Baroreceptor Unloading Research Articles

The left ventricle increases contractility in response to baroreceptor unloading, which is sympathetically mediated in the anesthetized rat.

Contemporary discussion of the baroreflex includes the efferent vascular-sympathetic and cardiovagal arms. Since sympathetic postganglionic neurons also innervate the left ventricle (LV), it is often assumed that the LV produces a sympathetically mediated increase in contractility during baroreceptor unloading, but this has not been characterized using a load-independent index of contractility. We aimed to determine 1) whether LV contractility increases in response to baroreceptor unloading and 2) whether such increases are mediated via the sympathetic or parasympathetic arm of the autonomic nervous system. Ten male Wistar rats were anesthetized (urethane) and instrumented with arterial and LV pressure-volume catheters to measure mean arterial pressure (MAP) and load-independent LV contractility [maximal rate of increase in pressure adjusted to end-diastolic volume (PAdP/dtmax)], respectively. Rats were placed in a servo-controlled lower-body negative pressure (LBNP) chamber to reduce MAP by 10% for 60 s to mechanically unload baroreceptors under control conditions. LBNP was repeated in each animal following infusions of cardiac autonomic blockers using esmolol (sympathetic), atropine (parasympathetic), and esmolol + atropine. Under control conditions, PAdP/dtmax increased during baroreceptor unloading (26 ± 6 vs. 31 ± 9 mmHg·s-1·μL-1, P = 0.031). During esmolol, there was no increase in LV contractility during baroreceptor unloading (11 ± 2 vs. 12 ± 2, P = 0.125); however, during atropine, there was an increase in LV contractility during baroreceptor unloading (26 ± 6 vs. 31 ± 9, P = 0.019). During combined esmolol and atropine, there was a small increase in contractility versus control (13 ± 3 vs. 15 ± 4, P = 0.046). Our results demonstrate that, in anesthetized rats, LV contractility increases in response to baroreceptor unloading, which is largely sympathetically mediated.NEW & NOTEWORTHY This study empirically demonstrates a sympathetically mediated increase in LV contractility in response to baroreceptor unloading using a load-independent index of cardiac contractility in the anesthetized rat.

The change in Baroreflex Regulation of Heart Rhythm after “Dry” Immersion Appears during Orthostasis, but not Lower Body Negative Pressure Test

The ratio of low-frequency (LF, ~0.1 Hz) waves of RR interval duration (RRI) and systolic blood pressure (SAP) reflects the cardiac baroreflex sensitivity (BRS). Gravitational unloading (GU) may alter BRS during the passive orthostatic test (HUT) and lower body negative pressure (LBNP) test. Both effects cause blood redistribution to the lower body, but HUT is accompanied by greater unloading of sinocarotid baroreceptors than LBNP and activation of the vestibulosympathetic reflex but GU effects on BRS in these tests have not been directly compared previously. In this study we tested the hypothesis that the effect of “dry” immersion (DI, on-ground model of GU) on BRS in the same subjects will be more pronounced during HUT than during LBNP, which causes a comparable decrease in stroke volume. Nine healthy men participated in two test sessions (before and after 7-day DI) consisting of five 3-min HUT (65°) and five 3-min LBNP (–35 mmHg) with averaging the parameters in each test. Wavelet analysis was used to determine the amplitude of the RRI and SAP waves in the range of 0.05–0.13 Hz. The amplitude of LF waves of SAP increased in both tests, after DI - more significantly in HUT. The amplitude of LF RRI waves decreased in the two tests; the degree of decrease did not differ between tests and did not change under the influence of DI. The α-coefficient (the ratio of the amplitudes of RRI and SAP LF waves) decreased equally in the two tests before DI, but after DI, the degree of α-coefficient reduction increased in HUT test but did not change in LBNP test. Thus, the effect of DI on BRS is evident in HUT, but not in LBNP, which may be explained by the more pronounced influence of HUT on the mechanisms of neural control of heart rhythm.

Effect of Lower Body Negative Pressure (LBNP) on Blood Pressure in Awake Rats and Effects of Anesthesia

