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Suvorexant (Belsomra(R)), a dual orexin receptor antagonist widely used in the treatment of insomnia, inhibits the arousal system in the brain. However, the drug’s ventilatory effects have not been fully explored. This study aims to investigate the expression of orexin receptors in respiratory neurons and the effects of suvorexant on ventilation. Immunohistology of brainstem orexin receptor OX2R expression was performed in adult mice (n = 4) in (1) rostral ventral respiratory group (rVRG) neurons projecting to the phrenic nucleus (PhN) retrogradely labeled by Fluoro-Gold (FG) tracer, (2) neurons immunoreactive for paired like homeobox 2b (Phox2b) in the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), and (3) neurons immunoreactive for neurokinin 1 receptor (NK1R) and somatostatin (SST) in the preBötzinger complex (preBötC). Additionally, we measured in vivo ventilatory responses to hyperoxic hypercapnia (5% CO2) and hypoxia (10% O2) before and after suvorexant pretreatment (10 and cumulative 100 mg/kg) in unrestrained mice (n = 10) in a body plethysmograph. We found the OX2R immunoreactive materials in pFRG/RTN Phox2b and preBötC NK1R/SST immunoreactive neurons but not in FG-labeled rVRG neurons, which suggests the involvement of orexin in respiratory control. Further, suvorexant expressly suppressed the hypercapnic ventilatory augmentation, otherwise unaffecting ventilation. Central orexin is involved in shaping the hypercapnic ventilatory chemosensitivity. Suppression of hypercapnic ventilatory augmentation by the orexin receptor antagonist suvorexant calls for caution in its use in pathologies that may progress to hypercapnic respiratory failure, or sleep-disordered breathing. Clinical trials are required to explore the role of targeted pharmacological inhibition of orexin in ventilatory pathologies.

Chronic intermittent hypoxia (CIH) has been used as a model to mimic nocturnal apnea, which is associated with hypertension. One of the mechanisms for hypertension in patients with nocturnal apnea is an enhancement of the plasma membrane response to acute hypoxia in carotid body glomus cells. Hypoxia is known to induce depolarization via inhibiting TWIK-related acid-sensitive K+ (TASK) channels, one type of leak K+ channels, in glomus cells. The present experiment was undertaken to immunocytochemically investigate the effects of CIH on the expression and intracellular localization of TASK1 channels and p11 that critically affect the trafficking of TASK1 to the cell surface. The expression levels of TASK1 proteins and p11 and their intracellular localization in rat carotid body glomus cells were not noticeably affected by CIH, suggesting that the enhanced membrane response to acute hypoxia is not due to an increase in surface TASK channels.

Microglia modulate cardiorespiratory activities during chronic hypoxia. It has not been clarified whether microglia are involved in the cardiorespiratory responses to acute hypoxia. Here we investigated this issue by comparing cardiorespiratory responses to two levels of acute hypoxia (13% O2 for 4 min and 7% O2 for 5 min) in conscious unrestrained rats before and after systemic injection of minocycline (MINO), an inhibitor of microglia activation. MINO increased blood pressure but not lung ventilation in the control normoxic condition. Acute hypoxia stimulated cardiorespiratory responses in MINO-untreated rats. MINO failed to significantly affect the magnitude of hypoxia-induced blood pressure elevation. In contrast, MINO tended to suppress the ventilatory responses to hypoxia. We conclude that microglia differentially affect cardiorespiratory regulation depending on the level of blood oxygenation. Microglia suppressively contribute to blood pressure regulation in normoxia but help maintain ventilatory augmentation in hypoxia, which underscores the dichotomy of central regulatory pathways for both systems.

