Sympathetic Nerve Activity Burst Research Articles

Influence of sex and sedentary conditions on sympathetic burst characteristics in prepubertal, postpubertal, and young adult rats.

Recent evidence indicates that sex-based differences in cardiovascular disease (CVD) begin early in life, particularly when associated with risk factors such as a sedentary lifestyle. CVD is associated with elevated sympathetic nerve activity (SNA), quantified as increased SNA burst activity in humans. Whether burst characteristics are influenced by sex or sedentary conditions at younger ages is unknown. The purpose of our study is to compare SNA bursts in active and sedentary female and male rats at ages including prepuberty and young adulthood. We hypothesized that burst characteristics and blood pressure are higher under sedentary conditions and lower in female rats compared with males. We analyzed splanchnic SNA (SpSNA) recordings from Inactin-anesthetized male and female rats at 4-, 8-, and 16-wk of age. Physically active and sedentary rats were each housed in separate, environmentally controlled chambers where physically active rats had free access to an in-cage running wheel. Sympathetic bursts were obtained by rectifying and integrating the raw SpSNA signal. Burst frequency, burst height, and burst width were calculated using the Peak Parameters extension in LabChart. Our results showed that sedentary conditions produced a greater burst width in 8- and 16-wk-old rats compared with 4-wk-old rats in both males and females (P < 0.001 for both). Burst frequency and incidence were both higher in 16-wk-old males compared with 16-wk-old females (P < 0.001 for both). Our results suggest that there are sedentary lifestyle- and sex-related mechanisms that impact sympathetic regulation of blood pressure at ages that range from prepuberty into young adulthood.NEW & NOTEWORTHY The mechanisms of decreased incidence of cardiovascular disease (CVD) in reproductive-age women compared with age-matched men are unknown. The strong association between elevated sympathetic activity and CVD led us to characterize splanchnic sympathetic bursts in female and male rats. Prepubescent males and females exhibited narrower sympathetic bursts, whereas young adult males had higher resting burst frequency compared with age-matched females. Sex-based regulation of sympathetic activity suggests a need for sex-dependent therapeutic strategies to combat CVD.

Sympathetic transduction of cardiac sympathetic nerve activity in healthy, conscious sheep.

Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a β-adrenoceptor blocker (propranolol) to determine the role of β-adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n=10, ∆: +2.1±1.4 beatsmin-1 , P=0.002) and CO (n=8, ∆: +100±150mLmin-1 , P=0.002) was elevated, followed by an increase in CoBF (n=9, ∆: +0.76mLmin-1 , P=0.001) and CVC (n=8, ∆: +0.0038mLmin-1 mmHg-1 , P=0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on β-adrenoceptors. KEY POINTS: Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end-organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by β-adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by β-adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

Sympathetic nerve activity reactivity is associated with cardiac fibrosis in humans

Abstract Background Hypertension causes cardiac remodelling and left ventricular hypertrophy (LVH) in some individuals but not others [1-3]. 90% of people with heart failure preserved ejection fraction (HFpEF) have hypertension. One possible mechanism is increased sympathetic drive resulting in cardiac fibrosis. Resting sympathetic nerve activity (SNA) is associated with cardiac remodelling in both animals and humans and progressively increases from hypertension to LVH to HFpEF. However, humans are not in a constant rested state, and are frequently exposed to multiple physiological stressors throughout the day, resulting in surges in SNA. Amplified SNA reactivity to stressors may contribute to cardiac remodelling more than elevated resting SNA levels, as intermittent β-adrenergic receptor stimulation with isoprenaline in mice has been shown to cause more severe cardiac fibrosis when compared to a sustained isoprenaline administration [4]. Purpose To determine whether resting SNA and/or SNA reactivity to a physiological stressor (cold pressor test) were associated with cardiac fibrosis in humans. Methods Nineteen (10M, 9F; 48 ± 13 years; BMI: 25.9 ± 3.2 kg/m²) participants with varying ambulatory blood pressures (SBP: 126±13 mmHg, DBP: 83±8 mmHg, SBP range: 111-153 mmHg, DBP range: 68-96 mmHg), provided written informed consent. Blood pressure (Finometer), heart rate (ECG) and muscle SNA (peroneal microneurography) were recorded simultaneously during a 5-minute baseline, and a 2-minute rest, 3-minute cold pressor test (3-4°C) and 5-minute recovery. Cardiac extracellular volume (ECV) was measured using magnetic resonance imaging (1.5T Avanto, Siemens) as an index of cardiac fibrosis. Simple linear regressions were conducted between baseline SNA and ECV, and change in SNA from rest to peak cold pressor test and ECV using SPSS. Results Resting SNA was not associated with ECV. However, the absolute change in SNA burst incidence (bursts/100 heartbeats) and burst frequency (bursts/minute, Figure 1) from rest to peak cold pressor test, were positively associated with ECV, showing that the greater the SNA response to a stressor, the higher the ECV. Specifically, for every 1 burst/100 heartbeat increase in burst incidence (from rest to peak cold pressor test), ECV increased by 0.120%, and for every 1 burst/minute increase in burst frequency (from rest to peak cold pressor test), ECV increased by 0.128%. Conclusion SNA reactivity but not resting SNA level was found to be a predictor of ECV, where the greater the SNA response to a stressor, the higher the ECV. This indicates that intermittent surges in SNA may be more important for promoting cardiac fibrosis than the overall level of resting SNA in humans.Figure 1.

