Peripheral Chemoreflex Response Research Articles

Carotid body ablation restores astrocyte/microglia morphology in the NTS and reduces hypertension following long-term intermittent hypoxia

Chronic intermittent hypoxia (CIH) heightened carotid body (CB) chemosensory discharges, which contributes to hypertension development. Previously, we reported that CB ablation significantly reduced blood pressure after 21 days of CIH; however, whether CB-mediated glial cell activation in the caudal Nucleus of the Solitary Tract (cNTS) following long-term CIH contribute to maintain high blood pressure and enhanced ventilatory chemoreflex remains unknown. To test this hypothesis, we exposed male C57BL6 mice to CIH (5% FIO2, 12 times/h, 8 h/day) for 60 days. At 45 days of CIH, CBs were selectively denervated, and animals returned to CIH for 15 more days. At the end of the experimental protocol, we measured arterial blood pressure, hypoxic ventilatory response (HVR) in awake mice and characterized astrocyte and microglia morphological features using Sholl analysis. CIH induces hypertension (MABP: 83.47±1.39 vs. 95.00±2.18 mmHg; Sham vs. CIH), increases the HVR (1.69±0.17 vs. 4.31±0.87 ΔVE/min; Sham vs. CIH), modify cNTS astrocytes phenotype (N° of branches: 13.01±0.66 vs. 11.31±0.52; cable length: 181.00±8.90 vs 148.10±1.48 μm, convex hull: 788.10±37.60 vs. 584.30±23.75 μm3; Sham vs. CIH), and microglia arborization (N° of branches: 196.10±8.35 vs. 376.30±16.80; cable length: 667.4±29.63 vs. 1267±60.47 μm, convex hull: 6177±362 vs. 9721±564 μm3; Sham vs. CIH). Importantly, CB denervation normalized the elevated blood pressure (MABP: 83.47±1.38 mmHg; CIHd), the altered peripheral chemoreflex response (HVR: 1.63±0.43 ΔVE/min; CIHd) and morphological changes in astrocytes (N °of branches: 17.23±0.88, cable length: 231.70±12.87, convex hull: 982.70±55.55 μm3) and microglia located in the cNTS (N° of branches 126.20±13.34; cable length: 126.2±13.3, Convex hull size: 3584±380 μm3; CIHd). Present results suggest that CBs play a crucial role in the maintenance of high arterial pressure and respiratory alterations induced by long-term CIH and may contribute to the formation of a neuroinflammatory niche at the cNTS by modifying glial cell activity. Supported by Fondecyt Grants 1211443 and 1220950. 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.

Paraventricular nucleus projections to the nucleus tractus solitarii are essential for full expression of hypoxia-induced peripheral chemoreflex responses.

