CO2 Ventilatory Response Research Articles

Comparison of Awake Respiratory Control Versus Sleep Obstructive Sleep Apnea Endotypes.

Most approaches to advance simplified physiology-based precision medicine strategies for obstructive sleep apnea (OSA) focus on sleep parameters (i.e., OSA endotypes). However, wakefulness physiology measures can also provide prediction insight for certain OSA therapies yet their relationship with sleep parameters has not been extensively investigated. This study aimed to investigate potential relationships between awake ventilatory control parameters and sleep OSA endotypes and their potential to predict changes in OSA severity with morphine. Data were acquired from a randomised, cross-over trial that investigated effects of morphine versus placebo on OSA severity and underlying mechanisms. Here, awake ventilatory chemoreflex testing prior to overnight polysomnography was compared with direct measures of sleep respiratory control (e.g., hypercapnic ventilatory responses and loop gain) and OSA endotypes during a separate overnight physiology study (pharyngeal critical closure pressure-Pcrit, muscle responsiveness via genioglossus intramuscular electromyography and arousal threshold via epiglottic pressure catheter to transient continuous positive airway pressure reductions). Twenty-one men with OSA completed both study arms. During placebo, 1) awake chemosensitivity correlated with Pcrit (r=0.726, p=0.001), 2) arousal threshold correlated with awake CO2 ventilatory response threshold (r=-0.467, p=0.047) and basal ventilation (r=-0.500, p=0.029). Awake chemosensitivity and Pcrit also correlated with the apnea-hypopnea index (p<0.001) during placebo. Awake chemosensitivity was predictive of changes in OSA severity with morphine(r=-0.535, p=0.013). In conclusion, awake measures of respiratory control are related to physiological endotypes such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine.

Melanin-concentrating hormone regulates the hypercapnic chemoreflex by acting in the lateral hypothalamic area.

What is the central question of this study? Melanin-concentrating hormone (MCH) suppresses the hypercapnic chemoreflex: what is the mechanism by which this effect is produced? What is the main finding and its importance? MCH acting in the lateral hypothalamic area but not in the locus coeruleus in rats, in the light period, attenuates the hypercapnic chemoreflex. The data provide new insight into the role of MCH in the modulation of the hypercapnic ventilatory response. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide involved in a broad range of homeostatic functions including regulation of the hypercapnic chemoreflex. We evaluated whether MCH modulates the hypercapnic ventilatory response by acting in the lateral hypothalamic area (LHA) and/or in the locus coeruleus (LC). Here, we measured pulmonary ventilation ( ), body temperature, electroencephalogram (EEG) and electromyogram (EMG) of unanaesthetized adult male Wistar rats before and after microinjection of MCH (0.4mM) or MCH receptor 1 (MCH1-R) antagonist (SNAP-94847; 63mM) into the LHA and LC, in room air and 7% CO2 conditions during wakefulness and sleep in the dark and light periods. MCH intra-LHA caused a decreased CO2 ventilatory response during wakefulness and sleep in the light period, while SNAP-94847 intra-LHA increased this response, during wakefulness in the light period. In the LC, MCH or the MCH1-R antagonist caused no change in the hypercapnic ventilatory response. Our results suggest that MCH, in the LHA, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light-inactive period in rats.

Melanin‐Concentrating Hormone (MCH) Decreases the Hypercapnic Ventilatory Response by Acting in the Lateral Hypothalamic Area (LHA)

