Search Results (8)

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by an impaired ventilatory response to hypercapnia and hypoxia, particularly during sleep, and frequently associated with autonomic dysfunction. It is caused by pathogenic variants in the PHOX2B gene. Although CCHS is typically diagnosed in the neonatal period, milder forms may present later in infancy or childhood, often triggered by respiratory infections. Case presentation: We report the case of 16-month-old male diagnosed with CCHS following an episode of hypoxemic–hypercapnic respiratory failure during respiratory syncytial virus (RSV) infection. His medical history included neonatal respiratory distress requiring oxygen therapy and recurrent wheezing. At 15 months, he developed acute respiratory distress with severe hypercapnia (PaCO₂ 70 mmHg), requiring admission to the Pediatric Intensive Care Unit and invasive mechanical ventilation. Persistent sleep-related hypercapnia and hypoxemia prompted evaluation for central hypoventilation, confirmed by means of transcutaneous capnography and nocturnal pulse oximetry. Genetic testing revealed a de novo nonsense mutation in exon 1 of PHOX2B (p.Tyr14Ter). Brain magnetic resonance imaging showed diffuse white matter changes suggestive of gliosis. Further investigations identified early-onset systemic hypertension, requiring antihypertensive therapy. The patient was discharged on nocturnal non-invasive ventilation and enrolled in a neurodevelopmental rehabilitation program. Conclusions: This case highlights the phenotypic variability of CCHS and the importance of considering this diagnosis in children presenting with unexplained hypercapnia and sleep-related hypoxemia. It underscores the need for comprehensive autonomic evaluation, including blood pressure monitoring. The p.Tyr14Ter variant may allow partial protein function, potentially accounting for the relatively mild phenotype. Full article

Background: Carbon dioxide (CO₂) is traditionally regarded as a metabolic by-product; however, growing evidence indicates that it plays an active regulatory role across multiple physiological systems. Acute hypercapnia elicits respiratory, cardiovascular, metabolic, immune, and neurocognitive responses, some of which may transiently influence exercise performance. This narrative review summarizes current evidence on CO₂ inhalation in healthy individuals and critically evaluates whether controlled hypercapnia may serve as a targeted stimulus in sport and exercise contexts. Methods: A narrative review of peer-reviewed English-language articles indexed in PubMed and Web of Science was conducted. A narrative approach was chosen due to the marked heterogeneity of study designs, hypercapnia-induction methods (e.g., CO₂ inhalation, voluntary hypoventilation, increased respiratory dead space), participant characteristics, and outcome measures, which precluded systematic synthesis. The review focused on studies involving healthy or physically active individuals and examined acute or short-term hypercapnic exposure. No strict publication date limits were applied. Studies conducted exclusively in clinical populations were excluded. Results: Short-term, controlled hypercapnia reliably increases ventilation, sympathetic activation, cerebral and muscular blood flow, and metabolic stress. Certain hypercapnia-based interventions—such as voluntary hypoventilation or added respiratory dead space—may enhance buffering capacity, reduce lactate accumulation and improve maximal oxygen uptake (VO₂max) during submaximal efforts and repeated-sprint performance during high-intensity, short-duration exercise. However, CO₂ inhalation frequently induces dyspnea, anxiety, and cognitive disruption, and higher concentrations pose clear safety risks. Current evidence does not support long-term improvements in VO₂max or long-duration endurance performance following hypercapnia-based interventions. Conclusions: Controlled, intermittent hypercapnia may provide a targeted metabolic and ventilatory stimulus that enhances tolerance to high-intensity exercise, yet its application remains experimental and context-dependent. The risks associated with CO₂ inhalation in healthy individuals currently outweigh its potential benefits, and safe, effective training protocols have not been fully established. Further research is needed to clarify the mechanisms, long-term adaptations, and practical utility of hypercapnia-based training strategies. Full article

Sudden unexpected death in epilepsy (SUDEP) is a critical concern for individuals suffering from epilepsy, with respiratory dysfunction playing a significant role in its pathology. Fatal seizures are often characterized by central apnea and hypercapnia (elevated CO₂ levels), indicating a failure in ventilatory control. Research has shown that both human epilepsy patients and animal models exhibit a reduced hypercapnic ventilatory response in the interictal (non-seizure) period, suggesting an impaired ability to regulate breathing in response to high CO₂ levels. This review examines the role of central chemoreceptors—specifically the retrotrapezoid nucleus, raphe nuclei, nucleus tractus solitarius, locus coeruleus, and hypothalamus in this pathology. These structures are critical for sensing CO₂ and maintaining respiratory homeostasis. Emerging evidence also implicates neuropeptidergic pathways within these chemoreceptive regions in SUDEP. Neuropeptides like galanin, pituitary adenylate cyclase-activating peptide (PACAP), orexin, somatostatin, and bombesin-like peptides may modulate chemosensitivity and respiratory function, potentially exacerbating respiratory failure during seizures. Understanding the mechanisms linking central chemoreception, respiratory control, and neuropeptidergic signaling is essential to developing targeted interventions to reduce the risk of SUDEP in epilepsy patients. Full article

