The interactive effects of posture and biological sex on the control of muscle sympathetic nerve activity during rhythmic handgrip exercise.

Body posture and biological sex exhibit independent effects on the sympathetic neural responses to dynamic exercise. However, the neural mechanisms (e.g., baroreflex) by which posture impacts sympathetic outflow during rhythmic muscular contractions, and whether biological sex affects posture-mediated changes in efferent sympathetic nerve traffic during exercise, remain unknown. Thus, we tested the hypotheses that increases in muscle sympathetic nerve activity (MSNA) would be greater during upright compared with supine rhythmic handgrip (RHG) exercise, and that females would demonstrate smaller increases in MSNA during upright RHG exercise than males. Twenty young (30 [6] yr; means [SD]) individuals (9 males, 11 females) underwent 6 min of supine and upright (head-up tilt 45°) RHG exercise at 40% maximal voluntary contraction with continuous measurements of MSNA (microneurography), blood pressure (photoplethysmography), and heart rate (electrocardiogram). In the pooled group, absolute MSNA burst frequency (P < 0.001), amplitude (P = 0.009), and total MSNA (P < 0.001) were higher during upright compared with supine RHG exercise. However, body posture did not impact the peak change in MSNA during RHG exercise (range: P = 0.063-0.495). Spontaneous sympathetic baroreflex gain decreased from rest to RHG exercise (P = 0.006) and was not impacted by posture (P = 0.347). During upright RHG exercise, males demonstrated larger increases in MSNA burst amplitude (P = 0.002) and total MSNA (P = 0.001) compared with females, which coincided with greater reductions in sympathetic baroreflex gain among males (P = 0.004). Collectively, these data indicate that acute attenuation of baroreflex-mediated sympathoinhibition permits increases in MSNA during RHG exercise and that males exhibit a greater reserve for efferent sympathetic neural recruitment during orthostasis than females.NEW & NOTEWORTHY The impact of posture and sex on cardiovascular control during rhythmic handgrip (RHG) exercise is unknown. We show that increases in muscle sympathetic nerve activity (MSNA) during RHG are partly mediated by a reduction in sympathetic baroreflex gain. In addition, males demonstrate larger increases in total MSNA during upright RHG than females. These data indicate that the baroreflex partly mediates increases in MSNA during RHG and that males have a greater sympathetic vasoconstrictor reserve than females.

Contribution of platelets to disruption of the blood-brain barrier during arterial baroreflex dysfunction.

BACKGROUND: Arterial baroreflex dysfunction, like many other central nervous system disorders, involves disruption of the blood-brain barrier, but what causes such disruption in ABR dysfunction is unclear. Here we explored the potential role of platelets in this disruption. METHODS: ABR dysfunction was induced in rats using sinoaortic denervation, and the effects on integrity of the blood-brain barrier were explored based on leakage of Evans blue or FITC-dextran, while the effects on expression of CD40L in platelets and of key proteins in microvascular endothelial cells were explored using immunohistochemistry, western blotting and enzyme-linked immunosorbent assay. Similar experiments were carried out in rat brain microvascular endothelial cell line, which we exposed to platelets taken from rats with ABR dysfunction. RESULTS: Sinoaortic denervation permeabilized the blood-brain barrier and downregulated zonula occludens-1 and occludin in rat brain, while upregulating expression of CD40L on the surface of platelets and stimulating platelet aggregation. Similar effects of permeabilization and downregulation were observed in healthy rats that received platelets from animals with ABR dysfunction, and in rat brain microvascular endothelial cells, but only in the presence of lipopolysaccharide. These effects were associated with activation of NF-κB signaling and upregulation of matrix metalloprotease-9. These effects of platelets from animals with ABR dysfunction were partially blocked by neutralizing antibody against CD40L or the platelet inhibitor clopidogrel. CONCLUSION: During ABR dysfunction, platelets may disrupt the blood-brain barrier when CD40L on their surface activates NF-kB signaling within cerebral microvascular endothelial cells, leading to upregulation of matrix metalloprotease-9. Our findings imply that targeting CD40L may be effective against cerebral diseases involving ABR dysfunction.

Baroreflex dynamics during the rest to exercise transient in acute normobaric hypoxia in humans.

