Peripheral Chemoreflex Activation Research Articles

Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.NEW & NOTEWORTHY This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.

Exercise derived myokine irisin as mediator of cardiorespiratory, metabolic and thermal adjustments during central and peripheral chemoreflex activation

Exercise elicits physiological adaptations, including hyperpnea. However, the mechanisms underlying exercise-induced hyperpnea remain unresolved. Skeletal muscle acts as a secretory organ, releasing irisin (IR) during exercise. Irisin can cross the blood–brain barrier, influencing muscle and tissue metabolism, as well as signaling in the central nervous system (CNS). We evaluated the effect of intracerebroventricular or intraperitoneal injection of IR in adult male rats on the cardiorespiratory and metabolic function during sleep–wake cycle under room air, hypercapnia and hypoxia. Central IR injection caused an inhibition on ventilation (VE) during wakefulness under normoxia, while peripheral IR reduced VE during sleep. Additionally, central IR exacerbates hypercapnic hyperventilation by increasing VE and reducing oxygen consumption. As to cardiovascular regulation, central IR caused an increase in heart rate (HR) across all conditions, while no change was observed following peripheral administration. Finally, central IR attenuated the hypoxia-induced regulated hypothermia and increase sleep episodes, while peripheral IR augmented CO2-induced hypothermia, during wakefulness. Overall, our results suggest that IR act mostly on CNS exerting an inhibitory effect on breathing under resting conditions, while stimulating the hypercapnic ventilatory response and increasing HR. Therefore, IR seems not to be responsible for the exercise-induced hyperpnea, but contributes to the increase in HR.

Acute Intermittent Hypoxia Induces Chemoreflex-Independent Sympathetic Plasticity and Improves Cardiovascular Function in a Rodent Model of Spinal Cord Injury

Background: Cardiovascular complications are one of the leading causes of morbidity and mortality in people with spinal cord injury (SCI). Activation of spinal sympathetic circuitry is critical to offset cardiovascular dysregulation and disease in those with high-level SCI. Acute intermittent hypoxia (AIH) elicits plasticity (i.e., a gradual increase in nerve activity post-AIH exposure) in phrenic and non-phrenic spinal motor circuitry and improves motor function — yet the cardiovascular benefits of AIH after SCI are largely unexplored. Aims: Determine mechanisms (Aim 1) and potential benefits (Aim 2) of AIH-induced sympathetic plasticity post-SCI. Hypothesis: We hypothesized that AIH elicits chemoreflex-dependent sympathetic plasticity and improves cardiovascular function in rats with SCI. Methods: For Aim 1, 40 adult (10-12 weeks) male Wistar rats were subjected to a spinal cord contusion injury (T3, 300 kdyn) and randomly assigned to 5 groups of 8 each: AIH alone, AIH after carotid body denervation (CBX, no peripheral chemoreflex), time control with no intervention (TC), simulated hemorrhage (to mimic AIH-induced hypotension), and AIH plus phenylephrine (to prevent hypotension during hypoxic episodes). Two weeks post-SCI recovery, rats were anesthetized with urethane (~2.1g.kg−1 i.v.) and underwent femoral venous and arterial catheterizations to monitor blood pressure (BP), sample arterial blood gases, and enable intravenous fluid and drug delivery. Additionally, splanchnic sympathetic nerve activity (sSNA) was recorded using a suction electrode at baseline and for up to 90-min following each experimental paradigm. AIH consisted of 10 x 1 min episodes of FiO2 = 0.1 (balanced N2) interspersed with 2 min of FiO2 = 1. Hexamethonium bromide (30 mg.kg−1) was infused to subtract noise levels from each recording, after which rats were euthanized with chloral hydrate. For Aim 2, 19 additional rats were subjected to the same injury model and time post-injury and allocated to 2 groups: AIH ( n = 11) and TC ( n = 8). These rats were instrumented with left-ventricular (LV) and arterial catheters and assessed simultaneously for cardiac and peripheral hemodynamic function at baseline and 90-min post-AIH/TC. Results: Aim 1) When expressed as % change from baseline, sSNA increased at 90-min post-treatment in AIH (93±67%, P = 0.02) and CBX (193±182%, P &lt; 0.001), but not TC rats (50±45%, P = 0.40). Preventing BP reduction during hypoxic episodes with i.v. phenylephrine blocked the increase in sSNA 90-min post-AIH (12±66%, P &gt; 0.99). Mimicking the AIH-induced BP reduction with simulated hemorrhage (10 x 1-min BP reductions of ~20-25 mmHg equal to those during AIH, interspersed by 2-min of euvolemia), increased sSNA 90-min post-intervention (106±86%, P = 0.01). Aim 2) The changes in maximal LV pressure (AIH = 11±8 mmHg vs. TC = 2±5 mmHg, P = 0.05) and mean arterial pressure (AIH = 8±7 mmHg vs. TC = 0±4 mmHg, P = 0.05) were greater at 90-min post-AIH treatment. Conclusions: We conclude that AIH elicits sympathetic plasticity and improves cardiovascular function post-SCI. Since AIH-induced sympathetic plasticity remains in the presence of a bilateral CBX, is replicated by episodic simulated hemorrhage, and is blocked by phenylephrine, AIH-induced sympathetic plasticity is independent of carotid (peripheral) chemoreflex activation, and is closely linked to episodic hypotension. We suggest that AIH-induced sympathetic plasticity arises from episodic reductions in spinal/medullary cardiovascular centers blood flow (and oxygen delivery) post-SCI. International Spinal Research Trust and Natural Sciences, Engineering Research Council of Canada, International Collaboration on Repair Discoveries. 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.