MCH plays an inhibitory role in the central hypercapnic chemoreflex, but the mechanisms were unclear so far. In this study, we tested the hypothesis that MCH1‐R receptors activation in LHA and/or Locus coeruleus (LC) is involved in the modulation of hypercapnic ventilatory response during the sleep/wake cycle. To do this, we measured pulmonary ventilation (VE), body temperature, EEG and EMG of unanesthetized male Wistar rats before and after microinjection of the MCH agonist (MCH, 0.4 mM) into the LHA and LC, or the MCH1‐R antagonist (SNAP‐94847; 63 mM), into the LHA, in room air and in 7% CO2 during wakefulness and sleep, in the dark and light periods. MCH intra‐LHA decreased the CO2 ventilatory response by 27% during wakefulness (VE = 1923 ± 384; n = 7 versus 2645 ± 293 mL kg‐1 min‐1; n = 6; P &lt; 0.0001) and 16% during sleep (VE = 1914 ± 228; n = 6 versus2273 ± 243 mL kg‐1 min‐1; n = 4; P &lt; 0.005) in the light, but not in the dark period while SNAP‐94847 intra‐LHA caused an increased CO2 ventilatory response during wakefulness in the light period, compared with the control group (VE = 2547 ± 277; n = 6 versus 2106 ± 329 mL kg‐1 min‐1; n = 6; P &lt; 0.05). In the LC, MCH caused no change in the hypercapnic ventilatory response of rats. Our results suggest that MCH via MCH1‐R in the LHA, but not in the LC, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light‐inactive period in rats.

Ventilatory response to CO2 with Read's rebreathing method in normal infants.

Methods of evaluating the ventilatory response to CO2 (VRCO2 ) of the respiratory center include the steady-state and the rebreathing method. Although the rebreathing method can evaluate the ventilatory response continuously to gradually increasing CO2 , the rebreathing method has been rarely performed in infants. The aim of this study was to investigate whether we could perform the VRCO2 with the rebreathing method in normal infants. The subjects were 80 normal infants. The gestational age was 39.9 (39.3-40.3) weeks, and the birth body weight was 3142 (2851-3451) grams. We performed the VRCO2 with Read's rebreathing method, measuring the increase in minute volume (MV) in response to the increase in EtCO2 by rebreathing a closed circuit. The value of VRCO2 was calculated as follow: VRCO2 (ml/min/mmHg/kg) = ΔMV/ΔEtCO2 /body weight. We performed the examination without adverse events. The age in days at examination was 3 (2-4), and the examination time was 150 ± 38 s. The maximum EtCO2 was 51.1 (50.5-51.9) mmHg. The value of VRCO2 was 34.6 (29.3-42.8). The intraclass correlation coefficient of the VRCO2 of cases with multiple measurements was 0.79. This study suggests that the rebreathing method can evaluate the ventilatory response to high blood CO2 in a short examination time. We conclude that the rebreathing method is useful even in infants. In the future, we plan to measure the VRCO2 of preterm infants, and evaluate the respiratory center of infants in more detail.

Minocycline treatment effects on cognition, sleep, breathing and body temperature in a model for sporadic Alzheimer's disease

AbstractBackgroundChronic inflammation plays an important role in the cascade of molecular events in the brain of patients with Alzheimer's disease (AD). Preclinical studies have shown that minocycline has a potent anti‐inflammatory effect exerted by its neuroprotective action in various neurodegenerative diseases, such as AD. Thus, we tested the hypothesis that minocycline treatment could reverse / minimize the cognitive and respiratory and sleep deficits of our sporadic AD model.MethodWe used as an animal model for sporadic Alzheimer’s disease (AD) induced by icv injection of streptozotocin (STZ) (2 mg/kg). After five consecutive days of daily dosing with minocycline (30 mg / kg, i.p) the animals were submitted to the experiments. We evaluated memory and learning by Barnes' maze (n = 12), ventilatory parameters during sleep and wakefulness by the whole body plethysmography method and sleep time by electroencephalography method. We evaluate body temperature also during all experiments.ResultThe minocycline treatment improved learning and memory of the STZ‐AD model (n = 12, p &lt; 0.05). But it did not decrease the sensitivity of STZ‐AD model to CO2 ventilatory response during wakefulness Placebo (VE mean ± standard deviation: STZ‐AD = 2477.5 ± 514.8 mL. Kg−1. min−1 vs VE Placebo‐Vehicle = 2005.1 ± 364.2 mL. Kg−1. min−1) vs Minocycline (VE Minocycline‐STZ‐AD = 2535.0 ± 246.7 vs VE Minocycline‐Vehicle = 1936.0 ± 226.4 mL. Kg−1. min−1) (P &gt;0.05 test Two‐Way ANOVA). Similarly, minocycline treatment had no effect on reversal of wakefulness increase in STZ‐AD model (% Time spent in awake state mean ± standard deviation: Placebo‐STZ = 66.4 ± 17.7 vs Placebo‐Vehicle = 53.0 ± 9.9 % ) (Minocycline‐STZ = 66.6 ± 8.2 vs Minocycline‐Vehicle = 44.8 ± 11.7 %). No difference was observed in the body temperature of the animals during the experiments, but the hypoxia promoted a regulated fall in body temperature.ConclusionIn summary, our data suggest that minocycline is a promising drug to minimize cognitive dysfunctions in the AD model without changing the respiratory and sleep‐wake cycle parameters.