PURPOSE: We hypothesised that during a rest-to-exercise transient in hypoxia (H), compared to normoxia (N), (i) the initial baroreflex sensitivity (BRS) decrease would be slower and (ii) the fast heart rate (HR) and cardiac output (CO) response would have smaller amplitude (A1) due to lower vagal activity in H than N. METHODS: Ten participants performed three rest-to-50 W exercise transients on a cycle-ergometer in N (ambient air) and three in H (inspired fraction of O2 = 0.11). R-to-R interval (RRi, by electrocardiography) and blood pressure profile (by photo-plethysmography) were recorded non-invasively. Analysis of the latter provided mean arterial pressure (MAP) and stroke volume (SV). CO = HR·SV. BRS was calculated by modified sequence method. RESULTS: Upon exercise onset in N, MAP fell to a minimum (MAPmin) then recovered. BRS decreased immediately from 14.7 ± 3.6 at rest to 7.0 ± 3.0 ms mmHg-1 at 50 W (p < 0.01). The first BRS sequence detected at 50 W was 8.9 ± 4.8 ms mmHg-1 (p < 0.05 vs. rest). In H, MAP showed several oscillations until reaching a new steady state. BRS decreased rapidly from 10.6 ± 2.8 at rest to 2.9 ± 1.5 ms mmHg-1 at 50 W (p < 0.01), as the first BRS sequence at 50 W was 5.8 ± 2.6 ms mmHg-1 (p < 0.01 vs. rest). CO-A1 was 2.96 ± 1.51 and 2.31 ± 0.94 l min-1 in N and H, respectively (p = 0.06). HR-A1 was 7.7 ± 4.6 and 7.1 ± 5.9 min-1 in N and H, respectively (p = 0.81). CONCLUSION: The immediate BRS decrease in H, coupled with similar rapid HR and CO responses, is compatible with a withdrawal of residual vagal activity in H associated with increased sympathetic drive.

Vasoconstriction during non-hypotensive hypovolemia is not associated with activation of baroreflex: A causality-based approach.

Non-hypotensive hypovolemia simulated with oscillatory lower body negative pressure in the range of -10 to -20 mmHg is associated with vasoconstriction {increase in total peripheral vascular resistance (TPVR)}. Due to the mechanical stiffening of vessels, there is a disjuncture of mechano-neural coupling at the level of arterial baroreceptors which has not been investigated. The study was designed to quantify both the cardiac and vascular arms of the baroreflex using an approach based on Wiener-Granger causality (WGC) - partial directed coherence (PDC). Thirty-three healthy human volunteers were recruited and continuous heart rate and blood pressure {systolic (SBP), diastolic (DBP), and mean (MBP)} were recorded. The measurements were taken in resting state, at -10 mmHg (level 1) and -15 mmHg (level 2). Spectral causality - PDC was estimated from the MVAR model in the low-frequency band using the GMAC MatLab toolbox. PDC from SBP and MBP to RR interval and TPVR was calculated. The PDC from MBP to RR interval showed no significant change at -10 mmHg and -15 mmHg. No significant change in PDC from MBP to TPVR at -10 mmHg and -15 mmHg was observed. Similar results were obtained for PDC estimation using SBP as input. However, a significant increase in TPVR from baseline at both levels of oscillatory LBNP (p-value <0.001). No statistically significant change in PDC from blood pressure to RR interval and blood pressure to TPVR implies that vasoconstriction is not associated with activation of the arterial baroreflex in ≤-15 mmHg LBNP. Thereby, indicating the role of cardiopulmonary reflexes during the low level of LBNP simulated non-hypotensive hypovolemia.

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

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

Arterial Baroreflex Dysfunction Promotes Neuroinflammation by Activating the Platelet CD40L/Nuclear Factor Kappa B Signaling Pathway in Microglia and Astrocytes.

Arterial baroreflex (ABR) dysfunction has previously been associated with neuroinflammation, the most common pathological feature of neurological disorders. However, the mechanisms mediating ABR dysfunction-induced neuroinflammation are not fully understood. In the present study, we investigated the role of platelet CD40 ligand (CD40L) in neuroinflammation in an in vivo model of ABR dysfunction, and microglia and astrocyte activation in vitro. ABR dysfunction was induced in Sprague‒Dawley rats by sinoaortic denervation (SAD). We used ELSA and immunofluorescence to assess the effect of platelet CD40L on glial cell polarization and the secretion of inflammatory factors. By flow cytometry, we found that rats subjected to SAD showed a high level of platelet microaggregation and upregulation of CD40L on the platelet surface. The promotion of platelet invasion and accumulation was also observed in the brain tissues of rats subjected to SAD. In the animal model and cultured N9 microglia/C6 astrocytoma cells, platelet CD40L overexpression promoted neuroinflammation and activated M1 microglia, A1 astrocytes, and the nuclear factor kappa B (NFκB) signaling pathway. These effects were partially blocked by inhibiting platelet activity with clopidogrel or inhibiting CD40L-mediated signaling. Our results suggest that during ABR dysfunction, CD40L signaling in platelets converts microglia to the M1 phenotype and astrocytes to the A1 phenotype, activating NFκB and resulting in neuroinflammation. Thus, our study provides a novel understanding of the pathogenesis of ABR dysfunction-induced neuroinflammation and indicates that targeting platelet CD40L is beneficial for treating central nervous system (CNS) disorders associated with ABR dysfunction.

