Sympathetic Neural Activity Research Articles

Baroreflex control of sympathetic vasomotor activity and resting arterial pressure at high altitude: insight from Lowlanders and Sherpa

Hypoxia, a potent activator of the sympathetic nervous system, is known to increase muscle sympathetic nerve activity (MSNA) to the peripheral vasculature of native Lowlanders during sustained high altitude (HA) exposure. We show that the arterial baroreflex control of MSNA functions normally in healthy Lowlanders at HA, and that upward baroreflex resetting permits chronic activation of basal sympathetic vasomotor activity under this condition. The baroreflex MSNA operating point and resting sympathetic vasomotor outflow both are lower for highland Sherpa compared to acclimatizing Lowlanders; these lower levels may represent beneficial hypoxic adaptation in Sherpa. Acute hyperoxia at HA had minimal effect on baroreflex control of MSNA in Lowlanders and Sherpa, raising the possibility that mechanisms other than peripheral chemoreflex activation contribute to vascular sympathetic baroreflex resetting and sympathoexcitation. These findings provide a better understanding of sympathetic nervous system activation and the control of blood pressure during the physiological stress of sustained HA hypoxia. Exposure to high altitude (HA) is characterized by heightened muscle sympathetic neural activity (MSNA); however, the effect on arterial baroreflex control of MSNA is unknown. Furthermore, arterial baroreflex control at HA may be influenced by genotypic and phenotypic differences between lowland and highland natives. Fourteen Lowlanders (12 male) and nine male Sherpa underwent haemodynamic and sympathetic neural assessment at low altitude (Lowlanders, low altitude; 344m, Sherpa, Kathmandu; 1400m) and following gradual ascent to 5050m. Beat-by-beat haemodynamics (photoplethysmography) and MSNA (microneurography) were recorded lying supine. Indices of vascular sympathetic baroreflex function were determined from the relationship of diastolic blood pressure (DBP) and corresponding MSNA at rest (i.e. DBP 'operating pressure' and MSNA 'operating point'), as well as during a modified Oxford baroreflex test (i.e. 'gain'). Operating pressure and gain were unchanged for Lowlanders during HA exposure; however, the operating point was reset upwards (48±16vs. 22±12 bursts 100HB-1 ,P=0.001). Compared to Lowlanders at 5050m, Sherpa had similar gain and operating pressure, although the operating point was lower (30±13 bursts 100HB-1 , P=0.02); MSNA burst frequency was lower for Sherpa (22±11 vs. 30±9 bursts min-1 P=0.03). Breathing 100% oxygen did not alter vascular sympathetic baroreflex function for either group at HA. For Lowlanders, upward baroreflex resetting promotes heightened sympathetic vasoconstrictor activity and maintains blood pressure stability, at least during early HA exposure; mechanisms other than peripheral chemoreflex activation could be involved. Sherpa adaptation appears to favour a lower sympathetic vasoconstrictor activity compared to Lowlanders for blood pressure homeostasis.

Selective Reductions in Pulmonary Artery Pressure Lowers Sympathetic Neural Activity in Healthy Humans at High Altitude