Lower body negative pressure (LBNP) has been used for decades in a variety of settings and species to model orthostatic challenge (OC) and baroreceptor unloading. However, due to physical constraints, measurements of blood pressure (BP) during LBNP have always been made in anesthetized animals, where cardiovascular reflexes are blunted or even blocked. In terminal procedures, for example, urethane is often used in an attempt to preserve some measure of autonomic reflex function during OC. More recently, investigators have used isoflurane in animals fitted with BP telemeters in order to perform longitudinal studies, but the extent to which various cardiovascular reflexes may be preserved is unknown. Here we have developed a novel method to apply lower body negative pressure in awake rats instrumented for BP measurement. Rats were placed into a tubular restraining device (5 cm diameter X 21 cm length), that is divided into an upper and lower chamber by two adjacent latex septa with small holes (~ 2 cm). Rats were positioned so that the septa form a seal at the lower margin of the thorax, thereby creating independent upper and lower chambers. Negative pressure was then applied to the lower chamber using a high-volume vacuum and the pressure controlled using an adjustable damper. BP measurements in response to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by induction of anesthesia and repetition of the LBNP protocol. The effects of pentobarbital (50mg/kg), ketamine/xylazine (70/6 mg/kg) and isoflurane (3%) were determined on separate days. BP and heart rate (HR) responses are shown in the Table. We found that BP was remarkably preserved in awake rats up to at least -9 mmHg LBNP, and thereafter (at -12 and -15 mmHg) decreased modestly. There was a robust baroreceptor-mediated increase in HR beginning at -6 mmHg. By contrast, under each anesthetic, blood pressure decreased dramatically and progressively with increasing LBNP, and the reflex increases in HR were entirely blocked (and actually inverted). These data indicate that the awake rat has robust mechanisms to preserve cardiovascular function during OC, and that these mechanisms are severely compromised during anesthesia. University of Cincinnati College of Medicine Innovation Seed Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pain perception during baroreceptor unloading by lower body negative pressure.

People with high blood pressure have reduced sensitivity to pain, known as blood pressure hypoalgesia. One proposed mechanism for this is altered baroreceptor sensitivity. In healthy volunteers, stimulating the carotid baroreceptors causes reduced sensitivity to acute pain; however, this effect may be confounded by a rise in blood pressure due to baroreflex stimulation. The present study tests whether baroreceptor unloading contributes to the physiological mechanism of blood pressure-related hypoalgesia. In the present study, pain perception to thermal stimulation of the forearm was studied in 20 healthy volunteers during baroreceptor unloading by lower body negative pressure (LBNP) at -5 and -20 mmHg. Blood pressure and heart rate were measured continuously throughout. To address issues relating to stimulation order, the sequence of LBNP stimulation was counterbalanced across participants. Increased heart rate was observed at a LBNP of -20 mmHg, but not -5 mmHg, but neither stimulus had an effect on blood pressure. There was no change in warm or cold sensory detection thresholds, heat or cold pain thresholds nor perceived pain from a 30s long thermal heat stimulus during LBNP. Therefore, baroreceptor unloading with maintained systemic blood pressure did not alter pain perception. The current study does not support the hypothesis that an altered baroreflex may underlie the physiological mechanism of blood pressure-related hypoalgesia. This work provides evidence that, when measured in normotensive healthy young adults, the baroreflex response to simulated hypovolaemia did not lead to reduced pain sensitivity (known as blood pressure hypoalgesia).

Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males

The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. Methods30 young, healthy, sodium loaded, non-obese males were exposed to −15 mmHg LBNP, −30 mmHg LBNP, −15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. ResultsAll intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; −15 mmHg: −3.1 ± 0.9 %, −30 mmHg: −2.9 ± 0.6 %, −15 mmHg + aslikiren: −1.8 ± 0.6 %). −15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. ConclusionSympathetic stimulation for 90 min via LBNP at −30 mmHg LBNP compared to −15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.

Testosterone-associated blood pressure dysregulation in women with androgen excess polycystic ovary syndrome.

