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Muscle sympathetic nerve activity (MSNA) can be acquired from humans using the technique of microneurography. The resulting integrated neurogram displays pulse-synchronous bursts of sympathetic activity, which undergoes processing for standard MSNA metrics including burst frequency, height, area, incidence, total activity, and latency. The procedure for detecting bursts of MSNA and calculating burst metrics is tedious and differs widely among laboratories worldwide. We sought to develop an open-source, cross-platform web application that provides a standardized approach for burst identification and a tool to increase research reproducibility for those measuring MSNA. We compared the performance of this web application against a manual scoring approach under conditions of rest, chemoreflex activation (n = 9, 20-min isocapnic hypoxia), and metaboreflex activation (n = 13, 2-min isometric handgrip exercise and 4-min postexercise circulatory occlusion). The intraclass correlation coefficient (ICC) indicated good to strong agreement between scoring approaches for burst frequency (ICC = 0.92–0.99), incidence (ICC = 0.94–0.99), height (ICC = 0.76–0.88), total activity (ICC = 0.85–0.99), and latency (ICC = 0.97–0.99). Agreement with burst area was poor to moderate (ICC = 0.04–0.67) but changes in burst area were similar with chemoreflex and metaboreflex activation. Scoring using the web application was highly efficient and provided data visualization tools that expedited data processing and the analysis of MSNA. We recommend the open-source web application be adopted by the community for the analysis of MSNA. NEW & NOTEWORTHY The basic analysis of muscle sympathetic nerve activity (MSNA) requires the identification of pulse-synchronous bursts from the integrated neurogram before standard MSNA metrics can be quantified. This process is a time-consuming task requiring an experienced microneurographer to visually identify and manually label bursts. We developed an open-source, cross-platform application permitting a standardized approach for sympathetic burst identification and present the performance of this application against a manual scorer under basal conditions and during sympathoexcitatory stresses. [ABSTRACT FROM AUTHOR]

Introduction: Parabrachial Kölliker-Fuse (KF) complex, located in dorsolateral part of the pons, is involved in the respiratory control, however, its role in the baroreflex and chemoreflex responses has not been established yet. This study was performed to test the contribution of the KF to chemoreflex and baroreflex and the effect of microinjection of a reversible synaptic blocker (Cocl2) into the KF in urethane anesthetized rats. Methods: Activation of chemoreflex was induced by systemic hypoxia caused by N2 breathing for 30 seconds "hypoxic- hypoxia methods" and baroreflex was evoked by intravenous injection (i.v.) of phenylephrine (Phe, 20 µg /kg/0.05–0.1 mL). N2 induced generalized vasodilatation followed by tachycardia reflex and Phe evoked vasoconstriction followed by bradycardia. Results: Microinjection of Cocl2 (5 mM/100 nL/side) produced no significant changes in the Phe-induced hypertension and bradycardia, whereas the cardiovascular effect of N2 was significantly attenuated by the injection of CoCl2 to the KF. Conclusion: The KF played no significant role in the baroreflex, but could account for cardiovascular chemoreflex in urethane anesthetized rats.

Furthermore, peak sympatho-excitation via central and peripheral chemoreflex activation has been found to be greater in females when compared with males, but not during peripheral chemoreflex activation, raising the possibility that central chemoreflex control of MSNA may be augmented in females. Keywords: chemoreflex; G-force; muscle sympathetic nerve activity; POTS; sex differences EN chemoreflex G-force muscle sympathetic nerve activity POTS sex differences 4055 4057 3 09/19/22 20220915 NES 220915 While the stretch-sensitive baroreceptors are first called to mind in acute control of blood pressure (BP), other acute reflex adjustments are necessary to maintain allostasis, notably central and peripheral chemoreflexes. Interestingly, the raised MSNA and raised ventilation during combined central and peripheral chemoreflex activation was greater than the sum of the individual central and peripheral chemoreceptor responses - and this response was similar between the sexes. [Extracted from the article]

Orexin neurons are active in wakefulness and mostly silent in sleep. In adult rats and humans, orexin facilitates the hypercapnic ventilatory response but has little effect on resting ventilation. The influence of orexin on breathing in the early postnatal period, and across states of vigilance, have not been investigated. This is relevant as the orexin system may be impaired in Sudden Infant Death Syndrome (SIDS) cases. We addressed three hypotheses: 1) orexin provides a drive to breathe in infancy; 2) the effect of orexin depends on stage of postnatal development; and 3) orexin has a greater influence on breathing in wakefulness compared with sleep. Whole body plethysmography was used to monitor breathing of infant rats at three ages: postnatal days (P) 7–8, 12–14, and 17–19. Respiratory variables were analyzed in wakefulness (W), quiet sleep (QS), and active sleep (AS), following suvorexant (5 mg/kg ip), a dual orexin receptor antagonist, or vehicle (DMSO). Effects of suvorexant on ventilatory responses to graded hypercapnia (FICO2 = 0.02, 0.04, 0.06), hypoxia (FIO2 = 0.10), and hyperoxia (FIO2 = 1.0) at P12–14 were also tested. At P12–14, but not at other ages, suvorexant significantly reduced respiratory frequency in all states, reduced the ventilatory equivalent in QW and QS, and increased PaCO2 to ˜5 mmHg. Suvorexant had no effect on ventilatory responses to graded hypercapnia or hypoxia. Hyperoxia eliminated the effects of suvorexant on respiratory frequency at P12–14. Our data suggest that orexin preserves eupneic frequency and ventilation in rats, specifically at ˜2 wk of age, perhaps by facilitating tonic peripheral chemoreflex activity [ABSTRACT FROM AUTHOR]

The South American rattlesnake, Crotalus durissus , has been successfully used as an experimental model to study control of the cardiovascular system in squamate reptiles. Recent technical advances, including equipment miniaturization, have lessened the impact of instrumentation on in vivo recordings, and an increased range of anesthetic drugs has improved recording conditions for in situ preparations. Nevertheless, any animal-based experimental approach has to manage limitations regarding the avoidance of pain and stress the stability of the preparation and duration of experiments and the potentially overriding effects of anesthesia. To address such aspects, we tested a new experimental preparation, the decerebrate rattlesnake, in a study of the autonomic control of cardiovascular responses following the removal of general anesthesia. The preparation exhibited complex cardiovascular adjustments to deal with acute increases in venous return (caused by tail lifting), to compensate for blood flow reduction in the cephalic region (caused by head lifting), for body temperature control (triggered by an external heating source), and in response to stimulation of chemoreceptors (triggered by intravenous injection of NaCN). The decerebrate preparation retained extensive functional integrity of autonomic centers, and it was suitable for monitoring diverse cardiac and vascular variables. Furthermore, reanesthetizing the preparation markedly blunted cardiovascular performance. Isoflurane limited the maintenance of recovered cardiovascular variables in the prepared animal and reduced or abolished the observed cardiovascular reflexes. This preparation enables the recording of multiple concomitant cardiovascular variables for the study of mechanistic questions regarding the central integration of autonomic reflex responses in the absence of anesthesia. [ABSTRACT FROM AUTHOR]

