Impact of maternal obesity on resting muscle sympathetic nerve activity during uncomplicated pregnancy: a longitudinal assessment.

Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to greater activity of the sympathetic nervous system, which is associated with hypertensive disorders of pregnancy. We hypothesized that resting muscle sympathetic nerve activity (MSNA) would be greater in women with obesity during pregnancy when compared with normal-weight women. Blood pressure, heart rate, and MSNA were recorded during 5 min of supine rest in 14 normal-weight women [body mass index (BMI) 22.1 ± 2.1 (SD) kg/m2] and 14 women with obesity (BMI 33.9 ± 3.5 kg/m2) during (early and late) pregnancy and postpartum. All women had uncomplicated pregnancies. Resting MSNA burst frequency was not different between groups during early (normal weight 17 ± 10 vs. obesity 22 ± 15 bursts/min, P = 0.35) but was significantly greater in the obesity group during late pregnancy (23 ± 13 vs. 35 ± 15 bursts/min, P = 0.031) and not different postpartum (10 ± 6 vs. 9 ± 7 bursts/min, P = 0.74). These findings were also apparent when comparing burst incidence and total activity. Although still within the normotensive range, systolic blood pressure was greater in the obesity group across all time points (P = 0.002). Diastolic blood pressure was lower during pregnancy compared with postpartum (P < 0.001) and not different between groups (P = 0.488). Heart rate increased throughout pregnancy in both groups (P < 0.001). Our findings suggest that maternal obesity is associated with greater increases in sympathetic activity even during uncomplicated pregnancy. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy.NEW & NOTEWORTHY The impact of maternal obesity on resting muscle sympathetic nerve activity was examined during (early and late) and after uncomplicated pregnancy. Resting muscle sympathetic nerve activity is not different during early pregnancy or postpartum but is significantly elevated in women with obesity during late pregnancy when compared with normal-weight women. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy.

Baroreflex resetting of human sympathetic action potential subpopulations during exercise.

This study tested the hypothesis that during fatiguing volitional exercise in humans, descending cortical signals and ascending skeletal muscle metaboreflex signals exert divergent control over baroreflex resetting of sympathetic action potential (AP) discharge. We quantified the baroreflex gain for sympathetic AP clusters within the muscle sympathetic nerve activity neurogram (peroneal microneurography and continuous wavelet transform) during baseline (BSL), the first 2-min of a 5-min isometric handgrip (20% of maximal effort; IHG1), the last 2-min of IHG (IHG2), and during postexercise circulatory occlusion (PECO) in seven healthy participants. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability (%) versus diastolic blood pressure (DBP; mmHg) for 10 normalized AP clusters. Compared with BSL, during IHG1, AP baroreflex threshold functions were only reset to greater DBP and baroreflex gain was unaffected. Compared with BSL, during IHG2 and PECO, baroreflex functions were reset to greater DBP and to greater AP firing probabilities, with medium-sized APs demonstrating the largest upward resetting (e.g., cluster 3 BSL: 26 ± 7%, cluster 3 IHG2: 78 ± 22%, cluster 3 PECO: 88 ± 46%). Compared with BSL, AP baroreflex threshold gain was not different during IHG2 but was increased during PECO, with medium-sized APs demonstrating the largest increase in baroreflex gain (e.g., cluster 3 BSL: -6.31 ± 3.1%/mmHg, cluster 3 IHG2: -6.18 ± 5.4%/mmHg, cluster 3 PECO: -12.13 ± 6.5%/mmHg). These findings indicate that during IHG exercise, descending cortical signaling and ascending skeletal muscle metaboreceptor signals differentially affect baroreflex resetting of subpopulations of human muscle sympathetic postganglionic neurons.NEW & NOTEWORTHY This study provides new insight to baroreflex resetting of MSNA during exercise in humans. Both fatiguing IHG and PECO reset baroreflex control of sympathetic APs to higher blood pressures and greater MSNA. However, only PECO increased baroreflex threshold gain of medium-sized sympathetic APs, an effect that was concealed when focusing on the integrated MSNA neurogram to quantify baroreflex gain. These data suggest that descending central versus ascending muscle metaboreflex mechanisms differentially affect baroreflex resetting of sympathetic APs.

Influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity in healthy adults.

We examined the influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity (MSNA) in healthy adults. Data were assessed from 224 volunteers (88 females), aged 18-76 yr, in whom resting MSNA (microneurography) and peak oxygen uptake (V̇o2peak; incremental exercise test) were evaluated. When separated into younger (<50 yr) and older (≥50 yr) subgroups, there were inverse relationships between relative V̇o2peak (mL·kg-1·min-1) and MSNA burst frequency in younger males (R2 = 0.21, P < 0.0001) and older females (R2 = 0.36, P < 0.01), but not older males (R2 = 0.05, P = 0.08) or younger females (R2 = 0.03, P = 0.14). Similar patterns were observed with absolute V̇o2peak (L·min-1) and percent-predicted (based on age, sex, weight, height, and modality), and with burst incidence. Sex and age influence the relationship between aerobic fitness and resting MSNA, and, thus, must be considered as key variables when studying these potential associations; inverse relationships are strongest in younger males and older females.NEW & NOTEWORTHY Our data reveal for the first time that associations between aerobic fitness and resting muscle sympathetic nerve activity are sex and age specific; inverse relationships are evident in younger males (<50 yr) and older females (≥50 yr), but absent in younger females (<50 yr) and older males (≥50 yr).

Impaired sympathetic neural recruitment during exercise pressor reflex activation in women with post-traumatic stress disorder.

Muscle sympathetic nerve activity (MSNA) increases during isometric exercise via increased firing of low-threshold action potentials (AP), recruitment of larger, higher-threshold APs, and synaptic delay modifications. Recent work found that women with post-traumatic stress disorder (PTSD) demonstrate exaggerated early-onset MSNA responses to exercise; however, it is unclear how PTSD affects AP recruitment patterns during fatiguing exercise. We hypothesized that women with PTSD (n = 11, 43 [11] [SD] years) would exhibit exaggerated sympathetic neural recruitment compared to women without PTSD (controls; n = 13, 40 [8] years). MSNA and AP discharge patterns (via microneurography and a continuous wavelet transform) were measured during 1 min of baseline, isometric handgrip exercise (IHG) to fatigue, 2 min of post-exercise circulatory occlusion (PECO), and 3 min of recovery. Women with PTSD were unable to increase AP content per burst compared to controls throughout IHG and PECO (main effect of group: P = 0.026). Furthermore, relative to controls, women with PTSD recruited fewer AP clusters per burst during the first (controls: ∆1.3 [1.2] vs. PTSD: ∆-0.2 [0.8]; P = 0.016) and second minute (controls: ∆1.2 [1.1] vs. PTSD: ∆-0.1 [0.8]; P = 0.022) of PECO, and fewer subpopulations of larger, previously silent axons during the first (controls: ∆5 [4] vs. PTSD: ∆1 [2]; P = 0.020) and second minute (controls: ∆4 [2] vs. PTSD: ∆1 [2]; P = 0.021) of PECO. Conversely, PTSD did not modify the AP cluster size-latency relationship during baseline, the end of IHG, or PECO (all P = 0.658-0.745). Collectively, these data indicate that women with PTSD demonstrate inherent impairments in the fundamental neural coding patterns elicited by the sympathetic nervous system during IHG and exercise pressor reflex activation.

Posture-related changes in sympathetic baroreflex sensitivity during normal pregnancy.