The impact of 6 months of exercise-based cardiac rehabilitation on sympathetic neural recruitment during apneic stress.

The current study evaluated the hypothesis that 6 mo of exercise-based cardiac rehabilitation (CR) would improve sympathetic neural recruitment in patients with ischemic heart disease (IHD). Microneurography was used to evaluate action potential (AP) discharge patterns within bursts of muscle sympathetic nerve activity (MSNA), in 11 patients with IHD (1 female; 61 ± 9 yr) pre (pre-CR) and post (post-CR) 6 mo of aerobic and resistance training-based CR. Measures were made at baseline and during maximal voluntary end-inspiratory (EI-APN) and end-expiratory apneas (EE-APN). Data were analyzed during 1 min of baseline and the second half of apneas. At baseline, overall sympathetic activity was less post-CR (all P < 0.01). During EI-APN, AP recruitment was not observed pre-CR (all P > 0.05), but increases in both within-burst AP firing frequency (Δpre-CR: 2 ± 3 AP spikes/burst vs. Δpost-CR: 4 ± 3 AP spikes/burst; P = 0.02) and AP cluster recruitment (Δpre-CR: -1 ± 2 vs. Δpost-CR: 2 ± 2; P < 0.01) were observed in post-CR tests. In contrast, during EE-APN, AP firing frequency was not different post-CR compared with pre-CR tests (Δpre-CR: 269 ± 202 spikes/min vs. Δpost-CR: 232 ± 225 spikes/min; P = 0.54), and CR did not modify the recruitment of new AP clusters (Δpre-CR: -1 ± 3 vs. Δpost-CR: 0 ± 1; P = 0.39), or within-burst firing frequency (Δpre-CR: 3 ± 3 AP spikes/burst vs. Δpost-CR: 2 ± 2 AP spikes/burst; P = 0.21). These data indicate that CR improves some of the sympathetic nervous system dysregulation associated with cardiovascular disease, primarily via a reduction in resting sympathetic activation. However, the benefits of CR on sympathetic neural recruitment may depend upon the magnitude of initial impairment.

Augmented pressor responses to individual bursts of muscle sympathetic nerve activity in human obesity

Obesity is associated with increased sympathetic outflow and hypertension. However, it remains unclear whether the systemic pressor response to spontaneous bursts of sympathetic nerve activity (i.e., sympathetic transduction) is augmented in obesity. Therefore, we tested the hypothesis that transduction of muscle sympathetic nerve activity (MSNA) to arterial blood pressure (BP) is significantly higher in obese vs. lean adults. Also, because obesity alters regulation of BP over the 24-hour period, we further examined the extent to which sympathetic transduction is associated with ambulatory 24-hour BP variability (standard deviation). MSNA (microneurography) and arterial BP (finger cuff) were measured continuously for 10 min under resting conditions in 20 young/middle-age obese participants and 20 age- and sex-matched lean controls. Signal averaging was used to characterize beat-by-beat changes in mean arterial pressure (MAP) for 15 cardiac cycles following each MSNA burst. MSNA was not significantly elevated in obese vs. lean participants (25±11 vs. 21±10 bursts/min, P=0.27). However, transduction of MSNA to BP was significantly elevated in obese vs. lean participants when considering multiple successive bursts (P<0.01) and all bursts (P<0.01). Similarly, increases in burst amplitude evoked greater MAP responses with obese having the largest peak increases (3.8±1.7 vs. 2.7±1.6 mmHg, P=0.03). Multiple regression indicated that sympathetic transduction was a significant determinant of 24-hour MAP variability (β=0.47, P<0.01), independent of age, BMI, MSNA, and 24-hour MAP (all P>0.05). These findings demonstrate that transduction of MSNA to BP is augmented in human obesity. Sympathetic transduction also appears to contribute to higher BP variability independent of obesity.