Chronically elevated sympathetic neural activity is a characteristic of many disease states. Tonic chemoreflex activation has been implicated in the development of sympathetic overactivity; however, other reflexes may also contribute. For example, in an animal model, stimulation of pulmonary baroreceptors induces a reflex increase in sympathetic neural activity. In humans, pulmonary pressure has been shown to be related to basal sympathetic activity in pulmonary hypertension; however a critical step in determining a causal link is to establish whether changing pulmonary pressure alters sympathetic outflow. In this pilot study, we exposed thirteen healthy humans (5 females, 28 [ ± 7] years) to high altitude hypoxia (HA; 4383m), a setting known to increase both pulmonary pressure and sympathetic activation, before selectively lowering pulmonary pressure via inhalation of the pulmonary vasodilator nitric oxide. Muscle sympathetic nerve activity (MSNA; Microneurography), blood pressure (BP; Photoplethysmography), heart rate (HR; Electrocardiogram), and peripheral oxygen saturation (SPO2; Pulse oximetry) were continually measured during ambient air breathing (Amb) and during a 6‐minute inhalation of nitric oxide (iNO; 40ppm in 21% O2). Pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and stroke volume (SV) were determined via cardiac ultrasound. iNO reduced PASP (−23 ± 12%) and PVR (−21 ± 16%) compared to Amb (Table 1). iNO also reduced MSNA burst frequency (−18 ± 18%), burst incidence (−16 ± 17%) and total activity (−21 ± 20%) compared to Amb. MSNA changes during iNO were not related to changes in SPO2 (r = −0.16, P = 0.61) or MAP (r = −0.28, P = 0.35). Our data demonstrate that selectively reducing pulmonary pressure reduces sympathetic nerve activity in healthy humans; therefore, this provides evidence for a causal link in the relationship between pulmonary pressure and basal sympathetic activity. Further investigation is warranted to establish whether elevated pulmonary pressure is a mechanism contributing to chronically elevated sympathetic outflow in disease.Support or Funding InformationThis study was supported by the Natural Sciences and Engineering Research Council of Canada and a Canada Research Chair in Cerebrovascular Physiology grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Response of respiratory system to noxious stimuli and correlation between respiratory parameters and pain sensitivity parameters

Background: Pain is multidimensional feeling that varies among individual patients. Pain is the main reason for visiting hospital. Pain is necessary for healthy survival of animal. People with lose of pain sensitivity have reduced life expectancy. Aims and Objectives: The objective of our study is to find any correlation between two respiratory parameters and three pain parameters among medical students. Second is to determine gender difference between pain sensitivity parameters and respiratory system response to experimental pain. Materials and Methods: In this study, a total of 100 medical students (male 57 and female 43) were participated. The cold pressor test was used to give pain as noxious stimuli. Respiratory parameters (respiratory rate and vital capacity) and pain sensitivity parameters (pain rating using visual analog scale, pain tolerance, and pain threshold) were measured. Results: Respiratory reactivity in response to experimental pain applied by cold pressor test in both sexes was not found significant in this study. Second, we found no remarkable correlation between respiratory system and pain sensitivity in both sexes. Conclusion: Respiratory system stimulates in response to pain because of both sympathetic and parasympathetic neural activity. There is no correlation between respiratory and pain sensitivity.

Microvascular mechanisms limiting skeletal muscle blood flow with advancing age.

Effective oxygen delivery to active muscle fibers requires that vasodilation initiated in distal arterioles, which control flow distribution and capillary perfusion, ascends the resistance network into proximal arterioles and feed arteries, which govern total blood flow into the muscle. With exercise onset, ascending vasodilation reflects initiation and conduction of hyperpolarization along endothelium from arterioles into feed arteries. Electrical coupling of endothelial cells to smooth muscle cells evokes the rapid component of ascending vasodilation, which is sustained by ensuing release of nitric oxide during elevated luminal shear stress. Concomitant sympathetic neural activation inhibits ascending vasodilation by stimulating α-adrenoreceptors on smooth muscle cells to constrict the resistance vasculature. We hypothesized that compromised muscle blood flow in advanced age reflects impaired ascending vasodilation through actions on both cell layers of the resistance network. In the gluteus maximus muscle of old (24 mo) vs. young (4 mo) male mice (corresponding to mid-60s vs. early 20s in humans) inhibition of α-adrenoreceptors in old mice restored ascending vasodilation, whereas even minimal activation of α-adrenoreceptors in young mice attenuated ascending vasodilation in the manner seen with aging. Conduction of hyperpolarization along the endothelium is impaired in old vs. young mice because of "leaky" membranes resulting from the activation of potassium channels by hydrogen peroxide released from endothelial cells. Exposing the endothelium of young mice to hydrogen peroxide recapitulates this effect of aging. Thus enhanced α-adrenoreceptor activation of smooth muscle in concert with electrically leaky endothelium restricts muscle blood flow by impairing ascending vasodilation in advanced age.