We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via altered sympathetic nervous system activity (SNSA), reduced integrated baroreflex gain and increased renin-angiotensin system (RAS) activation. We measured resting SNSA (microneurography), integrated baroreflex gain, and RAS with lower body negative pressure in obese insulin-resistant (IR) women with AE-PCOS [n = 8, 23 ± 4 yr; body mass index (BMI) = 36.3 ± 6.4 kg/m2] and obese IR controls (n = 7, control, 29 ± 7 yr; BMI = 34.9 ± 6.8 kg/m2), at baseline (BSL), after 4 days of gonadotropin-releasing hormone antagonist (ANT, 250 μg/day) and 4 days of ANT + testosterone (ANT + T, 5 mg/day) administration. Resting BP was similar between groups for systolic blood pressure (SBP; 137 ± 14 vs. 135 ± 14 mmHg, AE-PCOS, control) and diastolic BP (89 ± 21 vs. 76 ± 10 mmHg, AE-PCOS, control). BSL integrated baroreflex gain was similar between groups [1.4 ± 0.9 vs. 1.0 ± 1.3 forearm vascular resistance (FVR) U/mmHg], but AE-PCOS had lower SNSA (10.3 ± 2.0 vs. 14.4 ± 4.4 burst/100 heartbeats, P = 0.04). In AE-PCOS, T suppression increased integrated baroreflex gain, which was restored to BSL with ANT + T (4.3 ± 6.5 vs. 1.5 ± 0.8 FVR U/mmHg, ANT, and ANT + T, P = 0.04), with no effect in control. ANT increased SNSA in AE-PCOS (11.2 ± 2.4, P = 0.04). Serum aldosterone was greater in AE-PCOS versus control (136.5 ± 60.2 vs. 75.7 ± 41.4 pg/mL, AE-PCOS, control, P = 0.04) at BSL but was unaffected by intervention. Serum angiotensin-converting enzyme was greater in AE-PCOS versus control (101.9 ± 93.4 vs. 38.2 ± 14.7 pg/mL, P = 0.04) and reduced by ANT in AE-PCOS (77.7 ± 76.5 vs. 43.4 ± 27.3 µg/L, ANT, and ANT + T, P = 0.04) with no impact on control. Obese, IR women with AE-PCOS showed decreased integrated baroreflex gain and increased RAS activation compared with control.NEW & NOTEWORTHY Here we present evidence for an important role of testosterone in baroreflex control of blood pressure and renal responses to baroreceptor unloading in women with a common, high-risk androgen excess polycystic ovary syndrome (AE-PCOS) phenotype. These data indicate a direct effect of testosterone on the vascular system of women with AE-PCOS independent of body mass index (BMI) and insulin-resistant (IR). Our study indicates that hyperandrogenemia is a central underlining mechanism of heightened cardiovascular risk in women with PCOS.

Model-based spectral causality of cardiovascular variability interactions during head-down tilt

Objective. Cardiovascular control mechanisms are commonly studied during baroreceptor unloading induced by head-up tilt. Conversely, the effect of a baroreceptor loading induced by head-down tilt (HDT) is less studied especially when the stimulus is of moderate intensity and using model-based spectral causality markers. Thus, this study computes model-based causality markers in the frequency domain derived via causal squared coherence and Geweke spectral causality approach from heart period (HP) and systolic arterial pressure (SAP) variability series. Approach. We recorded HP and SAP variability series in 12 healthy men (age: from 41 to 71 yrs, median: 57 yrs) during HDT at −25°. The approaches are compared by considering two different bivariate model structures, namely the autoregressive and dynamic adjustment models. Markers are computed in traditional frequency bands utilized in cardiovascular control analysis, namely the low frequency (LF, from 0.04 to 0.15 Hz) and high frequency (HF, from 0.15 to 0.4 Hz) bands. Main results. We found that: (i) the two spectral causality metrics are deterministically related but spectral causality markers exhibit different discriminative ability; (ii) HDT reduces the involvement of the baroreflex in regulating HP-SAP variability interactions in the LF band, while leaving unmodified the action of mechanical feedforward mechanisms in both LF and HF bands; (iii) this conclusion does not depend on the model structure. Significance. We conclude that HDT can be utilized to reduce the impact of baroreflex and to study the contribution of regulatory mechanisms different from baroreflex to the complexity of cardiovascular control in humans.

Changes of the cardiac baroreflex bandwidth during postural challenges.

Baroreflex is commonly typified from heart period (HP) and systolic arterial pressure (SAP) spontaneous variations in the frequency domain mainly by estimating its sensitivity. However, an informative parameter linked to the rapidity of the HP response to SAP changes, such as the baroreflex bandwidth, remains unquantified. We propose a model-based parametric approach for estimating the baroreflex bandwidth from the impulse response function (IRF) of the HP-SAP transfer function (TF). The approach accounts explicitly for the action of mechanisms modifying HP regardless of SAP changes. The method was tested during graded baroreceptor unloading induced by head-up tilt (HUT) at 15°, 30°, 45°, 60°, and 75° (T15, T30, T45, T60, and T75) in 17 healthy individuals (age: 21-36 yr; 9 females and 8 males) and during baroreceptor loading obtained via head-down tilt (HDT) at -25° in 13 healthy men (age: 41-71 yr). The bandwidth was estimated as the decay constant of the monoexponential IRF fitting. The method was robust because the monoexponential fitting described adequately the HP dynamics following an impulse of SAP. We observed that 1) baroreflex bandwidth is reduced during graded HUT and this narrowing is accompanied by the reduction of the bandwidth of mechanisms that modify HP regardless of SAP changes and 2) baroreflex bandwidth is not affected by HDT but that of SAP-unrelated mechanisms becomes wider. This study provides a method for estimating a baroreflex feature that provides different information compared with the more usual baroreflex sensitivity while accounting explicitly for the action of mechanisms changing HP irrespective of SAP.

