Baroreflex Unloading Research Articles

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.

Action potential subpopulations within human muscle sympathetic nerve activity: Discharge properties and governing mechanisms.

Sympathetic emissions directed towards the skeletal muscle circulation - muscle sympathetic nerve activity (MSNA) - represent a key mechanism for maintaining homeostasis and supporting human survival during physiological stress. Pulse-rhythmic bursts formed by the synchronous discharge of differently-sized sympathetic action potentials (APs) represent the primary characteristic of MSNA. Of the APs firing under baseline conditions (reflecting low-threshold c-fibre activity), a range of subpopulations exists, of which three general categories can be discussed based on their peak-to-peak amplitude in the filtered raw neurogram - small, medium, and large. These subpopulations express nonuniform discharge, recruitment, and synchronization patterns. The subpopulation of medium APs fires synchronously in most bursts, while the subpopulations of small and large APs fire less often. However, 30% of total AP discharge occurs asynchronously between sympathetic bursts, a pattern expressed most often by small APs. In response to physiological stress (e.g., baroreflex unloading), the subpopulation of medium APs exhibits the largest increase in firing probability and a subpopulation of previously-silent larger and faster-conducting APs (reflecting high-threshold c-fibre activity) becomes recruited. Heterogeneous discharge, synchronization, and recruitment thresholds among AP subpopulations stem from differential regulation within the sympathetic organization including the arterial baroreflex and paravertebral ganglia. Indeed, the arterial baroreflex strongly regulates medium APs at baseline and enhances its control over this subpopulation during periods of baroreflex unloading. Conversely, small and large APs express weak baroreflex control. Trimethaphan infusion has revealed that ganglionic processes including nicotinic and non-nicotinic mechanisms may contribute to heterogenous firing behaviours among low-threshold AP subpopulations. This review highlights recent work revealing new insight to the discharge properties expressed by, and mechanisms governing, AP subpopulations within human MSNA.

Cardiovascular Responses During Graded Lower‐Body Negative Pressure in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) represents approximately half of the known cases of heart failure in the United States, with equally poor outcomes and rising prevalence compared to heart failure with reduced ejection fraction (HFrEF). While changes in autonomic nervous system function is a well‐known feature of HFrEF pathophysiology, whether patients with HFpEF experience a similar decrement remains unknown. Therefore, we sought to evaluate the reflex cardiovascular responses to baroreflex unloading achieved via graded levels of lower‐body negative pressure (LBNP) in patients with HFpEF compared to healthy, age‐matched controls (CON). In six participants (three HFpEF (1 male, 70±3 yrs) and three CON (2 male, 74±2 yrs)), we assessed forearm blood flow (FBF; Doppler ultrasound), mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram) and forearm vascular conductance (FVC) at rest and throughout graded levels of LBNP (−10, −20, −30 and −40 mmHg). At rest, there were no significant differences between HFpEF and CON in FBF (109±32 vs. 85±29 ml/min), MAP (90±4 vs. 96±3 mmHg), HR (60±5 vs. 61±5 bpm), or FVC (1.19±0.33 vs. 0.89±0.28 ml/min/mmHg). The reflex tachycardic response to baroreflex unloading induced by LBNP was similar between patients with HFpEF and CON. Vasoconstriction in response to LBNP decreased FBF to a similar level in both HFpEF and CON (−10: 102±31 vs. 88±28 ml/min; −20: 95±30 vs. 76±25 ml/min; −30: 91±30 vs. 78±28 ml/min; −40: 91±33 vs. 71±21 ml/min, HFpEF vs. CON), with similar changes in FVC. Together, these preliminary data suggest that baroreflex‐mediated cardiac and vascular responses are not altered in patients with HFpEF, suggesting an absence of overt autonomic dysfunction is this patient group.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313, R56AG057584, T32HL139451) and the U.S. Department of Veterans Affairs (I01RX001311, I01RX001697, I01RX002323, I01RX000182).