Hypertension depresses arterial baroreflex control of both heart rate and cardiac output during rest, exercise, and metaboreflex activation.

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach-unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

Baroreflex responses to limb venous distension in humans.

The venous distension reflex (VDR) is a pressor response evoked by peripheral venous distension and accompanied by increased muscle sympathetic nerve activity (MSNA). The effects of venous distension on the baroreflex, an important modulator of blood pressure (BP), have not been examined. The purpose of this study was to examine the effect of the VDR on baroreflex sensitivity (BRS). We hypothesized that the VDR will increase the sympathetic BRS (SBRS). Beat-by-beat heart rate (HR), BP, and MSNA were recorded in 16 female and 19 male young healthy subjects. To induce venous distension, normal saline equivalent to 5% of the forearm volume was infused into the veins of the occluded forearm. SBRS was assessed from the relationship between diastolic BP and MSNA during spontaneous BP variations. Cardiovagal BRS (CBRS) was assessed with the sequence technique. Venous distension evoked significant increases in BP and MSNA. Compared with baseline, during the maximal VDR response period, SBRS was significantly increased (-3.1 ± 1.5 to -4.5 ± 1.6 bursts·100 heartbeats-1·mmHg-1, P < 0.01) and CBRS was significantly decreased (16.6 ± 5.4 to 13.8 ± 6.1 ms·mmHg-1, P < 0.01). No sex differences were observed in the effect of the VDR on SBRS or CBRS. These results indicate that in addition to its pressor effect, the VDR altered both SBRS and CBRS. We speculate that these changes in baroreflex function contribute to the modulation of MSNA and BP during limb venous distension.

Autonomic cardiovascular reflex control of hemodynamics during exercise in heart failure with reduced ejection fraction and the effects of exercise training.

Heart failure with reduced ejection fraction is associated with increased exercise intolerance, morbidity, and mortality. Importantly, exercise intolerance in heart failure with reduced ejection fraction is a key factor limiting patient quality of life and survival. Exercise intolerance in heart failure with reduced ejection fraction stems from a multi-organ failure to maintain homeostasis at rest and during exercise, including the heart, skeletal muscle, and autonomic nervous system, lending itself to a system constantly trying to "catch-up". Hemodynamic control during exercise is regulated primarily by the autonomic nervous system, whose operation, in turn, is partly regulated via reflexive information from exercise-stimulated receptors throughout the body (e.g., arterial baroreflex, central and peripheral chemoreceptors, and the muscle metabo- and mechanoreflexes). Persons with heart failure with reduced ejection fraction exhibit malfunctioning autonomic reflexes, which lead to exaggerated sympathoexcitation and attenuated parasympathetic tone. Chronic elevation of sympathetic activity is associated with increased morbidity and mortality. In this review, we provide an overview of how each main exercise-related autonomic reflex is changed in heart failure with reduced ejection fraction, and the role of exercise training in attenuating or reversing the counterproductive changes.

Carotid Baroreceptor Magnetic Activation and Beat-to-Beat Blood Pressure Variability, Implications to Treat Abrupt Blood Pressure Elevation in Labile Hypertension.

Mounting evidence suggests enhanced blood pressure (BP) variability (BPV) independent role in cardiovascular (CV) damage. The goal was to estimate the effect of the carotid baroreceptor (CB) magnetic stimulation on sudden high BP elevation. Mean femoral arterial BP (MAP), heart rate (HR), baroreflex sensitivity (BRS), and ear lobe skin microcirculatory blood flow, by microphotoelectric plethysmography (MPPG), were simultaneously recorded in conscious rabbits sedated by pentobarbital intravenous (i.v.) infusion (5 mg/kg/h) after 40 min CB exposure to 350 mT static magnetic field (SMF), by Nd2 -Fe14 -B magnets (n = 14), or sham magnets exposure (n = 14). BRS was assessed from HR and MAP responses to abrupt hypotension induced by i.v. bolus injections of nitroprusside (Ni) and abrupt MAP elevation (MAPAE ) by i.v. bolus of phenylephrine (Ph). Beat-to-beat BPV was estimated by MAP standard deviation. SMF CB exposure significantly increased BRSNi (74.5 ± 17.8%, P < 0.001) and microcirculation (23.8% ± 11.0%, P = 0.039); decreased MAP (-5.7 ± 1.7%, P < 0.014) and phenylephrine-induced MAPAE (-19.1%, P = 0.043). MAPAE positively correlated with resting MAP (r = 0.342, P = 0.0383) and MAP SD (r = 0.383, P = 0.0194), and inversely with BRSPh (r = -0.47, P = 0.0156). SMF CB exposure enhanced the nitroprusside, which acts by releasing nitric oxide (NO), vasodilatory effect. This indicates arterial baroreflex to improve vessel sensitivity to NO, which is a new physiology with BP buffering effect. A positive correlation of MAP SD to phenylephrine BP ramps suggests a causal relationship and BPV prognostic significance to forecast abrupt BP elevation. Mechano/baroreceptor magneto-sensing property proposed to be the basic physiology by which SMFs boost CV autonomic regulation with potential implementation in high CV risk labile arterial hypertensive disease. © 2022 Bioelectromagnetics Society.