The hypothalamic paraventricular nucleus (PVN) is essential to peripheral chemoreflex neurocircuitry, but the specific efferent pathways utilized are not well defined. The PVN sends dense projections to the nucleus tractus solitarii (nTS), which exhibits neuronal activation following a hypoxic challenge. We hypothesized that nTS-projecting PVN (PVN-nTS) neurons contribute to hypoxia-induced nTS neuronal activation and cardiorespiratory responses. To selectively target PVN-nTS neurons, rats underwent bilateral nTS nanoinjection of retrogradely transported adeno-associated virus (AAV) driving Cre recombinase expression. We then nanoinjected into PVN AAVs driving Cre-dependent expression of Gq or Gi designer receptors exclusively activated by designer drugs (DREADDs) to test the degree that selective activation or inhibition, respectively, of the PVN-nTS pathway affects the hypoxic ventilatory response (HVR) of conscious rats. We used immunohistochemistry for Fos and extracellular recordings to examine how DREADD activation influences PVN-nTS neuronal activation by hypoxia. Pathway activation enhanced the HVR at moderate hypoxic intensities and increased PVN and nTS Fos immunoreactivity in normoxia and hypoxia. In contrast, PVN-nTS inhibition reduced both the HVR and PVN and nTS neuronal activation following hypoxia. To further confirm selective pathway effects on central cardiorespiratory output, rats underwent hypoxia before and after bilateral nTS nanoinjections of C21 to activate or inhibit PVN-nTS terminals. PVN terminal activation within the nTS enhanced tachycardic, sympathetic and phrenic (PhrNA) nerve activity responses to hypoxia whereas inhibition attenuated hypoxia-induced increases in nTS neuronal action potential discharge and PhrNA. The results demonstrate the PVN-nTS pathway enhances nTS neuronal activation and is necessary for full cardiorespiratory responses to hypoxia. KEY POINTS: The hypothalamic paraventricular nucleus (PVN) contributes to peripheral chemoreflex cardiorespiratory responses, but specific PVN efferent pathways are not known. The nucleus tractus solitarii (nTS) is the first integration site of the peripheral chemoreflex, and the nTS receives dense projections from the PVN. Selective GqDREADD activation of the PVN-nTS pathway was shown to enhance ventilatory responses to hypoxia and activation (Fos immunoreactivity (IR)) of nTS neurons in conscious rats, augmenting the sympathetic and phrenic nerve activity (SSNA and PhrNA) responses to hypoxia in anaesthetized rats. Selective GiDREADD inhibition of PVN-nTS neurons attenuates ventilatory responses, nTS neuronal Fos-IR, action potential discharge and PhrNA responses to hypoxia. These results demonstrate that a projection from the PVN to the nTS is critical for full chemoreflex responses to hypoxia.

Effect of Central Chemoreceptors on the Peripheral Chemoreflex Response to Hypoxia

In the absence of central chemoreceptor input, the slope of the hypoxic ventilatory response (HVR) to progressive oxyhemoglobin desaturation (L·min-1·mmHg-1·%SaO2-1) – a measure of peripheral chemoreflex sensitivity – increases linearly with carbon dioxide tension (PCO2). We assessed whether this relationship remains linear with increasing central PCO2 in humans. Over four days, 20 participants (10 females; mean±SD age: 24±4 years) completed three repetitions of modified rebreathing with end-tidal PO2 (PETO2) clamped at 150, 70, 60, and 45 mmHg. End-tidal PCO2 (PETCO2), PETO2, ventilation (V̇E), and SaO2 were measured breath-by-breath by dual gas analyser, pneumotach, and pulse oximetry. The V̇E vs PETCO2 relationship in the hyperoxic test gave the central chemoreflex response to PCO2 and the hypoxic tests provided a combined central-peripheral chemoreflex response. The V̇E vs PETCO2 relationship of repeated trials were linear-interpolated, combined, averaged into 1 mmHg bins, and fit with a linear function (V̇ES, L·min-1·mmHg-1) to provide hyperoxic and hypoxic profiles. HVR was computed at 1 mmHg intervals of PETCO2 as follows: the difference in V̇E between the three hypoxic profiles and the hyperoxic profile (ΔV̇E) was calculated; these three ΔV̇E values were plotted against their corresponding SaO2; and linear regression determined HVR (L·min-1·mmHg-1·%SaO2-1). Steps were repeated at each PETCO2 to produce the HVR vs PCO2 relationship. Each participant’s HVR vs PETCO2 relationship was fit with a linear and polynomial function and Akaike Information Criterion identified the best-fit model. One-way repeated measures analysis of variance assessed between-condition differences. V̇ES rose (p<0.001) with isoxic PO2 from 3.7±1.5 L·min-1·mmHg-1 at 150 mmHg to 4.4±1.8, 5.0±1.6, and 6.0±2.2 L·min-1·mmHg-1 at 70, 60, and 45 mmHg, respectively. Mean SaO2 fell progressively (99.3%, 93.7%, 90.4%, and 80.5% for 150, 70, 60, and 45 mmHg, respectively; p<0.001). In all individuals, HVR increased with PETCO2 and this relationship was best described by a linear model in 75% of participants. In most participants, the peripheral chemoreflex-mediated HVR maintained a linear relationship with PETCO2 despite increasing central chemoreflex activation. Data suggest that central chemoreceptors did not alter the peripheral chemoreflex response to low O2. Natural Sciences and Engineering Research Council of Canada 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.