Cardiovascular and respiratory evaluation in adenosine A2A receptor knockout mice submitted to short-term sustained hypoxia.

Sustained hypoxia (SH) in mice induces changes in the respiratory pattern and increase in the parasympathetic tone to the heart. Among adenosine G-protein-coupled receptors (GPCRs), the A2A receptors are especially important in mediating adenosine actions during hypoxia due to their expression in neurons involved with the generation and modulation of the autonomic and respiratory functions. Herein, we performed an in vivo evaluation of the baseline cardiovascular and respiratory parameters and their changes in response to SH in knockout mice for A2A receptors (A2A KO). SH produced similar and significant reductions in mean arterial pressure and heart rate in both wild-type (WT) and A2A KO mice when compared to their respective normoxic controls. Mice from WT and A2A KO groups submitted to normoxia or SH presented similar cardiovascular responses to peripheral chemoreflex activation (KCN). Under normoxic conditions A2A KO mice presented a respiratory frequency (fR ) significantly higher in relation to the WT group, which was reduced in response to SH. These data show that the lack of adenosine A2A receptors in mice does not affect the cardiovascular parameters and the autonomic responses to chemoreflex activation in control (normoxia) and SH mice. We conclude that the A2A receptors play a major role in the control of respiratory frequency and in the tachypnoeic response to SH in mice. NEW FINDINGS: What is the central question of this study? Are cardiovascular and respiratory parameters and their changes in response to sustained hypoxia (SH) altered in adenosine A2A receptor knockout mice? What is the main finding and its importance? Cardiovascular parameters and their changes in response to SH were not altered in A2A KO mice. The respiratory frequency in A2A KO was higher than in WT mice. In response to SH the respiratory frequency increased in WT, while it was reduced in A2A KO mice. A2A receptors play a major role in the modulation of respiratory frequency and in the tachypnoeic response to SH in mice.

Arterial stiffness and peripheral chemoreflex responsiveness in electronic cigarette users

Electronic cigarettes (e-cigarettes) are marketed as less harmful alternatives to tobacco smoking, but the short- and long-term health consequences are unclear. Raised arterial stiffness and increased peripheral chemoreflex sensitivity are pathogenic features of several clinical conditions and associated with adverse outcomes. The aim of this study was to determine if regular e-cigarettes use is associated with increased arterial stiffness and elevated peripheral chemoreflex responsiveness.Eight healthy e-cigarettes users (E-cig; &gt;12 months, 6 women, 27±5yr, 26.0±4.5kg/m2 mean±SD) and 13 healthy non-e-cigarettes user controls (HC; 8 women, 26±4yr, 22.4±3.4kg/m2,) were studied under 3 conditions (each for 5min) in the following order: room-air, isocapnic hyperoxia (1.0 fraction of inspired oxygen [FiO2]; peripheral chemoreflex deactivation) and isocapnic hypoxia (0.1 FiO2; peripheral chemoreflex activation). In each condition, arterial stiffness was evaluated by the aortic augmentation index (AIx) and aortic pulse wave velocity (PWV) (SphygmoCor), while heart rate (HR), mean arterial pressure (MAP), and minute ventilation (V̇E) were monitored.In room air, AIx was higher in E-cig compared to HC (18.4±3.4 vs. 8.1±2.5%, P=0.023), while PWV (5.7±0.3 vs. 5.8±0.8m/sec, P=0.731), HR (68±6 vs. 70±9beats/min, P=0.616), MAP (83±4 vs. 83±7mmHg/min, P=0.920), and V̇E (12.7±2.2 vs. 13.9±3.1L/min, P=0.515) were not different. During isocapnic hyperoxia, AIx was unchanged in both E-cig (21.9±11.2%, P=0.327) and HC (9.2±7.9%, P=1.000) versus room air, with AIx remaining higher in E-cig (P=0.006). There were no changes from isocapnic hyperoxia to room air in both E-cig and HC in aortic PWV (Δ0.1±0.1 and Δ0.1±0.2m/sec, P=0.894), HR (Δ-3±3 and Δ-2±3beats/min, P=0.482), MAP (Δ0.3±2.2 and Δ-0.9±2.1mmHg/min, P=0.528) and V̇E (Δ1.1±2.0 vs. Δ1.2±4.6L/min, P=0.124). During isocapnic hypoxia, AIx was unchanged in E-cig (14.7±9.5%, P=0.288) versus room air, but was decreased in HC (2.8±9.4%, P=0.006), such that AIx remained higher in E-cig than HC (P=0.009). HR increased similarly during isocapnic hypoxia in both E-cig (77±7beats/min, P&lt;0.001) and HC (82±7beats/min, P&lt;0.001) compared to room air. In E-cig and HC no change was observed in aortic PWV (Δ0.4±0.4 and Δ0.2±1.4m/sec, P=0.254), MAP (Δ-0.2±2.0 and Δ0.3±2.3mmHg/min, P=0.609) and V̇E (Δ 1.4±1.0 vs. Δ1.1±1.4L/min, P=0.638) during isocapnic hypoxia relative to room air.These preliminary findings suggest that arterial stiffness is higher in young e-cigarettes users, and that the normal hypoxia-induced reduction in arterial stiffness in young non-e-cigarette users is absent in e-cigarettes users. Future studies are needed to determine if the altered effects of hypoxia on arterial stiffness in young e-cigarettes users is associated with exaggerated peripheral chemoreflex mediated sympatho-excitation and/or local endothelial/vascular smooth muscle mechanisms, and if it is reversible on cessation of e-cigarette use. Health Research Council of New Zealand (Ref# 19/687. JPF, JFRP), and the Sidney Taylor Trust (JFRP). This is the full abstract presented at the American Physiology Summit 2023 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.