Hypothalamic paraventricular nucleus augments baroreflex sensitivity, role of angiotensin II

The hypothalamic paraventricular nucleus (PVN) is an important brain region involved in control of the cardiovascular system. Direct injection of angiotensin II (AngII) into the PVN produces a short or long pressor response. This study was performed in anesthetized rats to find whether the parvocellular part of the paraventricular nucleus (PVNp) affects the baroreflex. And if so, what is the effect of AngII injected into the PVNp on the baroreflex? Drugs were microinjected into the PVNp while blood pressure and heart rate were recorded continuously. We found that microinjection of AT1 and AT2 receptor antagonists into the PVNp region did not affect the baseline mean arterial pressure (MAP) and heart rate (HR) indicating that under normal conditions AngII may not provide tonic activity, at least in anaesthetized animals. Bilateral microinjections of a synaptic blocker (CoCl2) into the PVNp attenuated the baroreflex gains in responses to loading and unloading of baroreceptors, indicating that PVNp is involved in the baroreflex rate component. Microinjection of AngII into the PVNp increased MAP and HR. However, AngII slightly attenuated the baroreflex rate component using its two receptors AT1 and AT2. Collectively, these findings suggest that the PVNp as a whole is involved in the baroreflex. But AngII attenuates the heart rate response of the baroreflex through AT1 and AT2 receptors.

Abstract 054: Altered Valsalva Maneuver Hemodynamics In Postural Tachycardia Syndrome

Postural Tachycardia Syndrome (POTS) is often associated to subtle cardiovascular autonomic alterations. Valsalva maneuver (VM) is commonly used in clinical settings to assess autonomic functions. Specific hemodynamic responses during VM phases can support POTS diagnosis and can provide pathophysiological characterization.We hypothesize that POTS patients present differences in VM morphology with respect to healthy controls. We conducted a case-control study enrolling subjects with prior clinical diagnosis of POTS and controls. ECG and finger blood pressure were continuously recorded during an against-resistance expiratory effort, producing a 30-mmHg straining pressure for 15 seconds in supine. Hemodynamic parameters were computed in absolute terms at baseline, early (VM2e) and late (VM2l) phase 2, phase 3 (VM3) and phase 4 (VM4) and in inter-phase changes. We studied 13 POTS and 12 controls matched for age (28 ±2 vs 31 ±3 ; p=0.98) and BMI (24.2 ± 1.0 vs 23.2 ± 0.8; p=0.46). Mean HR was increased at baseline (80 ±4 vs 69 ±3 bpm; p<0.05). POTS had higher absolute SBP during VM3 (90 ±4 vs 76 ±4 mmHg; p<0.05) and VM4 (124 ±5 vs 112 ±3 mmHg; p<0.05). Figure shows higher HR increment (22 ± 2 vs 12 ±4 bpm; p<0.05) during VM2e and greater SBP rise (17 ± 4 vs 10 ±3 mmHg; p<0.05) in VM2l compared to controls. VM4 SBP overshoot increase was similar (17 ± 3 vs 14 ± 3 mmHg; p=0.36). POTS have higher SBP rise during VM2l and higher VM2e HR increase. These results suggest that VM analysis can aid clinical diagnosis and that maximal baroreceptor unloading creates higher tachycardic response and vasoconstriction in POTS.

Direct evidence of a sympathetically‐mediated cardio‐inotropic response to baroreceptor unloading in rats

RationaleThe baroreflex is a cardio‐autonomic reflex that is responsible for buffering acute oscillations in blood pressure. Contemporary evidence suggests that, when stimulated, baroreceptors activate a neural reflex arc via two efferent pathways: the vascular‐sympathetic arm to control peripheral resistance, and the cardio‐vagal arm to control heart rate. However, since sympathetic post‐ganglionic fibres innervate both the vasculature and left ventricle (LV) it follows that the heart may also contribute to hemodynamic regulation during baroreceptor unloading through alterations in cardiac inotropy, yet to our knowledge this has not been empirically tested using a load‐independent index of LV inotropy.Aim1) To determine whether there is an increase in LV inotropy in response to baroreceptor unloading, and 2) to parse out whether this response occurs via sympathetic activation, parasympathetic withdrawal, or a combination of the two.HypothesesThere will be an increase in LV inotropy in response to baroreceptor unloading, and this response will occur via activation of the sympathetic nervous system.Methods10 male Wistar rats were anesthetized (urethane) and instrumented with a LV pressure‐volume catheter to measure the maximal rate of pressure generation for a given end‐diastolic volume (dP/dtmax–EDV mmHg·s‐1·µl‐1) as a load‐independent metric of cardiac inotropic function. Each rat was then placed in a customized servo‐controlled lower‐body negative pressure (LBNP) chamber that was programmed to reduce mean arterial pressure (MAP) by 10% for 60s to mechanically unload baroreceptors. The protocol was repeated in the same animal following infusions of lactated ringers (control), esmolol (β1 adrenergic receptor antagonist; blocks cardiac sympathetic transmission), atropine (muscarinic receptor antagonist; blocks cardiac parasympathetic transmission), and esmolol+atropine (full cardiac autonomic blockade). Between‐condition differences in LV inotropy were assessed using mixed‐models with Bonferroni corrected post‐hoc pairwise comparisons.ResultsUnder control conditions, dP/dtmax–EDV increased significantly (25.8±4.9 vs 29.9±6.7 mmHg·s‐1·µl‐1; p=0.002) during unloading. Sympathetic and full cardiac blockade significantly reduced baseline dP/dtmax–EDV (10.8±2.1 and 13.5±3.0 mmHg·s‐1·µl‐1, respectively; p<0.001 for both), and abolished the response to baroreceptor unloading (10.6±2.1 and 14.3±4.0 mmHg·s‐1·µl‐1, respectively; p=0.999 for both). Parasympathetic blockade had no effect on baseline dP/dtmax–EDV (26.1±5.5 mmHg·s‐1·µl‐1; p=0.999) and the increase in dP/dtmax–EDV during baroreceptor unloading was maintained (30.5±8.3 mmHg·s‐1·µl‐1; p<0.001).ConclusionThese results provide direct evidence of a sympathetically‐mediated increase in cardiac inotropic function in response to baroreceptor unloading in rats.