Carotid body feedback and hypoxia may serve to enhance respiratory–sympathetic nerve coupling (respSNA) and act as a driver of increased blood pressure. Using the Lewis polycystic kidney (LPK) rat model of chronic kidney disease, we examined respSNA in adult female rodents with CKD and their response to acute hypoxia or hypercapnia compared to Lewis control animals. Under urethane anesthesia, phrenic nerve activity, splanchnic sympathetic nerve activity (sSNA), and renal sympathetic nerve activity (rSNA) were recorded under baseline conditions and during mild hypoxic or hypercapnic challenges. At baseline, tonic SNA and blood pressure were greater in female LPK rats versus Lewis rats (all P < 0.05) and respSNA was at least two-fold larger [area under the curve (AUC), sSNA: 7.8 ± 1.1 vs. 3.4 ± 0.7 μV s, rSNA: 11.5 ± 3 vs. 4.8 ± 0.7 μV s, LPK vs. Lewis, both P < 0.05]. Mild hypoxia produced a larger pressure response in LPK [Δ mean arterial pressure (MAP) 30 ± 6 vs. 12 ± 6 mmHg] and augmented respSNA (ΔAUC, sSNA: 8.9 ± 3.4 vs. 2 ± 0.7 μV s, rSNA: 6.1 ± 1.2 vs. 3.1 ± 0.7 μV s, LPK vs. Lewis, all P ≤ 0.05). In contrast, central chemoreceptor stimulation produced comparable changes in blood pressure and respSNA (ΔMAP 13 ± 3 vs. 9 ± 5 mmHg; respSNA ΔAUC, sSNA: 2.5 ± 1 vs. 1.3 ± 0.7 μV s, rSNA: 4.2 ± 0.9 vs. 3.5 ± 1.4 μV s, LPK vs. Lewis, all P > 0.05). These results demonstrate that female rats with CKD exhibit heightened respSNA coupling at baseline that is further augmented by mild hypoxia, and not by hypercapnia. This mechanism may be a contributing driver of hypertension in this animal model of CKD.

Carotid body feedback and hypoxia may serve to enhance respiratory–sympathetic nerve coupling (respSNA) and act as a driver of increased blood pressure. Using the Lewis polycystic kidney (LPK) rat model of chronic kidney disease, we examined respSNA in adult female rodents with CKD and their response to acute hypoxia or hypercapnia compared to Lewis control animals. Under urethane anesthesia, phrenic nerve activity, splanchnic sympathetic nerve activity (sSNA), and renal sympathetic nerve activity (rSNA) were recorded under baseline conditions and during mild hypoxic or hypercapnic challenges. At baseline, tonic SNA and blood pressure were greater in female LPK rats versus Lewis rats (all P < 0.05) and respSNA was at least two-fold larger [area under the curve (AUC), sSNA: 7.8 ± 1.1 vs. 3.4 ± 0.7 μV s, rSNA: 11.5 ± 3 vs. 4.8 ± 0.7 μV s, LPK vs. Lewis, both P < 0.05]. Mild hypoxia produced a larger pressure response in LPK [Δ mean arterial pressure (MAP) 30 ± 6 vs. 12 ± 6 mmHg] and augmented respSNA (ΔAUC, sSNA: 8.9 ± 3.4 vs. 2 ± 0.7 μV s, rSNA: 6.1 ± 1.2 vs. 3.1 ± 0.7 μV s, LPK vs. Lewis, all P ≤ 0.05). In contrast, central chemoreceptor stimulation produced comparable changes in blood pressure and respSNA (ΔMAP 13 ± 3 vs. 9 ± 5 mmHg; respSNA ΔAUC, sSNA: 2.5 ± 1 vs. 1.3 ± 0.7 μV s, rSNA: 4.2 ± 0.9 vs. 3.5 ± 1.4 μV s, LPK vs. Lewis, all P > 0.05). These results demonstrate that female rats with CKD exhibit heightened respSNA coupling at baseline that is further augmented by mild hypoxia, and not by hypercapnia. This mechanism may be a contributing driver of hypertension in this animal model of CKD. [ABSTRACT FROM AUTHOR]

Non-invasive assessment of ventilatory control stability or loop gain (which is a key contributor in a number of sleep-related breathing disorders) has proven to be cumbersome. We present a novel multivariate autoregressive model that we hypothesize will enable us to make time-varying measurements of loop gain using nothing more than spontaneous fluctuations in ventilation and CO2. The model is adaptive to changes in the feedback control loop and therefore can account for system non-stationarities (e.g. changes in sleep state) and it is resistant to artifacts by using a signal quality measure. We tested this method by assessing its ability to detect a known increase in loop gain induced by proportional assist ventilation (PAV). Subjects were studied during sleep while breathing on continuous positive airway pressure (CPAP) alone (to stabilize the airway) or on CPAP+PAV. We show that the method tracked the PAV-induced increase in loop gain, demonstrating its time-varying capabilities, and it remained accurate in the face of measurement related artifacts. The model was able to detect a statistically significant increase in loop gain from 0.14±10 on CPAP alone to 0.21±0.13 on CPAP+PAV (p

Abstract Background Lipopolysaccharide (LPS)-induced systemic inflammation (SI) is associated with neuroinflammation in the brain, hypotension, tachycardia, and multiple organs dysfunctions. Considering that during SI these important cardiovascular and inflammatory changes take place, we measured the sensitivity of the cardiovascular reflexes baroreflex, chemoreflex, and Bezold-Jarisch that are key regulators of hemodynamic function. We also evaluated neuroinflammation in the nucleus tractus solitarius (NTS), the first synaptic station that integrates peripheral signals arising from the cardiovascular and inflammatory status. Methods We combined cardiovascular recordings, immunofluorescence, and assays of inflammatory markers in male Wistar rats that receive iv administration of LPS (1.5 or 2.5 mg kg−1) to investigate putative interactions of the neuroinflammation in the NTS and in the anteroventral preoptic region of the hypothalamus (AVPO) with the short-term regulation of blood pressure and heart rate. Results LPS induced hypotension, tachycardia, autonomic disbalance, hypothermia followed by fever, and reduction in spontaneous baroreflex gain. On the other hand, during SI, the bradycardic component of Bezold-Jarisch and chemoreflex activation was increased. These changes were associated with a higher number of activated microglia and interleukin (IL)-1β levels in the NTS. Conclusions The present data are consistent with the notion that during SI and neuroinflammation in the NTS, rats have a reduced baroreflex gain, combined with an enhancement of the bradycardic component of Bezold-Jarisch and chemoreflex despite the important cardiovascular impairments (hypotension and tachycardia). These changes in the cardiac component of Bezold-Jarisch and chemoreflex may be beneficial during SI and indicate that the improvement of theses reflexes responsiveness though specific nerve stimulations may be useful in the management of sepsis.