Dynamics of cardiovascular and baroreflex readjustments during a light-to-moderate exercise transient in humans.

PURPOSE: We hypothesised that, during a light-to-moderate exercise transient, compared to an equivalent rest-to-exercise transient, (1) a further baroreflex sensitivity (BRS) decrease would be slower, (2) no rapid heart rate (HR) response would occur, and (3) the rapid cardiac output (CO) response would have a smaller amplitude (A1). Hence, we analysed the dynamics of arterial baroreflexes and the HR and CO kinetics during rest-to-50 W (0-50 W) and 50-to-100 W (50-100 W) exercise transients. METHODS: 10 subjects performed three 0-50 W and three 50-100 W on a cycle ergometer. We recorded arterial blood pressure profiles (photo-plethysmography) and R-to-R interval (RRi, electrocardiography). The former were analysed to obtain beat-by-beat mean arterial pressure (MAP) and stroke volume (SV). CO was calculated as SV times HR. BRS was measured by modified sequence method. RESULTS: During 0-50 W, MAP transiently fell (- 9.0 ± 5.7 mmHg, p < 0.01) and BRS passed from 15.0 ± 3.7 at rest to 7.3 ± 2.4 ms mmHg-1 at 50 W (p < 0.01) promptly (first BRS sequence: 8.1 ± 4.6 ms mmHg-1, p < 0.01 vs. rest). During 50-100 W, MAP did not fall and BRS passed from 7.2 ± 2.6 at 50 W to 3.3 ± 1.3 ms mmHg-1 at 100 W (p < 0.01) slowly (first BRS sequence: 5.3 ± 3.1 ms mmHg-1, p = 0.07 vs. 50 W). A1 for HR was 9.2 ± 6.0 and 6.0 ± 4.5 min-1 in 0-50 W and 50-100 W, respectively (p = 0.19). The corresponding A1 for CO were 2.80 ± 1.54 and 0.91 ± 0.55 l∙min-1 (p < 0.01). CONCLUSION: During 50-100 W, with respect to 0-50 W, BRS decreased more slowly, in absence of a prompt pressure decrease. BRS decrease and rapid HR response in 50-100 W were unexpected and ascribed to possible persistence of some vagal tone at 50 W.

A closed-loop approach to the study of the baroreflex dynamics during posture changes at rest and at exercise in humans.

We hypothesized that during rapid uptilting at rest, due to vagal withdrawal, arterial baroreflex sensitivity (BRS) may decrease promptly and precede the operating point (OP) resetting, whereas different kinetics are expected during exercise steady state, due to lower vagal activity than at rest. To test this, eleven subjects were rapidly (<2 s) tilted from supine (S) to upright (U) and vice versa every 3 min, at rest and during steady-state 50 W pedaling. Mean arterial pressure (MAP) was measured by finger cuff (Portapres) and R-to-R interval (RRi) by electrocardiography. BRS was computed with the sequence method both during steady and unsteady states. At rest, BRS was 35.1 ms·mmHg-1 (SD = 17.1) in S and 16.7 ms·mmHg-1 (SD = 6.4) in U (P < 0.01), RRi was 901 ms (SD = 118) in S and 749 ms (SD = 98) in U (P < 0.01), and MAP was 76 mmHg (SD = 11) in S and 83 mmHg (SD = 8) in U (P < 0.01). During uptilt, BRS decreased promptly [first BRS sequence was 19.7 ms·mmHg-1 (SD = 5.0)] and was followed by an OP resetting (MAP increase without changes in RRi). At exercise, BRS and OP did not differ between supine and upright positions [BRS was 7.7 ms·mmHg-1 (SD = 3.0) and 7.7 ms·mmHg-1 (SD = 3.5), MAP was 85 mmHg (SD = 13) and 88 mmHg (SD = 10), and RRi was 622 ms (SD = 61) and 600 ms (SD = 70), respectively]. The results support the tested hypothesis. The prompt BRS decrease during uptilt at rest may be ascribed to a vagal withdrawal, similarly to what occurs at exercise onset. The OP resetting may be due to a slower control mechanism, possibly an increase in sympathetic activity.

Heartbeats entrain breathing via baroreceptor-mediated modulation of expiratory activity.

