Central Chemosensitivity Research Articles

Medication-induced central sleep apnea: a unifying concept.

Medication-induced central sleep apnea (CSA) is one of the eight categories of causes of CSA but in the absence of awareness and careful history may be misclassified as primary CSA. While opioids are a well-known cause of respiratory depression and CSA, non-opioid medications including sodium oxybate, baclofen, valproic acid, gabapentin, and ticagrelor are less well-recognized. Opioids-induced respiratory depression and CSA are mediated primarily by µ-opioid receptors, which are abundant in the pontomedullary centers involved in breathing. The non-opioid medications, sodium oxybate, baclofen, valproic acid, and gabapentin, act upon brainstem gamma-aminobutyric acid (GABA) receptors, which co-colonize with µ-opioid receptors and mediate CSA. The pattern of ataxic breathing associated with these medications is like that induced by opioids on polysomnogram. Finally, ticagrelor also causes periodic breathing and CSA by increasing central chemosensitivity and ventilatory response to carbon dioxide. Given the potential consequences of CSA and the association between some of these medications with mortality, it is critical to recognize these adverse drug reactions, particularly because discontinuation of the offending agents has been shown to eliminate CSA.

Loop gain response to increased cerebral blood flow at high altitude.

To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). "Controller-gain" sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep. Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2-5 μg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR). A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P < 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1). Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR "controller gain," rather than "plant gain," because PaCO2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change.

Obstructive sleep apnea in children with Down syndrome: contribution of upper airway and chemosensitivity.

The high prevalence of obstructive sleep apnea syndrome (OSAS) in children with Down syndrome (DS) has been attributed to a reduced upper airway size, while the role of ventilatory control is unclear. The objectives of our case-control study were to evaluate the upper airway reduction in children with DS and moderate to severe OSAS as compared to typically developing (TD) children with similar OSAS severity and to evaluate the degree of chemical loop gain modifications including its components: controller and plant gains (CG, PG). Thirteen children with DS were matched for age, sex, OSAS severity and ethnicity with 26 TD children. They had undergone acoustic rhinometry and pharyngometry, chemical LG obtained during awake tidal breathing measurement and hypercapnic-hyperoxic ventilatory response testing. As compared to TD, children with DS depicted reduced oropharyngeal dimensions, significantly lower CG and LG and no different PG. Their hypercapnic ventilatory response slopes were not different. We concluded that the decreased CG in DS was related to decreased peripheral chemoreceptor sensitivity, and while central chemosensitivity was normal, the former explained the increased end-tidal PCO2 observed in children with DS as compared to TD. Pharyngeal dimensions are reduced in children with DS and OSAS. Reduced upper airway size and nocturnal alveolar hypoventilation in children with Down syndrome (DS) have been previously reported. We confirmed that children with DS and moderate-to-severe OSA have reduced oropharyngeal size as compared to typically developing children with similar OSAS severity and demonstrated decreased peripheral chemosensitivity explaining the alveolar hypoventilation observed in children with DS. Central chemosensitivity appears to be intact in children with DS and moderate to severe OSAS Our results support growing evidence that Down syndrome is associated with autonomic nervous system dysfunction.

Central CO2 chemosensitivity and CO2 controller gain independently contribute to daytime PCO2 in young subjects with congenital central hypoventilation syndrome.

Whether peripheral chemoreceptor response is altered in congenital central hypoventilation syndrome (CCHS) remains debated. Our aim was to prospectively evaluate both peripheral and central CO2 chemosensitivity and to evaluate their correlations with daytime PCO2 and arterial desaturation during exercise in CCHS. To this end, tidal breathing was recorded in CCHS patients allowing the calculation of loop gain and its components (steady-state controller [assumed to mainly be peripheral chemosensitivity] and plant gains using a bivariate [PETCO2 and ventilation] constrained model), a hyperoxic, hypercapnic ventilatory response test (central chemosensitivity), and a six-minute walk test (arterial desaturation). The results of loop gain were compared to those previously obtained in a healthy group of similar age. The study prospectively included 23 subjects with CCHS, without daytime ventilatory support; the subjects had a median age of 10 (5.6 to 27.4) years (15 females) with moderate polyalanine repeat mutation (PARM: 20/25, 20/26, n=11), severe PARM (20/27, 20/33, n=8), or non-PARM (n=4). As compared to 23 healthy subjects (4.9 to 27.0 years), the subjects with CCHS had a decreased controller gain and an increased plant gain. Mean daytime PETCO2 level of subjects with CCHS correlated negatively to both Log(controller gain) and the slope of CO2 response. Genotype was not related to chemosensitivity. Arterial desaturation on exercise correlated negatively with Log(controller) gain but not with the slope of the CO2 response. In conclusion, we demonstrate that peripheral CO2 chemosensitivity is altered in some patients with CCHS and that the daytime PETCO2 depends on central and peripheral chemoreceptor responses.