Chronic intermittent hypoxia (CIH) increases basal sympathetic nervous system activity, augments chemoreflex-induced sympathoexcitation, and raises blood pressure. All effects are attenuated by systemic or intracerebroventricular administration of angiotensin II type 1 receptor (AT1R) antagonists. This study aimed to quantify the effects of CIH on AT1R- and AT2R-like immunoreactivity in the rostroventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), central regions that are important components of the extended chemoreflex pathway. Eighteen Sprague-Dawley rats were exposed to intermittent hypoxia (FIO2 = 0.10, 1 min at 4-min intervals) for 10 hr/day for 1, 5, 10, or 21 days. After exposure, rats were deeply anesthetized and transcardially perfused with phosphate buffered saline (PBS) followed by 4% paraformaldehyde in PBS. Brains were removed and sectioned coronally into 50 µm slices. Immunohistochemistry was used to quantify AT1R and AT2R in the RVLM and the PVN. In the RVLM, CIH significantly increased the AT1R-like immunoreactivity, but did not alter AT2R immunoreactivity, thereby augmenting the AT1R:AT2R ratio in this nucleus. In the PVN, CIH had no effect on immunoreactivity of either receptor subtype. The current findings provide mechanistic insight into increased basal sympathetic outflow, enhanced chemoreflex sensitivity, and blood pressure elevation observed in rodents exposed to CIH.

Objective: Birth asphyxia (BA) is often associated with seizures that may exacerbate the ensuing hypoxic–ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, that commence already during the insult. This is in stark contrast to clinical BA, in which seizures are typically seen upon recovery. Here, we introduce a term‐equivalent rat model of BA, in which seizures are triggered after exposure to asphyxia. Methods: Postnatal day 11–12 male rat pups were exposed to steady asphyxia (15 min; air containing 5% O2 + 20% CO2) or to intermittent asphyxia (30 min; three 5 + 5‐min cycles of 9% and 5% O2 at 20% CO2). Cortical activity and electrographic seizures were recorded in freely behaving animals. Simultaneous electrode measurements of intracortical pH, Po2, and local field potentials (LFPs) were made under urethane anesthesia. Results: Both protocols decreased blood pH to <7.0 and brain pH from 7.3 to 6.7 and led to a fall in base excess by 20 mmol·L–1. Electrographic seizures with convulsions spanning the entire Racine scale were triggered after intermittent but not steady asphyxia. In the presence of 20% CO2, brain Po2 was only transiently affected by 9% ambient O2 but fell below detection level during the steps to 5% O2, and LFP activity was nearly abolished. Post‐asphyxia seizures were strongly suppressed when brain pH recovery was slowed down by 5% CO2. Significance: The rate of brain pH recovery has a strong influence on post‐asphyxia seizure propensity. The recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which leads to seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one in which, consistent with clinical BA, behavioral and electrographic seizures are triggered after and not during the BA‐mimicking insult. [ABSTRACT FROM AUTHOR]

• SH reduces the amplitude of evoked GABAergic currents in NTS-VLM neurons of rats. • SH changes inhibitory transmission in NTS-VLM neurons by pre-synaptic mechanisms. • The frequency of spontaneous inhibitory currents in NTS-VLM neurons was reduced by SH. • Changes in GABAergic modulation of NTS-VLM neurons by SH may affect chemoreflex. Peripheral chemoreflex is activated during short-term sustained hypoxia (SH), and the first synapse of these afferents is located in Nucleus Tractus Solitarius (NTS). NTS neurons projecting to the ventral lateral medulla (NTS-VLM) are part of the respiratory pathways of the chemoreflex. SH increases the magnitude of basal respiratory parameters in rats from Wistar-Hannover strain. In this study, we hypothesized that the observed changes in the respiratory pattern in response to SH were due to changes in the GABAergic modulation of the synaptic transmission of NTS-VLM neurons. We used an electrophysiological approach to record the synaptic activity of NTS neurons labeled with a retrograde tracer previously microinjected into VLM of Wistar-Hannover rats submitted to 24 h SH. The data are showing that: (a) the amplitude of evoked inhibitory currents in NTS-VLM neurons of SH rats was reduced and not accompanied by any change in rise-time and decay-time; (b) the 1/CV2 and the number of failures in response to evoked currents were also affected by SH; (c) the frequency of spontaneous inhibitory currents was reduced by SH without changes in amplitude and half-width. These effects of SH were observed in NTS-VLM neurons located in caudal and intermediate NTS, but not in NTS-VLM neurons located in the rostral NTS. We conclude that SH causes a reduction in inhibitory modulation onto NTS-VLM neurons by pre-synaptic mechanisms, which may contribute to the observed changes in the respiratory pattern of Wistar-Hannover rats submitted to SH. [ABSTRACT FROM AUTHOR]

Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO2/H+ and regulate several aspects of breathing, including inspiration and active expiration. [ABSTRACT FROM AUTHOR]

Aims: Increased chemosensitivity to carbon dioxide (CO2 ) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF.Methods and Results: The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate-severe CA [nocturnal apnoea-hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1 week, with a crossover design (1 week of wash-out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14-73%, P = 0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P = 0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone-related serious adverse events.Conclusions: Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF. [ABSTRACT FROM AUTHOR]

We demonstrated that changes in CO2 values cause oscillations in the cortical activity in δ-and α-bands. The analysis of the regional field power (RFP) showed evidence that different cortical areas respond with different time delays to CO2 challenges. An opposite behavior was found for the end-tidal O2. We suppose that the different cortical time delays likely expresse specific ascending pathways to the cortex, generated by chemoreceptor nuclei in the brain stem. Although the brain stem is in charge of the automatic control of ventilation, the cortex is involved in the voluntary control of breathing but also receives inputs from the brain stem, which influences the perception of breathing, the arousal state and sleep architecture in conditions of hypoxia/hypercapnia. We evaluated in 11 healthy subjects the effects of breath hold (BH; 30 s of apneas and 30 s of normal breathing) and BH-related CO2/O2 changes on electroencephalogram (EEG) global field power (GFP) and RFP in nine different areas (3 rostrocaudal sections: anterior, central, and posterior; and 3 sagittal sections: left, middle, and right) in the δ- and α-bands by cross correlation analysis. No significant differences were observed in GFP or RFP when comparing free breathing (FB) with the BH task. Within the BH task, the shift from apnea to normal ventilation was accompanied by an increase in the δ-power and a decrease in the α-power. The end-tidal pressure of CO2 (PETCO2) was positively correlated with the δ-band and negatively with the α-band with a positive time shift, whereas an opposite behavior was found for the end-tidal pressure of O2 (PETO2). Notably, the time shift between PETCO2 / PETO2 signals and cortical activity at RFP was heterogenous and seemed to follow a hierarchical activation, with the δ-band responding earlier than the α-band. Overall, these findings suggest that the effect of BH on the cortex may follow specific ascending pathways from the brain stem and be related to chemoreflex stimulation. NEW & NOTEWORTHY We demonstrated that the end tidal CO2 oscillation causes oscillations of delta and alpha bands. The analysis of the regional field power showed that different cortical areas respond with different time delays to CO2 challenges. An opposite behavior was found for the end-tidal O2. We can suppose that the different cortical time delay response likely expresses specific ascending pathways to the cortex generated by chemoreceptor nuclei in the brainstem. [ABSTRACT FROM AUTHOR]