NEW FINDINGS: Cardio-ventilatory coupling refers to the onset of inspiration occurring at a preferential latency following the last heartbeat (HB) in expiration. According to the cardiac-trigger hypothesis, the pulse pressure initiates an inspiration via baroreceptor activation. However, the central neural substrate mediating this coupling remains undefined. Using a combination of animal data, human data and mathematical modelling, this study tests the hypothesis that the HB, by way of pulsatile baroreflex activation, controls the initiation of inspiration that occurs through a rapid neural activation loop from the carotid baroreceptors to Bötzinger complex expiratory neurons. ABSTRACT: Cardio-ventilatory coupling refers to a heartbeat (HB) occurring at a preferred latency prior to the next breath. We hypothesized that the pressure pulse generated by a HB activates baroreceptors that modulate brainstem expiratory neuronal activity and delay the initiation of inspiration. In supine male subjects, we recorded ventilation, electrocardiogram and blood pressure during 20-min epochs of baseline, slow-deep breathing and recovery. In in situ rodent preparations, we recorded brainstem activity in response to pulses of perfusion pressure. We applied a well-established respiratory network model to interpret these data. In humans, the latency between a HB and onset of inspiration was consistent across different breathing patterns. In in situ preparations, a transient pressure pulse during expiration activated a subpopulation of expiratory neurons normally active during post-inspiration, thus delaying the next inspiration. In the model, baroreceptor input to post-inspiratory neurons accounted for the effect. These studies are consistent with baroreflex activation modulating respiration through a pauci-synaptic circuit from baroreceptors to onset of inspiration.

Global REACH 2018: Andean highlanders, chronic mountain sickness and the integrative regulation of resting blood pressure.

NEW FINDINGS: What is the central question of this study? Does chronic mountain sickness (CMS) alter sympathetic neural control and arterial baroreflex regulation of blood pressure in Andean (Quechua) highlanders? What is the main finding and its importance? Compared to healthy Andean highlanders, basal sympathetic vasomotor outflow is lower, baroreflex control of muscle sympathetic nerve activity is similar, supine heart rate is lower and cardiovagal baroreflex gain is greater in mild CMS. Taken together, these findings reflect flexibility in integrative regulation of blood pressure that may be important when blood viscosity and blood volume are elevated in CMS. ABSTRACT: The high-altitude maladaptation syndrome chronic mountain sickness (CMS) is characterized by excessive erythrocytosis and frequently accompanied by accentuated arterial hypoxaemia. Whether altered autonomic cardiovascular regulation is apparent in CMS is unclear. Therefore, during the 2018 Global REACH expedition to Cerro de Pasco, Peru (4383 m), we assessed integrative control of blood pressure (BP) and determined basal sympathetic vasomotor outflow and arterial baroreflex function in eight Andean natives with CMS ([Hb] 22.6 ± 0.9 g·dL-1 ) and seven healthy highlanders ([Hb] 19.3 ± 0.8 g·dL-1 ). R-R interval (RRI, electrocardiogram), beat-by-beat BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest and during pharmacologically induced changes in BP (modified Oxford test). Although [Hb] and blood viscosity (7.8 ± 0.7 vs. 6.6 ± 0.7 cP; d = 1.7, P = 0.01) were elevated in CMS compared to healthy highlanders, cardiac output, total peripheral resistance and mean BP were similar between groups. The vascular sympathetic baroreflex MSNA set-point (i.e. MSNA burst incidence) and reflex gain (i.e. responsiveness) were also similar between groups (MSNA set-point, d = 0.75, P = 0.16; gain, d = 0.2, P = 0.69). In contrast, in CMS the cardiovagal baroreflex operated around a longer RRI (960 ± 159 vs. 817 ± 50 ms; d = 1.4, P = 0.04) with a greater reflex gain (17.2 ± 6.8 vs. 8.8 ± 2.6 ms·mmHg-1 ; d = 1.8, P = 0.01) versus healthy highlanders. Basal sympathetic vasomotor activity was also lower compared to healthy highlanders (33 ± 11 vs. 45 ± 13 bursts·min-1 ; d = 1.0, P = 0.08). In conclusion, our findings indicate adaptive differences in basal sympathetic vasomotor activity and heart rate compensate for the haemodynamic consequences of excessive erythrocyte volume and contribute to integrative blood pressure regulation in Andean highlanders with mild CMS.

Peripheral chemoreflex control of fetal heart rate decelerations overwhelms the baroreflex during brief umbilical cord occlusions in fetal sheep.