Normal pregnancy is associated with vast adjustments in cardiovascular autonomic control. Sympathetic baroreflex sensitivity has been reported to be attenuated during pregnancy in animal models, but most studies in humans are cross-sectional and findings from longitudinal case studies are inconclusive. It remains unclear how sympathetic baroreflex sensitivity is altered longitudinally during pregnancy within an individual in different body postures. Therefore, this study examined the impact of posture on sympathetic baroreflex sensitivity in 24 normal-weight normotensive pregnant women. Spontaneous sympathetic baroreflex sensitivity was assessed during early (6-11 weeks) and late (32-36 weeks) pregnancy and 6-10 weeks postpartum in the supine posture and graded head-up tilt (30° and 60°). In addition, data from the postpartum period were compared with (and no different to) 18 age-matched non-pregnant women to confirm that the postpartum period was reflective of a non-pregnant condition (online supplement). When compared with postpartum (-3.8 ± 0.4 bursts/100 heartbeats/mmHg), supine sympathetic baroreflex sensitivity was augmented during early pregnancy (-5.9 ± 0.4 bursts/100 heartbeats/mmHg, P < 0.001). However, sympathetic baroreflex sensitivity at 30° or 60° head-up tilt was not different between any phase of gestation (P > 0.05). When compared to supine, sympathetic baroreflex sensitivity at 60° head-up tilt was significantly blunted during early (Δ2.0 ± 0.7 bursts/100 heartbeats/mmHg, P = 0.024) and late (Δ1.5 ± 0.6 bursts/100 heartbeats/mmHg, P = 0.049) pregnancy but did not change postpartum (Δ0.4 ± 0.6 bursts/100 heartbeats/mmHg, P = 1.0). These data show that time-course changes in sympathetic baroreflex sensitivity are dependent on the posture it is examined in and provides a foundation of normal blood pressure regulation during pregnancy for future studies in women at risk for adverse pregnancy outcomes.

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.

Low-dose ketamine affects blood pressure, but not muscle sympathetic nerve activity, during progressive central hypovolemia without altering tolerance.

KEY POINTS: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. Given that a haemorrhagic injury on the battlefield is almost always associated with pain, it is paramount that the administered pain medication does not disrupt the physiological mechanisms that are beneficial in defending against the haemorrhagic insult. Current guidelines from the US Army's Committee on Tactical Combat Casualty Care (CoTCCC) for the selection of pain medications administered to a haemorrhaging soldier are based upon limited scientific evidence, with the clear majority of supporting studies being conducted on anaesthetized animals. Specifically, the influence of low-dose ketamine, one of three analgesics employed in the pre-hospital setting by the US Army, on haemorrhagic tolerance in humans is unknown. For the first time in conscious males and females, the findings of the present study demonstrate that the administration of an analgesic dose of ketamine does not compromise tolerance to a simulated haemorrhagic insult. Increases in muscle sympathetic nerve activity during progressive lower-body negative pressure were not different between trials. Despite the lack of differences for muscle sympathetic nerve activity responses, mean blood pressure and heart rate were higher during moderate hypovolemia after ketamine vs. placebo administration. ABSTRACT: Haemorrhage is the leading cause of battlefield and civilian trauma deaths. For a haemorrhaging soldier, there are several pain medications (e.g. ketamine) recommended for use in the prehospital, field setting. However, the data to support these recommendations are primarily limited to studies in animals. Therefore, it is unknown whether ketamine adversely affects physiological mechanisms responsible for maintenance of arterial blood pressure (BP) during haemorrhage in humans. In humans, ketamine has been demonstrated to raise resting BP, although it has not been studied with the concomitant central hypovolemia that occurs during haemorrhage. Thus, the present study aimed to test the hypothesis that ketamine does not impair haemorrhagic tolerance in humans. Thirty volunteers (15 females) participated in this double-blinded, randomized, placebo-controlled trial. A pre-syncopal limited progressive lower-body negative pressure (LBNP; a validated model for simulating haemorrhage) test was conducted following the administration of ketamine (20 mg) or placebo (saline). Tolerance was quantified as a cumulative stress index and compared between trials using a paired, two-tailed t test. We compared muscle sympathetic nerve activity (MSNA; microneurography), beat-to-beat BP (photoplethysmography) and heart rate (electrocardiogram) responses during the LBNP test using a mixed effects model (time [LBNP stage] × drug). Tolerance to the LBNP test was not different between trials (Ketamine: 635 ± 391 vs. Placebo: 652 ± 360 mmHg‧min, p = 0.77). Increases in MSNA burst frequency (time: P < 0.01, trial: p = 0.27, interaction: p = 0.39) during LBNP stages were no different between trials. Despite the lack of differences for MSNA responses, mean BP (time: P < 0.01, trial: P < 0.01, interaction: p = 0.01) and heart rate (time: P < 0.01, trial: P < 0.01, interaction: P < 0.01) were higher during moderate hypovolemia after ketamine vs. placebo administration (P < 0.05 for all, post hoc), but not at the end of LBNP. These data, which are the first to be obtained in conscious humans, demonstrate that the administration of low-dose ketamine does not impair tolerance to simulated haemorrhage or mechanisms responsible for maintenance of BP.