Adenosine in the lateral hypothalamus/perifornical area does not participate on the CO2 chemoreflex

The Lateral Hypothalamus/Perifornical Area (LH/PFA) has been shown to be involved with the hypercapnic ventilatory response, in a state-dependent manner. We have demonstrated that purinergic signaling through ATP in the LH/PFA has an excitatory effect in ventilatory response to CO2 in awake rats in the dark phase of the diurnal cycle, but it is unknown whether the ATP metabolite adenosine, acting in the LH/PFA, modulates the ventilatory responses to hypercapnia. Here, we studied the effects of the microdialysis of adenosine (A1/A2 adenosine receptors agonist; 17 mM) and an A1 receptor antagonist (DPCPX; 0.1 mM) into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 during the light and the dark phases of the diurnal cycle. The microdialysis of adenosine and DPCPX caused no change in the CO2 ventilatory responses of rats during wakefulness or NREM sleep in either the dark or light period. Our data suggest that adenosine in the LH/PFA does not contribute to the hypercapnic ventilatory response in conscious rats.

Comparison of the CO2 ventilatory response through development in three rodent species: Effect of fossoriality

Burrowing rodents have a blunted ventilatory response to CO2 in comparison to non-burrowing rodents. Non-burrowing rats display a period during development where ventilatory responses to hypercarbia become transiently blunted. This study examined the ventilatory responses to CO2 of rats, hamsters and ground squirrels through neonatal development to determine whether the blunted adult response of burrowing species is a retention of the blunting period seen in rats or present from birth. All three species increased ventilation in response to hypercarbia on the day of birth (70–170% in response to 5% CO2; 100–250% in response to 7% CO2). Rats in our study exhibited the triphasic ventilatory response (when expressed as %Δ) to CO2 previously described. In golden-Syrian hamsters, the ventilatory response slowly and progressively waned to a blunted adult response while in the 13-lined ground squirrels, the early ventilatory response to CO2 decreased within days and remained attenuated through development. Our study shows three distinct developmental patterns in the hypercarbic ventilatory response.

ATP in the lateral hypothalamus/perifornical area enhances the CO2 chemoreflex control of breathing.

What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO2 /H+ -dependent drive to breathe. The lateral hypothalamus/perifornical area (LH/PFA) is a central chemoreceptor site, which acts in an arousal state-dependent manner. It has been shown that purinergic signalling through ATP influences the CO2 /H+ responsiveness of other chemosensitive regions, but it is unknown whether ATP is also involved in the mechanisms that underlie LH/PFA chemoreception. Here, we studied the effects of microdialysis of a P2X-receptor agonist [α,β-methylene ATP (α,β-meATP), 10mm] and a non-selective P2-receptor antagonist [pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), 1mm] into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 . In the dark (active) phase, but not in the light, microdialysis of α,β-meATP caused an augmented hypercapnic ventilatory response during wakefulness, but not during non-REM sleep (P< 0.001). PPADS caused no change in CO2 ventilatory responses in either the dark period or the light period. Our data suggest that ATP in LH/PFA contributes to the hypercapnic ventilatory response in conscious rats during wakefulness in the dark phase of the diurnal cycle.

The effect of acute morphine on obstructive sleep apnoea: a randomised double-blind placebo-controlled crossover trial

ObjectiveAnaesthesiology guidelines suggest that opioids worsen obstructive sleep apnoea (OSA) despite no randomised controlled trial evidence. We therefore conducted a randomised controlled trial to evaluate the effects of a common...

