Hypercapnic Hypoxia Research Articles

Fos expression in A1/C1 neurons of rats exposed to hypoxia, hypercapnia, or hypercapnic hypoxia

The distribution of Fos expression in catecholaminergic neurons with immunoreactivity for dopamine β-hydroxylase (DBH) of the ventrolateral medulla was compared between rats exposed to hypoxia (10 % O2), hypercapnia (8 % CO2), and hypercapnic hypoxia (8 % CO2 and 10 % O2) for 2 h. Among the experimental groups, hypoxia-exposed rats had more Fos/DBH double-immunoreactive neurons than the control group (20 % O2) in the rostral area of the ventrolateral medulla, specifically in the range of + 150 μm to + 2,400 μm from the caudal end of the facial nerve nucleus. On the other hand, Fos/DBH double-immunoreactive neurons were scarcely observed in the ventrolateral medullary region of hypercapnia-exposed rats. The number of double-immunoreactive neurons in hypercapnic hypoxia-exposed rats was comparable to that in the control group. The present results suggest that adrenergic C1 neurons are specifically activated by hypoxia and are involved in the regulation of respiratory and circulatory functions.

Influence of hypercapnia and hypercapnic hypoxia on the heart rate response to apnea.

We aimed to determine the relative contribution of hypercapnia and hypoxia to the bradycardic response to apneas. We hypothesized that apneas with hypercapnia would cause greater bradycardia than normoxia, similar to the response seen with hypoxia, and that apneas with hypercapnic hypoxia would induce greater bradycardia than hypoxia or hypercapnia alone. Twenty-six healthy participants (12 females; 23 ± 2 years; BMI 24 ± 3 kg/m2) underwent three gas challenges: hypercapnia (+5 torr end tidal partial pressure of CO2 [PETCO2]), hypoxia (50 torr end tidal partial pressure of O2 [PETO2]), and hypercapnic hypoxia (combined hypercapnia and hypoxia), with each condition interspersed with normocapnic normoxia. Heart rate and rhythm, blood pressure, PETCO2, PETO2, and oxygen saturation were measured continuously. Hypercapnic hypoxic apneas induced larger bradycardia (-19 ± 16 bpm) than normocapnic normoxic apneas (-11 ± 15 bpm; p = 0.002), but had a comparable response to hypoxic (-19 ± 15 bpm; p = 0.999) and hypercapnic apneas (-14 ± 14 bpm; p = 0.059). Hypercapnic apneas were not different from normocapnic normoxic apneas (p = 0.134). After removal of the normocapnic normoxic heart rate response, the change in heart rate during hypercapnic hypoxia (-11 ± 16 bpm) was similar to the summed change during hypercapnia+hypoxia (-9 ± 10 bpm; p = 0.485). Only hypoxia contributed to this bradycardic response. Under apneic conditions, the cardiac response is driven by hypoxia.

Combined therapeutic acute intermittent hypercapnic hypoxia and exercise-based respiratory training improve breathing after chronic cervical spinal cord injury

Therapeutic acute intermittent hypoxia (tAIH) is simple, safe, and effective means of inducing respiratory motor plasticity and improving breathing in rodent models of acute cervical spinal cord injury (SCI). Unfortunately, tAIH effects on breathing function are less effective with chronic injury. On the other hand, tAIH restores non-respiratory (limb) motor function with chronic SCI, but only when combined with task specific training (TST). The effcacy of combined tAIH and respiratory TST on breathing ability in rodent models (or humans) with chronic SCI has not been investigated. Here, we explore the potential for tAIH and respiratory TST to increase breathing ability; we further differentiate automatic vs. volitional TST, since the ability to sustain independent breathing is dependent on automatic (and not volitional) breathing function, which relies on distinct neural pathways. Physical exercise increases breathing automatically in direct proportion to metabolic rate, regulating arterial blood gases by a mechanism independent of chemoreceptor feedback (i.e. “exercise hyperpnea”). Thus, in ongoing studies, we are exploring treadmill training as a form of task-specific respiratory training in rats with chronic cervical SCI. We focus on a refined tAIH protocol that combines hypoxia with hypercapnia during each episode (therapeutic acute intermittent hypercapnic hypoxia; or tAIHH), since preliminary data suggests that tAIHH is a more potent stimulus to respiratory motor plasticity vs. tAIH alone. Adult Sprague-Dawley rats with chronic C2 spinal cord hemisection were treated with either 4 weeks of either tAIHH (10, 5-min episodes of 10.5% O2, 4% inspired CO2) combined with treadmill exercise (30 min total run time, 30 cm/sec) or tAIHH alone. Breathing function was assessed in awake, freely moving rats using whole-body plethysmography. In preliminary analyses, breathing capacity (i.e., minute ventilation in response to maximal chemoreflex activation) was increased in chronically injured rats treated with daily tAIHH paired with treadmill training relative to rats treated with tAIHH alone (120.7mL/min/100g vs. 98.7mL/min/100g; p=0.0018). Similar improvements in breathing function were not observed with tAIHH alone. These are the first studies to investigate the therapeutic effcacy of combined tAIH and exercise-based respiratory training targeting automatic breathing. These initial results indicate that, similar to non-respiratory motor systems, pairing tAIHH with respiratory TST improves breathing function in rodents with chronic cervical SCI. Supported by: Craig H. Neilsen Foundation (SCIRP891379), and the McKnight Brain Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypercapnic hypoxia as a rehabilitation method for patients after ischemic stroke

