Basal Ventilation Research Articles

Impact of Serotonergic 5HT1A and 5HT2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson's Disease.

In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT1A and 5-HT2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO2 in O2) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO2 and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT1AR agonist 8-OH-DPAT and 5-HT2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.

Increased Abdominal Perimeter Differently Affects Respiratory Function in Men and Women.

Obesity is a worldwide epidemic being the main cause of cardiovascular, metabolic disturbances and chronic pulmonary diseases. The increase in body weight may affect the respiratory system due to fat deposition and systemic inflammation. Herein, we evaluated the sex differences in the impact of obesity and high abdominal circumference on basal ventilation. Thirty-five subjects, 23 women and 12 men with a median age of 61 and 67, respectively, were studied and classified as overweight and obese according to body mass index (BMI) and were also divided by the abdominal circumference. Basal ventilation, namely, respiratory frequency, tidal volume, and minute ventilation, was evaluated. In normal and overweight women, basal ventilation did not change, but obese women exhibited a decrease in tidal volume. In men, overweight and obese subjects did not exhibit altered basal ventilation. In contrast, when subjects were subdivided based on the abdominal perimeter, a higher circumference did not change the respiratory frequency but induced a decrease in tidal volume and minute ventilation in women, while in men these two parameters increased. In conclusion, higher abdominal circumference rather than BMI is associated with alterations in basal ventilation in women and men.

Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia.

Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O2 and CO2 levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2bΔ8, Atoh1cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b+/TH--expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that Phox2bΔ8 mutation in Atoh1-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.

Long-Term Hypercaloric Diet Consumption Exacerbates Age-Induced Dysmetabolism and Carotid Body Dysfunction: Beneficial Effects of CSN Denervation.

Carotid bodies (CBs) are metabolic sensors whose dysfunction is involved in the genesis of dysmetabolic states. Ageing induces significant alterations in CB function also prompting to metabolic deregulation. On the other hand, metabolic disease can accelerate ageing processes. Taking these into account, we evaluated the effect of long-term hypercaloric diet intake and CSN resection on age-induced dysmetabolism and CB function. Experiments were performed in male Wistar rats subjected to 14 or 44 weeks of high-fat high-sucrose (HFHSu) or normal chow (NC) diet and subjected to either carotid sinus nerve (CSN) resection or a sham procedure. After surgery, the animals were kept on a diet for more than 9 weeks. Metabolic parameters, basal ventilation, and hypoxic and hypercapnic ventilatory responses were evaluated. CB type I and type II cells, HIF-1α and insulin receptor (IR), and GLP-1 receptor (GLP1-R)-positive staining were analyzed by immunofluorescence. Ageing decreased by 61% insulin sensitivity in NC animals, without altering glucose tolerance. Short-term and long-term HFHSu intake decreased insulin sensitivity by 55 and 62% and glucose tolerance by 8 and 29%, respectively. CSN resection restored insulin sensitivity and glucose tolerance. Ageing decreased spontaneous ventilation, but short-term or long-term intake of HFHSu diet and CSN resection did not modify basal ventilatory parameters. HFHSu diet increased hypoxic ventilatory responses in young and adult animals, effects attenuated by CSN resection. Ageing, hypercaloric diet, and CSN resection did not change hypercapnic ventilatory responses. Adult animals showed decreased type I cells and IR and GLP-1R staining without altering the number of type II cells and HIF-1α. HFHSu diet increased the number of type I and II cells and IR in young animals without significantly changing these values in adult animals. CSN resection restored the number of type I cells in HFHSu animals and decreased IR-positive staining in all the groups of animals, without altering type II cells, HIF-1α, or GLP-1R staining. In conclusion, long-term hypercaloric diet consumption exacerbates age-induced dysmetabolism, and both short- and long-term hypercaloric diet intakes promote significant alterations in CB function. CSN resection ameliorates these effects. We suggest that modulation of CB activity is beneficial in exacerbated stages of dysmetabolism.