The present study examined the hypothesis that changes in the oxidation–reduction state of thiol residues in functional proteins play a major role in the expression of the ventilatory responses in conscious rats that occur during a hypoxic–hypercapnic (HH) gas challenge and upon return to room air. A HH gas challenge in vehicle-treated rats elicited robust and sustained increases in minute volume (via increases in frequency of breathing and tidal volume), peak inspiratory and expiratory flows, and inspiratory and expiratory drives while minimally affecting the non-eupneic breathing index (NEBI). The HH-induced increases in these parameters, except for frequency of breathing, were substantially diminished in rats pre-treated with the potent and lipophilic disulfide-reducing agent, L,D-dithiothreitol (100 µmol/kg, IV). The ventilatory responses that occurred upon return to room air were also substantially different in dithiothreitol-treated rats. In contrast, pre-treatment with a substantially higher dose (500 µmol/kg, IV) of the lipophilic congener of the monosulfide, N-acetyl-L-cysteine methyl ester (L-NACme), only minimally affected the expression of the above-mentioned ventilatory responses that occurred during the HH gas challenge or upon return to room air. The effectiveness of dithiothreitol suggests that the oxidation of thiol residues occurs during exposure to a HH gas challenge and that this process plays an essential role in allowing for the expression of the post-HH excitatory phase in breathing. However, this interpretation is contradicted by the lack of effects of L-NACme. This apparent conundrum may be explained by the disulfide structure affording unique functional properties to dithiothreitol in comparison to monosulfides. More specifically, the disulfide structure may give dithiothreitol the ability to alter the conformational state of functional proteins while transferring electrons. It is also possible that dithiothreitol is simply a more efficient reducing agent following systemic injection, although one interpretation of the data is that the effects of dithiothreitol are not due to its reducing ability. Full article

Serotonin or 5-hydroxytryptamine (5-HT) is a ubiquitous neuro-modulator–transmitter that acts in the central nervous system, playing a major role in the control of breathing and other physiological functions. The midbrain, pons, and medulla regions contain several serotonergic nuclei with distinct physiological roles, including regulating the hypercapnic ventilatory response, upper airway patency, and sleep–wake states. Obesity is a major risk factor in the development of sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), recurrent closure of the upper airway during sleep, and obesity hypoventilation syndrome (OHS), a condition characterized by daytime hypercapnia and hypoventilation during sleep. Approximately 936 million adults have OSA, and 32 million have OHS worldwide. 5-HT acts on 5-HT receptor subtypes that modulate neural control of breathing and upper airway patency. This article reviews the role of 5-HT in SDB and the current advances in 5-HT-targeted treatments for SDB. Full article

Parkinson’s disease (PD) is a neurological disorder characterized by progressive degeneration of the substantia nigra that affects mainly movement control. However, pathological changes associated with the development of PD may also alter respiration and can lead to chronic episodes of hypoxia and hypercapnia. The mechanism behind impaired ventilation in PD is unclear. Therefore, in this study, we explore the hypercapnic ventilatory response in a reproducible reserpine-induced (RES) model of PD and parkinsonism. We also investigated how dopamine supplementation with L-DOPA, a classic drug used to treat PD, would affect the breathing and respiratory response to hypercapnia. Reserpine treatment resulted in decreased normocapnic ventilation and behavioral changes manifested as low physical activity and exploratory behavior. The respiratory rate and the minute ventilation response to hypercapnia were significantly higher in sham rats compared to the RES group, while the tidal volume response was lower. All of this appears to be due to reduced baseline ventilation values produced by reserpine. L-DOPA reversed reduced ventilation, indicating a stimulatory effect of DA on breathing, and showed the potency of DA supplementation in restoring normal respiratory activity. Full article

Despite the severe respiratory problems reducing the quality of life for Alzheimer’s disease (AD) patients, their causes are poorly understood. We aimed to investigate hypoxic and hypercapnic respiratory responses in a transgenic mouse model of AD (AβPP V717I) overexpressing AβPP and mimicking early-onset AD. The cholinesterase inhibitor rivastigmine and the NMDA receptor antagonist memantine were used to investigate the effects of drugs, used to treat AD cognitive dysfunction, on breathing in hypoxia and hypercapnia. We found a significant increase in the respiratory response to hypercapnia and no difference in the hypoxic response in APP+ mice, compared with the control group (APP−). Memantine had no effect on respiration in either group, including responses to hypoxia and hypercapnia. Rivastigmine depressed resting ventilation and response to hypercapnia irrespective of the mice genotype. Reduction in hypoxia-augmented ventilation by rivastigmine was observed only in APP+ mice, which exhibited lower acetylcholinesterase activity in the hippocampus. Treatment with rivastigmine reduced the enzyme activity in both groups equally in the hippocampus and brainstem. The increased ventilatory response to hypercapnia in transgenic mice may indicate alterations in chemoreceptive respiratory nuclei, resulting in increased CO₂ sensitivity. Rivastigmine is a potent reductant of normoxic and hypercapnic respiration in APP+ and APP− mice. Full article

Receptors of the transient receptor potential (TRP) channels superfamily are expressed in many tissues and have different physiological functions. However, there are few studies investigating the role of these channels in cardiorespiratory control in mammals. We assessed the role of central and peripheral TRPV1 receptors in the cardiorespiratory responses to hypoxia (10% O₂) and hypercapnia (7% CO₂) by measuring pulmonary ventilation ( ${\dot{\mathrm{V}}}_{\mathrm{E}}$ ), heart rate (HR), mean arterial pressure (MAP) and body temperature (Tb) of male Wistar rats before and after intraperitoneal (AMG9810 [2.85 µg/kg, 1 mL/kg]) or intracebroventricular (AMG9810 [2.85 µg/kg, 1 µL] or AMG7905 [28.5 μg/kg, 1 µL]) injections of TRPV1 antagonists. Central or peripheral injection of TRPV1 antagonists did not change cardiorespiratory parameters or Tb during room air and hypercapnic conditions. However, the hypoxic ventilatory response was exaggerated by both central and peripheral injection of AMG9810. In addition, the peripheral antagonist blunted the drop in Tb induced by hypoxia. Therefore, the current data provide evidence that TRPV1 channels exert an inhibitory modulation on the hypoxic drive to breathe and stimulate the Tb reduction during hypoxia. Full article