Dyspnea is defined as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. It is a common symptom among patients with respiratory diseases that reduces daily activities, induces deconditioning, and is self-perpetuating. Although clinical interventions are needed to reduce dyspnea, its underlying mechanism is poorly understood depending on the intertwined peripheral and central neural mechanisms as well as emotional factors. Nonetheless, experimental and clinical observations suggest that dyspnea results from dissociation or a mismatch between the intended respiratory motor output set caused by the respiratory neuronal network in the lower brainstem and the ventilatory output accomplished. The brain regions responsible for detecting the mismatch between the two are not established. The mechanism underlying the transmission of neural signals for dyspnea to higher sensory brain centers is not known. Further, information from central and peripheral chemoreceptors that control the milieu of body fluids is summated at higher brain centers, which modify dyspneic sensations. The mental status also affects the sensitivity to and the threshold of dyspnea perception. The currently used methods for relieving dyspnea are not necessarily fully effective. The search for more effective therapy requires further insights into the pathophysiology of dyspnea.

As blood oxygenation decreases (hypoxemia), mammals mount cardiorespiratory responses, increasing oxygen to vital organs. The carotid bodies are the primary oxygen chemoreceptors for breathing, but sympathetic-mediated cardiovascular responses to hypoxia persist in their absence, suggesting additional high-fidelity oxygen sensors. We show that spinal thoracic sympathetic preganglionic neurons are excited by hypoxia and silenced by hyperoxia, independent of surrounding astrocytes. These spinal oxygen sensors (SOS) enhance sympatho-respiratory activity induced by CNS asphyxia-like stimuli, suggesting they bestow a life-or-death advantage. Our data suggest the SOS use a mechanism involving neuronal nitric oxide synthase 1 (NOS1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). We propose NOS1 serves as an oxygen-dependent sink for NADPH in hyperoxia. In hypoxia, NADPH catabolism by NOS1 decreases, increasing availability of NADPH to NOX and launching reactive oxygen species–dependent processes, including transient receptor potential channel activation. Equipped with this mechanism, SOS are likely broadly important for physiological regulation in chronic disease, spinal cord injury, and cardiorespiratory crisis.

In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO2) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO2 (PaCO2) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO2 concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO2 production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO2 are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO2 (PtcCO2). PtcCO2 monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO2 is inferior to PtcCO2 as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO2 reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO2 has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).

The hypothalamus is a higher center of the autonomic nervous system and maintains essential body homeostasis including respiration. The paraventricular nucleus, perifornical area, dorsomedial hypothalamus, and lateral and posterior hypothalamus are the primary nuclei of the hypothalamus critically involved in respiratory control. These hypothalamic nuclei are interconnected with respiratory nuclei located in the midbrain, pons, medulla and spinal cord. We provide an extensive review of the role of the above hypothalamic nuclei in the maintenance of basal ventilation, and modulation of respiration in hypoxic and hypercapnic conditions, during dynamic exercise, in awake and sleep states, and under stress. Dysfunction of the hypothalamus causes abnormal breathing and hypoventilation. However, the cellular and molecular mechanisms how the hypothalamus integrates and modulates autonomic and respiratory functions remain to be elucidated.

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots (P < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings.

Astrocytes are thought to play a crucial role in providing structure to the spinal cord and maintaining efficient synaptic function and metabolism because their fine processes envelop the synapses of neurons and form many neuronal networks within the central nervous system (CNS). To investigate whether putative astrocytes and putative neurons distributed on the ventral horn play a role in the modulation of lumbar locomotor central pattern generator (CPG) networks, we used extracellular recording and optical imaging techniques and recorded the neural output from the left L5 ventral root and the calcium activity of putative astrocytes and neurons in the L5 ventral horn at the same time when activating an isolated L1-L5 spinal cord preparation from rats aged 0-2 days. Optical measurements detected cells that showed a fluorescence intensity change under all experimental conditions, namely, (1) 5-HT + NMDA, (2) TTX, and (3) TTX + Low K