Effect of Facemask in Congenital Central Hypoventilation Syndrome

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder with a mutation in the PHOX2B gene. Patients need ventilatory support by noninvasive ventilation or tracheostomy to treat alveolar hypoventilation. Patients with CCHS have a defect in chemosensitivity signal integration. Recently, due to the COVID-19 pandemic, the entire world has had to get used to wearing medical masks (MM). Objectives: The aim of the study was to evaluate the effect of an MM on gas exchange and to determine the role of central and peripheral chemoresponsiveness on the partial pressure of transcutaneous carbon dioxide (PtcCO₂) in patients with CCHS wearing an MM. Methods: This study was based on the analysis of recordings obtained without and with an MM during hospitalization and was conducted to assess the impact of MM on PtcCO₂ and SpO₂ recordings with the SenTec Digital Monitor and their relationships with peripheral CO₂ chemosensitivity obtained during tidal breathing measurement and with the hypercapnic hyperoxic ventilatory response. Results: Sixteen patients were included (13 boys) and were 10.2 (7.5; 18.5) years old. The use of an MM had a negative impact on gas exchange in patients with CCHS. The median PtcCO₂ increased significantly. Peripheral chemosensitivity correlated with MM-induced PtcCO₂ changes (R = −0.72, p = 0.005), but central chemosensitivity (the hypercapnic ventilator response slope) did not (R = −0.22, p = 0.510). Conclusion: The use of an MM had a negative impact on gas exchange in patients with CCHS.

CO2 exposure enhances Fos expression in hypothalamic neurons in rats during the light and dark phases of the diurnal cycle.

Orexinergic (OX) neurons in the lateral hypothalamus (LH), perifornical area (PFA) and dorsomedial hypothalamus (DMH) play a role in the hypercapnic ventilatory response, presumably through direct inputs to central pattern generator sites and/or through interactions with other chemosensitive regions. OX neurons can produce and release orexins, excitatory neuropeptides involved in many functions, including physiological responses to changes in CO2/pH. Thus, in the present study, we tested the hypothesis that different nuclei (LH, PFA and DMH) where the orexinergic neurons are located, show distinct activation by CO2 during the light-dark cycle phases. For this purpose, we evaluated the Fos and OXA expression by immunohistochemistry to identify neurons that co-localize Fos + OXA in the LH, LPeF, MPeF and DMH in the light-inactive and dark-active phase in Wistar rats subjected to 3h of normocapnia or hypercapnia (7% CO2). Quantitative analyses of immunoreactive neurons show that hypercapnia caused an increase in the number of neurons expressing Fos in the LH, LPeF, MPeF and DMH in the light and dark phases. In addition, the number of Fos + OXA neurons increased in the LPeF and DMH independently of the phases of the diurnal cycle; whereas in the MPeF, this increase was observed exclusively in the light phase. Thus, we suggest that OX neurons are selectively activated by hypercapnia throughout the diurnal cycle, reinforcing the differential role of nuclei in the hypothalamus during central chemosensitivity.