Venous capacity and compliance in hypertensive adults: influence of hypoxia and hyperoxia.

In hypertension, the cardiorespiratory responses to peripheral chemoreflex activation (hypoxia) and inactivation (hyperoxia) are reportedly augmented, but the impact on peripheral venous function is unknown. We tested the hypothesis that in hypertensives, both hypoxia and hyperoxia evoke more pronounced changes in lower limb venous capacity and compliance, than in age-matched normotensives. In 10 hypertensive [HTN: 7 women; age: 71.7 ± 3.7 yr, mean blood pressure (BP): 101 ± 10 mmHg, mean ± SD] and 11 normotensive (NT: 6 women; age: 67.7 ± 8.0 yr, mean BP 89 ± 11 mmHg) participants, great saphenous vein cross-sectional area (GSV CSA; Doppler ultrasound) was measured during a standard 60 mmHg thigh cuff inflation-deflation protocol. Separate conditions of room air, hypoxia [fraction of inspired oxygen ([Formula: see text]): 0.10] and hyperoxia ([Formula: see text]: 0.50) were tested. In HTN, GSV CSA was decreased in hypoxia (5.6 ± 3.7 mm2, P = 0.041) compared with room air (7.3 ± 6.9 mm2), whereas no change was observed with hyperoxia (8.0 ± 9.1 mm2, P = 0.988). In NT, no differences in GSV CSA were observed between any condition (P = 0.299). Hypoxia enhanced GSV compliance in HTN (-0.0125 ± 0.0129 vs. -0.0288 ± 0.0090 mm2·100 mm2·mmHg-1, room air vs. hypoxia, respectively; P = 0.004), but it was unchanged in NT (-0.0139 ± 0.0121 vs. -0.0093 ± 0.0066 mm2·100 mm2·mmHg-1, room air vs. hypoxia, respectively; P < 0.541). Venous compliance was unaltered with hyperoxia in both groups (P < 0.05). In summary, compared with NT, hypoxia elicits a decrease in GSV CSA and enhanced GSV compliance in HTN, indicating enhanced venomotor responsiveness to hypoxia.NEW & NOTEWORTHY Hypertension remains a significant global health problem. Although hypertension research and therapies are keenly focused on the heart and arterial circulation, the venous circulation has been neglected comparatively. We determined whether hypoxia, known to cause peripheral chemoreflex activation, evoked more pronounced changes in lower limb venous capacity and compliance in hypertensives (HTN) than in age-matched normotensives (NT). We found that hypoxia reduced venous capacity in the great saphenous vein in HTN and increased its compliance twofold. However, hypoxia did not affect venous function in NT. Our data indicate the venomotor response to hypoxia is enhanced in hypertension, and this may contribute to the hypertensive state.

Central and peripheral chemoreflexes in humans with treated hypertension.

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68±5years; mean±SD) and 13 normotensives (NT; 65±6years) performed two modified rebreathing protocols in which the partial pressure of end-tidal carbon dioxide ( ) progressively increased while the partial pressure of end-tidal oxygen was clamped at either 150mmHg (isoxic hyperoxia; central chemoreflex activation) or 50mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation ( ; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory ( vs. slope) and sympathetic (MSNA vs. slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48±1.33 vs. 1.58±0.42Lmin-1 mmHg-1 , P=0.030: 3.32±1.90 vs. 1.77±0.62a.u.mmHg-1 , P=0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for (R2 =0.666, P<0.0001) and MSNA (R2 =0.698, P=0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. KEY POINTS: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented. In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN. We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age-matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities. During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow. These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN.

Ventilatory response to peripheral chemoreflex and muscle metaboreflex during static handgrip in healthy humans: evidence of hyperadditive integration.

