hypertensive rats (2K1C). Renal denervation of an ischaemic kidney (DxX - all visible bundles of nerves were dissected - 10% phenol) was performed 5weeks after clipping (gap width: 0.2mm). Ten days after DnX, BP was significantly reduced (16%) in the 2K1C compared with the undenervated 2K1C (p<0.05). DnX significantly reduced basal rSNA (control group (CT): 110±8, n=14; 2K1C: 150±8, n=12; 2K1C DnX: 89±7, spikes per second (spikes/s); p<0.05, n=8) and lSNA (CT: 137±8, n=8; 2K1C: 202±7, n=11; 2K1C DnX: 131±7, spikes/s; p<0.05, n=8) only in 2K1C rats. DnX significantly improved the arterial baroreceptor sensitivity of rSNA (CT: -2.3±0.2, n=11; 2K1C: -0.7±0.1, n=8; 2K1C DnX: -1.5±0.2, spikes/s/mmHg; p<0.05, n=5) and heart rate for tachycardic response (CT: -3.9±0.5, n=7; 2K1C: -1.9±0.1, n=8; 2K1C DnX: -3.3±0.4, bpm/mmHg; p<0.05, n=8), but not for lSNA in 2K1C rats. The results show that DnX normalized baseline sympathetic vasomotor activity to the lumbar and renal nerves, followed by a differential improvement in the arterial baroreceptor sensitivity. Whether the baroreceptor function sensitivity improvement induced by DnX is a cause or a consequence of BP reduction remains to be determined.

Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection—A Proof-of-Concept Study

IntroductionSympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD.MethodsNine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN.ResultsAt baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (–12.2 bursts/min1, 95% CI [–13.6, –10.7]) and LV mass (–27 g/m2, 95% CI [–47, –8]) were reduced. Mean ambulatory BP (systolic: –24 mm Hg, 95% CI [–42, –5] and diastolic: –13 mm Hg, 95% CI [–22, –4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: –25 mm Hg, 95% CI [–45, –5] and diastolic: –13 mm Hg, 95% CI [–24, –1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months.DiscussionCatheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.

Ventilatory and Carotid Body Chemosensory Responses In Rats Exposed To Short‐Term Sustained Hypoxia

Previous studies performed in in situ rat preparations reported that the exposure to short‐term (24 h) sustained hypoxia (SH) generates active expiration at rest, increases baseline sympathetic activity during expiration and enhances sympathetic responses to peripheral chemoreceptor stimulation. In the present study, we evaluated basal and hypoxic‐induced changes in ventilatory parameters of unanesthetized juvenile male Holtzman rats (80–90 g) previously exposed to SH (10% O2, 24 hs). In addition, we examined the chemosensory response of carotid body chemoreceptors of decerebrated, artificially‐perfused in situ preparations of juvenile rats (60–80 g) submitted to SH. At resting conditions, SH rats (n=12) exhibited augmented (P&lt;0.05) respiratory frequency (109±2 vs 97±1 cpm), tidal volume (14±1 vs 10±1 ml/kg) and minute ventilation (1550±137 vs 979±114 ml/kg.min) compared to control rats (n=12). SH rats also showed greater tachypneic and hyperventilatory responses (P&lt;0.05) to a new hypoxia episode (7% O2, 20 min) in comparison to control rats. The magnitude of increase in tidal volume was similar between groups. The in situ preparations of SH rats (n=8), but not controls (n=8), exhibited additional bursts in baseline abdominal motor activity, indicating the presence of active expiration at rest. Interestingly, basal afferent activity of carotid sinus nerve (CSN) was similar (0.67±0.18 vs 0.65±0.18 μV) between SH and control rats. Moreover, the CSN excitatory response to stimulation of peripheral chemoreceptors with potassium cyanide was not different between groups (ΔCSN: 1235±372 vs 922±278 %), although the in situ preparations of SH rats showed greater sympathoexcitatory reflex responses (P&lt;0.05). Our findings indicate that augmented basal ventilation and enhanced ventilatory and sympathetic responses to hypoxia in rats exposed to SH are not dependent on increased basal and sensorial activity of carotid body chemoreceptors, but may rely on central mechanisms.Support or Funding InformationFAPESP (2013/17.251‐6) and CNPq

Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice.

Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1-/-). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1-/- Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1-/-; however, minute diaphragm electromyogram activity increased in WT but not HO-1-/- The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1-/- CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1-/-, and 2) the baseline sympathetic activity in WT and HO-1-/-, which remained stable subsequently in WT but not in HO-1-/- We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.

Possible Respiratory Modulation of Sympathetic Activity in Rats After Sino‐aortic Denervation

It is well known that several days after sino‐aortic denervation (SAD) rats present normal levels of sympathetic activity and mean arterial pressure (MAP). However, the mechanisms involved in the modulation of the sympathetic activity after SAD remain unclear. Here we hypothesized that the respiratory network may contribute to the modulation of the pre‐sympathetic neurons preventing sustained increase in MAP in SAD rats. To study this mechanism we recorded the activities of phrenic, thoracic sympathetic (tSNA) and cervical vagus nerves (cVN) in male juvenile Wistar rats in the working heart‐brainstem preparation, at high or low respiratory drive induced by hypercapnia or hypocapnia, respectively (SAD, n = 26 and Sham, n = 33). The duration of inspiration significantly increased in SAD rats (1.46 ± 0.05 vs 1.14 ± 0.07 s, P &lt; 0.001). It was also observed that SAD increases cVN inspiratory activity (25 ± 1 vs 32 ± 2%, P &lt; 0.05) and decreases in its post‐inspiratory component (76 ± 1 vs 68 ± 2%, P &lt; 0.05), suggesting an increased upper airway resistance during inspiration in SAD rats. Regarding the baseline tSNA, no changes were observed in the baseline tSNA in all phases of the respiratory cycle in SAD rats, which presented significant reduction in the Traube‐Hering waves magnitude (2.57 ± 0.04 vs 1.19 ± 0.20 mmHg, P = 0.0048). In order to reveal the influence of the respiratory network on the modulation of sympathetic activity rats were exposed to hypercapnia (from 5 to 10 % of CO2) or hypocapnia (from 5 to 3 and 1 % of CO2). High respiratory drive induced by hypercapnia increases tSNA in all phases of respiration in Sham rats (n=13), but in SAD rats (n=14) a significant increase in tSNA was observed only during inspiration (43 ± 3% vs 55 ± 3%, P &lt; 0.01). On the other hand, hypocapnia reduced the respiratory drive and induced sympatho‐inhibition in the SAD (n=8) and in Sham rats (n=10). The data show that in spite of longer inspiratory activity, the baseline sympathetic activity is normal in SAD rats. Whether or not the longer inspiratory activity is driving the sympathetic activity in SAD rats is still matter for further investigation.Support or Funding InformationFAPESP, CAPES and CNPq

Are C1 Neurons Involved in the Sympathetic Overactivity Induced by Chronic Intermittent Hypoxia?

Chronic intermittent hypoxia (CIH) produces expiratory‐related sympatho‐excitation in rats, which might contribute to the development of hypertension. We evaluated the role of sympatho‐excitatory cathecolaminergic medullary C1 neurons in the CIH‐induced expiratory‐related sympatho‐excitation and hypertension in rats. In awake rats in vivo and in in situ perfused preparations of rat, C1 neurons were acutely silenced by application of the insect peptide allatostatin following cell‐specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor in control and CIH rats (10 days). In awake rats in vivo, inhibition of ~ 72% of the C1 neurons resulted in a profound and similar fall in arterial pressure and heart rate in control (n=12) and CIH rats (n=12). However, CIH rats still presented elevated arterial pressure after C1 inhibition (p&lt;0.05). In in situ, C1 inhibition resulted in reversible reductions of perfusion pressure, amplitude of inspiratory‐related bursts of thoracic sympathetic nerve and C1 pre‐sympathetic neurons activities in control (n=7) and CIH (n=9) rats. However, CIH‐ (n=9), acute hypoxia‐ (n=7) or CO2‐induced expiratory‐related sympatho‐excitation (n=10) were not affected by C1 inhibition. These data confirm a physiological role of C1 neurons in generating baseline sympathetic activity and arterial pressure. However, C1 neurons apparently are not involved in the expiratory‐related sympatho‐excitation and hypertension induced by CIH.Support or Funding InformationFAPESP and CNPQ