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

The presence of bradycardic arrhythmias during volitional apnea at altitude may be caused by chemoreflex activation/sensitization. We investigated whether bradyarrhythmic episodes became prevalent in apnea following short-term hypoxia exposure. Electrocardiograms (ECG; lead II) were collected from 22 low-altitude residents (F = 12; age=25 ± 5 years) at 671 m. Participants were exposed to normobaric hypoxia (SpO2 ~79 ± 3%) over a 5-h period. ECG rhythms were assessed during both free-breathing and maximal volitional end-expiratory and end-inspiratory apnea at baseline during normoxia and hypoxia exposure (20 min [AHX]; 5 h [HX5]). Free-breathing HR became elevated at AHX (78 ± 10 bpm; p < 0.0001) and HX5 (80 ± 12 bpm; p < 0.0001) compared to normoxia (68 ± 10 bpm), whereas apnea caused significant bradycardia at AHX (nadir end-expiratory -17 ± 14 bpm; p < 0.001) and HX5 (nadir end-expiratory -19 ± 15 bpm; p < 0.001), but not during normoxia (nadir end-expiratory -4 ± 13 bpm), with no difference in bradycardia responses between apneas at AHX and HX5. Conduction abnormalities were noted in five participants during normoxia (Premature Ventricular Contraction, Sinus Pause, Junctional Rhythm, Atrial Foci), which remained unchanged during apnea at AHX and HX5 (Premature Ventricular Contraction, Premature Atrial Contraction, Sinus Pause). End-inspiratory apneas were overall longer across conditions (normoxia p < 0.05; AHX p < 0.01; HX5 p < 0.001), with comparable HR responses to end-expiratory and fewer occurrences of arrhythmia. While short-term hypoxia is sufficient to elicit bradycardia during apnea, the occurrence of arrhythmias in response to apnea was not affected. These findings indicate that previously observed bradyarrhythmic events in untrained individuals at altitude only become prevalent following chronic hypoxia specificlly. [ABSTRACT FROM AUTHOR]

Introduction: Baroreflexes 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. Methods: We 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). Results: Hypoxia 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). Conclusion: We 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. [ABSTRACT FROM AUTHOR]

The larynx plays a key role in airway protection via the laryngeal chemoreflex (LCR). This involuntary reflex can be evoked when hazardous substances activate mucosal receptors, which send signals to be processed within the brainstem. Although the LCR is meant to be protective, the reflex can become hyperstimulated, even to benign stimuli, which can result in pathological disorders, such as chronic cough and inducible laryngeal obstruction. In this review, we will outline the mechanism of the LCR and its associated pathological disorders. [ABSTRACT FROM AUTHOR]

Abstract Progesterone and its analogues are known to influence ventilation. Therefore, the purpose of this study was to investigate the role of endogenous and pharmaceutical female sex hormones in ventilatory control during the activation of the metaboreflex, mechanoreflex, and CO2 chemoreflex. Women aged 18–30 taking (n = 14) or not taking (n = 12) oral contraceptives (OC and NOC, respectively) were tested in the low hormone (LH) and high hormone (HH) conditions corresponding to the early follicular and mid‐luteal phases (NOC) or placebo and high‐dose pills (OC). Women underwent three randomized trials: (a) 3 min of passive leg movement (PLM), (b) 2 min of 40% maximal voluntary handgrip exercise followed by 2 min of post‐exercise circulatory occlusion (PECO), and (c) 5 min of breathing 5% CO2. We primarily measured hemodynamics and ventilation. During PLM, the OC group had a smaller pressor response (p = .012). During PECO, the OC group similarly exhibited a smaller pressor response (p = .043) and also exhibited a greater ventilatory response (p = .024). Lastly, in response to breathing 5% CO2, women in the HH phase had a greater ventilatory response (p = .022). We found that OC use attenuates the pressor response to both the metaboreflex and mechanoreflex while increasing the ventilatory response to metaboreflex activation. We also found evidence of an enhanced CO2 chemoreflex in the HH phase. We hypothesize that OC effects are from the chronic upregulation of pulmonary and vascular β‐adrenergic receptors. We further suggest that the increased cyclic progesterone in the HH phase enhances the chemoreflex.

Aim. The goal of the study was to assess the impact of peripheral chemoreflex sensitivity on the rate of critical incidents in extensive abdominal operations.Materials and methods. The study included 176 patients who underwent major abdominal surgery under combined anesthesia. On the eve of surgery, sensitivity of peripheral chemoreflex was determined in all subjects. Sex, age, initial physical status, cardiovascular risk were also registered. During anesthesia hemodynamic, respiratory and metabolic critical incidents were registered.Results. In total, 158 critical incidents were observed. They were significantly more common in patients with high sensitivity to peripheral chemoreflex (72% vs. 48%, p

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

Progesterone and its analogues are known to influence ventilation. Therefore, the purpose of this study was to investigate the role of endogenous and pharmaceutical female sex hormones in ventilatory control during the activation of the metaboreflex, mechanoreflex, and CO2 chemoreflex. Women aged 18–30 taking (n = 14) or not taking (n = 12) oral contraceptives (OC and NOC, respectively) were tested in the low hormone (LH) and high hormone (HH) conditions corresponding to the early follicular and mid‐luteal phases (NOC) or placebo and high‐dose pills (OC). Women underwent three randomized trials: (a) 3 min of passive leg movement (PLM), (b) 2 min of 40% maximal voluntary handgrip exercise followed by 2 min of post‐exercise circulatory occlusion (PECO), and (c) 5 min of breathing 5% CO2. We primarily measured hemodynamics and ventilation. During PLM, the OC group had a smaller pressor response (p =.012). During PECO, the OC group similarly exhibited a smaller pressor response (p =.043) and also exhibited a greater ventilatory response (p =.024). Lastly, in response to breathing 5% CO2, women in the HH phase had a greater ventilatory response (p =.022). We found that OC use attenuates the pressor response to both the metaboreflex and mechanoreflex while increasing the ventilatory response to metaboreflex activation. We also found evidence of an enhanced CO2 chemoreflex in the HH phase. We hypothesize that OC effects are from the chronic upregulation of pulmonary and vascular β‐adrenergic receptors. We further suggest that the increased cyclic progesterone in the HH phase enhances the chemoreflex. [ABSTRACT FROM AUTHOR]