Role of central irisin in the cardiorespiratory and metabolic control of adult rats

Irisin has been identified as an important exercise‐induced myokine that acts in different physiological systems; however, little is known about the participation of irisin in cardiorespiratory and basal metabolic control. Therefore, the present study evaluated the effect of intracerebroventricular (icv) injection of vehicle or irisin (IR, 0.425 µg/µL) in the fourth ventricle (4V) of adult male rats on the cardiorespiratory and metabolic control during wakefulness and sleep under room air, hypercapnia (7% CO2) and hypoxia (10% O2). Our data show a tendency of reduction in basal ventilation of IR group during wakefulness (VEH: 1056.2 ± 61.8 vs IR: 816.9 ± 30.5 mL.Kg‐1.min‐1), due to a reduction in respiratory frequency (VEH: 105.1 ± 5.3 vs IR: 85.9 ± 5.1 breaths.min‐1) and a consequent decrease in arterial partial pressure of O2 (VEH: 95.1 ± 2.4 vs IR: 88.7 ± 3.1 mmHg). No difference was observed in metabolic rate; however, central IR promoted a reduction in the air convection requirement (VEH: 57.2 ± 4.7 vs IR: 39.6 ± 3.7). Regarding the cardiovascular parameters, central injection of IR caused a significant increase in heart rate during hypoxia exposure (VEH: 342.5 ± 38.0 vs IR: 406.2 ± 16.8 beats.min‐1) without changing arterial pressure. These effects were only observed in awake conditions, with no changes evidenced during sleep. No difference in cardiorespiratory and metabolic parameter were observed under CO2 exposure after central IR injection. Therefore, our preliminary results suggest that IR caused a hypoventilation under room air conditions, possibly due to a lower ventilation, increased heart rate under hypoxic conditions, suggesting that this myokine also acts in the central nervous system to modulate breathing and cardiovascular parameters.

Thyroid hormones during the perinatal period are necessary to respiratory network development of newborn rats

Thyroid hormones (THs) are essential for foetal brain development. Because the gestating mother is the main source of THs to the foetus, maternal hypothyroidism and/or premature birth compromise neurological outcomes in the offspring. Respiratory instability and recurrent apneas due to immaturity of the respiratory control network are major causes of morbidity in infants. Inadequate TH supply may be sufficient to delay perinatal maturation of the respiratory control system; however, this hypothesis remains untested. To address this issue, maternal hypothyroidism was induced by adding methimazole (MMI; 0.02% w/v) to the drinking water of pregnant dams from conception to postpartum day 4 (P4). The effect of TH supplementation on respiratory function was tested by injecting levothyroxine (L-T4) in newborns at P1. Respiratory function was assessed by plethysmography (in vivo) and recording of phrenic output from medullary preparations (in vitro). By comparison with controls, TH deficiency increased the frequency of apneas and decreased basal ventilation in vivo and prevented the age-dependent increase in phrenic burst frequency normally observed in vitro. The effects of TH deficiency on GABAergic modulation of respiratory activity were measured by bath application of muscimol (GABAA agonist) or bicuculline (GABAA antagonist). The phrenic burst frequency responses to GABAergic agents were consistently greater in preparations from TH deficient pups. L-T4 supplementation reversed part of the respiratory anomalies related to MMI treatment in vitro. We conclude that TH deficiency during the perinatal period is sufficient to delay maturation of the respiratory control network development. Excessive GABAergic inhibition may contribute to this effect.

A Neural Circuit Mechanism Controlling Breathing by Leptin in the Nucleus Tractus Solitarii.