Arterial baroreflex regulation of muscle sympathetic nerve activity during hypoxia and hypercapnia in healthy young men and women

Background In hypertension augmented vasoconstrictor sympathetic nerve activity (SNA) responses to both hypoxia and hypercapnia have been identified. The arterial baroreflex (ABR) normally restrains SNA, but whether ABR-SNA sensitivity is modified by peripheral, central or combined chemoreflex stimulation (i.e. hypoxia, hypercapnia and hypercapnic hypoxia) in young men and women is incompletely understood. We tested the hypothesis that ABR-SNA sensitivity is attenuated by hypoxia, hypercapnia and combined hypercapnic hypoxia thereby allowing SNA to rise. The existence of sex-differences in ABR-SNA sensitivity was also examined. Methods Ten (5 males) healthy individuals (aged 27±4 yr and BMI 24.2±2.7 kg/m2) volunteered to participate in the study. Muscle SNA (microneurography), ventilation and blood pressure were measured during randomized 5-min breathing trials; room-air, isocapnic hypoxia [10% inspired oxygen (O2)], hypercapnic hyperoxia [7% inspired carbon dioxide (CO2), 50%O2] and hypercapnic hypoxia (7%CO2, 10%O2). ABR-SNA sensitivity was determined as the slope of the linear relationship between SNA burst incidence (i.e., bursts/100 heart beats) and diastolic blood pressure. Results Compared to room-air, isocapnic hypoxia, hypercapnic hyperoxia and hypercapnic hypoxia elevated both muscle SNA (16±5, 20±6, 27±7 and 31±8 bursts/100 heart beats, respectively, p<0.001) and ventilation (7.3±2.5, 9.9±3.6, 21.4±4.3 and 31.1±5.5 L/min, respectively, p<0.001). No between-trial differences were observed in mean blood pressure (p=0.32). ABR-SNA slope was not different during room air, isocapnic hypoxia, hypercapnic hyperoxia and hypercapnic hypoxia (-3.76±1.12, -2.95±1.03, -3.97±2.08 and -2.53±2.24 bursts/100 heart beats/mmHg, respectively, p=0.67). No sex-differences in muscle SNA, ventilation, mean blood pressure and ABR-SNA slope were observed. Discussion These preliminary findings suggest that sympatho-excitation evoked by hypoxia, hypercapnia and hypercapnic hypoxia are similar between men and women and are not attributable to a concurrent reduction in ABR-SNA sensitivity. Thus, elevated SNA evoked by peripheral and central chemoreflexes reflects a primary reflex response of chemoreceptor origin.

Blunted sympathetic neurovascular transduction during normotensive pregnancy.

Normotensive pregnancy is associated with elevated sympathetic nervous system activity yet normal or reduced blood pressure. It represents a unique period of apparent healthy sympathetic hyperactivity. The present study models the blood pressure and heart rate (ECG R-R interval) responses to fluctuations in sympathetic nervous system activity aiming to understand neurocardiovascular transduction. The reported data clearly demonstrate that transduction of sympathetic nervous system signalling to systemic cardiovascular outcomes is reduced in normotensive pregnancy. These data are important for understanding how blood pressure regulation adapts during normotensive pregnancy and set the foundation for exploring similar mechanisms in hypertensive pregnancies. Previously, we described sympathetic nervous system hyperactivity yet decreased blood pressure responses to stress in normotensive pregnancy. To address the hypothesis that pregnant women have blunted neurocardiovascular transduction we assessed the relationship between spontaneous bursts of sympathetic nerve activity (SNA) and fluctuations in mean arterial blood pressure and R-R interval. Resting SNA, blood pressure and ECG were obtained in pregnant (third trimester, n=18) and non-pregnant (n=18) women matched for age and pre-/non-pregnant body mass index. Custom software modelled beat-by-beat pressure (photoplethysmography) and R-R interval in relation to sequences of SNA bursts and non-bursts (peroneal microneurography). Sequences were grouped by the number of bursts and non-bursts [singlets, doublets, triplets and quadruplet (four or more)] and mean blood pressure and R-R interval were tracked for 15 subsequent cardiac cycles. Similar sequences were overlaid and averaged. Peak mean pressure in relation to sequences of SNA was reduced in pregnant vs. non-pregnant women (doublets: 1.6±1.1mmHg vs. 3.6±3.1mmHg, P<0.05; triplets: 2.4±1.2mmHg vs. 3.4±2.1mmHg, P<0.05; quadruplets: 3.0±1.0mmHg vs. 5.5±3.7mmHg, P<0.05). The nadir R-R interval following burst sequences was also smaller in pregnant vs. non-pregnant women (singlets: -0.01±0.01s vs. -0.04±0.04s, P<0.05; doublets: -0.02±0.03s vs. -0.05±0.04s, P<0.05; triplets: -0.02±0.01s vs. -0.07±0.04s, P<0.05; quadruplets: -0.01±0.01s vs. -0.09±0.09s, P<0.05). There were no differences between groups in the mean arterial pressure and R-R interval responses to non-burst sequences. Our data clearly indicate blunted systemic neurocardiovascular transduction during normotensive pregnancy. We propose that blunted transduction is a positive adaptation protecting pregnant women from the cardiovascular consequences of sympathetic hyperactivity.