Sympathetic activation by lower body negative pressure decreases kidney perfusion without inducing hypoxia in healthy humans

PurposeThere is ample evidence that systemic sympathetic neural activity contributes to the progression of chronic kidney disease, possibly by limiting renal blood flow and thereby inducing renal hypoxia. Up to now there have been no direct observations of this mechanism in humans. We studied the effects of systemic sympathetic activation elicited by a lower body negative pressure (LBNP) on renal blood flow (RBF) and renal oxygenation in healthy humans.MethodsEight healthy volunteers (age 19–31 years) were subjected to progressive LBNP at − 15 and − 30 mmHg, 15 min per level. Brachial artery blood pressure was monitored intermittently. RBF was measured by phase-contrast MRI in the proximal renal artery. Renal vascular resistance was calculated as the MAP divided by the RBF. Renal oxygenation (R2*) was measured for the cortex and medulla by blood oxygen level dependent (BOLD) MRI, using a monoexponential fit.ResultsWith a LBNP of − 30 mmHg, pulse pressure decreased from 50 ± 10 to 43 ± 7 mmHg; MAP did not change. RBF decreased from 1152 ± 80 to 1038 ± 83 mL/min to 950 ± 67 mL/min at − 30 mmHg LBNP (p = 0.013). Heart rate and renal vascular resistance increased by 38 ± 15% and 23 ± 8% (p = 0.04) at − 30 mmHg LBNP, respectively. There was no change in cortical or medullary R2* (20.3 ± 1.2 s−1 vs 19.8 ± 0.43 s−1; 28.6 ± 1.1 s−1 vs 28.0 ± 1.3 s−1).ConclusionThe results suggest that an increase in sympathetic vasoconstrictor drive decreases kidney perfusion without a parallel reduction in oxygenation in healthy humans. This in turn indicates that sympathetic activation suppresses renal oxygen demand and supply equally, thus allowing adequate tissue oxygenation to be maintained.

Assessment of sympathetic neural activity in chronic insomnia: evidence for elevated cardiovascular risk.

Study Objectives Chronic insomnia affects up to 15 per cent of adults. Recent cross-sectional and prospective epidemiological studies report an association between insomnia and hypertension, including incident hypertension, yet mechanisms underlying the association remain unknown. We hypothesized that participants with chronic insomnia would have elevated sympathetic neural outflow, blunted baroreflex sensitivity, and augmented sympathetic neural and cardiovascular reactivity to stress when compared with good-sleeper controls. Methods Twelve participants with chronic insomnia (11 women, 1 man) and 12 controls (8 women, 4 men) underwent one night of laboratory polysomnography, two weeks of at-home wrist actigraphy, and one night of controlled laboratory sleep prior to a comprehensive morning autonomic function test. The autonomic function test consisted of simultaneous recordings of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram) during a 10 min supine baseline and a 2 min cold pressor test. Results Baseline blood pressure, heart rate, and MSNA were not different between groups, but sympathetic baroreflex sensitivity was significantly blunted in participants with insomnia (-2.1 ± 1.0 vs. -4.3 ± 1.3 bursts/100 heartbeats/mm Hg; p < 0.001). During the cold pressor test, systolic arterial pressure reactivity (Δ21 ± 11 vs. Δ14 ± 8 mm Hg; time × group = 0.04) and total MSNA reactivity (Δ127%, 54%-208% vs. Δ52%, 30%-81%; time × group = 0.02) were augmented in chronic insomnia. Conclusions Participants with chronic insomnia demonstrated impaired sympathetic baroreflex function and augmented neural cardiovascular responsiveness to stress, when compared with controls. These findings support growing evidence of cardiovascular risk and physiological hyperarousal in chronic insomnia. Clinical Trial Registration NCT02048878. https://clinicaltrials.gov/ct2/show/NCT02048878.

On the Interaction between Gaze Behavior and Physiological Responses when Viewing Garden Scenes.

Recent research has shown that design principles inherent in a Japanese style garden can reduce measures of stress in both healthy and dementia patients. However, it was not clear how subjects' visual interaction with the scene affected their physiological responses. To address that, we developed a novel non-invasive system to collect synchronized measurements of eye gaze and physiological indicators of sympathetic neural activity: the electrocardiogram, the blood volume pulse and the galvanic skin response, as subjects view a garden environment. We characterized the visual engagement of subjects using the average fixation duration, the saccade amplitude and the gaze transition entropy. We find a statistically significant positive correlation between gaze transition entropy and mean heart rate change. Our results suggest that the visual engagement of subjects with their environment may influence their physiological responses to it: more engagement may lead to more relaxation. Our results also highlight the importance of taking into account the detailed spatio-temporal characteristics of the gaze trajectory.