What is the central question of this study? What is the effect of peripheral chemoreflex and muscle metaboreflex integration on ventilation regulation, and what is the effect of integration on breathing-related sensations and emotions? What is the main finding and its importance? Peripheral chemoreflex and muscle metaboreflex coactivation during isocapnic static handgrip exercise appeared to elicit a hyperadditive effect with regard to ventilation and an additive effect with regard to breathing-related sensations and emotions. These findings reveal the nature of the integration between two neural mechanisms that operate during small-muscle static exercise performed under hypoxia. Exercise augments the hypoxia-induced ventilatory response in an exercise intensity-dependent manner. A mutual influence of hypoxia-induced peripheral chemoreflex activation and exercise-induced muscle metaboreflex activation might mediate the augmentation phenomenon. However, the nature of these reflexes' integration (i.e., hyperadditive, additive or hypoadditive) remains unclear, and the coactivation effect on breathing-related sensations and emotions has not been explored. Accordingly, we investigated the effect of peripheral chemoreflex and muscle metaboreflex coactivation on ventilatory variables and breathing-related sensations and emotions during exercise. Fourteen healthy adults performed 2-min isocapnic static handgrip, first with the non-dominant hand and immediately after with the dominant hand. During the dominant hand exercise, we (a) did not manipulate either reflex (control); (b) activated the peripheral chemoreflex by hypoxia; (c) activated the muscle metaboreflex in the non-dominant arm by post-exercise circulatory occlusion (PECO); or (d) coactivated both reflexes by simultaneous hypoxia and PECO use. Ventilation response to coactivation of reflexes (mean±SD, 13±6l/min) was greater than the sum of responses to separated activations of reflexes (mean±SD, 8±8l/min, P=0.005). Breathing-related sensory and emotional responses were similar between coactivation of reflexes and the sum of separate activations of reflexes. Thus, the peripheral chemoreflex and muscle metaboreflex integration during exercise appeared to be hyperadditive with regard to ventilation and additive with regard to breathing-related sensations and emotions in healthy adults.

Peripheral chemoreflex activation induces expiratory but not inspiratory excitation of C1 pre-sympathetic neurones of rats.

Stimulation of peripheral chemoreceptors, as during hypoxia, increases breathing and respiratory-related sympathetic bursting. Activation of catecholaminergic C1 neurones induces sympathoexcitation, while its ablation reduces the chemoreflex sympathoexcitatory response. However, no study has determined the respiratory phase(s) in which the pre-sympathetic C1 neurones are recruited by peripheral chemoreceptor and whether C1 neurone activation affects all phases of respiratory modulation of sympathetic activity. We addressed these unknowns by testing the hypothesis that peripheral chemoreceptor activation excites pre-sympathetic C1 neurones during inspiration and expiration. Using the in situ preparation of rat, we made intracellular recordings from baroreceptive pre-sympathetic C1 neurones during peripheral chemoreflex stimulation. We optogenetically activated C1 neurones selectively and compared any respiratory-phase-related increases in sympathetic activity with that which occurs following stimulation of the peripheral chemoreflex. Activation of peripheral chemoreceptors using cytotoxic hypoxia (potassium cyanide) increased the firing frequency of C1 neurones and both the frequency and amplitude of their excitatory post-synaptic currents during the phase of expiration only. In contrast, optogenetic stimulation of C1 neurones activates inspiratory neurones, which secondarily inhibit expiratory neurones, but produced comparable increases in sympathetic activity across all phases of respiration. Our data reveal that the peripheral chemoreceptor-mediated expiratory-related sympathoexcitation is mediated through excitation of expiratory neurones antecedent to C1 pre-sympathetic neurones; these may be found in the Kölliker-Fuse nucleus. Despite peripheral chemoreceptor excitation of inspiratory neurones, these do not trigger C1 neurone-mediated increases in sympathetic activity. These studies provide compelling novel insights into the functional organization of respiratory-sympathetic neural networks.

Sex differences in the sympathetic neurocirculatory responses to chemoreflex activation.