KEY POINTS: The majority of intrapartum decelerations are widely believed to be mediated by the baroreflex secondary to brief umbilical cord occlusions (UCOs) but this remains unproven. We examined the responses to brief-UCOs in fetal sheep and compared these to a phenylephrine-stimulated baroreflex in a separate cohort. A further cohort was instrumented with near-infrared spectroscopy to measure cerebral oxygenation during UCO. The first 3-4 s of the brief-UCOs were consistent with a baroreflex, and associated with a minor fall in fetal heart rate (FHR). Thereafter, the remainder of the FHR decelerations were highly consistent with the peripheral chemoreflex. The baroreflex is not sufficient to produce deep, rapid decelerations characteristic of variable decelerations and it is therefore likely to be a minor contributor to intrapartum decelerations. ABSTRACT: Fetal heart rate (FHR) monitoring is widely used to assess fetal wellbeing during labour, yet the physiology underlying FHR patterns remains incompletely understood. The baroreflex is widely believed to mediate brief intrapartum decelerations, but evidence supporting this theory is lacking. We therefore investigated the physiological changes in near-term fetal sheep during brief repeated umbilical cord occlusions (brief-UCOs, n = 15). We compared this to separate cohorts that underwent a phenylephrine challenge to stimulate the baroreflex (n = 9) or were instrumented with near-infrared spectroscopy and underwent prolonged 15-min complete UCO (prolonged-UCO, n = 9). The first 3-4 s of brief-UCOs were associated with hypertension (P = 0.000), a fall in FHR by 9.7-16.9 bpm (P = 0.002). The FHR/MAP relationship during this time was consistent with that observed during a phenylephrine-induced baroreflex. At 4-5 s, the FHR/MAP relationship began to deviate from the phenylephrine baroreflex curve as FHR fell independently of MAP until its nadir in association with intense peripheral vasoconstriction (P = 0.000). During prolonged-UCO, cerebral oxygenation remained steady until 4 s after the start of prolonged-UCO, and then began to fall (P = 0.000). FHR and cerebral oxygenation then fell in parallel until the FHR nadir. In conclusion, the baroreflex has a minor role in mediating the first 3-4 s of FHR decelerations during complete UCO, but thereafter the peripheral chemoreflex is the dominant mediator. Overall, the baroreflex is neither necessary nor sufficient to produce deep, rapid decelerations characteristic of variable decelerations; it is therefore likely to be a minor contributor to intrapartum decelerations.

Heterogeneous baroreflex control of sympathetic action potential subpopulations in humans.

KEY POINTS: Emission patterns in muscle sympathetic nerve activity stem from differently sized action potential (AP) subpopulations that express varying discharge probabilities. The mechanisms governing these firing behaviours are unclear. This study investigated the hypothesis that the arterial baroreflex exerts varying control over the different AP subpopulations. During baseline, medium APs expressed the greatest baroreflex slopes, while small and large APs exhibited weaker slopes. On going from baseline to lower body negative pressure (LBNP; simulated orthostatic stress), baroreflex slopes for some clusters of medium APs expressed the greatest increase, while slopes for large APs also increased but to a lesser degree. A subpopulation of previously silent larger APs was recruited with LBNP but these APs expressed weak baroreflex slopes. The arterial baroreflex heterogeneously regulates sympathetic AP subpopulations, exerting its strongest effect over medium APs. Weak baroreflex mechanisms govern the recruitment of latent larger AP subpopulations during orthostatic stress. ABSTRACT: Muscle sympathetic nerve activity (MSNA) occurs primarily in bursts of action potentials (AP) with subpopulations that differ in size and discharge probabilities. The mechanisms determining these discharge patterns remain unclear. This study investigated the hypothesis that variations in AP discharge are due to subpopulation-specific baroreflex control. We employed multi-unit microneurography and a continuous wavelet analysis approach to extract sympathetic APs in 12 healthy individuals during baseline (BSL) and lower body negative pressure (LBNP; -40, -60, -80 mmHg). For each AP cluster, the baroreflex threshold slope was measured from the linear regression between AP probability (%) and diastolic blood pressure (mmHg). During BSL, the baroreflex exerted non-uniform regulation over AP subpopulations: medium-sized AP clusters expressed the greatest slopes while clusters of small and large APs expressed weaker slopes. On going from BSL to LBNP, the baroreflex slopes for each AP subpopulation were modified differently. Baroreflex slopes (%/mmHg) for some medium APs (cluster 5: -4.4 ± 4 to -9.1 ± 5) expressed the greatest increase with LBNP, while slopes for large APs (cluster 9: -1.3 ± 1 to -2.6 ± 2) also increased, but to a lesser degree. Slopes for small APs present at BSL exhibited reductions with LBNP (cluster 2: -3.9 ± 3 to -2.2 ± 3). Larger previously silent AP clusters recruited with LBNP expressed weak baroreflex regulation (cluster 14: -0.9 ± 1%/mmHg). The baroreflex exerts the strongest control over medium-sized APs. Augmenting baroreflex gain and upward resetting of discrete AP subpopulations active at BSL, as well as recruiting larger previously silent APs with weak baroreflex control, facilitates elevated MSNA during orthostatic stress.

Arterial baroreflex regulation of muscle sympathetic single-unit activity in men: influence of resting blood pressure.