Exaggerated Alpha‐1 Adrenoreceptor Mediated Vasoconstriction in Young Black Men is not Influenced by Superoxide‐Mediated Oxidative Stress

Black individuals (BL) have a greater risk for hypertension and cardiovascular disease than other populations, the cause of which is likely multifactorial. However, vascular dysfunction appears to be a key preceding factor to the racial disparities observed. This observation has been demonstrated in young, otherwise healthy BL. Our group recently demonstrated that young BL men (BM) exhibit exaggerated sympathetic vascular transduction (SVT), i.e., greater vasoconstriction and pressor responses to spontaneous bursts of sympathetic nerve activity, at rest compared to young white men (WM). This response may be mediated by elevated oxidative stress, which may be 1) reducing nitric oxide (NO) bioavailability and subsequent vasodilatory capacity and/or 2) directly affecting blood vessel reactivity. In this regard, previous literature has established that young BM have elevated oxidative stress and reduced NO bioavailability relative to other populations. Whether these conditions contribute to increased SVT in BM is currently unknown. Accordingly, this study tested the hypothesis that BM have an exaggerated vasoconstrictor response to the selective α1‐adrenoreceptor agonist phenylephrine (PE) compared to WM which is augmented by elevated oxidative stress. To test this hypothesis, four intradermal microdialysis membranes were placed in the dorsal forearm of 3 WM and 6 BM (mean ± SD; age: 24±5 vs. 22±3 y) and the skin blood flow (SkBF) responses to intradermal infusion of PE were assessed. Following trauma resolution, each site received one of four infusions for 30‐min: lactated Ringer's (control), apocynin (NADPH oxidase inhibitor; 100 μM), allopurinol (xanthine oxidase inhibitor; 10 μM), or tempol (superoxide scavenger; 10 μM). Each site was then locally heated to 33°C for 10‐min to establish baseline SkBF. Each site then received a coinfusion of PE (100 mM) for 6‐min to elicit vasoconstriction, with the response presented as a percent reduction in cutaneous vascular conductance (CVC; flux/mean arterial pressure) from baseline (%CVCB). Following PE administration, BM exhibited exaggerated vasoconstriction compared to WM (control: −69.0±16.5 vs. −34.8±15.2 %CVCB; apocynin: −58.1±18.3 vs. −43.5± 2.4 %CVCB; allopurinol: −59.2±13.1 vs. −53.5±23.3 %CVCB; tempol: −63.5±18.1 vs. −37.7±16.7 %CVCB; main effect: P &lt; 0.01). However, no interaction effect was observed for the race‐by‐site comparison (P = 0.35), suggesting no effect of the drugs used across races. In conclusion, these preliminary data suggest that BM exhibit exaggerated α1‐adrenoreceptor‐mediated vasoconstriction compared to WM, which is consistent with previous literature. Furthermore, these preliminary findings indicate this response is not superoxide‐mediated, suggestive of a different, currently unknown controlling mechanism for exaggerated vasoconstriction.Support or Funding InformationUTA Start‐up funds to R. Matthew BrothersThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control.