Psychological stress activates the hypothalamus, augments the sympathetic nervous output, and elevates blood pressure via excitation of the ventral medullary cardiovascular regions. However, anatomical and functional connectivity from the hypothalamus to the ventral medullary cardiovascular regions has not been fully elucidated. We investigated this issue by tract-tracing and functional imaging in rats. Retrograde tracing revealed the rostral ventrolateral medulla was innervated by neurons in the ipsilateral dorsomedial hypothalamus (DMH). Anterograde tracing showed DMH neurons projected to the ventral medullary cardiovascular regions with axon terminals in contiguity with tyrosine hydroxylase-immunoreactive neurons. By voltage-sensitive dye imaging, dynamics of ventral medullary activation evoked by electrical stimulation of the DMH were analyzed in the diencephalon-lower brainstem-spinal cord preparation of rats. Although the activation of the ventral medulla induced by single pulse stimulation of the DMH was brief, tetanic stimulation caused activation of the DMH sustained into the post-stimulus phase, resulting in delayed recovery. We suggest that prolonged excitation of the DMH, which is triggered by tetanic electrical stimulation and could also be triggered by psychological stress in a real life, induces further prolonged excitation of the medullary cardiovascular networks, and could contribute to the pathological elevation of blood pressure. The connectivity from the DMH to the medullary cardiovascular networks serves as a chronological amplifier of stress-induced sympathetic excitation. This notion will be the anatomical and pathophysiological basis to understand the mechanisms of stress-induced sustained augmentation of sympathetic activity.

Autonomic respiratory rhythm is generated in the neuronal networks in the lower brainstem, and the generated neural respiratory output is transmitted to respiratory muscles via cranial and spinal cord motor nerves to control upper airway patency and intrathoracic pressure. Among the respiratory neuronal networks, the pre-Botzinger Complex located in the bilateral ventrolateral medulla is the kernel for respiratory rhythm generation. In this chapter, we overview the localization of the neuronal networks and anatomical and physiological connectivity among the respiratory neurons. We also introduce the influential theories on the physiological mechanisms of respiratory rhythm generation and discuss how respiratory rhythm is disturbed in pathological conditions.

ATP-sensitive potassium (KATP) channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a regulatory sulfonylurea receptor subunit (SUR1, SUR2A or SUR2B). Although Kir6.2 is widely distributed in the brain, the mechanisms that underlie the impact of Kir6.2 on emotional behavior are not yet fully understood. To clarify the role of Kir6.2 in emotional behavior, in the present study, we investigated the behavioral characteristics of Kir6.2-knockout (Kir6.2-/-) mice. Kir6.2-/- mice showed impaired general behavior in a locomotor activity test and open field test. In addition, anxiety-like behavior was observed in the open field test, elevated plus-maze test and light-dark test. In particular, excessive anxiety-like behavior was observed in female Kir6.2-/- mice. Moreover, we investigated whether Kir6.2 is expressed on monoamine neurons in the brain. Immunohistochemical studies showed that Kir6.2 was co-localized with tryptophan hydroxylase (TPH), a marker of serotonergic neurons, in dorsal raphe nuclei. Kir6.2 was also co-localized with tyrosine hydroxylase (TH), a marker of dopaminergic/noradrenergic neurons, in the ventral tegmental area and locus coeruleus. Next, we checked the protein levels of TH and TPH in the midbrain. Interestingly, TPH expression was significantly elevated in female Kir6.2-/- mice. These results suggest that Kir6.2 in monoamine neurons, especially serotonergic neurons, could play a key role in emotional behavior.

Respiratory activities are produced by medullary respiratory rhythm generators and are modulated from various sites in the lower brainstem, and which are then output as motor activities through premotor efferent networks in the brainstem and spinal cord. Over the past few decades, new knowledge has been accumulated on the anatomical and physiological mechanisms underlying the generation and regulation of respiratory rhythm. In this review, we focus on the recent findings and attempt to elucidate the anatomical and functional mechanisms underlying respiratory control in the lower brainstem and spinal cord. Electronic supplementary material The online version of this article (doi:10.1007/s12576-016-0475-y) contains supplementary material, which is available to authorized users.