Leptin, an adipocyte-derived peptide hormone, has been shown to facilitate breathing. However, the central sites and circuit mechanisms underlying the respiratory effects of leptin remain incompletely understood. The present study aimed to address whether neurons expressing leptin receptor b (LepRb) in the nucleus tractus solitarii (NTS) contribute to respiratory control. Both chemogenetic and optogenetic stimulation of LepRb-expressing NTS (NTSLepRb) neurons notably activated breathing. Moreover, stimulation of NTSLepRb neurons projecting to the lateral parabrachial nucleus (LPBN) not only remarkably increased basal ventilation to a level similar to that of the stimulation of all NTSLepRb neurons, but also activated LPBN neurons projecting to the preBötzinger complex (preBötC). By contrast, ablation of NTSLepRb neurons projecting to the LPBN notably eliminated the enhanced respiratory effect induced by NTSLepRb neuron stimulation. In brainstem slices, bath application of leptin rapidly depolarized the membrane potential, increased the spontaneous firing rate, and accelerated the Ca2+ transients in most NTSLepRb neurons. Therefore, leptin potentiates breathing in the NTS most likely via an NTS-LPBN-preBötC circuit.

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.

Respiratory Control by Phox2b-expressing Neurons in a Locus Coeruleus-preBötzinger Complex Circuit.

The locus coeruleus (LC) has been implicated in the control of breathing. Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2b (Phox2b) gene that is expressed in LC neurons. The present study was designed to address whether stimulation of Phox2b-expressing LC (Phox2bLC) neurons affects breathing and to reveal the putative circuit mechanism. A Cre-dependent viral vector encoding a Gq-coupled human M3 muscarinic receptor (hM3Dq) was delivered into the LC of Phox2b-Cre mice. The hM3Dq-transduced neurons were pharmacologically activated while respiratory function was measured by plethysmography. We demonstrated that selective stimulation of Phox2bLC neurons significantly increased basal ventilation in conscious mice. Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses. Moreover, stimulation of Phox2bLC neurons enhanced the activity of preBötzinger complex neurons. Finally, axons of Phox2bLC neurons projected to the preBötzinger complex. Collectively, Phox2bLC neurons contribute to the control of breathing most likely via an LC-preBötzinger complex circuit.

Ventilatory acclimatization to hypoxia: Time to express a critical central message.

Ventilatory acclimatization to hypoxia: Time to express a critical central message.

Участие оксида азота в механизмах влияния провоспалительного цитокина ИЛ-1β на гиперкапнический вентиляционный ответ

The aim of the current study was to compare the respiratory effects of IL-1β before and after pre-treatment with L-NAME, a nonspecific NO-synthases inhibitor. The experiments were performed on tracheotomised anaesthetised rats. The hypercapnic ventilatory response was measured by means of the rebreathing method using a hyperoxic-hypercapnic gas mixture (60 % O2, 7 % CO2) before and after the cerebroventricular administration of human recombinant IL-1β in the amount of 500 ng dissolved in 10 μl of saline. In order to determine the role of the NO-pathway in the ventilatory effects of IL-1β, L-NAME, a non-specific inhibitor of NO-synthase, was used. As a result, the slope of the ventilatory response to carbon dioxide decreased almost twofold at 40 min. after the cerebroventricular administration of IL-1β. In contrast, the basal level of lung ventilation increased after the elevation of IL-1β in CSF. L-NAME pre-treatment reduced these respiratory effects of IL-1β. The data indicate that the inhibitor of NO-synthase significantly reduces the effect of the pro-inflammatory cytokine IL-1β. The authors conclude that the ability of IL-1β to enhance basal ventilation and to reduce the ventilatory hypercapnic response may be mediated by NO-dependent mechanisms.