We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test-re-test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age-related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti-hypertensive medication. Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra-indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during β-blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs. OM (0.10±0.01mmHg (%s)(-1) , n=23 vs. 0.06±0.01mmHg (%s)(-1) , n=18; P=0.003). Transduction was lowest in YW (0.02±0.01mmHg (%s)(-1) , n=23) and increased during β-blockade (0.11±0.01mmHg (%s)(-1) ; P<0.001). Transduction in PMW (0.07±0.01mmHg (%s)(-1) , n=23) was greater compared to YW (P=0.001), and was not altered during β-blockade (0.06±0.01mmHg (%s)(-1) ; P=0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55±1.5years. This measure of transduction captures age- and sex-differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.

Sympathetic Neurovascular Regulation During Pregnancy: A Longitudinal Case Study

Pregnancy is associated a ~50% increase in blood volume, ~40% increase in cardiac output (Q), offset by a drop in total peripheral resistance (TPR). While limited data indicate a concurrent increase in sympathetic nerve activity (SNA) in normal pregnancy, suggesting reduced transduction of SNA into TPR, longitudinal neurovascular adaptation during gestation remains poorly understood.We conducted a longitudinal assessment of SNA and TPR in a 36 year old woman during her second pregnancy. Measures were made on 2 occasions in the month prior to conception, 4 occasions during pregnancy (9, 24, 30, and 38 wks gestation) and again 10 wks postpartum. Mean arterial pressure (MAP; Finometer) and Q (ModelFlow) were measured and used to calculate TPR. SNA was measured using microneurography (peroneal nerve).There was a gestationally dependent increase in SNA burst frequency (r2=0.970, P&lt;0.01) and incidence (r2=0.977, P&lt;0.01); frequency (24 bpm to 59 bpm) and incidence (34 b/100hb to 65 b/100hb) increased 145% and 89% respectively by 38 wks compared to early follicular values. However, transduction (TPR/SNA Burst Frequency) decreased throughout pregnancy (r2=0.952, P&lt;0.05; 0.80 au to 0.21 au). By 10 wks postpartum, SNA (24 bpm; 28 b/100hb) had returned to pre‐pregnant values whereas transduction (0.44au) remained lower.These longitudinal data highlight the progressive sympoathoexcitation during pregnancy which is offset by a concurrent reduction in neurovascular transduction. Sympathetic hyperactivity reverses early in the post‐partum whereas transduction remains decreased. Funded by WCHRI, NSERC, HPF

Active vasodilation by sympathetic outflow to limb skin in a patient with progressive aphasia

Despite considerable interest, a pure vasodilator response by skin sympathetic nerve activity (SSNA) bursts in human limbs has not been observed in previous studies. In a patient with progressive nonfluent aphasia, SSNA, sympathetic skin response, and skin blood flow were simultaneously recorded at rest and during electrical stimulation. There was a very low frequency of SSNA bursts at rest, and when electrical stimulation was delivered, reflex bursts of SSNA were always observed followed by a sympathetic skin response and an increase in skin blood flow. The reflex latency of SSNA was slightly prolonged and the mean amplitude of reflex SSNA bursts was lower after electrical stimulation, compared with the responses in healthy controls. We report for the first time that the active vasodilator component of cutaneous sympathetic activity in limbs was recorded without any vasoconstrictor component in a patient with progressive aphasia.

Differential regulation of sympathetic burst frequency and amplitude following acute hypoxia in humans

Current evidence suggests that the persistent sympathetic nerve activity (SNA), commonly observed after exposure to hypoxia (HX), is mediated by chemoreceptor sensitization and or baroreflex resetting. Evidence in humans and animals suggests that these reflexes may independently regulate the frequency (gating) and amplitude (neuronal recruitment) of SNA bursts. In humans (n = 7), we examined the regulation of SNA following acute isocapnic HX (5 min; end-tidal P(O2) = 45 Torr) and euoxic hypercapnia (HC; 5 min; end-tidal P(CO2) = +10 from baseline). HX increased SNA burst frequency (21 ± 7 to 28 ± 8 bursts/min, P < 0.05) and amplitude (99 ± 10 to 125 ± 19 au, P < 0.05) as did HC (14 ± 6 to 22 ± 10 bursts/min, P < 0.05 and 100 ± 12 to 133 ± 29 au, P < 0.05, respectively). Burst frequency (26 ± 7 bursts/min, P < 0.05), but not amplitude (97 ± 12 au), remained elevated 10 min post-HX. The change in burst amplitude (but not frequency) was significantly related to the measured change in ventilation (r(2) = 0.527, P < 0.001). Both frequency and amplitude decreased during recovery following HC. These data indicate the differential regulation of pattern and magnitude of sympathetic outflow in humans with sympathetic persistence following HX being specific to burst frequency and not amplitude.