Sex Differences in Sympathetic Control of Vascular Tone: Influences of Aging

Reproductive hormones have important non‐reproductive influences on cardiovascular structure and function. In women, these include important effects on the autonomic control of the circulation. Women under the age of 40 tend to have less tonic activity of sympathetic vasoconstrictor nerves in the periphery (usually measured as muscle sympathetic nerve activity), as well as smaller hearts and lower cardiac output compared to men of similar age and health status. Together, these result in a tendency for lower blood pressures in young women, including decreased risk for hypertension, and increased risk of hypotensive disorders such as orthostatic intolerance. Female reproductive hormones (particularly estrogen) appear to contribute to increased functional activity of vascular beta‐2 adrenergic receptors, which offset alpha‐adrenergic vasoconstriction and result in less vasoconstriction for a given amount of sympathetic neural activity (or local norepinephrine), also contributing to the lower blood pressure in young women compared to young men. At menopause, the influences of the hormones decreases, and sex differences are minimized or reversed: sympathetic nerve activity and blood pressure increase to levels similar to, or higher than, those seen in older men. The vasodilator influence of beta‐2 receptors decreases, and sympathetic nerve activity becomes more tightly linked to vasoconstriction and blood pressure. Sympathetic neural activity thus becomes a greater contributor to blood pressure with aging in both men and women, and is a factor in the increased risk of hypertension in older age in both sexes.Support or Funding InformationFunded by USAMRMC; author views not official US Army or DOD policyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sleep Deprivation and Sympathetic Neural Control in Older Adults

Epidemiological studies have suggested a link between sleep deprivation and hypertension, and that this link is stronger in women. Our laboratory recently reported that baseline sympathetic neural responses to total sleep deprivation (TSD) were different in young men and women, with a greater shift towards sympathetic predominance in young women. Postmenopausal women are at high risk for hypertension. In the present study, we hypothesize that TSD will alter sympathetic neural activity in older adults, with greater sympathoexcitation in postmenopausal women. Nine participants between the ages of 55 and 75 years (9 women and 7 men) participated in the study. Subjects were tested twice one month apart, once after 24‐hour TSD and once after normal sleep. Wrist actigraphy was worn 5 days prior to each testing to confirm normal sleep patterns. We recorded muscle sympathetic nerve activity (MSNA; microneurography), beat‐to‐beat blood pressure (finger plethsmography), and heart rate (electrocardiogram) during 5 min of supine, awake rest. TSD elicited divergent MSNA responses in older men and women. Specifically, MSNA burst frequency increased in postmenopausal women (31±3 to 35±3 burst/min), but not older men (39±3 to 36±4 burst/min; time × condition, p = 0.036). This shift towards sympathetic predominance in women was also observed when MSNA was quantified as burst incidence (time × condition, p = 0.034). TSD did not alter baseline mean arterial pressure (men, 89±5 to 87±3 mmHg; women, 84±4 to 84±3) or heart rate (men, 55±3 to 55±4 beats/min; 58±3 to 60±4 beats/min) in either group (time, p&gt;0.05; time × condition, p&gt; 0.05). In summary, 24‐hour TSD elicits divergent MSNA responses in older men and women, with greater sympathoexcitation in postmenopausal women. These findings provide new mechanistic insight into reported links between sleep deprivation and hypertension.Support or Funding InformationFunding support from the National Institutes of Health (HL‐122919) and Portage Health Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Assessment of sympathetic neural activity in chronic insomnia: evidence for elevated cardiovascular risk.