CENTRAL SLEEP APNEA AND CHEYNE STOKES BREATHING IN A PATIENT WITH ACROMEGALY

TYPE: Case Report TOPIC: Sleep Disorders INTRODUCTION: Acromegaly is a rare disease with an overproduction of growth hormone (GH) and insulin which cause an abnormal growth of soft tissues and bony structures leading to different complications including sleep disordered breathing SBD. Obstructive sleep apnea (OSA) is the most common SDB but central sleep apnea have been described in acromegaly. CSA-CSB is frequent in heart failure and stroke but hasn’t been described in acromegaly. CASE PRESENTATION: A 63-year-old male patient with acromegaly and pituitary adenoma post resection with residual disease was complaining of daytime sleepiness and fragmented sleep. Polysomnography showed CSA-CSB as indicated in the table. MRI brain was negative for stroke. Echo showed normal size and function in both left and right ventricle with ejection fraction (EF) = > 55%. Doppler findings do not suggest pulmonary hypertension. Patient does not use hypnotic and opioid medication. DISCUSSION: In this case report, we present a rare presentation of rare disease which is CSA-CSB in patient with acromegaly. To the best of our knowledge, this the first report of such complication. OSA is more common than CSA in acromegaly. Positive correlation between CSA and high level of GH has been demonstrated in some studies. It increases the central chemosensitivity to hypercapnia. This exaggerate respiratory drive to hypercapnia and causing periodic CSA. CONCLUSIONS: Although obstructive sleep apnea is the most common type of SDB but we need to consider that some patients may present and diagnosed with CSA-CSB that require different treatment. DISCLOSURE: Nothing to declare. KEYWORD: Sleep disordered breathing, Acromegaly, Cheyne Stokes breathing, Obstructive apnea, Central apnea.

The Elevated Central Chemosensitivity in Obstructive Sleep Apnea Patients with Hypertension.

PurposeHypertension is a common comorbidity in obstructive sleep apnea (OSA), in which dysfunction of the autonomic nervous system plays an integral part. Chemoreflex is essential for ventilatory control and cardiovascular activity. This study aimed to determine whether central chemosensitivity was increased in OSA patients with hypertension and the potential role of the autonomic nerve activity in this relationship.Patients and MethodsA total of 77 men with OSA were included in this cross-sectional study. We measured hypercapnic ventilatory response (HCVR) by the rebreathing method under isoxic hyperoxia to test the central ventilatory chemosensitivity since hyperoxia silences the peripheral chemoreceptors’ response to CO2. To elevate the autonomic nerve activity, time-domain, frequency-domain, and non-linear variables of heart rate variability were calculated over 5-min records. Univariate and multivariate linear regression analyses were used to find the determinants of HCVR.ResultsThe median HCVR was 2.3 (1.8, 3.3), 2.1 (1.6, 3.0), and 3 (2.2, 3.7) L/min/mmHg in all participants, OSA patients, and OSA patients with hypertension, respectively. Hypertension was significantly associated with elevated HCVR after adjusting for age, central obesity, OSA severity, daytime sleepiness, and diabetes mellitus. Compared with OSA patients, OSA patients with hypertension had higher body mass index, worse nocturnal hypoxia, and lower time-domain variables and frequency-domain variables. After adjusting for age, apnea-hypopnea index, central obesity, and beta-blocker usage, approximate entropy was independently negatively associated with HCVR in OSA patients with hypertension.ConclusionThis study demonstrated elevated central chemosensitivity in OSA patients with hypertension. Compared with OSA patients, OSA patients with hypertension had attenuated parasympathetic nerve activity. This study preliminarily illustrated that elevated central chemosensitivity might be associated with weak adaptability of the cardiac autonomic nervous system in OSA patients with hypertension.

Altered chemosensitivity to CO2 during exercise.

The effect of exercise on chemosensitivity to carbon dioxide (CO2) has been controversial. Most studies have been based on rebreathing to alter inspired CO2 which is poorly tolerated in exercise. Instead, inhaling a fixed 3% CO2 from rest to moderate exercise was found to be well tolerated by seven normal subjects enabling CO2 chemosensitivity to be studied with minimal negative reaction. Results showed that chemosensitivity to CO2 following 5–6 min of stimulation was significantly enhanced during mild exercise (p < 0.01). This motivated exploring how much of the dynamic ventilatory response to mild exercise breathing air could be predicted by a model with central and peripheral chemosensitivity. Chemoreceptor stimulation combined with hypercapnia has been associated with long‐term facilitation of ventilation (LTF). 3% CO2 inhalation during moderate exercise led to ventilation augmentation consistent with LTF following 6 min of exercise in seven normal human subjects (p < 0.01). Increased ventilation could not be attributed to hypercapnia or metabolic changes. Moderate exercise breathing air resulted in significantly less augmentation. In conclusion, both peripheral and central chemosensitivity to CO2 increased in exercise with the peripheral chemoreceptors playing a dominant role. This separation of central and peripheral contributions was not previously reported. This chemoreceptor stimulation can lead to augmented ventilation consistent with LTF.

Oxygenation pattern and compensatory responses to hypoxia and hypercapnia following bilateral carotid body resection in humans.