The arterial baroreflex has dominant control over multiunit muscle sympathetic nerve activity (MSNA) burst occurrence, but whether this extends to all single units or is influenced by resting blood pressure status is unclear. In 22 men (32 ± 8 yr), we assessed 68 MSNA single units during sequential bolus injections of nitroprusside and phenylephrine (modified Oxford). Sympathetic baroreflex sensitivity (sBRS) was quantified as the weighted negative linear regression slope between diastolic blood pressure (DBP) and single-unit spike firing probability and multiple spike firing. Strong negative linear relationships (r ≥ -0.50) between DBP and spike firing probability were observed in 63/68 (93%) single units (-2.27 ± 1.27%·cardiac cycle-1·mmHg-1 [operating range, 18 ± 8 mmHg]). In contrast, only 45/68 (66%) single units had strong DBP-multiple spike firing relationships (-0.13 ± 0.18 spikes·cardiac cycle-1·mmHg-1 [operating range, 14 ± 7 mmHg]). Participants with higher resting DBP (65 ± 3 vs. 77 ± 3 mmHg, P < 0.001) had similar spike firing probability sBRS (low vs. high, -2.08 ± 1.08 vs. -2.46 ± 1.42%·cardiac cycle-1·mmHg-1, P = 0.33), but a smaller sBRS operating range (20 ± 6 vs. 16 ± 9 mmHg, P = 0.01; 86 ± 24 vs. 52 ± 25% of total range, P < 0.001) and a higher proportion of single units without arterial baroreflex control outside this range [6/31 (19%) vs. 21/32 (66%), P < 0.001]. Participants with higher resting DBP also had fewer single units with arterial baroreflex control of multiple spike firing (79 vs. 53%, P = 0.04). The majority of MSNA single units demonstrate strong arterial baroreflex control over spike firing probability during pharmacological manipulation of blood pressure. Changes in single-unit sBRS operating range and control of multiple spike firing may represent altered sympathetic recruitment patterns associated with the early development of hypertension.NEW & NOTEWORTHY Muscle sympathetic single units can be differentially controlled during stress. In contrast, we demonstrate that 93% of single units maintain strong arterial baroreflex control during pharmacological manipulation of blood pressure. Interestingly, the operating range and proportion of single units that lose arterial baroreflex control outside of this range are influenced by resting blood pressure levels. Altered single unit, but not multiunit, arterial baroreflex control may represent changes in sympathetic recruitment patterns in early stage development of hypertension.

Sympathetic arterial baroreflex hysteresis in humans: different patterns during low- and high-pressure levels.

Fluctuations in diastolic pressure modulate muscle sympathetic nerve activity (MSNA) through the arterial baroreflex. A higher sympathetic baroreflex sensitivity (sBRS) to pressure falls compared with rises has been reported; however, the underlying mechanisms are unclear. We assessed whether beat-to-beat falling and rising diastolic pressures operate on two distinct baroreflex response curves. Twenty-two men (32 ± 8 yr) underwent sequential bolus injections of nitroprusside and phenylephrine (modified Oxford test) with continuous recording of heart rate, blood pressure, and MSNA. The weighted negative linear regression slope between falling or rising diastolic pressure and MSNA burst incidence quantified sBRSfall and sBRSrise, respectively. The diastolic pressure evoking a MSNA burst incidence of 50 (T50) was calculated. sBRSfall was greater than sBRSrise (-6.24 ± 2.80 vs. -4.34 ± 2.16 bursts·100 heartbeats-1·mmHg-1, P = 0.01) and had a narrower operating range (14 ± 8 vs. 20 ± 10 mmHg, P = 0.01) that was shifted rightward (T50, 75 ± 9 and 70 ± 11 mmHg, P < 0.001). At diastolic pressures below baseline, sBRSfall was less than sBRSrise (-1.81 ± 1.31 vs. -3.59 ± 1.70 bursts·100 heartbeats-1·mmHg-1, P = 0.003) as low absolute pressures operated closer to the saturation plateau on the falling, compared with the rising pressure curve. At pressures above baseline, sBRSfall was greater than sBRSrise (-5.23 ± 1.94 and -3.79 ± 1.67 bursts·100 heartbeats-1·mmHg-1, P = 0.03). These findings demonstrate that the sympathetic arterial baroreflex possesses two response curves for processing beat-to-beat diastolic pressure falls and rises. The falling pressure curve is rightward shifted, which reduces sensitivity to falling pressure at low absolute pressures. This demonstrates that the direction of the hysteresis is influenced by the prevailing pressure level relative to each baroreflex response curve.NEW & NOTEWORTHY The findings show that the arterial baroreflex processes diastolic pressure dependent on the direction of pressure change from the previous beat, yielding two distinct baroreflex response curves to falling and rising pressure. Overall, the falling pressure curve is rightward shifted and more sensitive. The rightward shift caused a hysteresis reversal at hypotensive pressures as the falling pressure saturation plateau of the sigmoid response curve occurred at higher pressures than the rising pressure curve.