ATP in the Lateral Hypothalamus/Perifornical area (LH/PFA) Increases CO2 Chemoreflex.

The Lateral Hypothalamus/Perifornical area (LH/PFA) is a chemosensitive site and participates in the CO2 ventilatoy response in a vigilance‐state‐dependent manner. Studies provide evidence of a physiological role for ATP in central chemoreception. We tested the hypothesis that ATP acting on LH/PFA contributes to the CO2 ventilatory response. To this end, ventilation (VE) was recorded in unanesthetized rats by whole body plethysmograph, together with EEG and EMG. We dialyzed into the LH/PFA vehicle and then α,β‐methyleneATP (selective P2X receptor agonist; 10 mM) or PPADS (purinergic antagonist; 1 mM), and studied its effects on VE in air and hypercapnia (7% CO2) during the light and dark period of the diurnal cycle. During wakefulness, but not during sleep, α,β‐methyleneATP microdialysis augmented the hypercapnic ventilatory response by 25% during the dark‐active period (2288 ± 80 mL/kg/min) compared with its vehicle (1786 ± 161 mL/kg/min) (P&lt; 0.01), but not during the light. This effect was due to an increased tidal volume. No effect was observed in normocapnia or in a separate group of animals who had the microdialysis probe misplaced (peri‐LH/PFA). PPADS did not change the ventilatory parameters in all groups. These results suggest that ATP exerts, in the LH/PFA, an excitatory modulation in the hypercapnic chemoreflex during wakefulness in the dark‐active period of the diurnal cycle.Support or Funding InformationFAPESPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Brainstem catecholaminergic neurones and breathing control during postnatal development in male and female rats

The brainstem catecholaminergic (CA) modulation on ventilation changes with development. We determined the role of the brainstem CA system in ventilatory control under normocapnic and hypercapnic conditions during different phases of development [postnatal day (P)7-8, P14-15 and P20-21] in male and female Wistar rats. Brainstem CA neurones produce a tonic inhibitory drive that affects breathing frequency in P7-8 rats and provide an inhibitory drive during hypercapnic conditions in both males and females at P7-8 and P14-15. In pre-pubertal rats, brainstem CA neurones become excitatory for the CO2 ventilatory response in males but remain inhibitory in females. Diseases such as sudden infant death syndrome, congenital central hypoventilation syndrome and Rett syndrome have been associated with abnormalities in the functioning of CA neurones; therefore, the results of the present study contribute to a better understanding of this system. The respiratory network undergoes significant development during the postnatal phase, including the maturation of the catecholaminergic (CA) system. However, postnatal development of this network and its effect on the control of pulmonary ventilation ( ) is not fully understood. We investigated the involvement of brainstem CA neurones in respiratory control during postnatal development [postnatal day (P)7-8, P14-15 and P20-21], in male and female rats, through chemical injury with conjugated saporin anti-dopamine β-hydroxylase (DβH-SAP). Thus, DβH-SAP (420ngμL-1 ), saporin (SAP) or phosphate buffered solution (PBS) was injected into the fourth ventricle of neonatal Wistar rats of both sexes. and oxygen consumption were recorded 1week after the injections in unanaesthetized neonatal and juvenile rats during room air and hypercapnia. The resting ventilation was higher in both male and female P7-8 lesioned rats by 33%, with a decrease in respiratory variability being observed in males. The hypercapnic ventilatory response (HCVR) was altered in male and female lesioned rats at all postnatal ages. At P7-8, the HCVR for males and females was increased by 37% and 30%, respectively. For both sexes at P14-15 rats, the increase in during hypercapnia was 37% higher for lesioned rats. A sex-specific difference in HCRV was observed at P20-21, with lesioned males showing a 33% decrease, and lesioned females showing an increase of 33%. We conclude that brainstem CA neurones exert a tonic inhibitory effect on in the early postnatal days of the life of a rat, increase variability in P7-8 males and modulate HCRV during the postnatal phase.

Predicting response to oxygen therapy in obstructive sleep apnoea patients using a 10-minute daytime test.