Five years after bilateral carotid body resection (bCBR) performed in four patients, the absence of the hypoxic ventilatory response persisted, suggesting no compensatory regrowth. Breathing hypoxic gas mixtures (15% and 12%) results in a lower (by ∼10%) minimal blood oxygen saturation ( ) in bCBR patients compared to heart failure subjects (CHF) with intact peripheral chemoreceptors. After bCBR, patients were characterized by a greater short-term variability in during mild hypoxia in comparison to the CHF group. The ventilatory response to hypercapnia was preserved following bCBR and was sufficient to maintain minimal at levels comparable to controls when combined with hypoxia. Bilateral CBR - a novel treatment modality for sympathetically mediated diseases - should be used with caution due to the risk of significant desaturation even during mild hypoxia equivalent to that experienced during long-haul air travel and high altitude. Carotid body resection has been proposed as a novel treatment for sympathetically mediated diseases but the safety of bilateral carotid body resection (bCBR) for blood oxygenation during hypoxic stress (long-haul flights or high altitude) remains uncertain. Also unknown is whether central ventilatory drive is sufficient to maintain adequate oxygen saturation when exposed to hypercapnia with concomitant hypoxia. Thus, we administered: 15% O2 , 12% O2 , 5% CO2 /12% O2 and 5% CO2 /95% O2 to a group of four patients with congestive heart failure (65±2.9years) in whom bCBR was performed 5years earlier. Ventilatory, haemodynamic and blood oxygen saturation ( ) responses were recorded non-invasively and compared to control groups with intact peripheral chemoreceptors (both healthy and heart failure patients). First, we confirmed that the ventilatory response to hypoxia was eliminated in patients with bCBR, although the increase in cardiac output was preserved. Second, administration of hypoxic gas mixtures resulted in a larger decrease in and greater short-term variability of the leading to a lower minimal for both hypoxia levels in the bCBR group compared to heart failure controls (82.5±1.2% vs. 91.6±2.3% for 15% O2 and 73.8±4.0% vs. 83.7±3.1% for 12% O2 ). Third, in bCBR patients the ventilatory response to hypercapnia was present and sufficient to maintain a minimal at a level comparable to heart failure controls following administration of 5% CO2 /12% O2 (88.7±4.2% vs. 91.1±2.8%). We conclude that bCBR carries a risk of significant oxygen desaturation even during mild hypoxia. Despite preservation of central chemosensitivity, future studies should focus on unilateral CBR or on pharmacological modulation of peripheral chemosensitivity.

Elevated exercise ventilation in mild COPD is not linked to enhanced central chemosensitivity

BackgroundThe purpose of this study was to determine if altered central chemoreceptor characteristics contributed to the elevated ventilation relative to carbon dioxide production (V̇E/V̇CO2) response during exercise in mild chronic obstructive pulmonary disease (COPD). MethodsTwenty-nine mild COPD and 19 healthy age-matched control participants undertook lung function testing followed by symptom-limited incremental cardiopulmonary exercise testing . On a separate day, basal (non-chemoreflex) ventilation (V̇EB), the central chemoreflex ventilatory recruitment threshold for CO2 (VRTCO2), and central chemoreflex sensitivity (V̇ES) were assessed using the modified Duffin’s CO2 rebreathing method. Resting arterialized blood gas data were also obtained. ResultsAt standardized exercise intensities, absolute V̇E and V̇E/V̇CO2 were consistently elevated and the end-tidal partial pressure of CO2 was relatively decreased in mild COPD versus controls (all p < 0.05). There were no between-group differences in resting arterialized blood gas parameters, basal V̇E, VRTCO2, or V̇ES (all p > 0.05). ConclusionThese data have established that excessive exercise ventilation in mild COPD is not explained by altered central chemosensitivity.

Mitochondrial KATP channels contribute to the protective effects of hydrogen sulfide against impairment of central chemoreception of rat offspring exposed to maternal cigarette smoke.