Chronic insomnia affects up to 15 per cent of adults. Recent cross-sectional and prospective epidemiological studies report an association between insomnia and hypertension, including incident hypertension, yet mechanisms underlying the association remain unknown. We hypothesized that participants with chronic insomnia would have elevated sympathetic neural outflow, blunted baroreflex sensitivity, and augmented sympathetic neural and cardiovascular reactivity to stress when compared with good-sleeper controls. Twelve participants with chronic insomnia (11 women, 1 man) and 12 controls (8 women, 4 men) underwent one night of laboratory polysomnography, two weeks of at-home wrist actigraphy, and one night of controlled laboratory sleep prior to a comprehensive morning autonomic function test. The autonomic function test consisted of simultaneous recordings of muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat blood pressure (finger plethysmography), and heart rate (electrocardiogram) during a 10 min supine baseline and a 2 min cold pressor test. Baseline blood pressure, heart rate, and MSNA were not different between groups, but sympathetic baroreflex sensitivity was significantly blunted in participants with insomnia (-2.1 ± 1.0 vs. -4.3 ± 1.3 bursts/100 heartbeats/mm Hg; p < 0.001). During the cold pressor test, systolic arterial pressure reactivity (Δ21 ± 11 vs. Δ14 ± 8 mm Hg; time × group = 0.04) and total MSNA reactivity (Δ127%, 54%-208% vs. Δ52%, 30%-81%; time × group = 0.02) were augmented in chronic insomnia. Participants with chronic insomnia demonstrated impaired sympathetic baroreflex function and augmented neural cardiovascular responsiveness to stress, when compared with controls. These findings support growing evidence of cardiovascular risk and physiological hyperarousal in chronic insomnia. NCT02048878. https://clinicaltrials.gov/ct2/show/NCT02048878.

Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 µg·kg-1·min-1, n = 13) or PE (0.2-1.0 µg·kg-1·min-1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Sympathetic neural activity supporting healthy life and physical activity

Sympathetic neural activity supporting healthy life and physical activity

Higher exercise intensity delays postexercise recovery of impedance-derived cardiac sympathetic activity.

Systolic time intervals (STIs) provide noninvasive insights into cardiac sympathetic neural activity (cSNA). As the effect of exercise intensity on postexercise STI recovery is unclear, this study investigated the STI recovery profile after different exercise intensities. Eleven healthy males cycled for 8 min at 3 separate intensities: LOW (40%-45%), MOD (75%-80%), and HIGH (90%-95%) of heart-rate (HR) reserve. Bio-impedance cardiography was used to assess STIs - primarily pre-ejection period (PEP; inversely correlated with cSNA), as well as left ventricular ejection time (LVET) and PEP:LVET - during 10 min seated recovery immediately postexercise. Heart-rate variability (HRV), i.e., natural-logarithm of root mean square of successive differences (Ln-RMSSD), was calculated as an index of cardiac parasympathetic neural activity (cPNA). Higher preceding exercise intensity elicited a slower recovery of HR and Ln-RMSSD (p < 0.001), and these measures did not return to baseline by 10 min following any intensity (p ≤ 0.009). Recovery of STIs was also slower following higher intensity exercise (p ≤ 0.002). By 30 s postexercise, higher preceding intensity resulted in a lower PEP (98 ± 14 ms, 75 ± 6 ms, 66 ± 5 ms for LOW, MOD, and HIGH, respectively, p < 0.001). PEP recovered to baseline (143 ± 11 ms) by 5 min following LOW (139 ± 13 ms, p = 0.590) and by 10 min following MOD (145 ± 17 ms, p = 0.602), but was still suppressed at 10 min following HIGH (123 ± 21 ms, p = 0.012). Higher preceding exercise intensity attenuated the recovery of indices for cSNA (from STIs) and cPNA (from HRV) in a graded dose-response fashion. While exercise intensity must be considered, acute recovery may be a valuable period during which to concurrently monitor these noninvasive indices, to identify potentially abnormal cardiac autonomic responses.

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.

Muscle Sympathetic Nerve Activity Is Associated with Liver Insulin Sensitivity in Obese Non-Diabetic Men.