Influence of multiparity on sympathetic nerve activity during normal pregnancy.

Recent evidence suggests an elevated risk of cardiovascular disease development in multiparous women. Therefore, we investigated the effects of multiparity on within-pregnancy sympathetic neural regulation in normotensive, pregnant women. We retrospectively analyzed heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA; n = 8) data from 10 women whom participated in microneurographic research studies during two sequential pregnancies (i.e., PREG1 and PREG2). There was no difference in resting BP between pregnancies (P > 0.05), whereas HR trended higher in PREG2 versus PREG1 (P = 0.06). MSNA burst frequency was greater in PREG2 versus PREG1 after adjusting for age (32 ± 12 vs. 22 ± 12 bursts/min; P = 0.049), whereas burst incidence did not differ (40 ± 16 vs. 34 ± 17 bursts/100 heartbeats; P = 0.21). Sympathetic baroreflex sensitivity was not different between PREG1 and PREG2 (P > 0.05). Our results may highlight a possible role of altered within-pregnancy sympathetic neural regulation in the observed relationship in women between parity and future cardiovascular disease risk.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the effects of multiparity on within-pregnancy sympathetic neural regulation. We observed augmented muscle sympathetic nerve activity in women's second studied pregnancy versus their first. Conversely, blood pressure and sympathetic baroreflex sensitivity did not differ, whereas a trend for increased heart rate was observed. Our results highlight a possible role of altered within-pregnancy sympathetic neural regulation in the relationship between increased parity and cardiovascular disease development.

Early onset neurocirculatory response to static handgrip is associated with greater blood pressure variability in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric illness that is more prevalent in women, and accumulating evidence suggests a link between PTSD and future development of cardiovascular disease. The underlying mechanisms are unclear, but augmented sympathetic reactivity to daily stressors may be involved. We measured muscle sympathetic nerve activity (MSNA), blood pressure (BP), and heart rate responses in 14 women with PTSD and 14 healthy women (controls) during static handgrip (SHG) exercise to fatigue at 40% of maximal voluntary contraction (MVC). Two minutes of postexercise circulatory arrest (PECA) was followed immediately after SHG to fatigue. MVC and the time to fatigue during SHG did not differ between groups (both P > 0.05). At the first 30 s of SHG, women with PTSD showed augmented sympathetic neural [mean ± SD, ∆MSNA burst frequency (BF): 5 ± 4 vs. 2 ± 3 bursts/30 s, P = 0.02 and ∆MSNA total activity (TA): 82 ± 58 vs. 25 ± 38 arbitrary units/30 s, P = 0.004] and pressor (∆systolic BP: 10 ± 5 vs. 4 ± 3 mmHg, P = 0.003) responses compared with controls. However, MSNA and BP responses at fatigue and during PECA were not different between groups. More interestingly, the augmented initial neural and pressor responses to SHG were associated with greater awake systolic BP variability during ambulation in women with PTSD (MSNA BF: r = 0.55, MSNA TA: r = 0.62, and SBP: r = 0.69, all P < 0.05). These results suggest that early onset exercise pressor response in women with PTSD may be attributed to enhanced mechano- rather than metaboreflexes, which might contribute to the mechanisms underlying the link between PTSD and cardiovascular risk.NEW & NOTEWORTHY The novel findings of the current study are that women with posttraumatic stress disorder (PTSD) exhibited augmented sympathetic neural and pressor responses at the first 30 s of submaximal isometric muscle contraction. More interestingly, exaggerated neurocirculatory responses at the onset of muscle contraction were associated with greater ambulatory awake systolic blood pressure fluctuations in women with PTSD. Our findings expand the knowledge on the physiological mechanisms that perhaps contribute to increased risk of cardiovascular disease in such a population.