Medullary and Hypothalamic Functional Magnetic Imaging During Acute Hypoxia in Tracing Human Peripheral Chemoreflex Responses

[Figure: see text].

Acute effects of increased gut microbial fermentation on the hypoxic ventilatory response in humans

What is the central question of this study? Is there a link between gut microbial fermentation and ventilatory responsiveness to hypoxia in humans? What is the main finding and its importance? Increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to transient hypoxia. These findings imply a capacity for gut microbiota to modulate the peripheral chemoreflex response to hypoxia in humans. Recent animal data indicate the presence of a bidirectional link between gut microbial activity and respiratory control. Nevertheless, the presence of a similar association between gut microbiota and peripheral chemoreceptor responsiveness to hypoxia in humans has not been reported to date. Therefore, we performed a within subject, placebo-controlled study in a group of 16 healthy individuals (eight men; mean±SD age 25.9±5.2years). Participants underwent two tests (in a random order), receiving lactulose, which stimulates gut fermentation, or placebo. Ventilatory and haemodynamic responses to transient hypoxia were evaluated before and 2h after the test meal. The magnitude of these responses was related to the net hydrogen content in the exhaled air, reflecting gut fermentation intensity. A lactulose meal, compared to placebo, caused an increase in the minute ventilation (Hyp-VI; l/min/ ) and breathing rate (Hyp-BR; breaths/min/ ) responses to hypoxia (for Hyp-VI, mean±SD -0.03±0.059 in placebo test vs. 0.05±0.116 in lactulose test, P=0.03; for Hyp-BR, -0.015±0.046 vs. 0.034±0.054, P=0.01). The magnitude of these responses was positively correlated with the lactulose-induced hydrogen excretion (for Hyp-VI, r=0.62, P=0.01; for Hyp-BR, r=0.73, P=0.001). Changes in the resting parameters during normoxia did not differ significantly between the tests. Our results demonstrate that the increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to the transient hypoxia, which implies a capacity for gut microbiota to modulate the peripheral chemoreflex in humans.

Acetylcholinesterase inhibition prevents alterations in cardiovascular autonomic control and gastric motility in L-NAME-induced hypertensive rats

AimsAutonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. Materials and methodsDaily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6–12 animals per group; total number of animals used: 78). Key findingsL-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SignificanceAcetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.

Comparative Assessment of Central and Peripheral Chemoreceptor Reflex Regulation of Muscle Sympathetic Nerve Activity and Ventilation