Corticospinal excitability for flexor carpi radialis decreases with baroreceptor unloading during intentional co-contraction with opposing forearm muscles.

Concurrent activation of antagonistic muscles (co-contraction) is used for stiffening a joint, whereas its neural control under hemodynamic stress (e.g., posture change, high gravity, and hemorrhage) is unknown. Corticospinal excitability during co-contraction may be altered with baroreceptor unloading due to potential modulations in spinal and/or inhibitory pathways (e.g., disynaptic group I inhibition and GABA-mediated intracortical inhibition). The purpose of this study was to understand the effect of baroreceptor unloading on corticospinal excitability during co-contraction in humans. Motor evoked potential and cortical silent period in a wrist flexor muscle were examined using transcranial magnetic stimulation in two groups of healthy young adults. All subjects performed isometric contraction of the wrist flexors (flexion) and co-contraction of the wrist flexors and extensors (co-contraction). Spinal disynaptic inhibition was also assessed with the ratio of H-reflex responses to unconditioned and conditioned electrical stimulations of the peripheral nerves for the muscles. In one of the groups, baroreflex unloading was induced by applying lower body negative pressure. There was no significant effect of baroreflex unloading on cortical silent period or H-reflex measure of disynaptic inhibition. With baroreflex unloading, motor evoked potential area in the flexor carpi radialis was decreased during co-contraction but not during flexion. The results indicated that baroreceptor unloading decreases corticospinal excitability during co-contraction of antagonistic muscles, apparently by influencing neural pathways that were not probed with cortical silent period or spinal disynaptic inhibition.

Evidence for differential control of muscle sympathetic single units during mild sympathoexcitation in young, healthy humans.

Two subpopulations of muscle sympathetic single units with opposite discharge characteristics have been identified during low-level cardiopulmonary baroreflex loading and unloading in middle-aged adults and patients with heart failure. The present study sought to determine whether similar subpopulations are present in young healthy adults during cardiopulmonary baroreflex unloading ( study 1) and rhythmic handgrip exercise ( study 2). Continuous hemodynamic and multiunit and single unit muscle sympathetic nerve activity (MSNA) data were collected at baseline and during nonhypotensive lower body negative pressure (LBNP; n = 12) and 40% maximal voluntary contraction rhythmic handgrip exercise (RHG; n = 24). Single unit MSNA responses were classified as anticipated or paradoxical based on whether changes were concordant or discordant with the multiunit MSNA response, respectively. LBNP and RHG both increased multiunit MSNA burst frequency (∆5 ± 3 bursts/min, P < 0.001; ∆5 ± 8 bursts/min, P = 0.005), burst amplitude (∆5 ± 7%, P = 0.04; ∆13 ± 14%, P < 0.001), and total MSNA (∆302 ± 191 AU/min, P = 0.001; ∆585 ± 556 AU/min, P < 0.001). During LBNP and RHG, 43 and 64 muscle single units were identified, respectively, which increased spike frequency (∆9 ± 11 spikes/min, P < 0.001; ∆10 ± 19 spikes/min, P < 0.001) and the probability of multiple spike firing (∆10 ± 12%, P < 0.001; ∆11 ± 26%, P = 0.001). During LBNP and RHG, 36 (84%) and 39 (61%) single units possessed anticipated firing responses (∆12 ± 10 spikes/min, P < 0.001; ∆19 ± 19 spikes/min, P < 0.001), whereas 7 (16%) and 25 (39%) single units exhibited paradoxical reductions (∆-3 ± 1 spikes/min, P = 0.003; ∆-4 ± 5 spikes/min, P < 0.001). The observation of divergent subpopulations of muscle sympathetic single units in healthy young humans during two mild sympathoexcitatory stressors supports differential control at the fiber level as a fundamental characteristic of human sympathetic regulation. NEW & NOTEWORTHY The activity of muscle sympathetic single units was recorded during cardiopulmonary baroreceptor unloading and rhythmic handgrip exercise in young healthy humans. During both stressors, the majority of single units (84% and 61%) exhibited anticipated behavior concordant with the integrated muscle sympathetic response, whereas a smaller proportion (16% and 39%) exhibited paradoxical sympathoinhibition. These results support differential control of postganglionic muscle sympathetic fibers as a characteristic of human sympathetic regulation during mild sympathoexcitatory stress. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/differential-control-of-sympathetic-outflow-in-young-humans/ .