The purpose of this study was to determine whether there are sex differences in the cardiorespiratory and sympathetic neurocirculatory responses to central, peripheral, and combined central and peripheral chemoreflex activation. Ten women (29 ± 6 years, 22.8 ± 2.4 kg/m2: mean ± SD) and 10 men (30 ± 7 years, 24.8 ± 3.2 kg/m2) undertook randomized 5 min breathing trials of: room air (eucapnia), isocapnic hypoxia (10% oxygen (O2); peripheral chemoreflex activation), hypercapnic hyperoxia (7% carbon dioxide (CO2), 50% O2; central chemoreflex activation) and hypercapnic hypoxia (7% CO2, 10% O2; central and peripheral chemoreflex activation). Control trials of isocapnic hyperoxia (peripheral chemoreflex inhibition) and hypocapnic hyperoxia (central and peripheral chemoreflex inhibition) were also included. Muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; finger photoplethysmography) and minute ventilation (V˙ E; pneumotachometer) were measured. Total MSNA (P = 1.000 and P = 0.616), MAP (P = 0.265) and V˙ E (P = 0.587 and P = 0.472) were not different in men and women during eucapnia and during isocapnic hypoxia. Women exhibited attenuated increases in V˙ E during hypercapnic hyperoxia (27.3 ± 6.3 vs. 39.5 ± 7.5 l/min, P < 0.0001) and hypercapnic hypoxia (40.9 ± 9.1 vs. 53.8 ± 13.3 l/min, P < 0.0001) compared with men. However, total MSNA responses were augmented in women (hypercapnic hyperoxia 378 ± 215 vs. 258 ± 107%, P = 0.017; hypercapnic hypoxia 607 ± 290 vs. 362 ± 268%, P < 0.0001). No sex differences in total MSNA, MAP or V˙ E were observed during isocapnic hyperoxia and hypocapnic hyperoxia. Our results indicate that young women have augmented sympathetic responses to central chemoreflex activation, which explains the augmented MSNA response to combined central and peripheral chemoreflex activation.Key points Sex differences in the control of breathing have been well studied, but whether there are differences in the sympathetic neurocirculatory responses to chemoreflex activation between healthy women and men is incompletely understood.We observed that, compared with young men, young women displayed augmented increases in muscle sympathetic nerve activity during both hypercapnic hyperoxia (central chemoreflex activation) and hypercapnic hypoxia (central and peripheral chemoreflex activation) but had attenuated increases in minute ventilation.In contrast, no sex differences were found in either muscle sympathetic nerve activity or minute ventilation responses to isocapnic hypoxia (peripheral chemoreceptor stimulation).Young women have blunted ventilator, but augmented sympathetic responses, to central (hypercapnic hyperoxia) and combined central and peripheral chemoreflex activation (hypercapnic hypoxia), compared with young men. The possible causative association between the reduced ventilation and heightened sympathetic responses in young women awaits validation.

Sympathetic Neurocirculatory Responses to Chemoreflex Activation in Young Women and Men

Sex‐differences in the ventilatory responses to central and peripheral chemoreflex activation have been extensively examined. Along with the control of respiration, chemoreflexes play a key role in sympathetic regulation. Herein, we determined whether central, peripheral, and combined central and peripheral chemoreflex activation evoke differing sympathetic neurocirculatory responses in young women and men.In ten women (29±6 years, 23±2kg/m2: mean±SD) and ten men (30±7 years, 25±3kg/m2), we recorded muscle sympathetic nerve activity (MSNA), minute ventilation (V̇E) and mean arterial pressure (MAP) during 5‐min trials of breathing room‐air (eucapnia), isocapnic hypoxia (10% oxygen [O2]; peripheral chemoreflex activation), hypercapnic hyperoxia (7% carbon dioxide [CO2], 50% O2; central chemoreflex activation) and hypercapnic hypoxia (7% CO2, 10% O2). Trials were randomized. Women were studied in the early follicular phase of their menstrual cycle.During eucapnia and isocapnic hypoxia, no sex‐differences were observed in MSNA, V̇E and MAP (P&gt;0.05). During hypercapnic hyperoxia (∆278±215 vs. ∆158±107%, P=0.05) and hypercapnic hypoxia (∆507±290 vs. ∆262±268%, P=0.05) MSNA responses were augmented in women compared to men, however V̇E responses were attenuated (hypercapnic hyperoxia ∆15.2±6.7 vs. ∆25.6±6.7L/min, P=0.007; hypercapnic hypoxia ∆28.8±9.3 vs. ∆39.9±12.5L/min, P=0.004). MAP responses were similar in women and men (hypercapnic hyperoxia ∆10±2 vs. ∆23±2mmHg, P=0.35; hypercapnic hypoxia ∆16±3 vs. ∆25±3mmHg, P=0.35).In summary, young women have greater MSNA response to central chemoreflex activation than young men, which explains their augmented sympathetic response to combined central and peripheral chemoreflex activation. Future studies should determine the effect of menopause on these sex‐differences in the sympathetic neurocirculatory responses to chemoreflex activation.

Peripheral chemoreflex activation and cardiac function during hypoxemia in near-term fetal sheep without placental compromise.

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baseline were collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70%-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde, thus decreasing the aortic isthmus antegrade/retrograde blood flow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO) or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.NEW & NOTEWORTHY During fetal hypoxemia with intact placental circulation, peripheral chemoreflex was activated, as demonstrated by an increase in the descending aorta blood pressure, pulmonary vasoconstriction, and an increase in retrograde diastolic AoI blood flow, while both ventricular cardiac outputs remained stable. However, perfusion pressure in the cerebral circulation decreased. These changes were seen even during prolonged hypoxemia when significant metabolic acidosis developed. Weight-indexed LVCO or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.