We previously reported that maternal cigarette smoke (CS) exposure resulted in impairment of central chemoreception and induced mitochondrial dysfunction in offspring parafacial respiratory group (pFRG), the kernel for mammalian central chemoreception. We also found that hydrogen sulfide (H2S) could attenuate maternal CS exposure-induced impairment of central chemoreception in the rat offspring in vivo. Mitochondrial ATP sensitive potassium (mitoKATP) channel has been reported to play a significant role in mitochondrial functions and protect against apoptosis in neurons. Thus, we hypothesize here that mitoKATP channel plays a role in the protective effects of H2S on neonatal central chemoreception in maternal CS-exposed rats. Our findings revealed that pretreatment with NaHS (donor of H2S, 22.4mM) reversed the central chemosensitivity decreased by maternal CS exposure, and also inhibited cell apoptosis in offspring pFRG, however, 5-HD (blocker of mitoKATP channels, 19mM) attenuated the protective effects of NaHS. In addition, NaHS declined pro-apoptotic proteins related to mitochondrial pathway apoptosis in CS rat offspring pFRG, such as Bax, Cytochrome C, caspase9 and caspase3. NaHS or 5-HD alone had no significant effect on above indexes. These results suggest that mitoKATP channels play an important role in the protective effect of H2S against impairment of central chemoreception via anti-apoptosis in pFRG of rat offspring exposed to maternal CS.

Intra‐uterine Exposure to Diazepam Decrease the Ventilatory Response and Impairs the Motor Behavior of Males and Females at Post‐natal Life

Gestation is a critical period for the development of the respiratory system and interventions, such as the use of benzodiazepines (BZs) for treatment of psychic disorders, at this stage, may compromise this system. BZs, such as Diazepam (DZ) are one of the most common drugs prescribed to treat anxiety disorders but it can compromise the development of the respiratory system during the gestational period since it crosses the placental barrier binding at GABAA receptors. Despite of your widely prescription, it is still unknown the real consequences of the administration DZ during pregnancy on breathing control during post‐natal life. We administered DZ (1mg/Kg) or its vehicle, via osmotic pump, to pregnant rats during whole pregnancy (21 day) to understand the consequences of intra‐uterine exposure to DZ on the ventilatory responses of newborns rats. We used newborns rats (male and female) at post‐natal (P) day 0 (P0), P12 and P21. After 4 hours of their birth we evaluated chewing reflex and straightening reflex. Ventilation (Ve), tidal volume (VT), respiratory frequency (fR) and oxygen consumption (VO2) were measured by using head‐out plethysmograph for P0 and P12 and using whole‐body plethysmograph for P21. Animals were exposed to normocapnic‐normoxic, hypercapnia (7% CO2) and hypoxia (10% O2). The project was approved by the local ethics committee: CEUA Protocol: 2164/17. DZ treatment of the dams decreased gestational length compared to control group but did not affect the number of male and female pups as well did not affect the total number of pups per litter. There are no differences on the average of number of chewing or on straightening reflex time although we have observed that the treated animals show less variability on chewing reflex compared with their same gander control group. At P21, both treated males and females have shown a higher body weight compared to their control group. Under room air conditions, P0 treated females shown a decrease in their fR and VO2, P12 treated males shown a reduction in their Ve due a reduction in their VT and P21 treated males have a decrease on Ve and it was due a reduction on their VT and they also have a reduction on their Ve/VO2. Under hypercapnia, P0 treated males have decrease in their fR, P0 treated females have a decrease in their Ve due a reduction in their VT, P12 treated males have a decrease on fR and VO2, P12 treated females have a decrease in their Ve due a reduction in their VT and a reduction in their Ve/VO2. Under hypoxia, P0 treated females show a decrease on VT, P12 treated animals have a decrease in their Ve. Intra‐uterine exposure to diazepam reduces male ventilation at baseline, which may lead the need to use vital support for maintain their correct oxygenation. Regard reduction on treated females’ ventilation under hypercapnic but not at baseline or hypoxia, we suggest that central chemosensitivity of this group is decreased.Support or Funding InformationFinancial Support: FAPESP (2017/26367‐9) and CNPq.

Effects of optimized heart failure medication on central sleep apnea with Cheyne-Stokes respiration pattern in chronic heart failure with reduced left-ventricular ejection fraction.

Central Sleep Apnea with Cheyne Stokes Respiration (CSA-CSR) is often diagnosed in patients with chronic heart failure (CHF). CSA-CSR displays a periodic breathing pattern with a typical waxing and waning breathing with central sleep apnea phases in between. Optimization of heart failure medication with Angiotensin receptor neprilysin inhibition (ARNi) can effect phenotypic traits of CSA-CSR indicating improvements of both, hemodynamic parameters and central chemosensitivity.