We tested the hypothesis that central and peripheral chemoreceptor‐mediated sympathetic activation elicited by increases in CO2 tension (PCO2) mirror concurrent ventilatory responses. Twelve healthy young men (mean±SD; age: 24±4 yr; BMI: 24.5±1.3 kg·m−2) performed a modified rebreathing protocol designed to equilibrate central and peripheral chemoreceptor PCO2 tensions with end‐tidal PCO2 (PETCO2) at two isoxic end‐tidal PO2 (PETO2) tensions such that central chemoreceptor reflex responses (hyperoxia) can be isolated from additive peripheral responses (i.e., hypoxia minus hyperoxia). Subject's ventilation (volume turbine) and muscle sympathetic nerve activity (MSNA; microneurography, right fibular nerve) responses to rebreathing at isoxic PETO2 tensions of 150 mmHg (hyperoxia) and 50 mmHg (hypoxia) were recorded continuously. During rebreathing, the PETCO2 (mmHg) at which ventilation (L·min−1) and total MSNA (au) began to rise were identified as the PETCO2 recruitment thresholds (RT). Slopes of these responses above RT also were determined. In hyperoxic rebreathing (i.e., the central chemoreflex response), the mean RT for ventilation (46±3 mmHg) and MSNA (45±4 mmHg) did not differ (p>0.05). Mean slopes were 2.3±0.9 L·min−1·mmHg−1 and 2.1±1.5 au·mmHg−1, respectively. In hypoxic rebreathing (i.e., the summed central and peripheral chemoreflex response), the RT for both ventilation and MSNA were not different (41±3 mmHg vs 41±3 mmHg, p>0.05) but were lower (p<0.05) compared to hyperoxia. Mean slopes for ventilation (4.0±1.8 L·min−1·mmHg−1) and MSNA (5.1±3.4 au·mmHg−1) in hypoxia were greater than in hyperoxia yielding a mean peripheral chemoreflex sensitivity (hypoxic slope minus hyperoxic slope) of 1.7±0.1 L·min−1·mmHg−1 for ventilation and 3.0±2.6 au·mmHg−1 for MSNA. The 95% limits of agreement of RT between ventilation and MSNA for the central chemoreflex were −7 to 6 mmHg (bias=−1 mmHg, p>0.05) and −5 to 5 mmHg (bias=0 mmHg, p>0.05) for the peripheral chemoreflex. There was no relationship (p>0.05) between the ventilatory and MSNA sensitivity for either the central (r2=0.16) or peripheral (r2=0.01) chemoreceptor reflexes. These data highlight two novel findings: 1) ventilatory and sympathetic arms of the central and peripheral chemoreceptor reflexes are initiated at similar PETCO2 recruitment thresholds and 2) sympathetic responsiveness cannot be predicted from the sensitivities of the ventilatory central and peripheral chemoreceptor reflexes.Support or Funding InformationExperiments were funded by a Project Grant from the Canadian Institutes of Health Research (PJT 159491). Dr. Floras holds the Canada Research Chair in Integrative Cardiovascular Biology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pre- and post-inspiratory neurons change their firing properties in female rats exposed to chronic intermittent hypoxia

Obstructive sleep apnea patients face episodes of chronic intermittent hypoxia (CIH), which has been suggested as a causative factor for increased sympathetic activity (SNA) and hypertension. Female rats exposed to CIH develop hypertension and exhibit changes in respiratory–sympathetic coupling, marked by an increase in the inspiratory modulation of SNA. We tested the hypothesis that enhanced inspiratory-modulation of SNA is dependent on carotid bodies (CBs) and are associated with changes in respiratory network activity. For this, in CIH-female rats we evaluated the effect of CBs ablation on respiratory–sympathetic coupling, recorded from respiratory neurons in the working heart–brainstem preparation and from NTS neurons in brainstem slices. CIH-female rats had an increase in peripheral chemoreflex response and in spontaneous excitatory neurotransmission in NTS. CBs ablation prevents the increase in inspiratory modulation of SNA in CIH-female rats. Pre-inspiratory/inspiratory (Pre-I/I) neurons of CIH-female rats have a reduced firing frequency. Post-inspiratory neurons are active for a longer period during expiration in CIH-female rats. Further, using the computational model of a brainstem respiratory–sympathetic network, we demonstrate that a reduction in Pre-I/I neuron firing frequency simulates the enhanced inspiratory SNA modulation in CIH-female rats. We conclude that changes in respiratory–sympathetic coupling in CIH-female rats is dependent on CBs and it is associated with changes in firing properties of specific respiratory neurons types.

Blunted Respiratory Responses intheStreptozotocin-Induced Alzheimer's Disease Rat Model.