Astrocytic modulation of IKA, NMDA and AMPA currents in NTS neurons of rats is affected by sustained hypoxia

Short term sustained hypoxia (SH, FiO2 0.1, 24 h) produces cardiovascular and respiratory changes mainly due to peripheral chemoreflex activation. SH alters the electrophysiological properties of neurons in the NTS, where the first synapses of chemoreflex afferents are located. In the present study we evaluated alterations produced by SH on neuronal excitability and excitatory synaptic transmission in the NTS neurons integral to chemoreflex pathways. After SH protocol, brainstem slices were obtained for electrophysiological recordings using whole cell patch–clamp and fluoracetate (FAC) was used to produce metabolic inhibition of astrocytes. SH increased the action potential discharge in response to positive injected current into NTS neurons (p=0.0048). The presence of A‐type potassium current (IKA) was observed and its peak amplitude was larger in neurons from control [Vm = 10 mV, 1428 ± 600 pA (n=10)] than in SH rats [Vm = 10 mV, 334 ± 76 pA (n=10)]. Inhibition of astrocytes with FAC decreased the IKA amplitude in neurons from control rats [1227 ± 129 pA vs 605 ± 210 pA (n=7)], but not in SH rats [475 ± 110 pA vs 427 ± 114 pA (n=6)]. With respect to excitatory neurotransmission, SH increased AMPA/kainate [−183 ± 122 pA (n=10) vs −353 ± 101 pA (n=10)] and NMDA currents amplitude [61 ± 10 pA (n=7) vs 102 ± 37 pA (n=10)]. Astrocytic modulation on AMPA [aCSF: −353 ± 101 pA vs aCSF + FAC: −369 ± 76 pA, (n=10)] and NMDA currents [aCSF: 102 ± 37 pA vs aCSF + FAC: 108 ± 32 pA, (n=10)] was blunted by SH. In addition, SH increased AMPA current density [control: −6 ± 3.5 pA/pF (n=6) vs SH: −20 ± 12 pA/pF (n=7)]. The data shows that astrocyte modulation of synaptic transmission in NTS neurons integral to the chemoreflex pathways is reduced by SH, which may contribute to the observed increase in the chemoreflex responsiveness on this experimental model.Support or Funding InformationFAPESP, CAPES and CNPq

Testing individual baroreflex responses to hypoxia-induced peripheral chemoreflex stimulation

IntroductionBaroreflexes and peripheral chemoreflexes control efferent autonomic activity making these reflexes treatment targets for arterial hypertension. The literature on their interaction is controversial, with suggestions that their individual and collective influence on blood pressure and heart rate regulation is variable. Therefore, we applied a study design that allows the elucidation of individual baroreflex–chemoreflex interactions.MethodsWe studied nine healthy young men who breathed either normal air (normoxia) or an air–nitrogen–carbon dioxide mixture with decreased oxygen content (hypoxia) for 90 min, with randomization to condition, followed by a 30-min recovery period and then exposure to the other condition for 90 min. Multiple intravenous phenylephrine bolus doses were applied per condition to determine phenylephrine pressor sensitivity as an estimate of baroreflex blood pressure buffering and cardiovagal baroreflex sensitivity (BRS).ResultsHypoxia reduced arterial oxygen saturation from 98.1 ± 0.4 to 81.0 ± 0.4% (p < 0.001), raised heart rate from 62.9 ± 2.1 to 76.0 ± 3.6 bpm (p < 0.001), but did not change systolic blood pressure (p = 0.182). Of the nine subjects, six had significantly lower BRS in hypoxia (p < 0.05), two showed a significantly decreased pressor response, and three showed a significantly increased pressor response to phenylephrine in hypoxia, likely through reduced baroreflex buffering (p < 0.05). On average, hypoxia decreased BRS by 6.4 ± 0.9 ms/mmHg (19.9 ± 2.0 vs. 14.12 ± 1.6 ms/mmHg; p < 0.001) but did not change the phenylephrine pressor response (p = 0.878).ConclusionWe applied an approach to assess individual baroreflex–chemoreflex interactions in human subjects. A subgroup exhibited significant impairments in baroreflex blood pressure buffering and BRS with peripheral chemoreflex activation. The methodology may have utility in elucidating individual pathophysiology and in targeting treatments modulating baroreflex or chemoreflex function.

Efficacy of Electrical Baroreflex Activation Is Independent of Peripheral Chemoreceptor Modulation.

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67±8 years, body mass index: 31.6±5.2 kg/m2, 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end-tidal O2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO2 and O2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164±27 to 151±25 mm Hg (mean±SD, P<0.001), heart rate from 64±13 to 61±13 bpm (P=0.002), and muscle sympathetic nerve activity from 42±12 to 36±12 bursts/min (P=0.004). Hypoxia increased systolic blood pressure 8±12 mm Hg (P=0.057), heart rate 10±6 bpm (P<0.001), muscle sympathetic nerve activity 7±7 bursts/min (P=0.031), and ventilation 10±7 L/min (P=0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: -15±7 versus -14±8 mm Hg (P=0.938), heart rate: -2±3 versus -2±2 bpm (P=0.701), and muscle sympathetic nerve activity: -6±4 versus -4±3 bursts/min (P=0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise.

Selective denervation of the aortic and carotid baroreceptors in rats.