There is no satisfactory treatment for obstructive sleep apnoea (OSA). Supplemental low-flow oxygen therapy (LFO2) has been shown to reduce hypoxaemia and is well tolerated by patients with OSA. However, oxygen therapy may be beneficial only to certain subsets of patients with OSA. In this study, we evaluated a 10-min awake ventilatory chemoreflex test in predicting individual OSA response to 2 months of LFO2 therapy.At baseline, patients with OSA underwent ventilatory chemoreflex testing in the afternoon, prior to the overnight polysomnography. Subjects were reassessed with polysomnography after 2 months of nocturnal oxygen treatment.20 patients with OSA completed the study. After 2 months of O2 treatment, changes in the apnoea-hypopnoea index (AHI) were significantly correlated with baseline CO2 ventilatory response threshold (VRT) and chemosensitivity (p<0.05). In predicting a fall in AHI, the area under the receiver operating characteristic curve (AUC) was 0.79 for VRT and 0.89 for chemosensitivity. When these two variables were combined in a logistic regression model, the prediction effect became stronger with an AUC of 0.97, sensitivity of 0.92 and specificity of 0.83.Our awake ventilatory chemoreflex test could be considered a simple potential clinical tool to predict individual OSA response to oxygen therapy. It could provide a novel personalised medicine approach to OSA treatment.

Participation of locus coeruleus in breathing control in female rats

Several evidences indicate that the locus coeruleus (LC) is involved in central chemoreception responding to CO2/pH and displaying a high percentage of chemosensitive neurons (>80%). However, there are no studies about the LC-mediated hypercapnic ventilation performed in females. Therefore, we assessed the role of noradrenergic LC neurons in non-ovariectomized (NOVX), ovariectomized (OVX) and estradiol (E2)-treated ovariectomized (OVX+E2) rats in respiratory response to hypercapnia, using a 6-hydroxydopamine (6-OHDA) – lesion model. A reduction in the number of tyrosine hydroxylase (TH) immunoreactive neurons (51–90% in 3 animals of NOVX group, 20–42% of lesion in 5 animals of NOVX females, 61.3% for OVX and 62.6% for OVX+E2 group) was observed seven days after microinjection of 6-OHDA in the LC. The chemical lesion of the LC resulted in decreased respiratory frequency under normocapnic conditions in OVX and OVX+E2 group. Hypercapnia increased ventilation in all groups as consequence of increases in respiratory frequency (fR) and tidal volume (VT). Nevertheless, the hypercapnic ventilatory response was significantly decreased in 6-OHDA-NOVX>50% rats compared with SHAM-NOVX group and with females that had 20–42% of LC lesion. In OVX and OVX+E2 lesioned groups, no difference in CO2 ventilatory response was observed when compared to SHAM-OVX and SHAM-OVX+E2 groups, respectively. Neither basal body temperature (Tb) nor Tb reduction in response to hypercapnia were affected by E2 treatment, ovariectomy or LC lesion. Thus, our data show that LC noradrenergic neurons seem to exert an excitatory role on the hypercapnic ventilatory response in female rats, as evidenced by the results in NOVX animals with LC lesioned more than 50%; however, this modulation is not observed in OVX and OVX+E2 rats. In addition, LC noradrenergic neurons of OVX females seem to provide a tonic excitatory drive to maintain breathing frequency in normocapnia, and this response may not to be functionally influenced by E2.

Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe.

Cerebral blood flow is highly sensitive to changes in CO2/H+ where an increase in CO2/H+ causes vasodilation and increased blood flow. Tissue CO2/H+ also functions as the main stimulus for breathing by activating chemosensitive neurons that control respiratory output. Considering that CO2/H+-induced vasodilation would accelerate removal of CO2/H+ and potentially counteract the drive to breathe, we hypothesize that chemosensitive brain regions have adapted a means of preventing vascular CO2/H+-reactivity. Here, we show in rat that purinergic signaling, possibly through P2Y2/4 receptors, in the retrotrapezoid nucleus (RTN) maintains arteriole tone during high CO2/H+ and disruption of this mechanism decreases the CO2ventilatory response. Our discovery that CO2/H+-dependent regulation of vascular tone in the RTN is the opposite to the rest of the cerebral vascular tree is novel and fundamentally important for understanding how regulation of vascular tone is tailored to support neural function and behavior, in this case the drive to breathe.