Hypoxia sensors are essential for regulating local oxygen (O

Seizures are induced when subjects are exposed to severe hypoxia. It is followed by ventilatory fall-off and eventual respiratory arrest, which may underlie the pathophysiology of death in patients with epilepsy and severe respiratory disorders. However, the mechanisms of hypoxia-induced seizures have not been fully understood. Because astrocytes are involved in various neurological disorders, we aimed to investigate whether astrocytes are operational in seizure generation and respiratory arrest in a severe hypoxic condition. We examined the effects of astrocytic activation blockade on responses of EEG and ventilation to severe hypoxia. Adult mice were divided into two groups; in one group (n = 24) only vehicle was injected, and in the other group (n = 24) arundic acid, an inhibitory modulator of astrocytic activation, was administered before initiation of recording. After recording EEG and ventilation by whole body plethysmography in room air, the gas in the recording chamber was switched to 5% oxygen (nitrogen balanced) until a seizure and ventilatory depression occurred, followed by prompt switch back to room air. Severe hypoxia initially increased ventilation, followed by a seizure and ventilatory suppression in all mice examined. Fourteen mice without arundic acid showed respiratory arrest during loading of hypoxia. However, 22 mice pretreated with arundic acid did not suffer from respiratory arrest. Time from the onset of hypoxia to the occurrence of seizures was significantly longer in the group with arundic acid than that in the group without arundic acid. We suggest that blockade of astrocytic activation delays the occurrence of seizures and prevents respiratory arrest.

Summary Hypoxia sensors are essential for regulating local oxygen (O2) homeostasis within the body. This is especially pertinent within the CNS, which is particularly vulnerable to O2 deprivation due to high energetic demand. Here, we reveal hypoxia-monitoring function exerted by astrocytes through an O2-regulated protein trafficking mechanism within the CNS. Strikingly, cultured mouse astrocytes isolated from the parafacial respiratory group (pFRG) and retrotrapezoid nucleus (RTN) region are capable of rapidly responding to moderate hypoxia via the sensor cation channel transient receptor potential (TRP) A1 but, unlike multimodal sensory neurons, are inert to hyperoxia and other TRPA1 activators (carbon dioxide, electrophiles, and oxidants) in normoxia. Mechanistically, O2 suppresses TRPA1 channel activity by protein internalization via O2-dependent proline hydroxylation and subsequent ubiquitination by an E3 ubiquitin ligase, NEDD4-1 (neural precursor cell-expressed developmentally down-regulated protein 4). Hypoxia inhibits this process and instantly accumulates TRPA1 proteins at the plasma membrane, inducing TRPA1-mediated Ca2+ influx that triggers ATP release from pFRG/RTN astrocytes, potentiating respiratory center activity. Furthermore, astrocyte-specific Trpa1 disruption in a mouse brainstem-spinal cord preparation impedes the amplitude augmentation of the central autonomic respiratory output during hypoxia. Thus, reversible coupling of the TRPA1 channels with O2-dependent protein translocation allows astrocytes to act as acute hypoxia sensors in the medullary respiratory center.

Background and objective Body weight of patients with obstructive sleep apnea after initiation of nasal continuous positive airway pressure appears to increase. We hypothesized that intermittent hypoxia (IH) will decrease energy expenditure (EE), and that normoxic recovery will lead to body weight gains. Methods C57BL/6 J male mice were exposed to either 12 h/day of mild IH (alternating FIO2-10-11% and 21%; 640 s cycle), or severe IH (FIO2-6-7%-21%; 180 s cycle) or sham IH daily for 4 or 8 weeks. After exposures, EE was evaluated while mice were kept under normoxia for 5 weeks and organ histology was evaluated. Results EE was not decreased by IH. However, visceral white adipocyte size after normoxic recovery was significantly increased in severe IH in an intensity-dependent manner. Conclusion Our hypothesis that IH would decrease EE was not corroborated. However, IH and normoxic recovery seem to promote severity-dependent enlargement of visceral adipocytes, likely reflecting altered energy preservation mechanisms induced by IH.