Reduced perception of pain via baroreceptor unloading in patients with chronic back pain

Nociceptive transmission at the spinal cord is modulated by descending pain inhibitory systems originating in the brainstem that interact with neural cardiovascular pathways, such as baroreceptor input. However, data regarding antinociceptive properties of cardiopulmonary baroreceptors are largely mixed, and no studies have examined cardiopulmonary baroreceptor modulation of pain perception in patients with chronic pain. Therefore, we tested the hypothesis that cardiopulmonary baroreceptor unloading would reduce pain perception in chronic back pain (CBP) patients and healthy participants. Mechanical pressure pain threshold (algometer on the upper trapezius) and pain perception of a repetitive heat stimulus (thermode on the anterior forearm) was tested in 12 CBP patients and 8 healthy controls during supine lower body negative pressure (LBNP) of ‐10 mmHg and 0 mmHg (control condition). Pressure pain threshold during LBNP was significantly increased compared with the control condition in CBP patients (270 ± 31 vs. 240 ± 27 kPa, P=0.04) and healthy controls (293 ± 59 vs. 259 ± 50 kPa, P=0.02), indicating reduced pain perception. Similarly, the average pain rating (scale 0‐100) of the repetitive heat stimulus was significantly reduced during LBNP compared with the control condition in CBP patients (42 ± 6 vs. 48 ± 6, P<0.01). However, no significant change was observed in average pain rating of the repetitive heat stimulus during LBNP in healthy controls (38 ± 5 vs. 37 ± 7, P=0.89). Together, these preliminary findings suggest reduced pain perception during cardiopulmonary baroreceptor unloading with a potentially greater effect in patients with CBP compared with healthy individuals.

Ventricular-Vascular Uncoupling in Heart Failure: Effects of Arterial Baroreflex-Induced Sympathoexcitation at Rest and During Exercise.

Autonomic alterations in blood pressure are primarily a result of arterial baroreflex modulation of systemic vascular resistance and cardiac output on a beat-by-beat basis. The combined central and peripheral control by the baroreflex likely acts to maintain efficient energy transfer from the heart to the systemic vasculature; termed ventricular-vascular coupling. This level of control is maintained whether at rest or during exercise in healthy subjects. During heart failure, the ventricular-vascular relationship is uncoupled and baroreflex dysfunction is apparent. We investigated if baroreflex dysfunction in heart failure exacerbated ventricular-vascular uncoupling at rest, and during exercise in response to baroreceptor unloading by performing bilateral carotid occlusions in chronically instrumented conscious canines. We observed in healthy subjects that baroreceptor unloading caused significant increases in effective arterial elastance (Ea) at rest (1.2 ± 0.3 mmHg/ml) and during exercise (1.3 ± 0.2 mmHg/ml) that coincided with significant increases in stroke work (SW) (1.5 ± 0.2 mmHg/ml) and (1.6 ± 0.2 mmHg/ml) suggesting maintained ventricular-vascular coupling. Heart Failure significantly increased the effect of baroreceptor unloading on Ea at rest (3.1 ± 0.7 mmHg/ml) and during exercise (2.3 ± 0.5 mmHg/ml) whereas no significant increases in stroke work occurred, thus signifying further ventricular-vascular uncoupling. We believe that the enhanced ventricular-vascular uncoupling observed during baroreceptor unloading only worsens the already challenged orthostatic and exercise tolerance and thereby contributes to poor exercise performance and quality of life for heart failure patients.