Short-term water deprivation does not increase blood pressure variability or impair neurovascular function in healthy young adults.

High dietary salt increases arterial blood pressure variability (BPV) in salt-resistant, normotensive rodents and is thought to result from elevated plasma [Na+] sensitizing central sympathetic networks. Our purpose was to test the hypothesis that water deprivation (WD)-induced elevations in serum [Na+] augment BPV via changes in baroreflex function and sympathetic vascular transduction in humans. In a randomized crossover fashion, 35 adults [17 female/18 male, age: 25 ± 4 yr, systolic/diastolic blood pressure (BP): 107 ± 11/60 ± 7 mmHg, body mass index: 23 ± 3 kg/m2] completed two hydration protocols: a euhydration control condition (CON) and a stepwise reduction in water intake over 3 days, concluding with 16 h of WD. We assessed blood and urine electrolyte concentrations and osmolality, resting muscle sympathetic nerve activity (MSNA; peroneal microneurography; 18 paired recordings), beat-to-beat BP (photoplethysmography), common femoral artery blood flow (Doppler ultrasound), and heart rate (single-lead ECG). A subset of participants (n = 25) underwent ambulatory BP monitoring during day 3 of each protocol. We calculated average real variability as an index of BPV. WD increased serum [Na+] (141.0 ± 2.3 vs. 142.1 ± 1.7 mmol/L, P < 0.01) and plasma osmolality (288 ± 4 vs. 292 ± 5 mosmol/kg H2O, P < 0.01). However, WD did not increase beat-to-beat (1.9 ± 0.4 vs. 1.8 ± 0.4 mmHg, P = 0.24) or ambulatory daytime (9.6 ± 2.1 vs. 9.4 ± 3.3 mmHg, P = 0.76) systolic BPV. Additionally, sympathetic baroreflex sensitivity (P = 0.20) and sympathetic vascular transduction were not different after WD (P = 0.17 for peak Δmean BP following spontaneous MSNA bursts). These findings suggest that, despite modestly increasing serum [Na+], WD does not affect BPV, arterial baroreflex function, or sympathetic vascular transduction in healthy young adults.

Augmented resting beat-to-beat blood pressure variability in young, healthy, non-Hispanic black men.

NEW FINDINGS: What is the central question of this study? The prevalence of hypertension in black individuals exceeds that in other racial groups. Despite this well-known heightened risk, the underlying contributory factors remain incompletely understood. We hypothesized that young black men would exhibit augmented beat-to-beat blood pressure variability compared with white men and that black men would exhibit augmented total peripheral resistance variability. What is the main finding and its importance? We demonstrate that young, healthy black men exhibit greater resting beat-to-beat blood pressure variability compared with their white counterparts, which is accompanied by greater variability in total peripheral resistance. These swings in blood pressure over time might contribute to the enhanced cardiovascular risk profile in black individuals. ABSTRACT: The prevalence of hypertension in black (BL) individuals exceeds that in other racial groups. Recently, resting beat-to-beat blood pressure (BP) variability has been shown to predict cardiovascular risk and detect target organ damage better than ambulatory BP monitoring. Given the heightened risk in BL individuals, we hypothesized young BL men would exhibit augmented beat-to-beat BP variability compared with white (WH) men. Furthermore, given studies reporting reduced vasodilatation and augmented vasoconstriction in BL individuals, we hypothesized that BL men would exhibit augmented variability in total peripheral resistance (TPR). In 45 normotensive men (24 BL), beat-to-beat BP (Finometer) was measured during 10-20 min of quiet rest. Cardiac output and TPR were estimated (Modelflow method). Despite similar resting BP, BL men exhibited greater BP standard deviation (e.g. systolic BP SD; BL, 7.1 ± 2.2 mmHg; WH, 5.4 ± 1.5 mmHg; P = 0.006) compared with WH men, which was accompanied by a greater TPR SD (P = 0.003), but not cardiac output SD (P = 0.390). Other traditional measures of variability provided similar results. Histogram analysis indicated that BL men exhibited a greater percentage of cardiac cycles with BPs higher (> +10 mmHg higher) and lower (< -8 mmHg lower) than mean systolic BP compared with WH men (interaction, P < 0.001), which was accompanied by a greater percentage of cardiac cycles with high/low TPR (P < 0.001). In a subset of subjects (n = 30), reduced sympathetic baroreflex sensitivity was associated with augmented BP variability (r = -0.638, P < 0.001), whereas cardiac baroreflex sensitivity had no relationship (P = 0.447). Herein, we document an augmented beat-to-beat BP variability in young BL men, which coincided with fluctuations in vascular resistance and reduced sympathetic BRS.