The diaphragm is driven by phrenic motoneurons that are located in the cervical spinal cord. Although the anatomical location of the phrenic nucleus and the function of phrenic motoneurons at a single cellular level have been extensively analyzed, the spatiotemporal dynamics of phrenic motoneuron group activity have not been fully elucidated. In the present study, we analyzed the functional and structural characteristics of respiratory neuron population in the cervical spinal cord at the level of the phrenic nucleus by voltage imaging, together with histological analysis of neuronal and astrocytic distribution in the cervical spinal cord. We found spatially distinct two cellular populations that exhibited synchronized inspiratory activity on the transversely cut plane at C4–C5 levels and on the ventral surface of the mid cervical spinal cord in the isolated brainstem–spinal cord preparation of the neonatal rat. Inspiratory activity of one group emerged in the central portion of the ventral horn that corresponded to the central motor column, and the other appeared in the medial portion of the ventral horn that corresponded to the medial motor column. We identified by retrogradely labeling study that the anatomical distributions of phrenic and scalene motoneurons coincided with optically detected central and medial motor regions, respectively. Furthermore, we anatomically demonstrated closely located features of putative motoneurons, interneurons and astrocytes in these regions. Collectively, we report that phrenic and scalene motoneuron populations show synchronized inspiratory activities with distinct anatomical locations in the mid cervical spinal cord.

BackgroundUsual clinical practice for arterial blood gas analysis (BGA) in conscious patients involves a one-time arterial puncture to be performed after a resting period of 20–30 min. The aim of this study was to evaluate the use of transcutaneous BGA for estimating this gold standard arterial BGA.MethodsSpontaneously breathing Asian adults (healthy volunteers and respiratory patients) were enrolled (n = 295). Transcutaneous PO2(PtcO2) and PCO2(PtcCO2) were monitored using a transcutaneous monitor (TCM4, Radiometer Medical AsP, Denmark) with sensors placed on the chest, forearm, earlobe or forehead. Transcutaneous BGA at 1-min intervals was compared with arterial BGA at 30 min. Reasonable steps to find severe hypercapnia with PaCO2 > 50 mmHg were evaluated.ResultsSensors on the chest and forearm were equally preferred and used because of small biases (n = 272). The average PCO2bias was close to 0 mmHg at 4 min, and was almost constant (4–5 mmHg) with PtcCO2being higher than PaCO2at ≥8 min. The limit of agreement for PCO2narrowed over time: ± 13.6 mmHg at 4 min, ± 7.5 mmHg at 12–13 min, and ± 6.3 mmHg at 30 min. The limit of agreement for PO2also narrowed over time (± 23.1 mmHg at 30 min). Subgroup analyses showed that the PaCO2and PaO2levels, gender, and younger age significantly affected the biases. All hypercapnia subjects with PaCO2 > 50 mmHg (n = 13) showed PtcCO2 ≥ 50 mmHg for until 12 min.ConclusionsAlthough PtcCO2is useful, it cannot completely replace PaCO2because PCO2occasionally showed large bias. On the other hand, the prediction of PaO2using PtcO2was unrealistic in Asian adults. PtcCO2 ≥ 50 mmHg for until 12 min can be used as a screening tool for severe hypercapnia with PaCO2 > 50 mmHg.