Peripheral viscerosensory afferent signals are transmitted to the nucleus tractus solitarii (nTS) via release of glutamate. Following release, glutamate is removed from the extrasynaptic and synaptic cleft via excitatory amino acid transporters (EAATs), thus limiting glutamate receptor activation or over activation, and maintaining its working range. We have shown that EAAT block with the antagonist threo-β-benzyloxyaspartic acid (TBOA) depolarized nTS neurons and increased spontaneous excitatory postsynaptic current (sEPSC) frequency yet reduced the amplitude of afferent (TS)-evoked EPSCs (TS-EPSCs). Interestingly, chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea (OSA), produces similar synaptic responses as EAAT block. We hypothesized EAAT expression or function are downregulated after CIH, and this reduction in glutamate removal contributes to the observed neurophysiological responses. To test this hypothesis, we used brain slice electrophysiology and imaging of glutamate release and TS-afferent Ca2+ to compare nTS properties of rats exposed to 10 days of normoxia (Norm; 21%O2) or CIH. Results show that EAAT blockade with (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]- amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA) in Norm caused neuronal depolarization, generation of an inward current, and increased spontaneous synaptic activity. The latter augmentation was eliminated by inclusion of tetrodotoxin in the perfusate. TS stimulation during TFB-TBOA also elevated extracellular glutamate and decreased presynaptic Ca2+ and TS-EPSC amplitude. In CIH, the effects of EAAT block are eliminated or attenuated. CIH reduced EAAT expression in nTS, which may contribute to the attenuated function seen in this condition. Therefore, CIH reduces EAAT influence on synaptic and neuronal activity, which may lead to the physiological consequences seen in OSA and CIH. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?What is the contribution of the main acidic compounds accumulated during contractions, namely H+, lactic acid and inorganic phosphate, to evoke the metabolic component of the exercise pressor reflex?What is the main finding and its importance?We found that the pressor response to acidic stimuli is driven by the concentration of hydrogen ions and that lactate and inorganic phosphate act as potentiating agents. H+ ions, lactate and inorganic phosphate are produced by contracting skeletal muscles and evoke, in part, the metabolic component of the exercise pressor reflex. Owing to their disparate dissociation constants (i.e. pKa), the contribution of each acid to the muscle metaboreflex is unclear. This lack of information prompted us to determine the reflex pressor responses to injection of acidic saline, lactate (24 mm) and inorganic phosphate (86 mm) at various values of pH (from 2.66 to 7.5), alone or in combination, into the arterial supply of hindlimb skeletal muscle of decerebrate rats. In particular, we tested the hypothesis that the pressor response to an injection of a combination of lactate and phosphate at an acidic pH is greater than that evoked by injection of either phosphate or lactate alone at the same pH. We found that injection of acidic saline produced a pressor response only at a pH of 2.66 (7 ± 4 mmHg), an effect that was potentiated when the solution contained lactate (50 ± 20 mmHg). At a pH of 6.0, however, this effect was lost. At a pH of 6.0, only the injection of inorganic phosphate produced a significant pressor response (23 ± 12 mmHg). A large potentiating effect was found when lactate was added to the inorganic phosphate solution (39 ± 18 mmHg), an effect that was lost at a pH >7.0. Our findings led to the conclusion that the pressor response to injection of acidic solutions was driven by H+ ions and that inorganic phosphate and lactate functioned as sensitizing agents. [ABSTRACT FROM AUTHOR]

• Exposure to sustained hypoxia (10% O 2) up to 7 days induces time-dependent changes in glutamatergic signaling. • Functional alterations in excitatory amino acid transporters contribute to altered glutamatergic signaling. • EAAT expression increases over 7 days SH. Glutamate is the major excitatory neurotransmitter in the nucleus tractus solitarii (nTS) and mediates chemoreflex function during periods of low oxygen (i.e. hypoxia). We have previously shown that nTS excitatory amino acid transporters (EAATs), specifically EAAT-2, located on glia modulate neuronal activity, cardiorespiratory and chemoreflex function under normal conditions via its tonic uptake of extracellular glutamate. Chronic sustained hypoxia (SH) elevates nTS synaptic transmission and chemoreflex function. The goal of this study was to determine the extent to which glial EAAT-2 contributes to SH-induced nTS synaptic alterations. To do so, male Sprague-Dawley rats (4–7 weeks) were exposed to either 1, 3, or 7 days of SH (10% O 2 , 24 h/day) and compared to normoxic controls (21% O 2 , 24 h/day, i.e., 0 days SH). After which, the nTS was harvested for patch clamp electrophysiology, quantitative real-time PCR, immunohistochemistry and immunoblots. SH induced time- and parameter-dependent increases in excitatory postsynaptic currents (EPSCs). TS-evoked EPSC amplitude increased after 1D SH which returned at 3D and 7D SH. Spontaneous EPSC frequency increased only after 3D SH, which returned to normoxic levels at 7D SH. EPSC enhancement occurred primarily by presynaptic mechanisms. Inhibition of EAAT-2 with dihydrokainate (DHK, 300 µM) did not alter EPSCs following 1D SH but induced depolarizing inward currents (I hold). After 3D SH, DHK decreased TS-EPSC amplitude yet its resulting I hold was eliminated. EAAT-2 mRNA and protein increased after 3D and 7D SH, respectively. These data suggest that SH alters the expression and function of EAAT-2 which may have a neuroprotective effect. [ABSTRACT FROM AUTHOR]

Hippocampus is a limbic structure involved in the baroreflex and chemoreflex control that receives extensive cholinergic input from basal forebrain. Hippocampal muscarinic receptors activation by acetylcholine might evoke nitric oxide synthesis, which is an important neuromodulator of cardiovascular responses. Thus, we hypothesize that cholinergic and nitrergic neurotransmission within the DH modulates the baroreflex and chemoreflex function. We have used vasoactive drugs (phenylephrine and sodium nitroprusside), and potassium cyanide infused peripherally to induce, respectively, baroreflex or chemoreflex responses in awake animals. Bilateral injection into the DH of the acetylcholinesterase inhibitor (neostigmine) reduced baroreflex responses. Meanwhile, the non‐selective muscarinic receptor antagonist (atropine) or the M1‐selective muscarinic receptor antagonist increased baroreflex responses (pirenzepine). Furthermore, the neuronal nitric oxide synthase inhibitor (N‐propyl) or the intracellular NO scavenger (carboxy‐PTIO) increased baroreflex responses, as well as the selective inhibitor of NO‐sensitive guanylyl cyclase (ODQ), increased the baroreflex responses. Besides, bilateral administration of an ineffective dose of a neuronal nitric oxide synthase inhibitor abolished the reduction in the baroreflex responses evoked by an acetylcholinesterase inhibitor. On the other hand, we have demonstrated that hippocampal cholinergic neurotransmission did not influence the chemoreflex function. Taken together, our findings suggest that nNOS‐derived nitric oxide in the DH participates in acetylcholine‐evoked baroreflex responses. [ABSTRACT FROM AUTHOR]