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

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

Interaction between the muscle metaboreflex and the arterial baroreflex in control of arterial pressure and skeletal muscle blood flow.

The muscle metaboreflex and arterial baroreflex regulate arterial pressure through distinct mechanisms. During submaximal exercise muscle metaboreflex activation (MMA) elicits a pressor response virtually solely by increasing cardiac output (CO) while baroreceptor unloading increases mean arterial pressure (MAP) primarily through peripheral vasoconstriction. The interaction between the two reflexes when activated simultaneously has not been well established. We activated the muscle metaboreflex in chronically instrumented canines during dynamic exercise (via graded reductions in hindlimb blood flow; HLBF) followed by simultaneous baroreceptor unloading (via bilateral carotid occlusion; BCO). We hypothesized that simultaneous activation of both reflexes would result in an exacerbated pressor response owing to both an increase in CO and vasoconstriction. We observed that coactivation of muscle metaboreflex and arterial baroreflex resulted in additive interaction although the mechanisms for the pressor response were different. MMA increased MAP via increases in CO, heart rate (HR), and ventricular contractility whereas baroreflex unloading during MMA caused further increases in MAP via a large decrease in nonischemic vascular conductance (NIVC; conductance of all vascular beds except the hindlimb vasculature), indicating substantial peripheral vasoconstriction. Moreover, there was significant vasoconstriction within the ischemic muscle itself during coactivation of the two reflexes but the remaining vasculature vasoconstricted to a greater extent, thereby redirecting blood flow to the ischemic muscle. We conclude that baroreceptor unloading during MMA induces preferential peripheral vasoconstriction to improve blood flow to the ischemic active skeletal muscle.

Central correlation of muscle sympathetic nerve activation during baroreflex unloading – a microneurography–positron emission tomography study

The baroreceptor reflex controls spontaneous fluctuations in blood pressure. One major control variable of the baroreflex is the sympathetic vasoconstrictor activity to muscles [MSNA; burst frequency (BF) and burst incidence (BI)], which can be quantitatively assessed by microneurography. We aimed to investigate the central regions involved in baroreflex regulation of MSNA. Healthy men (mean age 25 years) participated in three experimental sessions. (i) Microneurography recordings of MSNA from the left peroneal nerve during rest and baroreflex unloading, induced by lower body negative pressure (LBNP; -40 mmHg). If MSNA could be reliably recorded throughout this procedure (n = 15), the subjects entered the positron emission tomography (PET) experiments. The two PET sessions took place in a randomised order. Cerebral glucose metabolism (18-fluorodeoxyglucose) was analysed after: (ii) baroreflex unloading (LBNP); and (iii) control condition (lying in the LBNP chamber without suction). The PET data were analysed employing SPM8. LBNP elicited a significant increase in MSNA in all successfully recorded subjects (BI: P = 0.001; F = 5.54; BF: P < 0.001; F = 36.59). As compared with the control condition, LBNP was associated with increased PET regional glucose metabolism bilaterally in the orbitofrontal cortex (OFC; BA 11, 47). Related to the rise of BF, there was increased activation of the left OFC (BA 11); related to the rise of BI there was increased activation of the brainstem corresponding to the rostral ventrolateral medulla. Our data support a role for the ventrolateral medulla and the OFC in baroreflex-mediated control of MSNA in humans.