ABSTRACT Introduction Experimental studies on animals have demonstrated a higher neuroprotective efficacy of hypercapnic hypoxia compared to normocapnic hypoxia. Respiratory training with hypercapnic hypoxia has shown a positive impact on the functional state of the nervous system in children with cerebral palsy (CP). It can be presumed that the combined effect of moderate hypercapnia and hypoxia will be promising for clinical application within the context of early rehabilitation after ischemic stroke. Methods A randomized triple-blind placebo-controlled study was conducted on 102 patients with ischemic stroke, aged 63.07 ± 12.1 years. All patients were diagnosed with ischemic stroke based on neuroimaging criteria and/or clinical criteria within the 48–72 hour timeframe. The experimental group (n = 50) underwent daily respiratory training with hypercapnic hypoxia (FetCO2 5–6%, FetO2 15–16%) using the ‘Carbonic’ device for 7–11 sessions of 20 minutes each day during the treatment process. The control group (placebo, n = 52) underwent training on a similar device modified for breathing atmospheric air. Neurological examinations were conducted on all patients before the study and on the day after completing the training course. Results The standard treatment demonstrated effectiveness in terms of neurological status scales in both groups. Intermittent exposure to hypercapnic hypoxia proved more effective in improving neurological function indicators in patients compared to the placebo group: NIHSS scale scores were 40% lower than in the placebo group (p < 0.001); mRS scale scores were 35% lower (p < 0.001); B-ADL-I and RMI indices were higher by 26% (p < 0.01) and 36% (p < 0.001), respectively; MoCA scale results were 13% higher (p < 0.05); HADS and BDI-II scale scores were lower by 35% (p < 0.05) and 25% (p < 0.05), respectively. The increase in MMSE scale scores in the intervention group was 54% higher (p < 0.001), and MoCA scale scores increased by 25% (p < 0.001). Conclusion Respiratory training with hypercapnic hypoxia improves the functional state of the nervous system in patients with ischemic stroke. After conducting further clarifying studies, hypercapnic hypoxia can be considered as an effective method of neurorehabilitation, which can be used as early as 48–72 hours after the onset of stroke.

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.

Ventilatory responses to independent and combined hypoxia, hypercapnia and hypobaria in healthy pre-term-born adults.

Pre-term birth is associated with physiological sequelae that persist into adulthood. In particular, modulated ventilatory responsiveness to hypoxia and hypercapnia has been observed in this population. Whether pre-term birth per se causes these effects remains unclear. Therefore, we aimed to assess pulmonary ventilation and blood gases under various environmental conditions, comparing 17 healthy prematurely born individuals (mean ± SD; gestational age, 28 ± 2weeks; age, 21 ± 4years; peak oxygen uptake, 48.1 ± 11.2mlkg-1 min-1 ) with 16 well-matched adults born at term (gestational age, 40 ± 1weeks; age, 22 ± 2years; peak oxygen uptake, 51.2 ± 7.7mlkg-1 min-1 ). Participants were exposed to seven combinations of hypoxia/hypobaria (equivalent to ∼3375m) and/or hypercapnia (3% CO2 ), at rest for 6min. Pulmonary ventilation, pulse oxygen saturation and the arterial partial pressures of O2 and CO2 were similar in pre-term and full-term individuals under all conditions. Higher ventilation in hypoxia compared to normoxia was only observed at terrestrial altitude, despite an equivalent (normobaric) hypoxic stimulus administered at sea level (0.138 ). Assessment of oscillations in key variables revealed that combined hypoxic hypercapnia induced greater underlying fluctuations in ventilation in pre-term individuals only. In general, higher pulse oxygen saturation fluctuations were observed with hypoxia, and lower fluctuations in end-tidal CO2 with hypercapnia, despite similar ventilatory oscillations observed between conditions. These findings suggest that healthy prematurely born adults display similar overall ventilation to their term-born counterparts under various environmental stressors, but that combined ventilatory stimuli could induce an irregular underlying ventilatory pattern. Moreover, barometric pressure may be an important factor when assessing ventilatory responsiveness to moderate hypoxic stimuli. KEY POINTS: Evidence exists for unique pulmonary and respiratory function under hypoxic conditions in adult survivors of pre-term birth. Whether pre-term birth per se causes these differences requires a comparison of conventionally healthy prematurely born adults with an appropriately matched sample of term-born individuals. According to the present data, there is no difference between healthy pre-term and well-matched term-born individuals in the magnitude of pulmonary ventilation or arterial blood gases during independent and combined hypobaria, hypoxia and hypercapnia. Terrestrial altitude (hypobaria) was necessary to induce differences in ventilation between normoxia and a hypoxic stimulus equivalent to ∼3375m of altitude. Furthermore, peak power in pulse oxygen saturation was similar between hypobaric normoxia and normobaric hypoxia. The observed similarities between groups suggest that ventilatory regulation under various environmental stimuli is not impaired by pre-term birth per se. Instead, an integrated combination of neonatal treatment strategies and cardiorespiratory fitness/disease status might underlie previously observed chemosensitivity impairments.