CYCLOOXYGENASE MECHANISMS IN THE REGULATION OF RESPIRATORY EFFECTS OF TUMOR NECROSIS FACTOR

Introduction. It is known that the systemic level of the major pro-inflammatory cytokine increases in many respiratory diseases such as asthma, COPD and sleep apnea [1, 2]. The lung ventilation changes and the pathological types of breathing are typical in these diseases. By the reason, the research of the respiratory effects of cytokine is actual. The aim of this study was to compare the respiratory effects of tumor necrosis factor - α (TNF-α) before and after pretreatment with diclofenac, a nonspecific cyclooxygenase (COX) inhibitor. Materials and methods. Тhe experiments were performed in tracheostomized anaesthetized with urethane rats. A respiratory flow head connected to a pneumotachometer (AD Instruments ML141 Spirometer, Dunedin, New Zealand) was used to measure peak airflow and respiratory rate. The hypoxic ventilatory response was measured by using rebreathing with hypoxic gas mixture before and after the tail vein injection of TNF-α (10 μg/rat). In order to determine the role of the cyclooxygenase pathway in the ventilatory effects of TNF-α, introperitoneal administration of diclofenac, a nonspecific COX inhibitor, was used (0.5 mg/rat). Results and discussion. We have shown that the increase in level of TNF-α in blood increased the parameters of respiration such as minute ventilation (by 40%), tidal volume (by 18%), and the mean inspiratory flow (by 33%). The slope of the hypoxic ventilatory response decreased from 6.06 ± 0.91 to 3.48 ± 0.38 ml/min-1 mmHg-1 (by 40%) 40 min after administration of TNF-α (p &lt; 0.05), the slope of tidal volume and mean inspiratory flow also decreased (by 27%) (p &lt; 0.05). After pretreatment with diclofenac, the influence of TNF-α on breathing was dampened, as no significant changes were observed. Conclusion. We concluded that the elevation of inflammatory cytokine level in blood intensifies ventilation during the resting breathing that may be associated with increased central inspiratory activity. At the same time TNF-α reduces the chemoreflex sensitivity to hypoxia, thereby worsening the compensatory capabilities of the respiratory system. Thus, the results of our study suggest participation of inflammatory cytokines in mechanisms of central breathing control and chemoreception. Diclofenac pretreatment eliminated the respiratory effects of TNF-α. The data indicate that the ability of TNF-α to enhance basal ventilation and to reduce the ventilatory hypoxic response is mediated by the COX pathway.

Erythropoietin and caffeine exert similar protective impact against neonatal intermittent hypoxia: Apnea of prematurity and sex dimorphism

Apnea of prematurity (AoP) is associated with severe and repeated episodes of arterial oxygen desaturation (intermittent hypoxia - IH), which in turn increases the number of apneas. So far, there is no data addressing whether IH leads to sex-specific respiratory consequences, neither if drugs targeting AoP are more effective in males or females. We used rat pups for investigating whether IH-mediated increase of apneas is sex-specific. We also tested whether caffeine (treatment of choice of AoP), erythropoietin (Epo - a neuroprotective factor and potent respiratory stimulant), and combination of both (caffeine+Epo) prevent the IH-mediated formation of apneas in a sex-dependent manner. Newborn rats exposed to IH (21% - 10% FIO2–8 h a day – 10 cycles per hour) during postnatal days (P) 3–10 were used in this work. Animals were administered drug vehicle, Epo, caffeine and Epo + caffeine (daily from P3 to P10) gavage. At P10 the frequency of apneas at rest (as an index of respiratory dysfunction induced by IH), and respiratory parameters were measured by plethysmography. Our results showed that IH significantly increases the number of apneas in male but not in female rat pups. Moreover, caffeine and Epo in males similarly prevented the increase of apneas induced by IH, and the administration of both drugs together did not provide a cumulative beneficial effect. No impact of drugs was evidenced in females. Apart from apneas, IH increased the normoxic basal ventilation (ventilation at rest) of male animals, and treatments did not prevent such alteration. Besides, no IH- nor treatment-mediated modulation of basal ventilation was found in the basal ventilation of female animals. Analysis of the activity of pro- and antioxidative molecules revealed that IH induces oxidative stress in the brainstem of male and female animals and that all tested treatments similarly prevented such oxidative imbalance in pups of both sexes. We concluded that neonatal IH and the treatments tested to prevent its respiratory consequences are sex-specific. The mechanics associated with such prevention are directly linked with the prevention of oxidative stress and the maturation of the brain. These findings are relevant to understanding better the AoP disorder and for proposing Epo as a new therapeutical tool.