Exercise pressor response and arterial baroreflex unloading during exercise in chronic kidney disease

Patients with chronic kidney disease (CKD) have poor exercise capacity, which contributes to cardiovascular risk. We sought to determine whether patients with stage 2 or stage 3 CKD have an augmented blood pressure (BP) response during exercise, and if so, whether overactivation of the sympathetic nervous system (SNS) during exercise might play a role. In 13 patients with CKD and hypertension and 13 controls with hypertension, we measured hemodynamics and muscle sympathetic nerve activity (MSNA) during the following maneuvers: low-level rhythmic handgrip (RHG 20%), which primarily stimulates mechanoreceptors, and moderate static handgrip exercise (SHG 30%) followed by posthandgrip circulatory arrest (PHGCA), which isolates metaboreceptors. During baseline studies, patients with CKD had significantly greater increases in mean arterial pressure (MAP) during SHG 30% (P = 0.045), RHG 20% (P = 0.031), and PHGCA (P = 0.043); however, the MSNA response was not augmented in patients with CKD compared with controls. We hypothesized that an augmented SNS response during exercise might be revealed in CKD if arterial baroreflex constraint was equalized using nitroprusside (NTP). These exercise maneuvers were repeated in patients with CKD during NTP infusion to equalize the BP response between groups, thereby relieving baroreflex-mediated suppression of SNS activity. With NTP infusion, patients with CKD had significantly increased MSNA responses during SHG 30% (P = 0.0044), and RHG 20% (P = 0.0064), but not during PHGCA (P > 0.05), suggesting increased reflex activation of the SNS during exercise, which may be mediated by mechanoreceptors but not metaboreceptors. Patients with CKD have an exaggerated BP response during rhythmic and static exercise with underlying SNS overactivation that is revealed during arterial baroreflex unloading during exercise.

Altered cortical activation patterns associated with baroreflex unloading following 24 h of physical deconditioning

Cardiovascular arousal is associated with patterned cortical activity changes. Head-down-tilt bed rest (HDBR) dimishes the baroreflex-mediated cardiac control. The present study tested the hypothesis that HDBR deconditioning would modify the forebrain organization for heart rate (HR) control during baroreflex unloading. Heart rate variability (HRV), blood pressure and plasma hormones were analysed at rest, whereas HR and cortical autonomic activation patterns (functional magnetic resonance imaging) were measured during graded and randomly assigned lower body negative pressure treatments (LBNP, -15 and -35 mmHg) both before (Pre) and after (Post) a 24 h HDBR protocol (study 1; n = 8). An additional group was tested before and following diuretic-induced hypovolaemia (study 2; n = 9; spironolactone, 100 mg day(-1) for 3 days) that mimicked the plasma volume lost during HDBR (-15% in both studies; P < 0.05). Head-down bed rest with hypovolaemia did not affect baseline HR, mean arterial pressure, HRV or plasma catecholamines. Head-down bed rest augmented the LBNP-induced HR response (P < 0.05), and this was associated with bed-rest-induced development of the following changes: (i) enhanced activation within the genual anterior cingulate cortex and the right anterior insular cortex; and (ii) deactivation patterns within the subgenual regions of the anterior cingulate cortex. Diuretic treatment (without HDBR) did not affect baseline HR and mean arterial pressure, but did reduce resting HRV and elevated circulating noradrenaline and plasma renin activity (P < 0.05). The greater HR response to LBNP following diuretic (P < 0.05) was associated with diminished activation of the right anterior insula. Our findings indicate that 24 h of HDBR minimized the impact of diuretic treatment on baseline autonomic and cardiovascular variables. The findings also indicate that despite the similar augmentation of HR responses to LBNP and despite similar pre-intervention cortical activation patterns, HDBR and diuretic treatment produced different effects on the cortical responses, with HDBR affecting anterior cingulate cortex and right insula regions, whereas diuretic treatment affected primarily the right insula alone, but in a direction that was opposite to HDBR. The data indicate that physical deconditioning can induce rapid functional changes within the cortical circuitry associated with baroreflex unloading, changes that are distinct from diuretic-induced hypovolaemia. The results suggest that physical activity patterns exert a rapid and notable impact on the cortical circuitry associated with cardiovascular control.