Abnormal sympathetic neural recruitment patterns and hemodynamic responses to cold pressor test in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is more prevalent in women and associated with greater risk of major forms of cardiovascular disease, but physiological mechanisms underlying this association remain unknown. We hypothesized that abnormal sympathetic responses to sympathoexcitatory stimuli might predispose PTSD patients to a greater risk of cardiovascular disease. We examined changes in integrated muscle sympathetic nerve activity (MSNA) burst and multiunit action potential (AP) recruitment patterns as well as hemodynamic responses during cold pressor test (CPT) in 14 women with PTSD and 14 healthy control subjects. Data were collected during 1-min baseline, 2-min CPT, and 3-min recovery. At baseline, blood pressure (BP) was not different between groups; however, heart rate and sympathetic neural activity were greater in women with PTSD [MSNA burst frequency (BF): 27 ± 13 vs. 18 ± 14 bursts/min (P = 0.04); AP frequency: 272 ± 152 vs. 174 ± 146 spikes/min (P = 0.03)]. In response to CPT, BP responses exhibited a significant group × time interaction (P = 0.01) highlighted by a significant diastolic BP main group effect (P = 0.048) despite the finding that increases in integrated MSNA burst responses were not different between groups (P > 0.05). However, compared with control subjects, AP firing frequency (group × time interaction P = 0.0001, group P = 0.02) and AP per burst (group × time interaction P = 0.03, group P = 0.03) were augmented in women with PTSD. Collectively, women with PTSD exhibited a greater pressor response and an exaggerated sympathetic neural recruitment pattern during sympathoexcitatory stimuli that may, in part, explain the propensity toward developing hypertension and cardiovascular disease later in life.NEW & NOTEWORTHY The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.

Reduced left ventricular diastolic function in women with posttraumatic stress disorder.

Women are two to three times more likely to develop posttraumatic stress disorder (PTSD) compared with men after exposure to a major trauma, and PTSD is associated with increased risk for cardiovascular disease in later life. The underlying mechanisms are unclear, but alterations in cardiac function may be involved. We hypothesized that women with PTSD have reduced left ventricular (LV) diastolic function. We studied 14 women with PTSD (PTSD group) and 14 women without PTSD (controls) using echocardiography Doppler to evaluate LV diastolic function, including peak velocities (E and A waves) in transmitral flow; diastolic, atrial kick, and systolic waveform velocities (e', a', and s') in tissue Doppler; the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'); and velocity of propagation (Vp) . Baseline characteristics including age, body size, blood pressure, and heart rate were not significantly different between the two groups. Compared with the control group, women with PTSD showed greater E/e' (controls vs. PTSD group: 7.0 ± 1.3 vs. 9.1 ± 1.3, P = 0.002) and smaller Vp (controls vs. PTSD group: 63.7 ± 11.3 vs. 47.5 ± 6.9 cm/s, P = 0.003). These results suggest that women with PTSD have reduced LV diastolic function, which may contribute, at least in part, to the increased risk of cardiovascular disease later in life.

Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans.

As a primary component of homeostasis, the sympathetic nervous system enables rapid adjustments to stress through its ability to communicate messages among organs and cause targeted and graded end organ responses. Key in this communication model is the pattern of neural signals emanating from the central to peripheral components of the sympathetic nervous system. But what is the communication strategy employed in peripheral sympathetic nerve activity (SNA)? Can we develop and interpret the system of coding in SNA that improves our understanding of the neural control of the circulation? In 1968, Hagbarth and Vallbo (Hagbarth KE, Vallbo AB. Acta Physiol Scand 74: 96-108, 1968) reported the first use of microneurographic methods to record sympathetic discharges in peripheral nerves of conscious humans, allowing quantification of SNA at rest and sympathetic responsiveness to physiological stressors in health and disease. This technique also has enabled a growing investigation into the coding patterns within, and cardiovascular outcomes associated with, postganglionic SNA. This review outlines how results obtained by microneurographic means have improved our understanding of SNA outflow patterns at the action potential level, focusing on SNA directed toward skeletal muscle in conscious humans.

Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress.

This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 ± 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 ± 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P < 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 ± 2; P < 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (HbSat: 56 ± 13 vs. 71 ± 6%; P < 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 ± 7; RBREnd: +11 ± 5) and total AP clusters (FRCApnea: +10 ± 2; RBREnd: +6 ± 4) (both P < 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P < 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress.NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress.

Effects of aging and coronary artery disease on sympathetic neural recruitment strategies during end-inspiratory and end-expiratory apnea.

In response to acute physiological stress, the sympathetic nervous system modifies neural outflow through increased firing frequency of lower-threshold axons, recruitment of latent subpopulations of higher-threshold axons, and/or acute modifications of synaptic delays. Aging and coronary artery disease (CAD) often modify efferent muscle sympathetic nerve activity (MSNA). Therefore, we investigated whether CAD (n = 14; 61 ± 10 yr) and/or healthy aging without CAD (OH; n = 14; 59 ± 9 yr) modified these recruitment strategies that normally are observed in young healthy (YH; n = 14; 25 ± 3 yr) individuals. MSNA (microneurography) was measured at baseline and during maximal voluntary end-inspiratory (EI) and end-expiratory (EE) apneas. Action potential (AP) patterns were studied using a novel AP analysis technique. AP frequency increased in all groups during both EI- and EE-apnea (all P < 0.05). The mean AP content per integrated burst increased during EI- and EE-apnea in YH (EI: Δ6 ± 4 APs/burst; EE: Δ10 ± 6 APs/burst; both P < 0.01) and OH (EI: Δ3 ± 3 APs/burst; EE: Δ4 ± 5 APs/burst; both P < 0.01), but not in CAD (EI: Δ1 ± 3 APs/burst; EE: Δ2 ± 3 APs/burst; both P = NS). When APs were binned into "clusters" according to peak-to-peak amplitude, total clusters increased during EI- and EE-apnea in YH (EI: Δ5 ± 2; EE: Δ6 ± 4; both P < 0.01), during EI-apnea only in OH (EI: Δ1 ± 2; P < 0.01; EE: Δ1 ± 2; P = NS), and neither apnea in CAD (EI: Δ -2 ± 2; EE: Δ -1 ± 2; both P = NS). In all groups, the AP cluster size-latency profile was shifted downwards for every corresponding cluster during EI- and EE-apnea (all P < 0.01). As such, inherent dysregulation exists within the central features of apnea-related sympathetic outflow in aging and CAD.

Central vs. peripheral determinants of sympathetic neural recruitment: insights from static handgrip exercise and postexercise circulatory occlusion.

Sympathetic outflow is modified during acute homeostatic stress through increased firing of low-threshold axons, recruitment of latent axons, and synaptic delay modifications. However, the role of central mechanisms versus peripheral reflex control over sympathetic recruitment remains unknown. Here, we examined sympathetic discharge patterns during fatiguing static handgrip (SHG) exercise and postexercise circulatory occlusion (PECO) to study the central vs. peripheral reflex elements of sympathetic neural coding. Muscle sympathetic nerve activity (MSNA; microneurography) was measured in six males (25 ± 3 yr) at baseline (3 min) and during 5 min of SHG exercise completed at 20% maximal voluntary contraction. Isolation of the peripheral metaboreflex component was achieved by PECO for 3 min. Action potential (AP) patterns were studied using wavelet-based methodology. Compared with baseline, total MSNA increased by minute 3 of SHG, remaining elevated throughout the duration of exercise and PECO (all P < 0.05). The AP content per burst increased above baseline by minute 4 of SHG (Δ4 ± 2), remaining elevated at minute 5 (Δ6 ± 4) and PECO (Δ4 ± 4; all P < 0.05). Similarly, total AP clusters increased by minute 4 of SHG (Δ5 ± 5) and remained elevated at minute 5 (Δ6 ± 3) and PECO (Δ7 ± 5; all P < 0.01), indicating recruitment of latent subpopulations. Finally, the AP cluster size-latency profile was shifted downward during minutes 4 (-32 ± 22 ms) and 5 (-49 ± 17 ms; both P < 0.05) of SHG but was not different than baseline during PECO (P > 0.05). Our findings suggest that central perceptual factors play a specific role in the synaptic delay aspect of sympathetic discharge timing, whereas peripheral reflex mechanisms affect recruitment of latent axons.