Interactive effects of apneic and baroreflex stress on neuronal coding strategies in human muscle sympathetic nerve activity

The sympathetic nervous system exhibits patterns of action potential (AP) discharge in human muscle sympathetic nerve activity that suggest coding strategies express reflex specificity. This study explored the interactive effects of baroreceptor unloading using lower body negative pressure (LBNP) and volitional end-expiratory apnea (APN) on sympathetic postganglionic neuronal discharge patterns inferred from the firing patterns of differently sized sympathetic AP clusters. Seven individuals were studied using multiunit microneurography (fibular) and a continuous wavelet approach to quantify AP discharge probability, recruitment, and latency during APN performed under ambient conditions, -10, and -40 mmHg LBNP. Compared with the ambient condition, LBNP increased AP discharge rate at -10 and -40 mmHg and recruited larger previously silent sympathetic neurons at -40 mmHg. Compared with spontaneous breathing, APN increased AP discharge when performed during the ambient condition (Δ351 ± 132 AP/min), -10 mmHg (Δ423 ± 184 AP/min), and -40 mmHg (Δ355 ± 278 AP/min; main effect APN: P < 0.01; LBNP-by-APN interaction: P = 0.55). APN recruited larger previously silent AP clusters during the ambient condition (Δ4 ± 3; P < 0.02) and -10 mmHg (Δ4 ± 3; P < 0.01), but not -40 mmHg (Δ0 ± 2; P = 0.53; LBNP-by-APN: P < 0.01). LBNP did not affect AP latency. However, APN reduced AP latency similarly during all conditions (ambient pressure: Δ-0.04 ± 0.04s, -10 mmHg: Δ-0.03 ± 0.03s, -40 mmHg: Δ-0.03 ± 0.04s; main effect APN: P < 0.01; LBNP-by-APN: P = 0.48). These data indicate that apneic and baroreflex mechanisms appear to additively modify the axonal discharge rate of previously active sympathetic postganglionic neurons and interact to affect recruitment of previously silent sympathetic neurons. Reductions in AP latency due to apneic stress were not impacted by baroreflex unloading.NEW & NOTEWORTHY Discrete physiological stressors differentially affect sympathetic postganglionic neuronal rate-, population-, and temporal-coding strategies. When performing end-expiratory apnea (APN) during graded baroreflex unloading via lower body negative pressure (LBNP), we found: 1) augmented sympathetic axonal firing probability, 2) recruitment of larger and previously silent sympathetic postganglionic neurons at ambient and -10 mmHg, but not -40 mmHg LBNP, and 3) APN reduced axonal discharge latency similarly across all conditions, independent of the level of baroreflex unloading.

Neck Chamber Technique Revisited: Low-Noise Device Delivering Negative and Positive Pressure and Enabling Concomitant Carotid Artery Imaging With Ultrasonography.

Background and Objectives: Recently, novel noiseless device for the assessment of baroreceptor function with the neck suction (NS) has been presented. In this study, we present another in-house approach to the variable-pressure neck chamber method. Our device offers further critical improvements. First, it enables delivery of negative (NS) as well as positive pressure (neck pressurizing, NP) in a noiseless manner. Second, we used small, 3D-printed cups positioned over the carotid sinuses instead of cumbersome neck collar to improve subject comfort and to test feasibility of tracking the pressure-induced changes in carotid artery with ultrasonography.Methods: Five healthy, non-smoking, normal-weight subjects aged 29 ± 3 years (mean ± SD) volunteered for the study. Heart rate (HR, bpm) and mean arterial pressure (MAP, mmHg) responses to short, 7-s long episodes of NS and NP were recorded. Each trial consisted of 12 episodes of variable-pressure: six episodes of NS (suction ranging between -10 and -80 mmHg) and six episodes of NP (pressure ranging between + 10 and + 80 mmHg). Carotid artery sonography was performed during the NS and NP in four subjects, on another occasion.Results: The variable-pressure episodes resulted consistently in the expected pattern of hemodynamic alterations: HR and MAP increases or decreases following the NP and NS, respectively, as evidenced by the coefficient of determination (R2) of ≥0.78 for the carotid-HR response curve (for all five participants) and the carotid-MAP response curve (for four out of five participants; the curve cannot be calculated for one subject). We found a linear, dose-dependent relation between the applied pressure and the systolic-diastolic difference in carotid artery diameter.Conclusion: The novel device enables noiseless stimulation and unloading of the carotid baroreceptors with the negative and positive pressure, respectively, applied on the subject’s neck via small, asymmetric and one-side flattened, 3D-printed cups. The unique design of the cups enables concomitant visualizing of the carotid artery during the NS or NP administration, and thereby direct monitoring of the intensity of mechanical stimulus targeting the carotid baroreceptors.