Arterial baroreflex control of muscle sympathetic nerve activity under orthostatic stress in humans

The mechanisms by which blood pressure is maintained against the orthostatic stress caused by gravity's effect on the fluid distribution within the body are important issues in physiology, especially in humans who usually adopt an upright posture. Peripheral vasoconstriction and increased heart rate (HR) are major cardiovascular adjustments to orthostatic stress and comprise part of the reflex response elicited via the carotid sinus and aortic baroreceptors (arterial baroreflex: ABR) and cardiopulmonary stretch receptors (cardiopulmonary baroreflex). In a series of studies, we have been characterizing the ABR-mediated regulation of cardiovascular hemodynamics and muscle sympathetic nerve activity (MSNA) while applying orthostatic stress in humans. We have found that under orthostatic stress, dynamic carotid baroreflex responses are modulated as exemplified by the increases in the MSNA, blood pressure, and HR responses elicited by carotid baroreflex unloading and the shorter period of MSNA suppression, comparable reduction and faster recovery of mean arterial blood pressure (MAP) and greater HR response to carotid baroreflex stimulation. Our results also show that ABR-mediated beat-to-beat control over burst incidence, burst strength and total MSNA is progressively modulated as orthostatic stress is increased until induction of syncope, and that the sensitivity of ABR control over the aforementioned MSNA variables is substantially reduced during the development of syncope. We suggest that in humans, the modulation of ABR function under orthostatic stress may be one of the mechanisms by which blood pressure is maintained and orthostatic hypotension limited, and impairment of ABR control over sympathetic vasomotor activity leads to the severe hypotension associated with orthostatic syncope.

Baroreceptor unloading in postural tachycardia syndrome augments peripheral chemoreceptor sensitivity and decreases central chemoreceptor sensitivity

While orthostatic tachycardia is the hallmark of postural tachycardia syndrome (POTS), orthostasis also initiates increased minute ventilation (Ve) and decreased end-tidal CO(2) in many patients. We hypothesized that chemoreflex sensitivity would be increased in patients with POTS. We therefore measured chemoreceptor sensitivity in 20 POTS (16 women and 4 men) and 14 healthy controls (10 women and 4 men), 16-35 yr old by exposing them to eucapneic hyperoxia (30% O(2)), eucapneic hypoxia (10% O(2)), and hypercapnic hyperoxia (30% O(2) + 5% CO(2)) while supine and during 70° head-upright tilt. Heart rate, mean arterial pressure, O(2) saturation, end-tidal CO(2), and Ve were measured. Peripheral chemoreflex sensitivity was calculated as the difference in Ve during hypoxia compared with room air divided by the change in O(2) saturation. Central chemoreflex sensitivity was determined by the difference in Ve during hypercapnia divided by the change in CO(2). POTS subjects had an increased peripheral chemoreflex sensitivity (in l·min(-1)·%oxygen(-1)) in response to hypoxia (0.42 ± 0.38 vs. 0.19 ± 0.17) but a decreased central chemoreflex sensitivity (l·min(-1)·Torr(-1)) CO(2) response (0.49 ± 0.38 vs. 1.04 ± 0.18) compared with controls. CO(2) sensitivity was also reduced in POTS subjects when supine. POTS patients are markedly sensitized to hypoxia when upright but desensitized to CO(2) while upright or supine. The interactions between orthostatic baroreflex unloading and altered chemoreflex sensitivities may explain the hyperventilation in POTS patients.

Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation

Increasing arterial blood pressure (AP) decreases ventilation, whereas decreasing AP increases ventilation in experimental animals. To determine whether a "ventilatory baroreflex" exists in humans, we studied 12 healthy subjects aged 18-26 yr. Subjects underwent baroreflex unloading and reloading using intravenous bolus sodium nitroprusside (SNP) followed by phenylephrine ("Oxford maneuver") during the following "gas conditions:" room air, hypoxia (10% oxygen)-eucapnia, and 30% oxygen-hypercapnia to 55-60 Torr. Mean AP (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), expiratory minute ventilation (V(E)), respiratory rate (RR), and tidal volume were measured. After achieving a stable baseline for gas conditions, we performed the Oxford maneuver. V(E) increased from 8.8 ± 1.3 l/min in room air to 14.6 ± 0.8 l/min during hypoxia and to 20.1 ± 2.4 l/min during hypercapnia, primarily by increasing tidal volume. V(E) doubled during SNP. CO increased from 4.9 ± .3 l/min in room air to 6.1 ± .6 l/min during hypoxia and 6.4 ± .4 l/min during hypercapnia with decreased TPR. HR increased for hypoxia and hypercapnia. Sigmoidal ventilatory baroreflex curves of V(E) versus MAP were prepared for each subject and each gas condition. Averaged curves for a given gas condition were obtained by averaging fits over all subjects. There were no significant differences in the average fitted slopes for different gas conditions, although the operating point varied with gas conditions. We conclude that rapid baroreflex unloading during the Oxford maneuver is a potent ventilatory stimulus in healthy volunteers. Tidal volume is primarily increased. Ventilatory baroreflex sensitivity is unaffected by chemoreflex activation, although the operating point is shifted with hypoxia and hypercapnia.

Effect of aging on arm and leg muscle sympathetic nerve activity in humans

Aging is associated with heterogeneous changes in sympathetic nervous system outflow to various organs. Previous studies have consistently reported pronounced increases in leg muscle sympathetic activity (MSNA) at rest with age. We tested the hypothesis that aging is associated with similar increases in arm and leg MSNA at rest. Moreover, we tested the hypothesis that baroreflex unloading elicits similar increases in arm and leg MSNA in older adults. To address these hypotheses we simultaneously measured arm and leg MSNA using microneurography in young (N=7; 23±1 years old; mean±SE) and older adults (n=5: 63±2) at rest and in response to lower body negative pressure (LBNP of ‐10, ‐20, and ‐40 mmHg) (older subjects only). MSNA at rest increased similarly with age in the arm (8±2 vs. 34±6 bursts/min for young and older, respectively; P&lt;0.05) and leg (9±2 vs. 35±6 bursts/min; P&lt;0.05). Moreover, LBNP elicited similar increases in leg (Δ4±2, Δ8±4, and Δ16±6 bursts/min, change from baseline for ‐10, ‐20, and ‐40 mmHg LBNP, respectively; main effect P&lt;0.05) as well as arm MSNA (Δ4±2, Δ2±2, and Δ15±6; main effect P&lt;0.05) in older adults. Collectively, these data indicate that aging is associated with similar increases in arm and leg MSNA at rest. Moreover, parallel increases in leg and arm MSNA occur during baroreflex unloading in older humans.Support: NIH AG24420, HL77670, M01 RR10732

Baroreflex and Muscle Metaboreflex

During heavy exercise, the arterial baroreflex and the reflexes evoked by the activation of those afferent nerve endings in the working skeletal muscles that are sensitive to metabolic changes (the so-called muscle metaboreflex) are hypothesized to be activated and, moreover, to interact in ways that lead to the modulation of the primary cardiovascular reflex responses. For the past few years, our group has been investigating the interaction between the arterial baroreflex and the muscle metaboreflex. We have focused our efforts in identifying the effects of muscle metaboreflex activation on the arterial baroreflex regulation of the cardiovascular hemodynamics and muscle sympathetic nerve activity (MSNA) in humans. In a series of studies, we have found that during muscle metaboreflex activation, dynamic carotid baroreflex responses are modulated, as exemplified by the augmentation of the MSNA, leg vascular conductance and blood pressure responses to carotid baroreflex unloading and the shorter suppression period of MSNA, diminished vasodilation, and reduced blood pressure response to carotid baroreflex stimulation. Furthermore, we have found that the modification of the arterial baroreflex-mediated beat-to-beat control of MSNA, which is seen during activation of the muscle metaboreflex (i.e., resetting and an increase in sensitivity), could be a consequence of the alteration in the arterial baroreflex control of both the occurrence and strength of the MSNA burst. In addition, we have demonstrated that the arterial baroreflex beat-to-beat control of MSNA is time-dependently modulated during isometric exercise. We suggest that the modulation of arterial baroreflex function during the activation of muscle metaboreflex is one of the mechanisms for increasing, or maintaining, blood pressure at the required pressure and thereby contributes to the regulation of the cardiovascular system during exercise.