Isometric exercise training lowers resting blood pressure and improves local brachial artery flow-mediated dilation equally in men and women.

INTRODUCTION: Isometric resistance training has repeatedly shown to be an effective exercise modality in lowering resting blood pressure (BP), yet associated mechanisms and sex differences in the response to training remain unclear. Exploration into potential sex differences in the response to isometric resistance training is necessary, as it may allow for more optimal and sex-based exercise prescription, thereby maximizing the efficacy of the training intervention. PURPOSE: Therefore, we investigated, in normotensives, whether sex differences exist in the response to isometric handgrip (IHG) training. METHODS: Resting BP and endothelium-dependent vasodilation (brachial artery flow-mediated dilation; FMD) were assessed in 11 women (23 ± 4 years) and 9 men (21 ± 2 years) prior to and following 8 weeks of IHG training (four, 2-min unilateral contractions at 30 % of maximal voluntary contraction; 3 days per week). RESULTS: Main effects of time were observed (all P < 0.05), whereby IHG training reduced systolic BP (Δ 8 ± 6 mmHg), diastolic BP (Δ 2 ± 3 mmHg), mean arterial pressure (Δ 4 ± 3 mmHg), and pulse pressure (Δ 5 ± 7 mmHg), accompanied by increases in absolute (Δ 0.09 ± 0.15 mm) and relative (Δ 2.4 ± 4.1 %) brachial artery FMD; however, no significant sex differences were observed in the magnitude of post-training change in any variable assessed (all P > 0.05). CONCLUSION: IHG training effectively lowers resting BP and improves endothelium-dependent vasodilation in men and women, without significant sex differences in the magnitude of response.

Coronary artery disease affects cortical circuitry associated with brain-heart integration during volitional exercise.

This study tested the hypothesis that coronary artery disease (CAD) alters the cortical circuitry associated with exercise. Observations of changes in heart rate (HR) and in cortical blood oxygenation level-dependent (BOLD) images were made in 23 control subjects [control; 8 women; 63 ± 11 yr; mean arterial pressure (MAP): 90 ± 9 mmHg] (mean ± SD) and 17 similarly aged CAD patients (4 women; 59 ± 9 yr; MAP: 87 ± 10 mmHg). Four repeated bouts each of 30%, 40%, and 50% of maximal voluntary contraction (MVC) force (LAB session), and seven repeated bouts of isometric handgrip (IHG) at 40% MVC force (fMRI session), were performed, with each contraction lasting 20 s and separated by 40 s of rest. There was a main effect of group (P = 0.03) on HR responses across all IHG intensities. Compared with control, CAD demonstrated less task-dependent deactivation in the posterior cingulate cortex and medial prefrontal cortex, and reduced activation in the right anterior insula, bilateral precentral cortex, and occipital lobe (P < 0.05). When correlated with HR, CAD demonstrated reduced activation in the bilateral insula and posterior cingulate cortex, and reduced deactivation in the dorsal anterior cingulate cortex, and bilateral precentral cortex (P < 0.05). The increased variability in expected autonomic regions and decrease in total cortical activation in response to the IHG task are associated with a diminished HR response to volitional effort in CAD. Therefore, relative to similarly aged and healthy individuals, CAD impairs the heart rate response and modifies the cortical patterns associated with cardiovascular control during IHG.