Differential regulation of sympathetic burst frequency and amplitude following acute hypoxia

Current evidence suggests that the persistent sympathetic nerve activity (SNA), commonly observed following exposure to hypoxia (HX), is mediated by chemoreceptor sensitization and baroreflex resetting. Evidence in animals suggests that these reflexes may independently regulate the frequency (gating) and amplitude (neuronal recruitment) of SNA bursts. In humans (n=7) we examined the regulation of SNA following acute isocapnic HX (5 min; end‐tidal PO2 = 45 Torr) and euoxic hypercapnia (HC; 5 min; end‐tidal PCO2 = +10 from baseline). HX increased SNA burst frequency (21±7 to 28±8 Burst/min, P&lt;0.05) and amplitude (99±10 to 125±19 au, P&lt;0.05) as did HC (14±6 to 22±10 bursts/min, P&lt;0.05 and 100±12 to 133±29 au, P&lt;0.05 respectively). Burst frequency (26±7 bursts/min, P&lt;0.05), but not amplitude (97±12 au), remained elevated 10 min post HX. Both frequency and amplitude decreased during recovery following HC. These data clearly indicate two separate mechanisms, related to HX, regulating the pattern and magnitude of sympathetic outflow in humans. This study was supported by NSERC.

Sympathetic nerves and the endothelium influence the vasoconstrictor effect of low concentrations of ouabain in pressurized small arteries

We hypothesized that in salt-dependent forms of hypertension, endogenous ouabain acts on arterial smooth muscle to cause enhanced vasoconstriction. Here, we tested for the involvement of the arterial endothelium and perivascular sympathetic nerve terminals in ouabain-induced vasoconstriction. Segments of rat mesenteric or renal interlobar arteries were pressurized to 70 mmHg at 37 degrees C and exposed to ouabain (10(-11)-10(-7) M). Removal of the endothelium enhanced ouabain-induced vasoconstriction by as much as twofold (at an ouabain concentration of 10(-9) M). A component of the ouabain-induced vasoconstriction is due to the enhanced spontaneous release of norepinephrine (NE) from nerve terminals in the arterial wall. The alpha(1)-adrenoceptor blocker prazosin (10(-6) M) decreased ouabain-induced vasoconstrictions by as much as 50%. However, neither the contraction induced by sympathetic nerve activity (SNA) nor the NE release evoked by SNA (measured directly by carbon fiber amperometry) was increased by ouabain (<10(-7) M). Nevertheless, the converse case was true: after brief bursts of SNA, vasoconstrictor responses to ouabain were transiently increased (1.75-fold). This effect may be mediated by neuropeptide Y and Y(1) receptors on smooth muscle. In arteries lacking the endothelium and exposed to prazosin, ouabain (10(-11) M and greater) caused vasoconstriction, indicating a direct effect of very "low" concentrations of ouabain on arterial smooth muscle. In conclusion, in intact arteries, the endothelium opposes ouabain (10(-11)-10(-7)M)-induced vasoconstriction, which is caused by both enhanced spontaneous NE release and direct effects on smooth muscle. Ouabain (<10(-7)M) does not enhance SNA-mediated contractions, but SNA enhances ouabain-induced contractions. The effects of endogenous ouabain may be accentuated in forms of hypertension that involve sympathetic nerve hyperactivity and/or endothelial dysfunction.

Sympathetic Nerves and Endothelium Influence the Vasoconstrictor Effect of Low Concentrations of Ouabain in Pressurized Small Arteries