Alzheimer's disease (AD) is known for the progressive decline of cognition and memory. In addition to these disease-defining symptoms, impairment of respiratory function is frequently observed and often expressed by sleep-disordered breathing or reduced ability to adjust respiration when oxygen demand is elevated. The mechanisms for this are widely unknown. Postmortem analysis from the brainstem of AD patients reveals pathological alterations, including in nuclei responsible for respiratory control. In this study, we analyzed respiratory responses and morphological changes in brainstem nuclei following intracerebroventricular (ICV) injections of streptozotocin (STZ), a rat model commonly used to mimic sporadic AD. ICV-STZ induced significant astrogliosis in the commissural part of the nucleus tractus solitarii, an area highly involved in respiration control. The astrogliosis was identified by a significant increase in S100B-immunofluorescence that is similar to the astrogliosis found in the CA1 region of the hippocampus. Using plethysmography, the control group displayed a typical age-dependent decrease of ventilation that was absent in the STZ rat group. This is indicative of elevated minute ventilation at rest after STZ treatment. Peripheral chemoreflex responses were significantly blunted in STZ rats as seen by a reduced respiratory rate and minute ventilation to hypoxia. Central chemoreflex responses to hypercapnia, on the other hand, only decreased in respiratory rate following STZ treatment. Overall, our results show that ICV-STZ induces respiratory dysfunction at rest and in response to hypoxia. This provides a new tool to study the underlying mechanisms of breathing disorders in clinical AD.

Labouring on decelerations: the fetal peripheral chemoreflex wins.

Recordings of fetal heart rate provide the clinician with the only non‐invasive tool to continuously monitor fetal wellbeing during labour. By far, the most debated component of fetal heart rate monitoring during labour is the significance of fetal heart rate decelerations, which almost invariably occur in association with uterine contractions. Over the years, proposed possible triggers for these reductions in fetal heart rate have included fetal head compression, baroreflexes, chemoreflexes, Bezold–Jarisch reflexes and/or myocardial depression. In this issue of The Journal of Physiology, Lear et al. (2016) propose that a unified understanding of the physiology underlying intrapartum fetal heart decelerations is critical to improve their interpretation. The review reminds us that normal labour is associated with intermittent interruptions of uteroplacental gas exchange, such that ‘technically’ all babies experience some sort of asphyxia to a certain extent during labour. Although intrapartum fetal asphyxia is a term that is often avoided clinically, as it conjures thoughts of injury, it is a biochemical reality and it is useful for clinicians to understand the parameters underlying it. Reviewing and evaluating the available literature, Lear and colleagues suggest that, on balance, typical intrapartum decelerations are most likely the result of transient episodes of fetal hypoxia or fetal asphyxia and the consequent activation of the fetal peripheral chemoreflex response.

5‐HT 1A Receptors in the Caudal Nucleus Tractus Solitarii Mediate Arousal to Hypoxic Hypercapnia in Male Rats

Serotonin (5-HT) neurons of the caudal raphe, 5-HT1A receptors of the caudal nucleus tractus solitarii (cNTS), and sinoaortic afferents contribute to sympathoexcitatory compensation from hemorrhage in unanesthetized rats. Here, we examined the role of the peripheral chemoreflex in 5-HT-dependent compensation, by testing whether acidosis similar to that seen in hemorrhage was sufficient to activate 5-HT neurons of the caudal raphe, and whether 5-HT1A receptors in the cNTS contributed to peripheral chemoreflex responses during acidosis. Hypoxic hypercapnia (10% O2/5% CO2), but not hypercapnia alone, increased c-Fos expression in 5-HT neurons of the caudal raphe (P<0.01). Short hairpin RNA-mediated knockdown of 5-HT1A receptors in the cNTS (n=13) did not produce consistent effects on ventilation during hypoxic hypercapnia compared to rats treated with a scrambled shRNA (n=15). Instead, 5-HT1A knockdown attenuated intermittent bouts of high frequency ventilation (sniffing) normally expressed during exposure to hypoxic hypercapnia (4.9 ± 1.1 vs 11.2 ± 2.4% of a 45 minute exposure, P< 0.05). Accordingly, cumulative breaths during gas exposure was reduced by 5-HT1A knockdown in the cNTS (2173 ± 520 vs 3887± 1312 breaths/45 min, log transformed P<0.001). The data support the hypothesis that peripheral chemoreflex activation augments the ability of a central chemoreflex stimulus to activate 5-HT neurons of the caudal raphe. In turn, activation of 5-HT1A receptors in the cNTS contributes to arousal as indicated by sniffing. Thus, we conclude that 5-HT1A receptors in the cNTS serve to promote arousal when both peripheral and central chemoreceptors are activated simultaneously, and may thereby promote sympathoexcitation during blood loss.