Biomolecular changes at ventrolateral medulla and respiratory deficit in an experimental model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non‐motor symptoms, and caused by degeneration of dopaminergic neurons of substantia nigra pars compacta (SNpc). Prior studies showed that in animal model of PD there is a decrease in the resting and hypercapnia‐induced respiratory rate and in the number of phox2b‐expressing RTN neurons. The aim of this study was to identify the extent to which RTN pharmacological rescue restores respiratory function and determine the extent of biomolecular changes following PD‐induction. Adult male Wistar rats with bilateral injections of 6‐hydroxy‐dopamine (6‐OHDA, 24 μg/μl) or vehicle into the striatum were used. For proteomic analyzes, laser capture and pressure catapulting was used for microdissection of the brain cuts. We also performed comparative proteomic studies followed by Ingenuity Pathway Analysis (IPA®) of the RTN region in PD‐induced rats. Stainless steel canullas were implanted into RTN region and injections of N‐methyl D‐aspartate (NMDA, 50 nl) were performed to verify the pharmacological activation of these neurons. Respiratory parameters were evaluated by whole body plethysmography. The results showed that sixty days after injection of 6‐OHDA, the number of SNpc catecholaminergic and RTN phox2b neurons reduced (73.1± 2 and 55.9 ± 17%, respectively). In PD‐animals, there is a reduction in basal ventilation, hypercapnia, hypoxia and maximal chemoreflex stimulation (MCS) (basal: 357 ± 19, vs. vehicle: 917 ± 22 ml/kg/min; hypercapnia: 1064 ± 35, vs. vehicle: 1921 ± 108 ml/kg/min; hypoxia: 711 ± 6, vs. vehicle: 1851 ± 102 ml/kg/min; MCS: 1195 ± 17, vs. vehicle: 2727 ± 26 ml/kg/min, p&lt;0.05). However, the activation of RTN by NMDA injection showed similar respiratory responses between PD and control animals (respiratory frequency: 149 ± 12, vs. control 155 ± 12 breaths/min; ventilation: 1028 ± 191, vs. vehicle: 985 ± 199 ml/kg/min; tidal volume: 6.9 ± 0.7, vs. vehicle: 6.4 ± 0.5 ml/kg, p&gt;0.05). The proteomic analyses of the RTN showed a biomolecular profile indicative of ongoing cell remodeling in PD‐induced animals. In PD‐group, some proteins showed a decreased fold change in quantity, such as MYH9 (cytoskeleton reorganization), CAMK2D (regulation of Ca2+ homeostasis), RAB6A (protein transport), whereas Dnah5 (cellular movement) and Rnh1 (ribonuclease inhibitor) were increased. In addition, other genes were functionally inhibited, such as ADORA‐2A (g‐protein receptor), IGF‐1 (growth factor) and SRF (transcription regulation) or activated, as RICTOR (kinases mediate responses to stress), MAP4K4 (kinase) and CAMK2A (NMDAR signaling complex). Our data suggest, therefore, that despite the fact that biomolecular changes occur at the RTN level, there may be persistence of an NMDA‐specific compensatory mechanism provided by the surviving neurons.Support or Funding InformationNIH/NHLBI, FAPESP, CNPq and CAPESThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of vagotomy on cardiovascular and heart rate variability alterations following chronic normobaric hypoxia in adult rabbits

Backgroundchronic hypoxia increases basal ventilation and pulmonary vascular resistance, with variable changes in arterial blood pressure and heart rate, but it’s impact on heart rate variability and autonomic regulation have been less well examined. We studied changes in arterial blood pressure, heart rate and heart rate variability (HRV) in rabbits subjected to chronic normobaric hypoxia (CNH; PB ~ 719 mmHg; FIO2 ~ 9.2%) for 14 days and assess the effect of autonomic control by acute bilateral vagal denervation.Resultsexposure to CNH stalled animal weight gain and increased the hematocrit, without affecting heart rate or arterial blood pressure. Nevertheless, Poincaré plots of the electrocardiographic R–R intervals showed a reduced distribution parallel to the line of identity, which interpreted as reduced long-term HRV. In the frequency domain, CNH reduced the very-low- (< 0.2 Hz) and high-frequency components (> 0.8 Hz) of the R–R spectrograms and produced a prominent component in the low-frequency component (0.2–0.5 Hz) of the power spectrum. In control and CNH exposed rabbits, bilateral vagotomy had no apparent effect on the short- and long-term HRV in the Poincaré plots. However, bilateral vagotomy differentially affected higher-frequency components (> 0.8 Hz); reducing it in control animals without modifying it in CNH-exposed rabbits.ConclusionsThese results suggest that CNH exposure shifts the autonomic balance of heart rate towards a sympathetic predominance without modifying resting heart rate or arterial blood pressure.