Baroreceptor Unloading at Rest and During Exercise in Heart Failure Exacerbates Ventricular‐Vascular Coupling

The arterial baroreflex is the primary reflex controlling arterial blood pressure on a beat-by-beat basis via modulation of autonomic output to change cardiac output and systemic vascular resistance. This moment-to-moment control of arterial pressure is well maintained with the transition from rest to exercise. However, in systolic heart failure (HF) baroreflex dysfunction can occur. Effective control of cardiac output occurs in part via efficient energy transfer from the left ventricle to the systemic circulation; known as ventricular-vascular coupling. Ventricular-vascular coupling can be evaluated by changes in stroke work and the relationship between effective arterial elastance to left ventricular maximal elastance. We investigated if the effects of baroreceptor unloading (via bilateral carotid occlusion) on effective arterial elastance and stroke work at rest, and during exercise were altered in HF, in conscious chronically instrumented canines. We hypothesized that in healthy subjects the baroreflex maintains ventricular-vascular coupling whereas in HF, exacerbated increases in effective arterial elastance as a result of baroreceptor unloading would cause decoupling of the ventricular-vascular interaction. We observed in healthy subjects that baroreceptor unloading significantly increased effective arterial elastance (Ea) and stroke work (SW) at rest (Ea: +1.6 ± 0.2 mmHg/ml) (SW: +1.8 ± 0.1 L/mmHg) and during exercise (Ea: +1.4 ± 0.2 mmHg/ml) (SW: +1.6 ± 0.2 L/mmHg) thus maintaining ventricular-vascular coupling. In HF, ventricular-vascular uncoupling is already apparent with higher effective arterial elastance and reduced maximal ventricular elastance. Baroreceptor unloading in HF further worsens ventricular-vascular coupling at rest and during exercise by eliciting ~2-3 fold increases in effective arterial elastance (EaΔREST +4.3 ± 0.3 mmHg/ml) (EaΔEX +2.5 ± 0.5 mmHg/ml) unaccompanied by much improvement in stroke work (SWΔREST +0.1 ± 0.5 L/mmHg) (SWΔEX +0.5 ± 0.1 L/mmHg). We conclude that the ability of the arterial baroreflex to raise cardiac output in heart failure is impaired in part due to further reflex induced uncoupling of the ventricular-vascular relationship. This likely contributes to impaired reflex control of arterial pressure during hypotensive challenges in HF.

MODULATION OF SYMPATHETIC NERVE ACTIVITY BY SGLT2 INHIBITOR EMPAGLIFLOZIN IN DIABETIC RABBITS

Objective: Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in patients with type-2 diabetes is associated with 38% reduction in cardiovascular mortality. We explored the notion that the mechanisms underlying these benefits may involve an action on the sympathetic nervous system (SNS). Design and method: Diabetes was induced by alloxan in New-Zealand White rabbits. We determined the associated changes in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) as well as baroreflex responses to changes in BP and norepinephrine spillover in conscious rabbits. The effects of one-week treatment with empagliflozin were compared to those of another blood glucose-lowering treatment insulin, the proximally-acting natriuretic acetazolamide, the ACE inhibitor perindopril, vehicle treatment and to an untreated diabetic group. Results: Diabetic rabbits were treated with daily insulin to maintain a stable elevation in blood glucose over 4 weeks (20.5 ± 0.4 mM vs 6.5 ± 0.4 mM in controls). BP was 9% greater in diabetic than non-diabetic rabbits (P = 0.02) but there were no differences in RSNA or HR. One-week treatment with empagliflozin (without insulin) lowered blood glucose by 43% but there was no difference in BP, HR or RSNA between these animals and untreated diabetic rabbits or those treated with acetazolamide. However, insulin treatment alone lowered blood glucose similarly to empagliflozin (32%) and increased HR (+10%) while perindopril lowered BP (-9%). In diabetic rabbits there was marked augmentation of the maximum RSNA response to baroreceptor unloading compared to non-diabetic (+69%, P &lt; 0.01). Empagliflozin attenuated the baroreflex by 34% and there was a similar reduction after acetazolamide (-29%, both P &lt; 0.05). Empagliflozin also attenuated the HR baroreflex (-8%) but insulin and perindopril had no effect on either baroreflex. Norepinephrine spillover to plasma was similar in diabetic and non-diabetic rabbits but was elevated after both empagliflozin and acetazolamide (+147% and + 134%, P &lt; 0.05). Conclusions: Empagliflozin normalised the maximal RSNA response to lowering BP, which was exaggerated in diabetic rabbits, without altering BP or resting RSNA. A similar action of the natriuretic acetazolamide suggests that the mechanism underlying the cardiovascular benefits of empagliflozin may involve increased sodium and water excretion.