The nucleus of the solitary tract (NTS) is an important area of the brainstem that receives and integrates afferent cardiorespiratory sensorial information, including those from arterial chemoreceptors and baroreceptors. It was described that acetylcholine (ACh) in the commissural subnucleus of the NTS (cNTS) promotes an increase in the phrenic nerve activity (PNA) and antagonism of nicotinic receptors in the same region reduces the magnitude of tachypneic response to peripheral chemoreceptor stimulation, suggesting a functional role of cholinergic transmission within the cNTS in the chemosensory control of respiratory activity. In the present study, we investigated whether cholinergic receptor antagonism in the cNTS modifies the sympathetic and respiratory reflex responses to hypercapnia. Using an arterially perfused in situ preparation of juvenile male Holtzman rats, we found that the nicotinic antagonist (mecamylamine, 5 mM), but not the muscarinic antagonist (atropine, 5 mM), into the cNTS attenuated the hypercapnia-induced increase of hypoglossal activity. Furthermore, mecamylamine in the cNTS potentiated the generation of late-expiratory (late-E) activity in abdominal nerve induced by hypercapnia. None of the cholinergic antagonists microinjected in the cNTS changed either the sympathetic or the phrenic nerve responses to hypercapnia. Our data provide evidence for the role of cholinergic transmission in the cNTS, acting on nicotinic receptors, modulating the hypoglossal and abdominal responses to hypercapnia. [ABSTRACT FROM AUTHOR]

Introduction: Parabrachial Kölliker-Fuse (KF) complex, located in dorsolateral part of the pons, is involved in the respiratory control, however, its role in the baroreflex and chemoreflex responses has not been established yet. This study was performed to test the contribution of the KF to chemoreflex and baroreflex and the effect of microinjection of a reversible synaptic blocker (Cocl2) into the KF in urethane anesthetized rats. Methods: Activation of chemoreflex was induced by systemic hypoxia caused by N2 breathing for 30 seconds "hypoxic-hypoxia methods" and baroreflex was evoked by intravenous injection (i.v.) of phenylephrine (Phe, 20 μg/kg/0.05-0.1 mL). N2 induced generalized vasodilatation followed by tachycardia reflex and Phe evoked vasoconstriction followed by bradycardia. Results: Microinjection of Cocl2 (5 mM/100 nL/side) produced no significant changes in the Pheinduced hypertension and bradycardia, whereas the cardiovascular effect of N2 was significantly attenuated by the injection of CoCl2 to the KF. Conclusion: The KF played no significant role in the baroreflex, but could account for cardiovascular chemoreflex in urethane anesthetized rats. [ABSTRACT FROM AUTHOR]

Enhanced central chemoreflex (CC) gain is observed in volume overload heart failure (HF) and is correlated with autonomic dysfunction and breathing disorders. The aim of this study was to determine the role of the CC in the development of respiratory and autonomic dysfunction in HF. Volume overload was surgically created to induce HF in male Sprague-Dawley rats. Radiotelemetry transmitters were implanted for continuous monitoring of blood pressure and heart rate. After recovering from surgery, conscious unrestrained rats were exposed to episodic hypercapnic stimulation [EHS; 10 cycles/5 min, inspiratory fraction of carbon dioxide (...) 7%] in a whole body plethysmograph for recording of cardiorespiratory function. To determine the contribution of CC to cardiorespiratory variables, selective ablation of chemoreceptor neurons within the retrotrapezoid nucleus (RTN) was performed via injection of saporin toxin conjugated to substance P (SSP-SAP). Vehicle-treated rats (HF+Veh and Sham+Veh) were used as controls for SSP-SAP experiments. Sixty minutes post-EHS, minute ventilation was depressed in sham animals relative to HF animals (Δ...E: -5.55 ± 2.10 vs. 1.24 ± 1.35 mL/min 100 g, P < 0.05; Sham+Veh vs. HF+Veh). Furthermore, EHS resulted in autonomic imbalance, cardiorespiratory entrainment, and ventilatory disturbances in HF+Veh but not Sham+Veh rats, and these effects were significantly attenuated by SSP-SAP treatment. Also, the apnea-hypopnea index (AHI) was significantly lower in HF+SSP-SAP rats compared with HF+Veh rats (AHI: 5.5 ± 0.8 vs. 14.4 ± 1.3 events/h, HF+SSP-SAP vs. HF+Veh, respectively, P < 0.05). Finally, EHS-induced respiratory-cardiovascular coupling in HF rats depends on RTN chemoreceptor neurons because it was reduced by SSP-SAP treatment. Overall, EHS triggers ventilatory plasticity and elicits cardiorespiratory abnormalities in HF that are largely dependent on RTN chemoreceptor neurons. [ABSTRACT FROM AUTHOR]

Chemoreflex neurocircuitry includes the paraventricular nucleus (PVN), but the role of PVN efferent projections to specific cardiorespiratory nuclei is unclear. We hypothesized that the PVN contributes to cardiorespiratory responses to hypoxia via projections to the nucleus tractus solitarii (nTS). Rats received bilateral PVN microinjections of adeno-associated virus expressing inhibitory designer receptor exclusively activated by designer drug (GiDREADD) or green fluorescent protein (GFP) control. Efficacy of GiDREADD inhibition by the designer receptor exclusively activated by designer drug (DREADD) agonist Compound 21 (C21) was verified in PVN slices; C21 reduced evoked action potential discharge by reducing excitability to injected current in GiDREADDexpressing PVN neurons. We evaluated hypoxic ventilatory responses (plethysmography) and PVN and nTS neuronal activation (cFos immunoreactivity) to 2 h hypoxia (10% O2) in conscious GFP and GiDREADD rats after intraperitoneal C21 injection. Generalized PVN inhibition via systemic C21 blunted hypoxic ventilatory responses and reduced PVN and also nTS neuronal activation during hypoxia. To determine if the PVN-nTS pathway contributes to these effects, we evaluated cardiorespiratory responses to hypoxia during selective PVN terminal inhibition in the nTS. Anesthetized GFP and GiDREADD rats exposed to brief hypoxia (10% O2, 45 s) exhibited depressor and tachycardic responses and increased sympathetic and phrenic nerve activity. C21 was then microinjected into the nTS, followed after 60 min by another hypoxic episode. In GiDREADD but not GFP rats, PVN terminal inhibition by nTS C21 strongly attenuated the phrenic amplitude response to hypoxia. Interestingly, C21 augmented tachycardic and sympathetic responses without altering the coupling of splanchnic sympathetic nerve activity to phrenic nerve activity during hypoxia. Data demonstrate that the PVN, including projections to the nTS, is critical in shaping sympathetic and respiratory responses to hypoxia. [ABSTRACT FROM AUTHOR]

Previous studies showed that chlorpyrifos (CPF) acute exposure impaired cardiorespiratory reflexes. Evidence also indicates that continuous exposure to organophosphorus compounds impairs cardiovascular function. However, the effect of intermittent exposure to CPF, as may be experienced in the real world, on tonic and reflex cardiorespiratory function remains unexplored. Wistar rats were injected with saline or CPF for 4 weeks (3 times/week) or 12 weeks (once/week) at the doses of 7 mg/kg and 10 mg/kg. After exposure, blood pressure (BP), heart rate (HR), respiratory rate (fR), tidal volume (VT), and minute volume (VE) were recorded. Systolic BP and pulse interval (PI) variability, HR spectrum, spontaneous baroreflex and chemoreflex function were also evaluated. Plasma butyrylcholinesterase and brainstem acetylcholinesterase activities were quantified. Enzymatic activity of the CPF animals was reduced after both treatment periods. Baseline BP, HR, and fR, as well as systolic BP and PI variability indices, did not change, after CPF treatment. VT and VE were elevated in CPF animals. CPF exposure increased the very low-frequency component of the HR spectrum. Baroreflex gain was reduced after CPF 4-week exposure. Chemoreflex bradycardia was reduced in the CPF-treated rats. These data show that intermittent exposure to CPF impairs cardiorespiratory function in rats. These results may have important clinical implications for workers seasonally exposed to these compounds. [ABSTRACT FROM AUTHOR]