Here, we tested the involvement of arterial endothelium and peri‐vascular sympathetic nerve terminals (NT) in ouabain‐induced vasoconstriction. Segments of rat arteries were pressurized and exposed to ouabain (10−11M–10−7M). Endothelium removal enhanced ouabain‐induced (10−9M) vasoconstriction as much as 2‐fold. A component of the ouabain‐induced vasoconstriction is due to enhanced spontaneous release of norepinephrine (NE) from NT's in the arterial wall. The α1‐adrenoceptor blocker, prazosin (10−6M) decreased ouabain induced vasoconstrictions by as much as 50%. The electrically evoked release of NE from sympathetic NT was not affected by ouabain (&lt; 10−7M). However, neither the ouabain induced contraction nor the NE release (measured directly by carbon fiber amperometry) was increased by sympathetic nerve activity (SNA). However, following brief bursts of SNA, vasoconstrictor responses to ouabain were transiently increased (1.75‐fold). In arteries lacking endothelium and exposed to prazosin, ouabain (&gt;10−11M) caused vasoconstriction, indicating a direct effect on arterial smooth muscle. Conclusions: Endothelium opposes ouabain induced vasoconstriction, which is caused by both enhanced spontaneous NE release and direct effects on smooth muscle. Ouabain does not enhance SNA mediated contractions, but SNA enhances ouabain‐induced contraction.NIH grants R01‐HL073094 &amp; P01‐HL078870

The influence of beat‐to‐beat changes in muscle sympathetic nerve activity on vascular conductance in humans

Sympathetic nerve activity (SNA) is important for beat‐to‐beat regulation of arterial blood pressure (BP). Previous studies have indicated that a burst of muscle SNA results in a peak BP response of ~3 mmHg with a latency of 5.5 seconds. This delay is thought to represent the transduction time of a SNA burst into a change in vascular smooth muscle tone. However, the influence of a SNA burst on beat‐to‐beat alterations in vascular conductance has not been clearly identified. Therefore, in 5 young men, muscle SNA, diastolic BP and brachial artery blood flow were measured. Changes in diastolic BP and calculated forearm vascular conductance (FVC) were characterized for 15 cardiac cycles following each individual muscle SNA burst to describe the latency and magnitude of peak changes in diastolic BP and FVC to the burst of muscle SNA. A clear increase in DBP (Δ 2.0±0.2 mmHg) followed a burst of muscle SNA with a latency of 5.9±0.7 seconds. In contrast, decreases in FVC after a burst of muscle SNA were not readily apparent. These preliminary results suggest that a clear magnitude and latency for increases in diastolic BP following a burst of muscle SNA can be identified on a beat to beat basis; however, related decreases in FVC are not easily observed. The pattern of muscle SNA firing (single burst vs. volley of bursts) and burst size warrants additional consideration. Support: NIH RO1HL093167

Insulin‐mediated increases in arterial baroreflex control of muscle sympathetic nerve activity following meal intake in humans

Animal studies indicate that insulin enhances arterial baroreflex (ABR) control of sympathetic nerve activity (SNA); however, the extent to which these findings can be extrapolated to humans is unknown. To begin to address this, we utilized a mixed meal as a physiological method to evoke sustained increases in plasma insulin. Muscle SNA and arterial blood pressure (BP) were measured in 10 subjects (25 ± 2 yr) before and for 120 minutes following mixed meal intake. Weighted linear regression analysis between muscle SNA and diastolic BP was used to determine the gain (i.e. sensitivity) of ABR control of SNA. Plasma insulin was significantly elevated within 30 minutes following meal intake (Δ29 ± 7 uIU; P&lt;0.05) and remained above baseline for up to 120 minutes. Similarly, 30 minutes after meal intake, ABR gain of muscle SNA burst incidence (−3.31 ± 0.64 vs. −5.13 ± 0.95 bursts/100 heart beats/mmHg; baseline vs. 30 min, P&lt;0.05) and total muscle SNA (−3.22 ± 0.60 vs. −5.89 ± 1.30 arbitrary units/beat/mmHg; baseline vs. 30 min, P&lt;0.05) was increased and remained elevated for the duration of the protocol. BP was unchanged by meal intake. In a subset of subjects the ABR muscle SNA gain remained unchanged during time control experiments. These preliminary findings suggest that increases in plasma insulin following meal intake enhance the gain of ABR control of muscle SNA in healthy humans.Support: NIH RO1HL093167

Amplified respiratory–sympathetic coupling in the spontaneously hypertensive rat: does it contribute to hypertension?