Disordered Breathing In An Aged Model of Ischemic Stroke

Respiratory dysfunction is a common complication of stroke associated with increased mortality. Stroke‐disorder breathing typically presents as Cheyne‐Stokes respiration which is thought to result from hyper‐activation of central chemoreceptors. We test this hypothesis by characterizing the CO2 ventilatory response before and after ischemic stroke. Further, since neurons in the retrotrapezoid nucleus are important chemoreceptors and their activity is regulated by KCNQ channels, we also test whether KCNQ channels can be targeted for the treatment of stroke related breathing problems. We used aged mice for these experiments because stroke mainly affects the elderly. Stroke was induced by middle cerebral artery occlusion (MCAO) and breathing was measured by plethysmography. Sham animals are subjected to the same surgery but with no occlusion. All MCAO‐treated mice exhibited hypoventilation with increased apneas (both frequency and duration) that were often preceded by short bursts of respiratory activity. Stroked mice also showed decreased respiratory stability as evidenced by a drop in approximate entropy. However, the ventilatory response to CO2 as similar between stroke and sham and systemic injection of retigabine further suppressed basal respiratory activity in MCAO/sham mice. These results show that MCAO‐treated mice exhibit a phenotype reminiscent of periodic breathing in stroke patients and they suggest that increased chemoreceptor gain is not the underlying cause of stroke‐disorder breathing.

Sex and Acetazolamide Effects on Chemoreflex and Periodic Breathing During Sleep at Altitude

Nocturnal periodic breathing occurs more frequently in men than in women with various clinical and pathophysiologic conditions. The mechanisms accounting for this sex-related difference are not completely understood. Acetazolamide effectively counteracts nocturnal periodic breathing, but it has been investigated almost exclusively in men. Our aim was to explore possible determinants of nocturnal periodic breathing in a high-altitude setting both in men and in women. We hypothesized that increased hypoxic chemosensitivity in men could be associated with the development of nocturnal periodic breathing at altitude more frequently than in women, and that acetazolamide, by leftward shifting the CO2 ventilatory response, could improve nocturnal periodic breathing at altitude in a sex-independent manner. Forty-four healthy lowlanders (21 women), randomized to acetazolamide or placebo, underwent cardiorespiratory sleep studies at sea level off treatment and under treatment on the first night after arrival at a 4,559-m altitude. Hypoxic and hypercapnic chemosensitivities were assessed at sea level. Men, more frequently than women, exhibited increased hypoxic chemosensitivity and displayed nocturnal periodic breathing at altitude. Acetazolamide leftward shifted the CO2 set point and, at altitude, improved oxygenation and reduced periodic breathing in both sexes, but to a larger extent in men. Hypoxic chemosensitivity directly correlated with the number of apneas/hypopneas at altitude in the placebo group but not in the acetazolamide group. The greater severity of periodic breathing during sleep displayed by men at altitude could be attributed to their increased hypoxic chemosensitivity. Acetazolamide counteracted the occurrence of periodic breathing at altitude in both sexes, modifying the apneic threshold and improving oxygenation. EU Clinical Trials Register, EudraCT; No.: 2010-019986-27; URL: https://www.clinicaltrialsregister.eu.

Neurochemical and electrical modulation of the locus coeruleus: contribution to CO2drive to breathe.

The locus coeruleus (LC) is a dorsal pontine region, situated bilaterally on the floor of the fourth ventricle. It is considered to be the major source of noradrenergic innervation in the brain. These neurons are highly sensitive to CO2/pH, and chemical lesions of LC neurons largely attenuate the hypercapnic ventilatory response in unanesthetized adult rats. Developmental dysfunctions in these neurons are linked to pathological conditions such as Rett and sudden infant death syndromes, which can impair the control of the cardio-respiratory system. LC is densely innervated by fibers that contain glutamate, serotonin, and adenosine triphosphate, and these neurotransmitters strongly affect LC activity, including central chemoreflexes. Aside from neurochemical modulation, LC neurons are also strongly electrically coupled, specifically through gap junctions, which play a role in the CO2 ventilatory response. This article reviews the available data on the role of chemical and electrical neuromodulation of the LC in the control of ventilation.