The pre-Bötzinger complex (preBötC) of the ventrolateral medulla is the kernel for inspiratory rhythm generation. However, it is not fully understood how inspiratory neural activity is generated in the preBötC and propagates to other medullary regions. We analyzed the detailed anatomical connectivity to and from the preBötC and functional aspects of the inspiratory information propagation from the preBötC on the transverse plane of the medulla oblongata. Tract-tracing with immunohistochemistry in young adult rats demonstrated that neurokinin-1 receptor- and somatostatin-immunoreactive neurons in the preBötC, which could be involved in respiratory rhythmogenesis, are embedded in the plexus of axons originating in the contralateral preBötC. By voltage-imaging in rhythmically active slices of neonatal rats, we analyzed origination and propagation of inspiratory neural activity as depolarizing wave dynamics on the entire transverse plane as well as within the preBötC. Novel combination of pharmacological blockade of glutamatergic transmission and mathematical subtraction of the video images under blockade from the control images enabled to extract glutamatergic signal propagations. By ultra-high-speed voltage-imaging we first demonstrated the inter-preBötC conduction process of inspiratory action potentials. Intra-preBötC imaging with high spatiotemporal resolution during a single spontaneous inspiratory cycle unveiled deterministic nonlinearities, i.e., chaos, in the population recruitment. Collectively, we comprehensively elucidated the anatomical pathways to and from the preBötC and dynamics of inspiratory neural information propagation: (1) From the preBötC in one side to the contralateral preBötC, which would synchronize the bilateral rhythmogenic kernels, (2) from the preBötC directly to the bilateral hypoglossal premotor and motor areas as well as to the nuclei tractus solitarius, and (3) from the hypoglossal premotor areas toward the hypoglossal motor nuclei. The coincidence of identified anatomical and functional connectivity between the preBötC and other regions in adult and neonatal rats, respectively, indicates that this fundamental connectivity is already well developed at the time of birth.

Objectives: Recent reports on venous blood gas analysis have shown that venous bicarbonate concentration is useful in the evaluation of the body acid-base status. Most of these reports have been based on the Bland-Altman analysis comparing arterial and venous blood gas values. We intended to elucidate any factors that decrease the agreement between venous and arterial bicarbonate concentrations, which might impair the usefulness of venous blood gas analysis. Methods: Healthy volunteers and patients with various diseases (n = 141) were evaluated by simultaneous arterial and venous blood sampling and Bland-Altman analysis. The venous-arterial bicarbonate concentration difference was compared between healthy volunteers and untreated respiratory alkalosis patients. Intentional hyperventilation (30 or 60 breaths/min, for 3 min) was also performed on 6 healthy volunteers and the venous-arterial bicarbonate concentration difference was evaluated. Results: The relative average bias in bicarbonate concentration was 2.00 mEq/l with venous bicarbonate higher than arterial bicarbonate with 95% limits of agreement of ±4.15 mEq/l. Hyperventilation challenges increased the venous-arterial bicarbonate concentration difference in an intensity-dependent manner. The venous-arterial bicarbonate concentration difference was higher in untreated respiratory alkalosis patients than in healthy volunteers (P Conclusion: Although venous bicarbonate may be useful to evaluate the body acid-base status, hyperventilation increases the venous-arterial bicarbonate concentration difference. Physicians should keep this phenomenon in mind.

This review tackles the unresolved issue of the existence of oxygen sensor in the body. The sensor that would respond to changes in tissue oxygen content, possibly along the hypoxia-normoxia-hyperoxia spectrum, rather than to a given level of oxygen, and would translate the response into lung ventilation changes, the major adaptive process. Studies on oxygen sensing, for decades, concentrated around the hypoxic ventilatory response generated mostly by carotid body chemoreceptor cells. Despite gaining a substantial insight into the cellular transduction pathways in carotid chemoreceptors, the exact molecular mechanisms of the chemoreflex have never been conclusively verified. The article briefly sums up the older studies and presents novel theories on oxygen, notably, hypoxia sensing. These theories have to do with the role of transient receptor potential cation TRPA1 channels and brain astrocytes in hypoxia sensing. Although both play a substantial role in shaping the ventilatory response to hypoxia, neither can yet be considered the ultimate sensor of hypoxia. The enigma of oxygen sensing in tissue still remains to be resolved.