Ultrastructural Changes in Hippocampal Region CA1 Neurons After Exposure to Permissive Hypercapnia and/or Normobaric Hypoxia.

Isolated exposure to intermittent hypoxia and permissive hypercapnia activates signaling mechanisms that induce ultrastructural changes in mitochondria and endoplasmic reticulum, accompanied by the development of maximal ischemic tolerance in neurons under the combined influence of these factors. However, there are a lack of data on the combined impact of these factors on the ultrastructure of neuronal organelles. The present study aims to comparatively assess the ultrastructural changes in neurons following isolated and combined exposure to hypoxia and hypercapnia, as well as to correlate these changes with the neuroprotective potential previously observed for these factors. Following a 15-session course of 30-min exposures to permissive hypercapnia (PCO2≈50mmHg) and/or normobaric hypoxia (PO2≈150mmHg), morphometric assessment was conducted to evaluate the extent of ultrastructural changes in hippocampal neurons (mitochondria, perinuclear space, and granular endoplasmic reticulum). It was found that in hippocampal neurons from the CA1 region, permissive hypercapnia resulted in increased mitochondrial size, expansion of membranous compartments of the granular endoplasmic reticulum, and perinuclear space. Normobaric hypoxia affected only mitochondrial size, while hypercapnic hypoxia specifically widened the perinuclear space. These ultrastructural changes objectively reflect varying degrees of the influence of hypoxia and hypercapnia on organelles responsible for energy metabolism, anti-apoptotic, and synthetic functions of neurons. This confirms the effect of potentiation of their neuroprotective effects under combined exposure and highlights the dominant role of the hypercapnic component in this mechanism.

0901 An odd presentation of a hidden curse

Abstract Introduction Congenital central hypoventilation syndrome (CCHS) is a rare disorder of respiratory deficiency due to a mutation in the PHOX2B gene. Clinical presentation may be mild in certain individuals due to different levels of ventilatory dysregulation. Methods We present the findings of exogenous ventilatory challenge testing and polysomnography (PSG) performed on a normocapnic adult female with late-onset (LO) CCHS patient. Results The patient was exposed to four separate ventilatory challenges. During exposure to hyperoxia using 100% oxygen (O2) administration, patient showed an inconsistent ventilatory response with a blunted and delayed increase in regional tissue oxygen saturation (rSO2). During hyperoxic hypercapnia with 5% carbon dioxide (CO2) and 95% O2, she demonstrated a reduced ventilatory response based on respiratory rate and tidal volume. During hypoxic hypercapnia, 7% CO2 and 14% O2, patient demonstrated a delayed and markedly attenuated ventilatory response. Hypoxia; 100% nitrogen inhalation did not result in increased ventilation. Ve slope, change in minute ventilation/change in end-tidal CO2 (EtCO2), with hypercapnia challenges was 4.88, which is lower than normal. Ventilatory EtCO2 threshold was 36 mmHg. PSG showed apnea-hypopnea index 3.3 with hypoxemia during rapid eye movement (REM), with an oxygen saturation nadir of 84%. EtCO2 baseline was around 36, peak was 50 and was associated with REM-related apnea events. Arterial blood gas was unremarkable. Conclusion CCHS is characterized by abnormal respiratory response to exogenous ventilatory challenge testing. Hyperoxia silences peripheral chemoreceptors (PC) responsible for stimulating ventilation in normal individuals. Hyperoxic hypercapnia silences PC but stimulates central chemoreceptors (CC). Hypoxic hypercapnia stimulates hyperventilation via both PC and CC. Our patient demonstrated inconsistent and reduced ventilatory responses to all four challenges. As expected, the classic chemosensory parameter, Ve slope, for hypercarbia challenge was markedly reduced. However, the ventilatory EtCO2 threshold fell well below threshold typically observed in CCHS. PSG noted greater alveolar hypoventilation during REM compared to non-REM, which is also atypical for CCHS. In conclusion, exogenous ventilatory challenge testing demonstrated derangements in ventilatory control typical in CCHS. Despite this, our patient had no evidence of daytime hypoventilation with normal CO2 threshold. This case illustrates the phenotypic variability present in LO-CCHS. Support (if any)