Developmental consequences of intra‐uterine exposure to cannabinoids: impact on the ventilatory system of newborns rats

The endocannabinoid system is already present in the central nervous system in the early stages of embryonic development, including in areas responsible for respiratory control. Cannabis sativa (marijuana) is the illicit drug most commonly used during pregnancy. However, the relationship between marijuana use and ventilatory problems in the offspring is uncertain. Therefore, the present study evaluated the effects of exposure to cannabinoids during the gestational period on the respiratory control system in P6–7 and P12–13 male rats. To this end, osmotic pumps were implanted subcutaneously in pregnant female rats at embryonic day 0 and delivered vehicle or CB1 receptor agonist (WIN55,212–2, 0.5 mg/Kg/day) for 21 days. Ventilation (VE) of newborn was recorded during normocapnia and hypercapnia (7% CO2), as well as the O2 consumption (VO2). Our data showed a 15% increase of hypercapnic ventilatory response in P6–7 WIN‐treated animals during 7% CO2 due to a higher respiratory frequency and an increase of the respiratory equivalent. For P12–13 rats, WIN‐treated animals showed a hyperventilation (VE/VO2) in basal conditions and an increase hypercapnic ventilatory response (~20%) due to an increase in both tidal volume and respiratory frequency. No difference in VO2 was observed between groups for both ages. Our results suggest that a chronic and over activation of endocannabinoid system during gestation alters basal ventilation and CO2‐drive to breathing during neonatal period.Support or Funding InformationSao Paulo Research Foundation (FAPESP) and National Council for Scientific and Technological Development (CNPq)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Leptin Signaling in the Carotid Body Regulates a Hypoxic Ventilatory Response Through Altering TASK Channel Expression.

Leptin is an adipose-derived hormone that plays an important role in the regulation of breathing. It has been demonstrated that obesity-related hypoventilation or apnea is closely associated with leptin signaling pathways. Perturbations of leptin signaling probably contribute to the reduced sensitivity of respiratory chemoreceptors to hypoxia/hypercapnia. However, the underlying mechanism remains incompletely understood. The present study is to test the hypothesis that leptin signaling contributes to modulating a hypoxic ventilatory response. The respiratory function was assessed in conscious obese Zucker rats or lean littermates treated with an injection of leptin. During exposure to hypoxia, the change in minute ventilation was lower in obese Zucker rats than chow-fed lean littermates or high fat diet-fed littermates. Such a change was abolished in all groups after carotid body denervation. In addition, the expression of phosphorylated signal transducers and activators of transcription 3 (pSTAT3), as well as putative O2-sensitive K+ channels including TASK-1, TASK-3 and TASK-2 in the carotid body, was significantly reduced in obese Zucker rats compared with the other two phenotype littermates. Chronic administration of leptin in chow-fed lean Zucker rats failed to alter basal ventilation but vigorously increased tidal volume, respiratory frequency, and therefore minute volume during exposure to hypoxia. Likewise, carotid body denervation abolished such an effect. In addition, systemic leptin elicited enhanced expression of pSTAT3 and TASK channels. In conclusion, these data demonstrate that leptin signaling facilitates hypoxic ventilatory responses probably through upregulation of pSTAT3 and TASK channels in the carotid body. These findings may help to better understand the pathogenic mechanism of obesity-related hypoventilation or apnea.