Although Cheyne-Stokes respiration (CSR) is an oscillatory phenomenon, the direct effects of cyclical hyperventilation and apnea on cardiopulmonary hemodynamics have been poorly investigated. The aim of the study was to examine the echocardiographic changes associated with CSR phases in a group of patients with systolic heart failure (HF) and daytime CSR. 14 HF patients (age 70 ± 9 years, LVEF 24 ± 5) underwent a thorough clinical evaluation, 24-h respiratory polygraphy, chemoreflex evaluation by rebreathing technique and neuro-hormonal assessment. Furthermore, they received a simultaneous echocardiographic and respiratory monitoring embedding the respiratory signal in the echocardiographic machine. All patients had daytime CSR (diurnal apnea-hypopnea index, AHI: 18.5, interquartile range: 15.3–39.5 events/h). Systolic pulmonary artery pressure and pulmonary vascular resistances (PVR) increased from hyperventilation to apnea (H 45.3 ± 11.4 vs A 52.4 ± 13.8 mmHg, p = 0.004, and H 3.3 ± 2.5 vs A 5.1 ± 3.2 Wood units, p = 0.0003, respectively), while acceleration time of the pulmonary artery decreased (H 110.1 ± 19.8 vs A 92.0 ± 19.9 ms, p = 0.001). During apnea a reduction of right and left ventricular outflow tract VTI (H 12.8 ± 4.9 versus A 9.9 ± 3.1, p = 0.002 and H 26.9 ± 8.8 versus A 22.8 ± 7.9 mm, p = 0.006, respectively), and a reduction in tricuspid annular plane systolic excursion (H 15.9 ± 4.4 versus A 14.4 ± 4.1 mm, p = 0.005) were also observed. Notably, PVR variation strongly correlated with chemosensitivity to hypercapnia (R = 0.89, p = 0.0004) and plasma norepinephrine level (R = 0.78, p = 0.003). In HF patients with CSR, an increase in pulmonary pressure and pulmonary vascular resistances was observed during apnea. Pulmonary vasoconstriction strongly correlated with chemosensitivity to hypercapnia and indexes of adrenergic activation. • Cheyne-Stokes respiration causes cardiopulmonary hemodynamic oscillations. • During apneas systolic pulmonary artery pressure increases due to vasoconstriction. • Changes in pulmonary vascular resistances correlates with CO 2 chemosensitivity. [ABSTRACT FROM AUTHOR]

• Autonomic reflex responses are critical to ensure survival. • Hypoxia triggers the carotid body mediated sympathoexcitatory peripheral chemoreflex response. • Sympathetic baroreflex activation buffers moment-to-moment changes in arterial blood pressure. • Hypoglycaemia, or glucoprivation, elicits the glucose counter-regulatory response to return blood glucose levels to normal. • The activation of reticular neurons is necessary to initiate each of these reflexes. Autonomic reflex responses are critical in restoring changes to circulatory factors reduced beyond the domain of homeostasis. Intermittent hypoxia triggers repeated activation of chemoreflexes, resulting in baroreflex dysfunction and widespread changes in cellular and neuronal activity regulated by sensory/motor pathways. Hypoglycaemia initiates a rapid neurally-mediated counter-regulatory response. This counter-regulatory response to hypoglycaemia increases plasma adrenaline levels, liver glycogenolysis, and thus blood glucose levels. Context-dependent activation of rostral ventral medullary neurons initiates baroreceptor unloading, peripheral chemoreflex firing and the counter-regulatory response to hypoglycaemia. In this review, we briefly focus on the functional integration between peripheral and medullary pathways comprising the sympathetic baroreflex, chemoreflexes, and the counter-regulatory response to hypoglycaemia. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the dynamics of baroreflex sensitivity (BRS) during laparoscopic colorectal surgery in patients with different chemoreflex sensitivity assessed with breath-holding test. The study included 80 patients (mean age, 68 ± 7 years) who underwent routine laparoscopic colorectal surgery under general/epidural anaesthesia. Patients were retrospectively divided into two groups: with normal (breath-holding duration ≥38 s, group N [n = 42]) or high (breath-holding duration <38 s, group H [n = 38]) chemoreflex sensitivity. BRS was initially evaluated after arterial catheter placement before induction, after induction, after pneumoperitoneum, after extubation, and 6 h and 24 h after extubation. Average BRS was significantly lower in the group with high peripheral chemoreflex sensitivity at all time points. The use of pneumoperitoneum did not significantly influence BRS in either group. After the surgery and 6 h after extubation, no significant changes were observed. After 6 h of the surgery, 11.9% of patients in group N and 57.8% of those in group H (p < 0.05) had severe baroreflex dysfunction (BRS < 3 ms/mmHg). After 24 h, only two patients in group N (vs 13 [34.2%] in group H, p < 0.05) had this dysfunction. Patients with high chemoreflex sensitivity have lower BRS, and it decreases further after anaesthesia induction. The recovery process can take up to 24 h, with an increased risk of perioperative complications in patients with high preoperative chemoreflex sensitivity. The use of pneumoperitoneum does not significantly affect BRS. [ABSTRACT FROM AUTHOR]