Cardiovascular fingolimod effects on rapid baroreceptor unloading are counterbalanced by baroreflex resetting

Background and purposeInitial cardiovascular fingolimod effects might compromise baroreflex responses to rapid blood pressure (BP) changes during common Valsalva-like maneuvers. This study evaluated cardiovascular responses to Valsalva maneuver (VM)-induced baroreceptor unloading and loading upon fingolimod initiation.Patients and methodsTwenty-one patients with relapsing-remitting multiple sclerosis performed VMs before and 0.5, 1, 2, 3, 4, 5, and 6 hours after fingolimod initiation. We recorded heart rate (HR) as RR intervals (RRI), systolic and diastolic BP (BPsys, BPdia) during VM phase 1, VM phase 2 early, VM phase 2 late, and VM phase 4. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. To assess cardiovagal activation upon baroreceptor loading, we calculated Valsalva ratios (VR) between maximal and minimal RRIs after strain release. Analysis of variance or Friedman tests with post hoc analysis compared corresponding parameters at the eight time points (significance: p < 0.05).ResultsRRIs at VM phase 1, VM phase 2 early, and VM phase 2 late were higher after than before fingolimod initiation, and maximal after 4 hours. Fingolimod did not affect the longest RRIs upon strain release, but after 3, 5, and 6 hours lowered the highest BPsys values during overshoot and all BPdia values, and thus reduced VRs. BRG was slightly higher after 3 and 5 hours, and significantly higher after 4 hours than before fingolimod initiation.ConclusionsVR-decreases 3–6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Stable and at the time of HR nadir significantly increased BRGs indicate improved responses to baroreceptor unloading. Thus, cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting.

Pulling back on the push-pull effect: use of lower body negative pressure to protect against drops in cerebral perfusion during airflight manoeuvres.

Pulling back on the push-pull effect: use of lower body negative pressure to protect against drops in cerebral perfusion during airflight manoeuvres.

SPARC‐Network‐Scale Interactions Among Simultaneously Recorded Brainstem Neurons In The Dorsal Medulla, Ventrolateral Medulla, And Pons: A Substrate For Central Autonomic Control And Processing Of Cardiovascular Afferent Feedback

The central autonomic control system provides parasympathetic and sympathetic drive to peripheral ganglia that regulate a host of visceral functions. Detailed knowledge of the network scale organization of this central circuit is incomplete. We hypothesized that functional synaptic interactions between many simultaneously recorded neurons in and around the nucleus of the tractus solitarius (NTS), the retrotrapezoid nucleus (RTN), ventral respiratory column (VRC) and pons would yield information about the network‐scale strategy that is employed by this system to regulate autonomic drive. Experiments were conducted in 73 decerebrated, paralyzed, and artificially ventilated cats. Multi‐electrode arrays including up to 100 channels were placed in the areas of the NTS, RTN, and VRC. A total of 2,643 neurons were challenged with alterations in blood pressure (BP) and cardiac modulation was assessed in 3,531 neurons. The spike activity patterns of many simultaneously recorded single neurons were evaluated during breathing, the cardiac cycle, increased activation of baroreceptors by inflation of a balloon in the abdominal aorta and unloading of baroreceptors by inflation of a balloon in the vena cava. There was no apparent anatomical segregation of neurons in these areas with regard to cardiac or BP modulation based on stereotaxic coordinates. Cross correlation analysis revealed robust excitatory and inhibitory functional interactions between neurons in the areas of the NTS, VRC, RTN, and pons. Plots customized to reveal patterns of information transfer between neurons in different areas provided evidence that units in the RTN and VRC were predominantly exciting those in the NTS area, while these same NTS neurons were exciting and inhibiting different neurons in the RTN and VRC. Specific evidence was found for putative intermediate ventrolateral medulla (iVLM) neurons that were excited by BP and involved in inhibitory interactions with putative rostral ventrolateral medulla (RVLM) neurons that were inhibited by increased BP. However, this mechanism was a low frequency feature of the dataset. Evidence for synaptic inhibition between neurons that responded to increased BP was a predominant finding. Among neurons that responded to decreased BP, evidence for synaptic excitation was more common. These results support differential organization of brainstem networks that mediate autonomic responses to increased BP relative to those that mediate decreased BP. The brainstem network that mediates sympatho‐inhibition in response to increased blood pressure is sparsely excitatory and may depend on abundant inhibitory mechanisms to enhance signal/noise ratios in support of information transmission from baroreceptors.Support or Funding InformationSupported by 3OT2OD023854