What is the central question of this study? The traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation, which does not permit their individual study in different situations. What is the main finding and its importance? We have described a new surgical approach capable of selective denervation of the arterial (aortic and carotid) baroreceptors, keeping the carotid bodies (chemoreceptors) intact. It is understood that this technique might be a useful tool for investigating the relative role of the baro- and chemoreceptors in several physiological and pathophysiological conditions. Studies have demonstrated that the traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation. The present study reports a new surgical approach to denervate the aortic and the carotid baroreceptors selectively, keeping the carotid bodies (peripheral chemoreceptors) intact. Wistar rats were subjected to specific aortic and carotid baroreceptor denervation (BAROS-X) or sham surgery (SHAM). Baroreflex activation was achieved by i.v. administration of phenylephrine, whereas peripheral chemoreflex activation was produced by i.v. administration of potassium cyanide. The SHAM and BAROS-X rats displayed significant hypertensive responses to phenylephrine administration. However, the reflex bradycardia following the hypertensive response caused by phenylephrine was remarkable in SHAM, but not significant in the BAROS-X animals, confirming the efficacy of the surgical procedure to abolish the baroreflex. In addition, the baroreflex activation elicited by phenylephrine increased carotid sinus nerve activity only in SHAM, but not in the BAROS-X animals, providing support to the notion that the baroreceptor afferents were absent. Instead, the classical peripheral chemoreflex hypertensive and bradycardic responses to potassium cyanide were similar in both groups, suggesting that the carotid body chemoreceptors were preserved after BAROS-X. In summary, we describe a new surgical approach in which only the baroreceptors are eliminated, while the carotid chemoreceptors are preserved. Therefore, it is understood that this procedure is potentially a useful tool for examining the relative roles of the arterial baroreceptors versus the chemoreceptors in several pathophysiological conditions, for instance, arterial hypertension and heart failure.

Lifelong high‐altitude hypoxia induces arterial baroreflex adaptations: new insights and future directions

Lifelong high‐altitude hypoxia induces arterial baroreflex adaptations: new insights and future directions

Baroreflex control of sympathetic vasomotor activity and resting arterial pressure at high altitude: insight from Lowlanders and Sherpa

Hypoxia, a potent activator of the sympathetic nervous system, is known to increase muscle sympathetic nerve activity (MSNA) to the peripheral vasculature of native Lowlanders during sustained high altitude (HA) exposure. We show that the arterial baroreflex control of MSNA functions normally in healthy Lowlanders at HA, and that upward baroreflex resetting permits chronic activation of basal sympathetic vasomotor activity under this condition. The baroreflex MSNA operating point and resting sympathetic vasomotor outflow both are lower for highland Sherpa compared to acclimatizing Lowlanders; these lower levels may represent beneficial hypoxic adaptation in Sherpa. Acute hyperoxia at HA had minimal effect on baroreflex control of MSNA in Lowlanders and Sherpa, raising the possibility that mechanisms other than peripheral chemoreflex activation contribute to vascular sympathetic baroreflex resetting and sympathoexcitation. These findings provide a better understanding of sympathetic nervous system activation and the control of blood pressure during the physiological stress of sustained HA hypoxia. Exposure to high altitude (HA) is characterized by heightened muscle sympathetic neural activity (MSNA); however, the effect on arterial baroreflex control of MSNA is unknown. Furthermore, arterial baroreflex control at HA may be influenced by genotypic and phenotypic differences between lowland and highland natives. Fourteen Lowlanders (12 male) and nine male Sherpa underwent haemodynamic and sympathetic neural assessment at low altitude (Lowlanders, low altitude; 344m, Sherpa, Kathmandu; 1400m) and following gradual ascent to 5050m. Beat-by-beat haemodynamics (photoplethysmography) and MSNA (microneurography) were recorded lying supine. Indices of vascular sympathetic baroreflex function were determined from the relationship of diastolic blood pressure (DBP) and corresponding MSNA at rest (i.e. DBP 'operating pressure' and MSNA 'operating point'), as well as during a modified Oxford baroreflex test (i.e. 'gain'). Operating pressure and gain were unchanged for Lowlanders during HA exposure; however, the operating point was reset upwards (48±16vs. 22±12 bursts 100HB-1 ,P=0.001). Compared to Lowlanders at 5050m, Sherpa had similar gain and operating pressure, although the operating point was lower (30±13 bursts 100HB-1 , P=0.02); MSNA burst frequency was lower for Sherpa (22±11 vs. 30±9 bursts min-1 P=0.03). Breathing 100% oxygen did not alter vascular sympathetic baroreflex function for either group at HA. For Lowlanders, upward baroreflex resetting promotes heightened sympathetic vasoconstrictor activity and maintains blood pressure stability, at least during early HA exposure; mechanisms other than peripheral chemoreflex activation could be involved. Sherpa adaptation appears to favour a lower sympathetic vasoconstrictor activity compared to Lowlanders for blood pressure homeostasis.