Hypoxia-Evoked Spinal Adenosine Kinetics in Rats with Chronic Spinal Cord Injury

Therapeutic acute intermittent hypoxia (tAIH) is emerging as a simple and effective means of improving motor function after spinal cord injury (SCI) and ALS. For example, daily AIH applied one-week after C2 spinal hemisection (C2Hx) improves breathing in rats. Unfortunately, studies using the same protocol with chronic cSCI (&gt;8 weeks) report less robust recovery, except when the rats are pretreated with an adenosine 2A receptor antagonist. Pro-inflammatory conditions, such as those experienced after SCI, increase CNS extracellular adenosine concentrations. Guided by increased understanding of adenosinergic signaling mechanisms constraining AIH-induced phrenic motor plasticity, we aimed to determine real-time in vivo dynamics of extracellular adenosine in response to hypoxia in the ventral cervical spinal cord in intact and spinally injured rats. We used enzyme-immobilized micro-biosensors for real time enzymatic detection of extracellular adenosine in the mid-cervical spinal cord of intact rats and rats with chronic C2Hx (&gt;8 weeks post-injury) during 5-min 13% O2, 1-min 9% O2 and 1-min 9% O2 + 4% CO2. Extracellular adenosine exhibits rapid kinetics with a time-constant of seconds, regardless of condition. Rats with chronic C2Hx were classified post hoc into 2 groups: normotensive (systolic blood pressure &gt; 120 mmHg) and hypotensive (systolic blood pressure &lt; 120 mmHg). Normotensive C2Hx rats had baseline adenosine levels comparable to intact rats; hypoxia-induced increases in adenosine were slightly reduced versus intact rats. On the other hand, hypotensive C2Hx rats had elevated baseline adenosine levels and almost completely diminished hypoxia-evoked adenosine increases. Hypercapnic hypoxia had minimal impact on adenosine levels during exposures, but lowered adenosine following each hypercapnic hypoxic episode. These results suggest that changes in cardiovascular hemodynamics in chronic SCI rats can alter basal tissue adenosine levels, possibly undermining the therapeutic efficacy of tAIH in the condition of chronic SCI. Further, hypercapnic hypoxia appears to minimize inhibitory effects of adenosine on tAIH-induced phrenic/diaphragm motor plasticity. Supported by: NIH HL147554, HL148030 &amp; OT2OD023854 and the University of Florida McKnight Brain Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Perinatal ethanol exposure alters respiratory chemoreflex responses in anesthetized rats

In the USA 10-15% of pregnant women drink alcohol (ethanol) leading to a variable compilation of developmental abnormalities, including deficits in critical homeostatic functions such as poor coordination of suckling, breathing, and swallowing. Here, we test the hypothesis that perinatal ethanol exposure alters respiratory chemoreflex responses in neonatal rats. Pregnant rats were exposed to 5% ethanol through their drinking water starting on embryonic day 5, which exposes the fetuses to ethanol during gestation and then after birth through the breast milk. Pups of both sexes were studied in the first week of life (postnatal days (P) 1-5). First, in awake pups, we used head-out plethysmography to assess the effects of ethanol exposure on the respiratory response to a brief, 5- minute episode of hypoxic hypercapnia (12% O2/5% CO2, balance N2, delivered through a nose cone). We found no significant differences in the frequency (P = 0.6667), tidal volume (P = 0.3627), or minute ventilation (P = 0.1582) responses to the challenge between control and ethanol exposed pups (2-way ANOVA, n = 6 control and 6 ethanol pups). In a second experiment, we used electromyography in anesthetized pups to study the diaphragm and tongue muscle responses to nasal occlusion, which results in strong muscle efforts but an absence of lung inflation, as well as hypoxia, hypercapnia, and acidosis. Here, we found that both diaphragm and tongue muscle EMG responses were significantly blunted in ethanol exposed animals compared to control. This included a decrease in the peak amplitude responses of both muscles (2-way ANOVA: diaphragm, P = 0.0175; tongue, P= 0.0317, n = 8 control and 8 ethanol pups), as well as a delay in the onset of the tongue muscle activation (Student’s unpaired T-test, P = 0.0219, n = 8 control and 8 ethanol pups). Together, these data indicate that perinatal ethanol exposure causes impairments in respiratory chemoreflex control, which appear to be highly dependent on level of arousal. NIH 5R01HD071302-08 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of fullerene C60 with antihypoxants