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

Sudden unexpected death in epilepsy (SUDEP) is a significant public health burden. The mechanisms of SUDEP are elusive, although cardiorespiratory dysfunction is a likely contributor. Clinical and animal studies indicate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death in many SUDEP cases. Our prior studies demonstrated that intraperitoneal (IP) injection of atomoxetine, a norepinephrine reuptake inhibitor (NRI) widely used to treat attention deficit hyperactivity disorder, suppresses S-IRA in DBA/1 mice. In the current study, we injected atomoxetine intracerebroventricularly (ICV) and measured its effect on S-IRA in DBA/1 mice to determine its central effects. Additionally, to test our hypothesis that atomoxetine reduces S-IRA via altering cardiorespiratory function, we examined the effect of atomoxetine on respiratory and cardiac function using non-invasive plethysmography and ECG in anesthetized DBA/1 mice, and on blood pressure and heart rate using a tail-cuff system in conscious DBA/1 mice. ICV administration of atomoxetine at 200–250nmol significantly reduced S-IRA evoked by acoustic stimulation in DBA/1 mice, consistent with a central atomoxetine effect on S-IRA. Peripheral atomoxetine administration at a dosage that reduces S-IRA (15mg/kg, IP) slightly increased basal ventilation and the ventilatory response to 7% CO2, but exerted no effect on heart rate in anesthetized DBA/1 mice. IP injection of atomoxetine produced no effect on the heart rate and blood pressures in conscious mice. These data suggest that atomoxetine suppresses S-IRA through direct effects on the CNS and potentially through enhanced lung ventilation in DBA/1 mice.

Increased ventilation in female erythropoietin-deficient mouse line is not progesterone and estrous stage-dependent

Previous studies suggest that chronic erythropoietin (Epo) deficiency in male mice does not alter normoxic/hypoxic ventilation. As effects of Epo are sex specific and as progesterone could be a respiratory stimulant, we evaluated the impact of Epo deficiency and its possible interaction with progesterone in ventilatory control in female mice during estrous cycle phases. Compared to wild type (WT) animals, Epo-TAgh female mice exhibited higher ventilation in hypoxia. However, when data were separated into luteal and follicular phases of the estrous cycle, basal ventilation and hypoxic ventilation were not different in both mice strains. As progesterone is known to be a potent respiratory stimulant, additional experiments were performed to elucidate its role. Interestingly, after mifepristone treatment, HVR was not modified in WT and Epo-TAgh mice, showing that the ventilatory stimulation observed in females was not directly mediated by progesterone. We conclude that Epo-TAgh female mice show no estrous stage-dependent increase of ventilatory control and progesterone independent response to hypoxia.

Baseline values of cardiovascular and respiratory parameters predict response to acute hypoxia in young healthy men.

The majority of the available works have studied distinct hypoxic responses of respiratory and cardiovascular systems. This study examines how these systems interact while responding to hypoxia and whether baseline metrics moderate reactions to a hypoxic challenge. Central hemodynamic, aortic wave reflection, and gas exchange parameters were measured in 27 trained young men before and after 10-min normobaric isocapnic hypoxia (10 % O2). Associations were assessed by correlation and multiple regression analyses. Hypoxic changes in the parameters of pulse wave analysis such as augmentation index (-114 %, p=0.007), pulse pressure amplification (+6 %, p=0.020), time to aortic reflection wave (+21 %, p<0.001) report on the increase in arterial distensibility. Specifically, initially compliant arteries blunt the positive cardiac chronotropic response to hypoxia and facilitate the myocardial workload. The degree of blood oxygen desaturation is directly correlated with both baseline values and hypoxic responses of aortic and peripheral blood pressures. The hypoxia-induced gain in ventilation (VE), while controlling for basal VE and heart rate (HR), is inversely associated with deltaHR and deltasystolic blood pressure. The study suggests that cardiovascular and respiratory systems mutually supplement each other when responding to hypoxic challenge.