A projection from the hypothalamic paraventricular nucleus (PVN) to nucleus tractus solitarii (nTS) is essential for cardiorespiratory responses to hypoxia

The PVN contributes to cardiorespiratory responses to peripheral chemoreflex activation. We have shown that hypoxia (Hx) activates PVN neurons that project to the nTS but the functional role of this nTS projection is not known. We hypothesized that selective inhibition/activation of the PVN to nTS pathway blunts/augments chemoreflex cardiorespiratory responses. Male SD rats received bilateral microinjections of retrograde AAV‐pgk‐Cre into the nTS. One week later, rats received bilateral PVN injections of Cre‐dependent AAV2‐DIO‐hSyn‐mCherry expressing inhibitory (Gi) or excitatory (Gq) DREADD, or control virus (mCh), and 3–5 weeks allowed for expression in nTS‐projecting PVN neurons. To evaluate the contribution of the PVN to nTS pathway to chemoreflex function, ventilatory responses (plethysmography) to progressive Hx (14–8% O2) were assessed in conscious animals before and after ip injection of saline or the synthetic selective DREADD ligand C21 (1mg/kg). We similarly evaluated Hx‐induced nTS neuronal activation (Fos immunohistochemistry); 60 min after ip saline or C21, conscious mCh (n=6) and Gi (n=4) rats were exposed to Hx (2 hr, 10% O2) and Gq rats were exposed to 12% O2. Saline had no effect on either ventilatory responses or nTS neuronal activation to Hx in any group. In Gi rats, selective inhibition of nTS‐projecting PVN neurons with C21 blunted hypoxic ventilatory responses to 10% and 8% O2 (n=8, p&lt;0.05) and appeared associated with decreased Hx‐induced nTS neuronal activation (581 ± 33 vs. 375 ± 150 cells; saline vs. C21; n=2 each). In contrast, selective activation of the PVN to nTS pathway by C21 in Gq rats (n=8) enhanced Hx ventilatory responses to milder hypoxia (14 and 12% O2, p&lt;0.05), and produced greater Hx‐induced Fos‐IR in the nTS (377 ± 45 vs. 550 ± 23 cells; saline vs. C21, n=3 ea). To confirm that altered cardiorespiratory chemoreflex responses were mediated by PVN terminals in the nTS, anesthetized rats were exposed to brief (45s) Hx episodes (10% O2, mCh and Gi rats; 12% O2, Gq rats) before and after bilateral nTS microinjection of C21 (0.1mM; 90nl/side). Mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PhrNA)] were measured. Under control conditions, Hx decreased MAP and increased HR, sSNA and PhrNA in all groups. Peak responses to 10% O2 were similar in mCh and Gi rats and greater than control responses to 12% O2 in Gq rats. nTS microinjection of C21 had minor baseline effects, which were not different among groups. nTS C21 did not alter the Hx‐induced increase in PhrNA of mCh rats (n=2). In Gi rats (n=3), DREADD‐mediated inhibition of PVN terminals in the nTS blunted both PhrNA (−63 ± 10%; p&lt;0.05) and sSNA (−32 ± 18%; p&lt;0.05) responses to Hx. In contrast, activation of PVN terminals in the nTS enhanced both PhrNA (+51 ± 36%) and sSNA (+166 ± 41%) responses to Hx in Gq rats (n=3). Together, these results suggest that a PVN to nTS pathway directly enhances nTS neuronal activation and cardiorespiratory responses to hypoxia.Support or Funding InformationRO1‐HL‐98602 F31‐HL‐140858This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Maternal dyslipidemia during pregnancy and lactation increases blood pressure and disrupts cardiorespiratory and glucose hemostasis in female rat offspring.

Hypertension and metabolic disorders evidenced in adults who have been exposed to nutritional insults during early life may be sex-dependent. We evaluated if blood pressure (BP), cardiorespiratory control, and metabolic parameters are affected in female offspring (FO) from dams fed a dyslipidaemic diet during pregnancy and lactation. FO was obtained from dams who received control (CTL) or dyslipidaemic diets during pregnancy and lactation. The effects of a maternal dyslipidaemic diet on BP, cardiorespiratory control, and biochemical parameters were assessed at 30 and 90 days of age. The experimental protocol based on a dyslipidaemic diet intervention was effective in developing maternal dyslipidemia. At 30 days of age, the FO from dyslipidaemic dams displayed disordered respiratory pattern, enhanced ventilatory response to hypercapnia (P < 0.05), and increased serum levels of total cholesterol and triglycerides (P < 0.05) when compared with CTL female offspring. At 90 days of age, FO from dyslipidaemic dams had augmented BP (P < 0.05), exacerbated cardiorespiratory responses to hypercapnia (P < 0.05), enhanced pressor responses to peripheral chemoreflex activation (P < 0.05), impaired baroreflex (P < 0.05), and larger delta variations in arterial pressure after ganglionic blockade (P < 0.05). Furthermore, during oral glucose and insulin tolerance tests, FO from dyslipidaemic dams exhibited altered glucose tolerance and insulin sensitivity (P < 0.05) when compared with FO from CTL dams. Altered breathing linked to enhanced central and peripheral chemosensitivity, impaired baroreflex, and augmented sympathetic tone may be predisposing factors for increased BP and metabolic disorders in female offspring from dyslipidaemic dams.