BACKGROUND: Drug improvement is often carried out with the help of chemical modifications that improve the receptor action or transport of drugs to their target tissues.&#x0D; AIM: The aim of this study was to investigate the effect of combinations of C60 fullerene with amtizol, 2-amino-4-acetylthiazolo[5,4-b]indole, metaprot, metaprot base, and rutin on antihypoxic activities in a model of acute hypoxia with hypercapnia.&#x0D; MATERIALS AND METHODS: Several compounds with mono-, bi-, and tricyclic structures were examined separately or combined with C60 fullerene. All compounds, except for rutin, were synthesized at the Department of Pharmacology of the S.M. Kirov Military Medical Academy and contain active amino groups, nitrogen, and sulfur atoms in the cycles: amtizol (3,5-diamino-1,2,4-thiadiazole), VM-606 (2-amino-4-acetylthiazolo[5,4-b]indole), Metaprot (2-ethylthiobenzimidazole hydrobromide monohydrate), and Metaprot base. All compounds demonstrated antihypoxic activity. Hypobaric hypoxia was simulated in a flow pressure chamber by lifting animals to a height of 10,000 m at a speed of 50 m/s and exposure for 60 min. The preparations were administered intraperitoneally 60 min before the experiment. The protective effect was evaluated by the average life expectancy at altitude. Hypoxia with hypercapnia was assessed on male white mice weighing 2022 g, which were placed in 200 mL glass jars with hermetic lids, which were lowered under water to prevent air leakage. The studied preparations and their complexes with fullerene in the form of a thin suspension with Tween-80 were administered intraperitoneally min before hypoxia. The lifespan of the animals was recorded.&#x0D; RESULTS: The formation of the complex and its properties depend on the development of a donoracceptor bond between the drug and fullerene. An increase in the bioavailability of amtizol in the form of a complex with C60 fullerene increased the antihypoxic activity of the mixture by 40%. For the first time, dynamic curves of the activities of amtizol and 2-amino-4-acetylthiazolo[5,4-b]indole depending on time were obtained in a model of hypercapnic hypoxia.&#x0D; CONCLUSION: Fullerene C60 enhances the antihypoxic activity of the studied compounds due to an increase in the bioavailability of the antihypoxant caused by the microporation of tissue membranes due to the action of fullerene C60.

Possible causes of narcosis-like symptoms in freedivers

During deep-sea freediving, many freedivers describe symptoms fairly similar to what has been related to inert gas narcosis in scuba divers. This manuscript aims to present the potential mechanisms underlying these symptoms. First, known mechanisms of narcosis are summarized while scuba diving. Then, potential underlying mechanisms involving the toxicity of gases (nitrogen, carbon dioxide and oxygen) are presented in freedivers. As the symptoms are felt during ascent, nitrogen is likely not the only gas involved. Since freedivers are frequently exposed to hypercapnic hypoxia toward the end of the dive, it is proposed that carbon dioxide and oxygen gases both play a major role. Finally, a new “hemodynamic hypothesis” based on the diving reflex is proposed in freedivers. The underlying mechanisms are undoubtedly multifactorial and therefore require further research and a new descriptive name. We propose a new term for these types of symptoms: freediving transient cognitive impairment.

Permissive hypercapnia and hypercapnic hypoxia inhibit signaling pathways of neuronal apoptosis in ischemic/hypoxic rats.