An act of balance: Interaction of central and peripheral chemosensitivity with inflammatory and anti-inflammatory factors in obstructive sleep apnoea

ObjectivesCentral and peripheral chemosensitivity i.e. ventilatory response to CO2 and O2 are thought to be decisive for ventilatory control instability in obstructive sleep apnoea (OSA). Obesity is associated with chronic low level inflammation. Whether body mass related inflammatory and anti-inflammatory factors influencing peripheral and central chemosensitivity differentially is unclear. MethodsVentilatory response to hypercapnic-hyperoxic and hypercapnic-hypoxic gas mixtures in patients with OSA (n = 46) and healthy individuals (n = 45) was measured. C-reactive protein (CRP), leptin, adiponectin, and endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) were measured in blood samples. ResultsMediation analysis revealed that association of chemoresponse to CO2 with apnoea hypopnea index (AHI) was fully mediated by body mass index (BMI). Regression analysis showed that CRP and leptin levels explained ˜25% and ˜15% of the variance in central CO2 response, while 2-AG explained ˜42% of the variance in peripheral response to hypoxia. ConclusionInflammatory and anti-inflammatory factors could explain differential alterations in peripheral and central ventilatory chemoresponse in patients with OSA.

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

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

Control of air-breathing in fishes: Central and peripheral receptors

This review considers the environmental and systemic factors that can stimulate air-breathing responses in fishes with bimodal respiration, and how these may be controlled by peripheral and central chemoreceptors. The systemic factors that stimulate air-breathing in fishes are usually related to conditions that increase the O2 demand of these animals (e.g. physical exercise, digestion and increased temperature), while the environmental factors are usually related to conditions that impair their capacity to meet this demand (e.g. aquatic/aerial hypoxia, aquatic/aerial hypercarbia, reduced aquatic hidrogenionic potential and environmental pollution). It is now well-established that peripheral chemoreceptors, innervated by cranial nerves, drive increased air-breathing in response to environmental hypoxia and/or hypercarbia. These receptors are, in general, sensitive to O2 and/or CO2/H+ levels in the blood and/or the environment. Increased air-breathing in response to elevated O2 demand may also be driven by the peripheral chemoreceptors that monitor O2 levels in the blood. Very little is known about central chemoreception in air-breathing fishes, the data suggest that central chemosensitivity to CO2/H+ is more prominent in sarcopterygians than in actinopterygians. A great deal remains to be understood about control of air-breathing in fishes, in particular to what extent control systems may show commonalities (or not) among species or groups that have evolved air-breathing independently, and how information from the multiple peripheral (and possibly central) chemoreceptors is integrated to control the balance of aerial and aquatic respiration in these animals.

Central Chemosensitivity is Augmented during Thermoneutral Head Out Water Immersion in Healthy Adults

Central Chemosensitivity is Augmented during Thermoneutral Head Out Water Immersion in Healthy Adults

Central chemosensitivity is augmented during 2h of thermoneutral head-out water immersion in healthy men and women.

What is the central question of the study? Is central chemosensitivity blunted during thermoneutral head-out water immersion in healthy humans? What is the main finding and its importance? Central chemosensitivity is augmented during thermoneutral head-out water immersion in healthy men and women. Thus, we suggest that the central chemoreceptors do not contribute to CO2 retention during head-out water immersion. Carbon dioxide retention occurs during water immersion. Therefore, we tested the hypothesis that central chemosensitivity to hypercapnia is blunted during 2h of thermoneutral head-out water immersion (HOWI) in healthy young adults. Twenty-six participants (age 22±2years; body mass index 24±3kgm-2 ; 14 women) participated in two experimental visits: a HOWI visit (HOWI) and a dry time-control visit (Control). Central chemosensitivity was assessed via a rebreathing test at baseline, 10, 60, 90 and 120min and after HOWI and Control. End-tidal CO2 tension (P ET ,CO2), minute ventilation, blood pressure and heart rate were recorded continuously. The P ET ,CO2 increased from baseline throughout HOWI (peak increase at 120min 2±2mmHg; P<0.001), and the change in P ET ,CO2 was greater throughout HOWI than Control (P<0.001). The change in minute and alveolar ventilation was not different throughout time (P≥0.173) or between conditions (P≥0.052). Central chemosensitivity was greater than at baseline throughout HOWI (peak increase 0.74±1.01lmin-1 mmHg-1 at 120min; P<0.001), and the change in central chemosensitivity was greater throughout HOWI than Control (P ≤ 0.006). We also divided the cohort into tertiles based on baseline central chemosensitivity (i.e. Low, Intermediate and High) and compared Low versus High during HOWI. Low demonstrated an increase in P ET ,CO2 starting at 10min (2±3mmHg; P<0.001), whereas High did not exhibit an increase in P ET ,CO2 until 60min (2±2mmHg; P=0.018). These data indicate that CO2 retention occurs throughout HOWI despite augmented central chemosensitivity and that having a high baseline central chemosensitivity might delay the onset of CO2 retention.