Sympathetic nerve activity (SNA) is elevated in established hypertension. We tested the hypothesis that SNA is elevated in neonate and juvenile spontaneously hypertensive (SH) rats prior to the development of hypertension, and that this may be due to augmented respiratory-sympathetic coupling. Using the working heart-brainstem preparation, perfusion pressure, phrenic nerve activity and thoracic (T8) SNA were recorded in male SH rats and normotensive Wistar-Kyoto (WKY) rats at three ages: neonates (postnatal day 9-16), 3 weeks old and 5 weeks old. Perfusion pressure was higher in SH rats at all ages reflecting higher vascular resistance. The amplitude of respiratory-related bursts of SNA was greater in SH rats at all ages (P < 0.05). This was reflected in larger Traube-Hering pressure waves in SH rats (1.4 +/- 0.8 versus 9.8 +/- 1.5 mmHg WKY versus SH rat, 5 weeks old, n = 5 per group, P < 0.01). Recovery from hypocapnic-induced apnoea and reinstatement of Traube-Hering waves produced a significantly greater increase in perfusion pressure in SH rats (P < 0.05). Differences in respiratory-sympathetic coupling in the SH rat were not secondary to changes in central or peripheral chemoreflex sensitivity, nor were they related to altered arterial baroreflex function. We have shown that increased SNA is already present in SH rats in early postnatal life as revealed by augmented respiratory modulation of SNA. This is reflected in an increased magnitude of Traube-Hering waves resulting in elevated perfusion pressure in the SH rat. We suggest that the amplified respiratory-related bursts of SNA seen in the neonate and juvenile SH rat may be causal in the development of their hypertension.

Baroreflex mechanisms regulating mean level of SNA differ from those regulating the timing and entrainment of the sympathetic discharges in rabbits

The arterial baroreflex pathway provides the fundamental basis for the short-term control of blood pressure via the rapid regulation of the mean level of sympathetic nerve activity (SNA) in response to changes in blood pressure. A central tenet in the generation and regulation of bursts of SNA is that input from the arterial baroreceptors also regulates the timing of the bursts of sympathetic activity. With the use of an implantable telemetry-based amplifier, renal SNA was recorded in intact and arterial baroreceptor-denervated (SAD) conscious rabbits. Data were collected continuously while animals were in their home cage. Mean levels of SNA were not different between SAD and baroreceptor-intact animals. Whereas SNA was unresponsive to changes in blood pressure in SAD rabbits, the timing of the bursts of SNA relative to the arterial pulse wave was maintained (time between the diastolic pressure and the next maximum SNA voltage averaged 107+/-12 ms SAD vs. 105+/-7 ms intact). Transfer function analysis between blood pressure and SNA indicates the average gain at the heart rate frequency was not altered by SAD, indicating strong coupling between the cardiac cycle and SNA bursts in SAD animals. Further experiments in anesthetized rabbits showed that this entrainment is lost immediately after performing baroreceptor denervation surgery and remained absent while the animal was under anesthesia but returned within 20 min of turning off the anesthesia. We propose that this finding indicates the regulation of the mean level of SNA requires the majority of input from baroreceptors to be functional; however, the regulation of the timing of the bursts in the conscious animal requires only minimal input, such as a sensitive trigger mechanism. This observation has important implications for understanding the origin and regulation of SNA.

Naloxone does not affect the cardiovascular and sympathetic adjustments to static exercise in humans

Previous studies suggested that endogenous opiates may attenuate the cardiovascular and sympathetic adjustments to static exercise. We tested whether this effect originates from exercising skeletal muscle. Eight men performed 2 min of static handgrip (30% maximum) followed by 2 min of posthandgrip muscle ischemia after three interventions: 1) control, 2) intra-arterial injection of naloxone HCl (60 micrograms) or vehicle (saline) in the exercising arm, and 3) systemic infusion of naloxone (4 mg) or vehicle. Naloxone and vehicle trials were performed double blind on separate days. Preexercise baseline muscle sympathetic nerve activity (burst frequency), heart rate, and blood pressure were similar across interventions on either day. During static handgrip, control, intra-arterial, and systemic administration of vehicle and naloxone elicited similar increases in total muscle sympathetic nerve activity (58 +/- 24 vs. 68 +/- 26, 146 +/- 49 vs. 132 +/- 42, 137 +/- 54 vs. 164 +/- 44%, respectively), heart rate (9 +/- 2 vs. 8 +/- 3, 16 +/- 3 vs. 16 +/- 2, 20 +/- 4 vs. 19 +/- 3 beats/min, respectively), and mean arterial pressure (22 +/- 4 vs. 21 +/- 4, 29 +/- 5 vs. 26 +/- 3, 28 +/- 4 vs. 27 +/- 4 mmHg, respectively). Additionally, there were no differences between vehicle and naloxone trials during posthandgrip muscle ischemia. Thus, contrary to previous reports, we conclude that the endogenous opiate peptide system does not modulate cardiovascular and sympathetic responses to brief periods of static exercise or muscle ischemia in humans.