In the present study, we aimed to test the hypothesis that hypercapnia, independently and/or in combination with hypoxia, can activate signaling pathways related to the inhibition of proapoptotic (caspase-dependent and caspase-independent) factors and the induction of antiapoptotic factors in facilitating adaptation to hypoxia/ischemia. Following exposure to permissive hypercapnia and/or normobaric hypoxia, the degree of apoptosis was evaluated in experimental ischemia models in vivoand in vitro. The percentages of caspase-3, apoptosis-inducing factor (AIF), Bax, and Bcl-2 in astrocytes and neurons derived from male Wistar rats were also calculated. In vitro, cells were subjected to various types of respiratory exposure (hypoxia and/or hypercapnia for 24 or 12h) as well as further sublethal chemical hypoxia. The percentages of these molecules in nerve cells in the ischemic penumbra of the brain after photothrombotic injury were also calculated. The degree of apoptosis was found to decrease in ischemic penumbra, mostly due to the hypercapnic component. It was also discovered that the levels of caspase-3, AIF, and Bax decreased in this region, whereas the Bcl-2 levels increased following exposure to hypercapnia and hypercapnic hypoxia. This integrative assessment of the rate of apoptosis/necrosis in astrocyte and neuron cultures shows that the combination of hypercapnia and hypoxia resulted in the maximum neuroprotective effect. The levels of apoptosis mediators in astrocyte and neuron cultures were calculated after modeling chemical hypoxia in vitro. These results show that the exposure models where permissive hypercapnia and normobaric hypoxia were combined also had the most pronounced inhibitory effects on apoptotic signaling pathways.

Acid-base and hematological regulation in chicken embryos during internal progressive hypercapnic hypoxia

Development of the capacity to mitigate potential disturbances to blood physiology in bird embryos is incompletely understood. We investigated regulation of acid-base and hematology in day 15 chicken embryos exposed to graded intrinsic hypercapnic hypoxia created by varying degrees of water submersion. Metabolic acidosis with additional respiratory or metabolic acidosis occurred at 2 h according to magnitude of submersion. Acid-base disturbance was partially compensated by metabolic alkalosis at 6 h, but compensatory metabolic alkalosis was absent at 24 h. Following submersion with only air cell exposed to air, both hypercapnic respiratory acidosis and metabolic acidosis occurred within 10 min. Subsequently, both forms of acidosis created lethal levels of [HCO3-] at ∼120 min. Blood hematology showed small but significant effects associated with induced acid-base disturbance. Increased Hct occurring during partial egg submersion lasting 24 h was attributed to an increase in MCV. By day 15 of development chicken embryos are able to partially compensate for and withstand all but severe induced internal hypoxic hypercapnia.

Early Postnatal Exposure to Intermittent Hypercapnic Hypoxia (IHH), but Not Nicotine, Decreases Reelin in the Young Piglet Hippocampus

This study evaluated the expression of reelin, an extracellular protein involved in lamination and migration of neurons, in the hippocampus of young piglets, and quantified to examine the following: (i) baseline levels within layers of the hippocampus and dentate gyrus (DG); (ii) differences between ventral and dorsal hippocampi; and (iii) changes attributable to postnatal exposure to continuous nicotine for 12 days, or intermittent hypercapnic hypoxia (IHH), with further analysis according to duration of IHH (1 vs 4 days). Additionally, we analysed whether any exposure altered DG morphology and whether it is related to altered reelin expression. Reelin was visualised via immunohistochemistry, and the number of positive reelin cells/mm2 was measured in the CA4/Hilus, layers of the DG, and the CA1. The dorsal DG had significantly more reelin within the subgranular zone compared to the ventral DG (p < 0.01). There was no difference in reelin between nicotine (n = 5) and controls (n = 5). IHH exposed piglets (n = 10) had significantly lowered reelin in the CA1 (p = 0.05), specifically the stratum pyramidale (p = 0.04) and the hippocampal fissure (p = 0.02), compared to their controls (n = 7); the duration of IHH had no effect. No exposure was associated with an alteration in DG morphology. This study shows that postnatal IHH exposure decreased reelin expression in the developing piglet hippocampal CA1, suggesting that IHH may result in altered neuronal migration.

Immune Defense in Hypoxic Waters: Impacts of CO2 Acidification.

AbstractPeriodic episodes of low oxygen (hypoxia) and elevated CO2 (hypercapnia) accompanied by low pH occur naturally in estuarine environments. Under the influence of climate change, the geographic range and intensity of hypoxia and hypercapnic hypoxia are predicted to increase, potentially jeopardizing the survival of economically and ecologically important organisms that use estuaries as habitat and nursery grounds. In this review we synthesize data from published studies that evaluate the impact of hypoxia and hypercapnic hypoxia on the ability of crustaceans and bivalve molluscs to defend themselves against potential microbial pathogens. Available data indicate that hypoxia generally has suppressive effects on host immunity against bacterial pathogens as measured by in vitro and in vivo assays. Few studies have documented the effects of hypercapnic hypoxia on crustaceans or bivalve immune defense, with a range of outcomes suggesting that added CO2 might have additive, negative, or no interactions with the effects of hypoxia alone. This synthesis points to the need for more partial pressure of O2 × low pH factorial design experiments and recommends the development of new host∶pathogen challenge models incorporating natural transmission of a wide range of viruses, bacteria, and parasites, along with novel in vivo tracking systems that better quantify how pathogens interact with their hosts in real time under laboratory and field conditions.