Central Chemosensitivity is Not Augmented during 60 min of Mild Hypercapnia in Healthy Adults

Carbon dioxide (CO2) retention occurs during head out water immersion (HOWI) despite an augmented central chemosensitivity. To this end, it is unclear if an augmented central chemosensitivity during HOWI is due to CO2 retention alone (i.e., mild hypercapnia) or the combined effects of HOWI (i.e., CO2 retention, central hypervolemia, increased work of breathing, etc.).PurposeWe tested the hypothesis that central chemosensitivity is augmented during dry conditions while breathing hypercapnic gas to match the CO2 retention that occurs during HOWI.MethodsTwelve healthy subjects (age: 24±3 y, BMI: 25±3‐‐ kg/m2, 6 women) completed two experimental visits: a thermoneutral HOWI visit (HOWI) and a dry mild hypercapnia visit (Control+CO2). We measured ventilation (pneumotachometer) and expired CO2 tension (PETCO2; capnography), as an index of CO2 retention, throughout both visits. HOWI consisted of 60 min of thermoneutral (35.0±0.1°C) water immersion to the neck. During Control+CO2, small amounts of CO2 were added to the inspirate to match PETCO2 values that were obtained during HOWI. During both visits, central chemosensitivity was evaluated at baseline, 10 min, 30 min, and 60 min via a rebreathing test where subjects rebreathed 7% CO2 and 93% O2 from a 10 L bag for 3.5 min. Central chemosensitivity was calculated as the slope of the linear regression line of minute ventilation vs. PETCO2 every 30 s throughout the test. Data were analyzed and reported as a change from baseline (mean±SD).ResultsThere were no statistical differences in PETCO2 (p=0.33), minute ventilation (p=0.99), or central chemosensitivity (p=0.59) between HOWI and Control+CO2 at baseline. PETCO2 increased from baseline during HOWI and Control+CO2 at 10 min (HOWI: 2±1 mmHg, p&lt;0.01; Control+CO‐2: 2±2 mmHg, p&lt;0.01), 30 min (HOWI: 1±2 mmHg, p&lt;0.01; Control+CO‐2: 1±2 mmHg, p&lt;0.01), and 60 min (HOWI: 2±2 mmHg, p&lt;0.01; Control+CO2: 2±2 mmHg, p&lt;0.01). The change in PETCO2 was not different between conditions at any time point (p≥0.52). Minute ventilation did not change from baseline during HOWI at any time point (p≥0.66), while it increased from baseline during Control+CO2 at 10 min (2.3±1.7 L/min, p&lt;0.01), 30 min (2.0±2.2 L/min, p&lt;0.01), and 60 min (1.6±1.6 L/min, p&lt;0.01). Minute ventilation was greater during Control+CO2 vs. HOWI at 10 min (p&lt;0.01), 30 min (p&lt;0.01), and 60 min (p&lt;0.01). During HOWI, central chemosensitivity increased from baseline at 10 min (0.32±0.34 L/min/mmHg, p=0.03), 30 min (0.35±0.38 L/min/mmHg, p=0.03), and 60 min (0.36±0.43 L/min/mmHg, p=0.03), while central chemosensitivity did not change during Control+CO2 at 10 min (−0.14±0.40 L/min/mmHg, p=0.74), 30 min (0.03±0.27 L/min/mmHg, p=0.99), and 60 min (0.01±0.47 L/min/mmHg, p=0.99). Central chemosensitivity was greater during HOWI vs. Control+CO2 at 10 min (p&lt;0.01), 30 min (p=0.05), and 60 min (p=0.03).ConclusionThese data indicate that central chemosensitivity is not augmented during dry conditions while breathing hypercapnic gas to match the CO2 retention that occurs during HOWI. Thus, it appears that an augmented central chemosensitivity during HOWI is a function of the combined effects of HOWI and not solely CO2 retention.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.