Abstract Familial dysautonomia (Riley–Day syndrome, hereditary sensory and autonomic neuropathy type III) is a rare autosomal recessive disease characterized by impaired development of primary sensory and autonomic neurons resulting in a severe neurological phenotype, which includes arterial baroreflex and chemoreflex failure with high frequency of sleep-disordered breathing and sudden death during sleep. Although a rare disease, familial dysautonomia represents a unique template to study the interactions between sleep-disordered breathing and abnormal chemo- and baroreflex function. In patients with familial dysautonomia, ventilatory responses to hypercapnia are reduced, and to hypoxia are almost absent. In response to hypoxia, these patients develop paradoxical hypoventilation, hypotension, bradycardia, and potentially, death. Impaired ventilatory control due to chemoreflex failure acquires special relevance during sleep when conscious control of respiration withdraws. Overall, almost all adult (85%) and pediatric (95%) patients have some degree of sleep-disordered breathing. Obstructive apnea events are more frequent in adults, whereas central apnea events are more severe and frequent in children. The annual incidence rate of sudden death during sleep in patients with familial dysautonomia is 3.4 per 1000 person-year, compared to 0.5–1 per 1000 person-year of sudden unexpected death in epilepsy. This review summarizes recent developments in the understanding of sleep-disordered breathing in patients with familial dysautonomia, the risk factors for sudden death during sleep, and the specific interventions that could prevent it. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) increases basal sympathetic nervous system activity, augments chemoreflex-induced sympathoexcitation, and raises blood pressure. All effects are attenuated by systemic or intracerebroventricular administration of angiotensin II type 1 receptor (AT1R) antagonists. This study aimed to quantify the effects of CIH on AT1R- and AT2R-like immunoreactivity in the rostroventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), central regions that are important components of the extended chemoreflex pathway. Eighteen Sprague-Dawley rats were exposed to intermittent hypoxia (FIO2 = 0.10, 1 min at 4-min intervals) for 10 hr/day for 1, 5, 10, or 21 days. After exposure, rats were deeply anesthetized and transcardially perfused with phosphate buffered saline (PBS) followed by 4% paraformaldehyde in PBS. Brains were removed and sectioned coronally into 50 µm slices. Immunohistochemistry was used to quantify AT1R and AT2R in the RVLM and the PVN. In the RVLM, CIH significantly increased the AT1R-like immunoreactivity, but did not alter AT2R immunoreactivity, thereby augmenting the AT1R:AT2R ratio in this nucleus. In the PVN, CIH had no effect on immunoreactivity of either receptor subtype. The current findings provide mechanistic insight into increased basal sympathetic outflow, enhanced chemoreflex sensitivity, and blood pressure elevation observed in rodents exposed to CIH. [ABSTRACT FROM AUTHOR]

Abstract Electrical stimulation of the carotid baroreflex has been thoroughly investigated for treating drug-resistant hypertension in humans. However, a previous study from our laboratory, performed in conscious rats, has demonstrated that electrical stimulation of the carotid sinus/nerve (CS) activated both the carotid baroreflex as well as the carotid chemoreflex, resulting in hypotension. Additionally, we also demonstrated that the carotid chemoreceptor deactivation potentiated this hypotensive response. Therefore, to further investigate this carotid baroreflex/chemoreflex interaction, besides the hemodynamic responses, we evaluated the respiratory responses to the electrical stimulation of the CS in both intact (CONT) and carotid chemoreceptors deactivated (CHEMO-X) conscious rats. CONT rats showed increased ventilation in response to electrical stimulation of the CS as measured by the respiratory frequency (fR), tidal volume (V T) and minute ventilation (V E), suggesting a carotid chemoreflex activation. The carotid chemoreceptor deactivation abolished all respiratory responses to the electrical stimulation of the CS. Regarding the hemodynamic responses, the electrical stimulation of the CS caused hypotensive responses in CONT rats, which were potentiated by the carotid chemoreceptors deactivation. Heart rate (HR) responses did not differ between groups. In conclusion, the present study showed that the electrical stimulation of the CS, in conscious rats, activates both the carotid baroreflex and the carotid chemoreflex driving an increase in ventilation and a decrease in AP. These findings further contribute to our understanding of the electrical stimulation of CS. [ABSTRACT FROM AUTHOR]

Hypoxia increases heart rate (HR) in humans by sympathetic activation and vagal withdrawal. However, in anaesthetized dogs hypoxia increases vagal activity and reduces HR if pulmonary ventilation does not increase and we evaluated whether that observation applies to awake humans. Ten healthy males were exposed to 15 min of normoxia and hypoxia (10.5% O2), while respiratory rate and tidal volume were volitionally controlled at values identified during spontaneous breathing in hypoxia. End-tidal CO2 tension was clamped at 40 mmHg by CO2 supplementation. β-Adrenergic blockade by intravenous propranolol isolated vagal regulation of HR. During spontaneous breathing, hypoxia increased ventilation by 3.2 ± 2.1 l/min ( P = 0.0033) and HR by 8.9 ± 5.5 beats/min ( P < 0.001). During controlled breathing, respiratory rate (16.3 ± 3.2 vs. 16.4 ± 3.3 breaths/min) and tidal volume (1.05 ± 0.27 vs. 1.06 ± 0.24 l) were similar for normoxia and hypoxia, whereas the HR increase in hypoxia persisted without (8.6 ± 10.2 beats/min) and with (6.6 ± 5.6 beats/min) propranolol. Neither controlled breathing ( P = 0.80), propranolol ( P = 0.64), nor their combination ( P = 0.89) affected the HR increase in hypoxia. Arterial pressure was unaffected ( P = 0.48) by hypoxia across conditions. The hypoxia-induced increase in HR during controlled breathing and β-adrenergic blockade indicates that hypoxia reduces vagal activity in humans even when ventilation does not increase. Vagal withdrawal in hypoxia seems to be governed by the arterial chemoreflex rather than a pulmonary inflation reflex in humans. NEW & NOTEWORTHY Hypoxia accelerates the heart rate of humans by increasing sympathetic activity and reducing vagal activity. Animal studies have indicated that hypoxia-induced vagal withdrawal is governed by a pulmonary inflation reflex that is activated by the increased pulmonary ventilation in hypoxia. The present findings, however, indicate that humans experience vagal withdrawal in hypoxia even if ventilation does not increase, indicating that vagal withdrawal is governed by the arterial chemoreflex rather than a pulmonary inflation reflex. [ABSTRACT FROM AUTHOR]

The paraventricular nucleus of the hypothalamus (PVN) contributes to both autonomic and neuroendocrine function. PVN lesion or inhibition blunts cardiorespiratory responses to peripheral chemoreflex activation, suggesting that the PVN is required for full expression of these effects. However, the role of efferent projections to cardiorespiratory nuclei and the neurotransmitters/neuromodulators that are involved is unclear. The PVN sends dense projections to the nucleus tractus solitarii (nTS), a region that displays neuronal activation following hypoxia. We hypothesized that acute hypoxia activates nTS-projecting PVN neurons. Using a combination of retrograde tracing and immunohistochemistry, we determined whether hypoxia activates PVN neurons that project to the nTS and examined the phenotype of these neurons. Conscious rats underwent 2 h normoxia (21% O2, n = 5) or hypoxia (10% O2, n = 6). Hypoxia significantly increased Fos immunoreactivity in nTS-projecting neurons, primarily in the caudal PVN. The majority of activated nTS-projecting neurons contained corticotropin-releasing hormone (CRH). In the nTS, fibers expressing the CRH receptor corticotropin-releasing factor receptor 2 (CRFR2) were colocalized with oxytocin (OT) fibers and were closely associated with hypoxia-activated nTS neurons. A separate group of animals that received a microinjection of adeno-associated virus type 2-hSyn-green fluorescent protein (GFP) into the PVN exhibited GFP-expressing fibers in the nTS; a proportion of these fibers displayed OT immunoreactivity. Thus, nTS CRFR2s appear to be located on the fibers of PVN OT neurons that project to the nTS. Taken together, our findings suggest that PVN CRH projections to the nTS may modulate nTS neuronal activation, possibly via OTergic mechanisms, and thus contribute to chemoreflex cardiorespiratory responses. [ABSTRACT FROM AUTHOR]