S118 The ventilatory response to CO2 within obstructive sleep apnea patients

IntroductionObstructive Sleep Apnea (OSA) is a condition defined by the collapse of the upper airway and cessation of respiration during sleep. The resulting hypoventilation leads to intermittent nocturnal hypoxia and...

Clinical Predictors and Hemodynamic Consequences of Elevated Peripheral Chemosensitivity in Optimally Treated Men With Chronic Systolic Heart Failure

AimsAugmented peripheral chemoreflex response is an important mechanism in the pathophysiology of chronic heart failure (CHF). This study characterizes prevalence and clinical predictors of this phenomenon in optimally managed male CHF patients, and seeks to describe the hemodynamic consequences of chemoreceptor hypersensitivity. Methods and ResultsThirty-four optimally managed CHF patients and 16 control subjects were prospectively studied. Hypoxic ventilatory response (HVR)—a measure of peripheral chemosensitivity—was calculated with the use of short nitrogen gas administrations. Systolic blood pressure (SBP) and heart rate (HR) following transient hypoxic challenges were recorded with a Nexfin monitor. Hemodynamic responses to hypoxia were expressed by the linear slopes between oxygen saturation (%) and SBP (mm Hg) or HR (beats/min). Elevated HVR was present in 15 (44%) of the CHF patients. Patients with elevated HVR exhibited higher levels of N-terminal pro–B-type natriuretic peptide, lower left ventricular ejection fraction, and higher prevalence of atrial fibrillation. CHF patients with elevated HVR had significantly greater SBP and HR responses to hypoxia than CHF patients with normal HVR. ConclusionsDespite comprehensive pharmacotherapy, elevated HVR is prevalent in CHF patients, related to severity of the disease and associated with augmented hemodynamic responses to hypoxia. CHF patients with elevated HVR may be prone to unfavorable hemodynamic changes.

Obstructive sleep apnea is associated with increased chemoreflex sensitivity in patients with metabolic syndrome.

Obstructive sleep apnea (OSA) is often observed in patients with metabolic syndrome (MetS). In addition, the association of MetS and OSA substantially increases sympathetic nerve activity. However, the mechanisms involved in sympathetic hyperactivation in patients with MetS + OSA remain to be clarified. We tested the hypothesis that chemoreflex sensitivity is heightened in patients with MetS and OSA. Prospective clinical study. Forty-six patients in whom MetS was newly diagnosed (ATP-III) were allocated into: (1) MetS + OSA (n = 24, 48 ± 1.8 yr); and (2) MetS - OSA (n = 22, 44 ± 1.7 yr). Eleven normal control subjects were also studied (C, 47 ± 2.3 yr). OSA was defined as an apnea-hypopnea index ≥ 15 events/hr (polysomnography). Muscle sympathetic nerve activity (MSNA) was measured by microneurography technique. Peripheral chemoreflex sensitivity was assessed by inhalation of 10% oxygen and 90% nitrogen (carbon dioxide titrated), and central chemoreflex sensitivity by 7% carbon dioxide and 93% oxygen. Physical characteristics and MetS measures were similar between MetS + OSA and MetS - OSA. MSNA was higher in MetS + OSA patients compared with MetS - OSA and C (33 ± 1.3 versus 28 ± 1.2 and 18 ± 2.2 bursts/min, P < 0.05). Isocapnic hypoxia caused a greater increase in MSNA in MetS + OSA than MetS - OSA and C (P = 0.03). MSNA in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.005). Further analysis showed a significant association between baseline MSNA and peripheral (P < 0.01) and central (P < 0.01) chemoreflex sensitivity. Min ventilation in response to hyperoxic hypercapnia was greater in MetS + OSA compared with C (P = 0.001). OSA increases sympathetic peripheral and central chemoreflex response in patients with MetS, which seems to explain, at least in part, the increase in sympathetic nerve activity in these patients. In addition, OSA increases ventilatory central chemoreflex response in patients with MetS.