Orexin induces excitation of respiratory neuronal network in isolated brainstem spinal cord of neonatal rat

Endogenous neuropeptides known as orexins (hypocretins) play important roles in the regulation of feeding, drinking, endocrine function, and sleep/wakefulness. Orexin neuron projection sites include the rostral ventrolateral medulla of brainstem, which is related to the control of breathing. Previous studies suggest that orexins modulate the central CO2 ventilatory response during wakefulness in rodent. In the present study, we examined the effects of the orexinergic system on central respiratory control by adding orexin into a superfusion medium in the isolated brainstem–spinal cord of neonatal rat. Exposure to orexin B resulted in dose-dependent increases in C4 burst rate via brainstem, but not spinal cord. These increases in C4 burst rate induced concomitant increases in the depolarizing cycle rate of pre-inspiratory (Pre-I) and inspiratory (Insp) neurons. Tonic discharge was induced on C4 recording, although the rhythmic bursts of Pre-I and Insp neurons were maintained. Expiratory (Exp) neurons were also depolarized on administration of orexin B. Our findings indicate that orexin B activates central respiratory activity, mainly through depolarization and decreases in membrane resistance in Pre-I and Insp neurons, and possibly through early initiation of the expiratory phase induced by depolarization of Exp neurons.

Age and gender influence the cardiorespiratory function and metabolic rate of broiler chicks during normocapnia and hypercapnia

Pulmonary ventilation (V⋅E), body temperature (Tb), mean arterial pressure (MAP), heart rate (fH) and metabolic rate (V⋅O2) were measured in 10 (d10)- and 21 (d21)-day-old male and female chicks exposed to 7% CO2. Under normocapnia, V⋅E was higher in d10 chicks than in d21 due to a higher tidal volume; in females a higher respiratory frequency (fR) was also observed. The d10 birds presented higher fH and V⋅O2. The d21 females showed the highest CO2 ventilatory response due to increased fR. MAP did not change during hypercapnia while a hypercapnic bradycardia occurred, except in d21 females. Hypercapnia induced a drop in Tb in all groups and an increase in V⋅O2 in d21 males. Overall, no gender effect is observed in cardiorespiratory and metabolic variables in d10 and d21 chicks under normocapnia, the differences in V⋅E and fH between ages may be related to distinct metabolic demands of these phases. The d21 female chicks seem to be more sensitive to hypercapnia.

Conditional knockdown of Kir4.1 in astrocytes blunts the hypercapnic respiratory response in awake mice (872.7)

Central chemoreception is the mechanisms by which the brain regulates breathing in response to changes in tissue CO2/H+. The retrotrapezoid nucleus (RTN) has been identified as a key locus for central respiratory control. Neurons in this region sense CO2/H+ in part by inhibition of TASK‐2 channels. RTN astrocytes are also chemosensitive and CO2‐evoked release of the gliotransmitter ATP most likely occurs via hemichannels. However, RTN astrocytes also respond to bath acidification with ~8 mV depolarization, which is mediated by inhibition of a Kir4.1‐like conductance. The contribution of this pH sensitive current in RTN astrocytes to central respiratory drive is yet to be determined. Here we generate a tamoxifen inducible, astrocyte specific Kir4.1 knockout (ciKir4.1KO) by crossing GFAP‐CreERT2 and a Kir4.1 floxed mouse lines. Whole‐body plethysmography experiments performed on 6 week old mice show that ciKir4.1KO animals breathe normally control conditions but exhibit a reduced tidal volume response to CO2 compared to tamoxifen treated GFAP‐CreERT2 Kir4.1 wild type (i.e., control) mice. These results suggest that Kir4.1 channels in astrocytes contribute to the CO2 ventilatory response in awake mice.Grant Funding Source: NIH HL104101 (DKM)