Objective: The Japanese drug use system allowed the “once-daily use” of inhaled corticosteroid (ICS) fluticasone furoate (FF) combined with a long acting beta-2 agonist (LABA) vilanterol (VI) against asthma for the first time in 2013. Until then, patients with asthma had to use ICS at least twice-daily. We investigated the real-world efficacy and problems of this drug (FF/VI). Methods: This was an open-label, uncontrolled, within-group time-series (before-after) design. Prior treatments of asthma (twice-daily use of ICS with or without LABA) were switched to once-daily use of FF/VI (200 μg/25 μg). Subjects were evaluated by lung function tests prior to, and 2–3 months after, the initiation of FF/VI. Questions on the asthma control test (ACT) and preference of drugs were asked to patients. Results: One hundred and twenty-eight Japanese asthma outpatients were enrolled from 2014–2018 and 107 subjects completed the study. Peak flow, instantaneous flow at 75% of the forced vital capacity (V75), V50, maximum mid-expiratory flow rate, forced expiratory volume in 1 s, and ACT score in FF/VI-using subjects were significantly increased (all p

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the compound's innate bioactivity is an area of limited understanding. In this investigation we seek to determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of thermal pain stimulus, using a 55 °C hotplate design, in conscious mice. The latency of withdrawal behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5-15.5 g/kg) in the same mouse was taken as a measure of thermal endurance. The findings were that the latency, on average, amounted to 15-30 s and it differed inappreciably between the sequential DMSO conditions. Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous thermal pain perception. The findings do not lend support to those literature reports that point to the plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the findings concern the mouse's footpad nociceptors which have specific morphology and stimulus transduction pathways, which cannot exclude DMSO's antinociceptive influence on other types of pain or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous noxious heat stimulus should be further explored with alternative experimental designs.

Dimethyl sulfoxide (DMSO) is one of the most commonly used solvents for hydrophobic substances in biological experiments. In addition, the compound exhibits a plethora of bioactivities, which makes it of potential pharmacological use of its own. The influence on respiration, and thus on arterial blood oxygenation, of DMSO is unclear, contentious, and an area of limited study. Thus, in the present investigation we set out to determine the influence on lung ventilation of cumulated doses of DMSO in the amount of 0.5, 1.5, 3.5, 7.5, and 15.5 g/kg; each dose given intraperitoneally at 1 h interval in conscious mice. Ventilation and its responses to 7 % hypoxia (N(2) balanced) were recorded in a whole body plethsymograph. We demonstrate a dose-dependent inhibitory effect of DMSO on lung ventilation and its hypoxic responsiveness, driven mostly by changes in the tidal component. The maximum safe dose of DMSO devoid of meaningful consequences for respiratory function was 3.5 g/kg. The dose of 7.5 g/kg of DMSO significantly dampened respiration, with yet well preserved hyperventilatory response to hypoxia. The highest dose of 15.5 g/kg severely impaired ventilation and its responses. The study delineates the safety profile of DMSO regarding the respiratory function which is essential for maintaining proper tissue oxygenation. Caution should be exercised concerning dose concentration of DMSO.

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the compound’s innate bioactivity is an area of limited understanding. In this investigation we seek to determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of thermal pain stimulus, using a 55 °C hotplate design, in conscious mice. The latency of withdrawal behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5–15.5 g/kg) in the same mouse was taken as a measure of thermal endurance. The findings were that the latency, on average, amounted to 15–30 s and it differed inappreciably between the sequential DMSO conditions. Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous thermal pain perception. The findings do not lend support to those literature reports that point to the plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the findings concern the mouse’s footpad nociceptors which have specific morphology and stimulus transduction pathways, which cannot exclude DMSO’s antinociceptive influence on other types of pain or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous noxious heat stimulus should be further explored with alternative experimental designs.