Contribution of the retrotrapezoid nucleus/parafacial respiratory region to the expiratory-sympathetic coupling in response to peripheral chemoreflex in rats

Central mechanisms of coupling between respiratory and sympathetic systems are essential for the entrainment between the enhanced respiratory drive and sympathoexcitation in response to hypoxia. However, the brainstem nuclei and neuronal network involved in these respiratory-sympathetic interactions remain unclear. Here, we evaluated whether the increase in expiratory activity and expiratory-modulated sympathoexcitation produced by the peripheral chemoreflex activation involves the retrotrapezoid nucleus/parafacial respiratory region (RTN/pFRG). Using decerebrated arterially perfused in situ rat preparations (60-80 g), we recorded the activities of thoracic sympathetic (tSN), phrenic (PN), and abdominal nerves (AbN) as well as the extracellular activity of RTN/pFRG expiratory neurons, and reflex responses to chemoreflex activation were evaluated before and after inactivation of the RTN/pFRG region with muscimol (1 mM). In the RTN/pFRG, we identified late-expiratory (late-E) neurons (n = 5) that were silent at resting but fired coincidently with the emergence of late-E bursts in AbN after peripheral chemoreceptor activation. Bilateral muscimol microinjections into the RTN/pFRG region (n = 6) significantly reduced basal PN frequency, mean AbN activity, and the amplitude of respiratory modulation of tSN (P < 0.05). With respect to peripheral chemoreflex responses, muscimol microinjections in the RTN/pFRG enhanced the PN inspiratory response, abolished the evoked late-E activity of AbN, but did not alter either the magnitude or pattern of the tSN reflex response. These findings indicate that the RTN/pFRG region is critically involved in the processing of the active expiratory response but not of the expiratory-modulated sympathetic response to peripheral chemoreflex activation of rat in situ preparations.

Activation of 5HT1A receptors in the nucleus tractus solitarius contributes to blood pressure compensation with blood loss and peripheral chemoreflex responses in the presence of acidosis

Caudal serotonin neurons and the 5‐HT1A receptor ( 1AR) agonist, 8‐OH‐DPAT, promote sympathetic‐mediated increases in cardiac output after blood loss. We hypothesize that the metabolic acidosis of hemorrhage activates serotonin neurons and 1AR in the nucleus tractus solitarius (NTS) to facilitate chemoreflex responses to carotid body hypoxia. Here, we tested ventilatory responses to hypoxic hypercapnia (10% O2, 5% CO2) and blood pressure responses to hemorrhage and subsequent 8‐OH‐DPAT administration in rats subjected to bilateral knockdown of the 1AR in the NTS. An adeno‐associated viral vector harboring a short hairpin RNA targeting the rat 1AR (1ARshRNA) or a scrambled shRNA (Scram) was injected into the caudal NTS of male Sprague Dawley rats. After 4 weeks, rats injected with the 1AshRNA (n=12) had lower cumulative minute ventilation during hypoxic hypercapnia vs. Scram‐injected rats (n=13, P&lt;0.01). Rats injected with 1AshRNA (n=8) had a more rapid fall in blood pressure with blood loss and an attenuated blood pressure response to 8‐OH‐DPAT injection (30 nmol/kg, iv, P&lt;0.01) vs. Scram‐injected rats (n=9). 1AshRNA injection decreased 1AR protein in the caudal NTS (−35%, P&lt;0.05). Thus, the beneficial hemodynamic effect of 8‐OH‐DPAT and endogenous serotonin in hemorrhage is related to activation of 1AR in the NTS and possibly to facilitation of chemoreflex responses to hypoxia. Funded by AHA 10PRE4000023.