Introduction: Muscle sympathetic nerve activity (MSNA) may play a role in insulin resistance in obesity. However, the direction and nature of the relationship between MSNA and insulin resistance in obesity remain unclear. We hypothesized that resting MSNA would correlate inversely with both muscle and liver insulin sensitivity and that it would be higher in insulin-resistant vs. insulin-sensitive subjects.Materials and methods: Forty-five non-diabetic obese subjects were studied. As no significant relationships were found in women, the data presented in on 22 men aged 48 ± 12 years. Two-step (15 and 80 mU/m2/min) hyperinsulinaemic-euglycaemic clamps were performed using deuterated glucose to determine liver and muscle insulin sensitivity. Clinical and metabolic parameters were assessed. MSNA was measured via a microelectrode inserted percutaneously into the common peroneal nerve.Results: MSNA burst frequency correlated inversely with liver insulin sensitivity (r = −0.53, P = 0.02) and positively with the hepatokines C-reactive protein (CRP) and fibroblast growth factor (FGF)-19 (r = 0.57, P = 0.006, and r = −0.47, P = 0.03, respectively). MSNA burst frequency was lower in Liversen compared to Liverres (27 ± 5 vs. 38 ± 2 bursts per minute; P = 0.03). Muscle insulin sensitivity was unrelated to MSNA.Discussion: Sympathetic neural activation is related to liver insulin sensitivity and circulating hepatokines CRP and FGF-19 in non-diabetic obese men. These results suggest a potential hepato-endocrine-autonomic axis. Future studies are needed to clarify the influence of MSNA on liver insulin sensitivity in men.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

The coupling between peripheral microcirculation and slow breathing

Vasomotion (rhythmic changes in arteriolar diameter) is believed to enhance tissue perfusion at low oxygenation levels. We hypothesized that slow breathing and vasomotion may correlate temporally (“coupling”), especially at low oxygenation levels. We paced down spontaneous breathing to about 5 or 6breaths/min in 14 healthy subjects using device-guided breathing (DGB), and continuously monitored respiration, transcutaneous oxygen pressure (“oxygenation”), and skin capillary blood flow ("microflow”) using a laser Doppler flowmeter. The coupling was expressed by cross-correlation calculated in 1-min time windows. Our main results illustrated that: (1) coupling increased gradually upon slowing breathing down in a subgroup, in which initial oxygenation was lower than a threshold of 30mmHg (0.3±0.2 vs. 0.07±0.2, P<10−6); (2) during DGB changes in oxygenation elicited opposite (relative) changes in microflow, with 4-fold higher sensitivity for low initial oxygenation relative to high (regression slope −0.094±0.010mmHg−1 vs. −0.020±0.002mmHg−1, P<10−6); (3) at low initial oxygenation, we observed larger coupling and (relative) microflow changes in younger subjects, and greater oxygenation changes in females (P<10−6 for all); (4) pulse pressure changes from before to after DGB were reduced by increased oxygenation changes during DGB (−5.5±7.4mmHg, r=−0.73, P<0.001). In conclusion, the present methodology can provide the variation trend of respiration–vasomotion coupling during DGB that may characterize microcirculation behavior at tissue oxygenation below a measurable threshold. The potential association of these trends and thresholds with pathologies or specific conditions of the cardiopulmonary system, and the possible role played by the neural sympathetic activity in that coupling, deserve further studies.

Epigenetic Mechanisms: New Targets for Heart Failure Pharmacopuncture.

Pharmacopuncture treatments are proposed for cardiovascular disease and heart failure [1]. Heart failure results from complex environment-gene interactions. β-adrenergic receptors and protein kinase A (PKA) interact with histones and related segments of deoxyribonucleic acid (DNA) at promoter regions of genes for messenger ribo nucleic acid (mRNA) transcription. This increases cardiac muscle mass and contractility in normal hearts. In heart failure, activation of β-adrenergic receptors and PKA promote pathological hypertrophy and decreased contractility. Experimental models show that prenatal exposure to hypoxia, cocaine, or nicotine increases susceptibility to heart failure when animals reach adulthood. Hypermethylation of DNA is an epigenetic mechanism associated with downregulation of the protein kinase C (PKC) gene in such models of heart failure. Downregulation of PKC is also produced by the stress-related hormone norepinephrine with upregulation of the hypoxia-inducible differentiation regulator Nix in norepinephrine-induced cardiac fibrosis [2]. Norepinephrine is also the main mediator of sympathetic neural activity. Sympathetic neural overactivity, a significant cofactor in human heart failure, is, therefore, implicated as a cofactor in this epigenetic mechanism for heart failure. Other epigenetic mechanism for cardiac hypertrophy and heart failure involve endothelin- 1 induced downregulation of the cardiac myocyte differentiation factor RE1-silencing transcription signaler (REST) and GATA zinc-finger domain-containing protein-1 (GATAD1) induced inhibition of histone deacetylase (HDAC-2) in cardiac myocytes harvested from autosomal-recessive dilated cardiac myopathy patients with heart failure [3]. In contrast, both the HDAC-2 in cardiac myocytes and the HDAC-1 in cardiac fibroblasts are upregulated in experimental animal models of congestive heart failure [4]. A prominent role for inflammation in heart failure is suggested by tumor necrosis factor (TNF-α), a proinflammatory cytokine, inducing hypermethylation of the sarcoplasmic reticulum calcium ATPase (SERCA-2A) gene in cardiac myocytes, associated with diastolic dysfunction and heart failure. An important role for epigenetic mechanisms in heart failure is also suggested by HDAC-dependent stimulation of the stress-apoptosis intracellular signaling pathway, which induces hypertrophy of both cardiac and vascular smooth muscle [5].

Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis

ObjectiveMetabolic challenges, such as a cold environment, stimulate sympathetic neural efferent activity to white adipose tissue (WAT) to drive lipolysis, thereby increasing the availability of free fatty acids as one source of fuel for brown adipose tissue (BAT) thermogenesis. WAT is also innervated by sensory nerve fibers that network to metabolic brain areas; moreover, activation of these afferents is reported to increase sympathetic nervous system outflow. However, the endogenous stimuli sufficient to drive WAT afferents during metabolic challenges as well as their functional relation to BAT thermogenesis remain unknown. MethodWe tested if local WAT lipolysis directly activates WAT afferent nerves, and then assessed whether this WAT sensory signal affected BAT thermogenesis in Siberian hamsters (Phodopus sungorus). Results2-deoxyglucose, a sympathetic nervous system stimulant, caused β-adrenergic receptor dependent increases in inguinal WAT (IWAT) afferent neurophysiological activity. In addition, direct IWAT injections of the β3-AR agonist CL316,243 dose-dependently increased: 1) phosphorylation of IWAT hormone sensitive lipase, an indicator of SNS-stimulated lipolysis, 2) expression of the neuronal activation marker c-Fos in dorsal root ganglion neurons receiving sensory input from IWAT, and 3) IWAT afferent neurophysiological activity, an increase blocked by antilipolytic agent 3,5-dimethylpyrazole. Finally, we demonstrated that IWAT afferent activation by lipolysis triggers interscapular BAT thermogenesis through a neural link between these two tissues. ConclusionsThese data suggest IWAT lipolysis activates local IWAT afferents triggering a neural circuit from WAT to BAT that acutely induces BAT thermogenesis.

Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning.

Sympathetic neural activation may be detrimentally involved in tissue injury caused by ischemia-reperfusion (IR). We examined the effects of experimental IR in the forearm on sympathetic nerve response, finger reactive hyperemia, and oxidative stress, and the protection afforded by applying remote ischemic preconditioning (RIPC). Ischemia was induced in the forearm for 20 min in healthy volunteers. RIPC was induced by applying two cycles, 5 min each, of ischemia and reperfusion to the upper leg immediately before IR. We examined muscle sympathetic nerve activity (MSNA) in the contralateral leg using microneurography, finger reactive hyperemia [ischemic reactive hyperemia index (RHI)], erythrocyte production of reduced gluthathione (GSH), and plasma nitric oxide (NO) concentration. In controls (no RIPC; n = 15), IR increased MSNA in the early and late phase of ischemia (70% at 5 min; 101% at 15 min). In subjects who underwent RIPC (n = 15), the increase in MSNA was delayed to the late phase of ischemia and increased only by 40%. GSH increased during ischemia in the control group (P = 0.05), but not in those who underwent RIPC. Nitrate and nitrite concentration, taken as an index of NO availability, decreased during the reperfusion period in control individuals (P < 0.05), while no change was observed in those who underwent RIPC. Experimental IR did not affect RHI in the control condition, but a significant vasodilatory response occurred in the RIPC group (P < 0.05). RIPC attenuated ischemia-induced sympathetic activation, prevented the production of an erythrocyte marker of oxidative stress and the reduction of NO availability, and ameliorated RHI.