Влияние гиперкапнической гипоксии на репродуктивную и копулятивную функции мужчин в комплексном лечении хронического абактериального простатита.

Introduction. The relationship between chronic abacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS) and male infertility is the subject of numerous studies, and therefore various methods for correcting pathospermia have been proposed. The main concept is that in one way or another it is necessary to create conditions for a more perfect penetration of drugs into the zone of the prostate-vesicular complex. In this regard, the search for new and pathogenetically substantiated methods of therapy for such a patient seems to be very relevant Aim of study. To evaluate the effect of hypercapnic hypoxia on reproductive and copulatory functions of men in the complex treatment of CP/CPPS. Materials and methods. The study involved 24 patients who applied to a urologist with complaints about the absence of conception in marriage for 1 year or more. The examination revealed pathospermia and symptoms of CP/CPPS in these patients. Assessment of the severity of symptoms of CP/CPPS was assessed using a questionnaire on the symptoms of chronic prostatitis using the NIH-CPSI questionnaire. In order to identify and monitor violations of the male copulatory function, ICF questionnaires created by O.B. Loran and A.S. Segal and the International Index of Erectile Function (MIEF-5). Reproductive function analysis was monitored using a semen analysis and sperm DNA fragmentation index test. The patients were divided into 2 groups of 12 people. Both groups received phenotypically directed pathogenetic and symptomatic therapy. For patients of the 2nd group, the complex treatment included breathing training procedures using the carbonic simulator, which ensures blood saturation with CO2, leading to the effect of hypercapnic hypoxia. This phenomenon contributes to angiogenesis and improvement of blood circulation in organs and systems. The effectiveness of the treatment was evaluated after 1 and 3 months. Results. According to the results of the NIH-CPSI questionnaire, 3 months after treatment, therapy in patients of group number 2 was more effective. According to the results of the MIEF 5 and ICF questionnaires in patients with CP/CPPS, a violation of erectile and ejaculatory function was revealed, and according to the results of the spermogram and the sperm DNA fragmentation test (IFD), pathospermia was noted, which was expressed in a decrease in the concentration of spermatozoa (group number 1 – 15.3 ± 1.6 million / ml, group number 2 – 16.8±2.2 million/ml), their progressive mobility (group number 1 – 24 ± 2.6%, and in group number 2 23.25 ± 2.9%.), normal morphology (group number 1 – 2.1 ± 0.17%, group number 2 – 2.5 ± 0.29%) and an increase in IFD (group number 1 – 17.9 ± 2.06%, group number 2 – 19.75± 1.9%). 3 months after treatment, the concentration of spermatozoa was 21.1±2.16 million/ml in group number 1, and 31.8±2.5 million/ml in group number 2. Progressive mobility in group number 1 – 31.4±2.2%, in group number 2 – 38.4±1.9%. Normal morphology in group number 1 is 3.1 ± 0.32%, in group number 2 – 4.6 ± 0.6%. IFD in group number 1 – 12.25 ± 0.6%, in group number 2 – 7.8 ± 1.3%. Conclusion. Patients of the group number 2, who trained on the breathing device «carbonic», achieved a more significant clinical effect from the therapy. Hypercapnic hypoxia, in the complex treatment of CP/CPPS, can contribute not only to the relief of pain and dysuric symptoms, but also to improve both the copulative and reproductive functions of men.

Assessment of ethylthiobenzimidazole and fabomotizole activity in a model of hypercapnic hypoxia with cutting off the brain hemispheres work

BACKGROUND: Resistance to hypoxia depends on the type of animal, its condition (fatigue, pre-exposure, pregnancy in females) and the conditions of the experiments.&#x0D; AIM: study the effect of ethylthiobenzimidazole (Metaprot, Bemityl) and fabomotizole (Afobazole), which were antihypoxants with an isothiourea group, on the resistance of male outbred mice to acute hypoxia with hypercapnia under conditions of isolated functioning of one of the cerebral hemispheres.&#x0D; MATERIALS AND METHODS: Acute hypoxia with hypercapnia was simulated by the cupping method by placing male mice in a closed hermetic volume (200 cm3) until the death of the animal. Previously, in some mice, one of the cerebral hemispheres was temporarily switched off according to the Leao method.&#x0D; RESULTS: It has been shown that ethylthiobenzimidazole and fabomotizole, administered intraperitoneally in equimolar doses (25 and 32.8 mg/kg, respectively) 30 min before a hypoxic episode, increase the life time of experimental animals when either of the hemispheres (right or left) is turned off approximately equally.&#x0D; CONCLUSIONS: Data are considered in terms of the possibility of using both drugs in the prevention and treatment of ischemic strokes.