Takotsubo cardiomyopathy associated with syncope

We report an 81-year-old Japanese patient with takotsubo cardiomyopathy associated with syncope with the possibility that the latter event evoked the former condition. Initial investigations revealed elevation of cardiac enzymes and electrocardiography changes consistent with acute myocardial infarction. The patient subsequently underwent cardiac catheterization that revealed left ventricular apical ballooning and decreased left ventricular ejection fraction without significant coronary artery lesions. A marked elevation in plasma norepinephrine, as a result of baroreflex unloading associated with profound hypotension or frank baroreflex failure, may well have caused takotsubo cardiomyopathy.

Effect of baroreflex loading on the responsiveness of the vestibulosympathetic reflex in humans

Activation of the vestibular otolith organs with head-down rotation (HDR) increases muscle sympathetic nerve activity (MSNA) in humans. Previously, we demonstrated this vestibulosympathetic reflex (VSR) elicits increases in MSNA during baroreflex unloading (i.e., lower body negative pressure) in humans. Whether such an effect persists during baroreflex loading is unknown. We tested the hypothesis that the ability of the VSR to increase MSNA is preserved during baroreflex unloading and inhibited during baroreflex loading. Ten subjects (26 +/- 1 yr) performed three trials of HDR to activate the VSR. These trials were performed after a period of sustained saline (control), nitroprusside (baroreflex unloading: 0.8-1.0 microg.kg(-1).min(-1)), and phenylephrine (baroreflex loading: 0.6-0.8 microg.kg(-1).min(-1)) infusion. Nitroprusside infusion decreased (Delta7 +/- 1 mmHg, where Delta is change; P < 0.001) and phenylephrine infusion increased mean arterial pressure (Delta8 +/- 1 mmHg; P < 0.001) at rest. HDR performed during the control [Delta3 +/- 2 bursts/min, Delta314 +/- 154 arbitrary units (au) total activity, Delta41 +/- 18% total activity; P < 0.05] and nitroprusside trials [Delta5 +/- 2 bursts/min, Delta713 +/- 241 au total activity, Delta49 +/- 20% total activity; P < 0.05] increased MSNA similarly despite significantly elevated levels at rest (13 +/- 2 to 26 +/- 3 bursts/min) in the latter. In contrast, HDR performed during the phenylephrine trial failed to increase MSNA (Delta0 +/- 1 bursts/min, Delta-15 +/- 33 au total activity, Delta-8 +/- 21% total activity). These results confirm previous findings that the ability of the VSR to increase MSNA is preserved during baroreflex unloading. In contrast, the ability of the VSR to increase MSNA is abolished during baroreflex loading. These results provide further support for the concept that the VSR may act primarily to defend against hypotension in humans.

Evidence that baroreflex feedback influences long-term incidental visual memory in men