Cardiovascular deconditioning augments baseline breathing as well as peripheral and central chemoreflex responses

Cardiovascular deconditioning (CVD) results in altered central autonomic regulation including baroreflex dysfunction. However, little is known regarding the effects of CVD on chemoreflex function. We hypothesized that CVD increases baseline breathing and peripheral (hypoxic ventilatory response, HVR) and central chemoreflex responses (hypercapnic ventilatory response, HCVR). Hindlimb unloaded (HU; 2 wks) rats were used to simulate CVD. Breathing and O2 saturation were evaluated (5 min) during normoxia, increasing severity of hypoxia (12%O2, 10%O2, 8%O2), and hypercapnia (5%CO2) to determine HVR and HCVR. Under normoxic conditions, O2 saturation and breathing rate were similar while tidal volume index (VT) was increased in HU vs. control rats. Increasing the intensity of hypoxia produced a progressive decrease in O2 saturation that was greater in HU vs. control rats. Hypoxia produced an intensity dependent augmentation of breathing rate, VT and minute ventilation (VE) in both groups. Increases in breathing rate during hypoxia were similar between groups. However, the VT response was augmented in HU rats. Hypercapnia also increased VE in both groups and VE was greater in HU vs. control rats due to increased VT. Preliminary data suggest that CVD due to HU increases VT under basal conditions. Furthermore, HU enhances the peripheral chemoreflex HVR and central chemoreflex HCVR due to increased VT. HL55306

Hydrogen sulfide contributes to the enhanced chemoreflex ventilatory response to acute hypoxia in heart failure rats

Increased sympathetic outflow is a major contributor to the progression of heart failure (HF). Potentiation of the peripheral chemoreflex has been related to the activation of the sympathetic nervous system in HF patients and in animal models. The carotid body (CB) plays a pivotal role in the increased peripheral chemosensitivity in HF animals. Hydrogen sulfide (H2S) has been proposed to be a key mediator in the hypoxic response of CB chemoreceptors. We hypothesized that H2S contributes to the potentiation of the peripheral chemoreflex response to hypoxia in HF rats. Using the irreversible inhibitor DL‐Propargylglycine (PAG), we tested the effects of inhibition of H2S production on the hypoxic (HVR) and hypercapnic ventilatory responses (HCVR) in HF rats. Experiments were performed on male Sprague‐Dawley rats (200 g) with coronary artery ligation‐induced HF. Ventilatory responses to acute hypoxic (FiO2 = 10%) or hypercapnic (FiCO2 = 7%) stimulation were obtained in unrestrained, freely‐moving rats using whole body plethysmography. HF rats exhibited increased HVR and HCVR compared to control rats. PAG treatment (100 mg/kg IP) reduced the increase in HVR in HF rats (p &lt; .05). However, PAG treatment potentiated the HCVR in HF rats (p &lt; .05). Our results indicate that H2S contributes to the enhanced HVR in HF rats. Moreover, H2S formation also impacts the HCVR suggesting a novel role of H2S on CO2 chemoreception in HF rats.

Hypercapnia attenuates inspiratory amplitude and expiratory time responsiveness to hypoxia in vagotomized and vagal-intact rats

A negative influence of central chemosensitivity on peripheral chemoreflex response has been demonstrated recently in a decerebrate-vagotomized rat preparation in situ with separate carotid body and brainstem perfusions. Here, we report similar negative influences of hypercapnia on the hypoxic respiratory response in anesthetized, spontaneously breathing rats before and after vagotomy and anesthetized, artificially ventilated rats after vagotomy. Baseline breathing patterns and responsiveness to hypercapnia and hypoxia varied widely between the three respiratory modes. Despite this, the responses in inspiratory amplitude and expiratory duration (and hence respiratory frequency and neural ventilation) to hypoxia varied inversely with the background CO2 level in all three groups. Results demonstrate a hypoadditive hypercapnic-hypoxic interaction in vivo that resembles the hypoadditive central-peripheral chemoreceptor interaction in situ for these respiratory variables in the rat, regardless of differences in vagal feedback, body temperature and ventilation method. These observations stand in contrast to previous reports of hyperadditive peripheral-central chemoreceptor interaction.

Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation

Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ∼21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.