Sympathetic nervous system (SNS) activity at the time of acquisition is associated with human memory. However, rather than SNS activity per se, it may be afferent baroreflex feedback that is responsible for this effect. A pharmacological design was employed to unload (SNP, sodium nitro-prusside) and load (norepinephrine) baroreceptors. In addition to two placebo periods, epinephrine and esmolol (a peripherally acting β1-blocker) served as control conditions for altered cardiac perception. During drug infusion blood pressure, heart rate, and perception of heartbeat were tested. Twenty-four healthy men were participated. The participants viewed emotional slides while their electromyographic eye blink responses to random noise bursts were measured (affective startle modulation paradigm) to determine potential drug impact on emotional processing. Subjects were not informed that memory testing would take place after 4 weeks. Drugs did not impact startle, thus indicating unbiased emotional processing at the time of acquisition. Norepinephrine had no effect on heartbeat perception, but improved ( p = .002) recognition memory. SNP ( p = .0001) increased heartbeat perception but impaired ( p = .038) recognition memory. Epinephrine, on the other hand, increased heartbeat perception ( p = .0001) yet did not impair but partially improve memory (effect on high arousing pictures only: p = .05). Heartbeat perception in the placebo condition did not correlate with recognition memory ( p’s > .5). We suggest that baroreflex unloading, with subsequent feedback activation of the SNS, impairs long-term incidental visual recognition memory in humans while baroreflex loading enhances it. Further, we propose that these memory effects are neither secondary to cardiac sensations that accompany SNS activation nor to altered emotional picture processing at the time of acquisition.

Persistent Sympathetic Activation During Chronic Antihypertensive Therapy

Previous studies have demonstrated that antihypertensive treatment resets baroreflex control of heart rate (HR) and increases cardiac vagal baroreflex sensitivity. However, it is uncertain whether baroreflex control of muscle sympathetic nerve activity (MSNA) also resets after treatment. We tested the hypothesis that chronic antihypertensive therapy alters baroreflex regulation of MSNA in patients with untreated moderate hypertension. Seven newly diagnosed patients with systolic blood pressure (BP) of 159+/-5 mm Hg (mean+/-SE) and diastolic BP of 103+/-4 mm Hg were studied before and after 1 to 2 weeks ' and 3 months (chronic) of antihypertensive treatment with losartan-hydrochlorothiazide (Hyzaar). MSNA and hemodynamics were measured supine, during a Valsalva maneuver (VM), and at 70 degrees head-up tilt (HUT) for 10 minutes. Data were compared with those obtained in 7 age-matched healthy controls. We found that Hyzaar lowered mean BP acutely and chronically by 20+/-4 and 23+/-3 mm Hg (both P<0.01) but did not change HR. Supine MSNA increased by 43+/-11% and 34+/-11% after acute and chronic treatment (both P<0.01). However, MSNA responses to VM and HUT did not differ after treatment compared with before treatment, indicating unchanged reflex control. These data indicate that sympathetic neural activity was augmented substantially by antihypertensive treatment with Hyzaar, consistent with an ongoing baroreflex unloading, and did not return to baseline or "reset" after 3 months of therapy. We speculate that persistent and marked sympathetic activation by the baroreflex may be a potential mechanism for hypertension that is refractory to antihypertensive therapy and may provide a target mechanism for persistent morbidity despite adequate BP control.

Modulation of arterial baroreflex dynamic response during muscle metaboreflex activation in humans.

We aimed to investigate the interaction between the arterial baroreflex and muscle metaboreflexes (as reflected by alterations in the dynamic responses shown by muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP) and heart rate (HR)) in humans. In nine healthy subjects (eight male, one female) who performed a sustained 1 min handgrip exercise at 50 % maximal voluntary contraction followed by forearm occlusion, a 5 s period of neck pressure (NP) (30 and 50 mmHg) or neck suction (NS)(-30 and -60 mmHg) was used to evaluate carotid baroreflex function at rest (CON) and during post-exercise muscle ischaemia (PEMI). In PEMI (as compared with CON): (a) the augmentations in MSNA and MAP elicited by 50 mmHg NP were both greater; (b) MSNA seemed to be suppressed by NS for a shorter period, (c) the decrease in MAP elicited by NS was smaller, and (d) MAP recovered to its initial level more quickly after NS. However, the HR responses to NS and NP were not different between PEMI and CON. These results suggest that during muscle metaboreflex activation, the dynamic arterial baroreflex response is modulated, as exemplified by the augmentation of the MSNA response to arterial baroreflex unloading (i.e. NP) and the reduction in the suppression of MSNA induced by baroreceptor stimulation (i.e. NS).