Sex differences in the sympathetic neurocirculatory responses to chemoreflex activation.

The purpose of this study was to determine whether there are sex differences in the cardiorespiratory and sympathetic neurocirculatory responses to central, peripheral, and combined central and peripheral chemoreflex activation. Ten women (29 ± 6 years, 22.8 ± 2.4 kg/m2: mean ± SD) and 10 men (30 ± 7 years, 24.8 ± 3.2 kg/m2) undertook randomized 5 min breathing trials of: room air (eucapnia), isocapnic hypoxia (10% oxygen (O2); peripheral chemoreflex activation), hypercapnic hyperoxia (7% carbon dioxide (CO2), 50% O2; central chemoreflex activation) and hypercapnic hypoxia (7% CO2, 10% O2; central and peripheral chemoreflex activation). Control trials of isocapnic hyperoxia (peripheral chemoreflex inhibition) and hypocapnic hyperoxia (central and peripheral chemoreflex inhibition) were also included. Muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; finger photoplethysmography) and minute ventilation (V˙ E; pneumotachometer) were measured. Total MSNA (P = 1.000 and P = 0.616), MAP (P = 0.265) and V˙ E (P = 0.587 and P = 0.472) were not different in men and women during eucapnia and during isocapnic hypoxia. Women exhibited attenuated increases in V˙ E during hypercapnic hyperoxia (27.3 ± 6.3 vs. 39.5 ± 7.5 l/min, P < 0.0001) and hypercapnic hypoxia (40.9 ± 9.1 vs. 53.8 ± 13.3 l/min, P < 0.0001) compared with men. However, total MSNA responses were augmented in women (hypercapnic hyperoxia 378 ± 215 vs. 258 ± 107%, P = 0.017; hypercapnic hypoxia 607 ± 290 vs. 362 ± 268%, P < 0.0001). No sex differences in total MSNA, MAP or V˙ E were observed during isocapnic hyperoxia and hypocapnic hyperoxia. Our results indicate that young women have augmented sympathetic responses to central chemoreflex activation, which explains the augmented MSNA response to combined central and peripheral chemoreflex activation.Key points Sex differences in the control of breathing have been well studied, but whether there are differences in the sympathetic neurocirculatory responses to chemoreflex activation between healthy women and men is incompletely understood.We observed that, compared with young men, young women displayed augmented increases in muscle sympathetic nerve activity during both hypercapnic hyperoxia (central chemoreflex activation) and hypercapnic hypoxia (central and peripheral chemoreflex activation) but had attenuated increases in minute ventilation.In contrast, no sex differences were found in either muscle sympathetic nerve activity or minute ventilation responses to isocapnic hypoxia (peripheral chemoreceptor stimulation).Young women have blunted ventilator, but augmented sympathetic responses, to central (hypercapnic hyperoxia) and combined central and peripheral chemoreflex activation (hypercapnic hypoxia), compared with young men. The possible causative association between the reduced ventilation and heightened sympathetic responses in young women awaits validation.

Sympathetic Neurocirculatory Responses to Chemoreflex Activation in Young Women and Men

Sex‐differences in the ventilatory responses to central and peripheral chemoreflex activation have been extensively examined. Along with the control of respiration, chemoreflexes play a key role in sympathetic regulation. Herein, we determined whether central, peripheral, and combined central and peripheral chemoreflex activation evoke differing sympathetic neurocirculatory responses in young women and men.In ten women (29±6 years, 23±2kg/m2: mean±SD) and ten men (30±7 years, 25±3kg/m2), we recorded muscle sympathetic nerve activity (MSNA), minute ventilation (V̇E) and mean arterial pressure (MAP) during 5‐min trials of breathing room‐air (eucapnia), isocapnic hypoxia (10% oxygen [O2]; peripheral chemoreflex activation), hypercapnic hyperoxia (7% carbon dioxide [CO2], 50% O2; central chemoreflex activation) and hypercapnic hypoxia (7% CO2, 10% O2). Trials were randomized. Women were studied in the early follicular phase of their menstrual cycle.During eucapnia and isocapnic hypoxia, no sex‐differences were observed in MSNA, V̇E and MAP (P&gt;0.05). During hypercapnic hyperoxia (∆278±215 vs. ∆158±107%, P=0.05) and hypercapnic hypoxia (∆507±290 vs. ∆262±268%, P=0.05) MSNA responses were augmented in women compared to men, however V̇E responses were attenuated (hypercapnic hyperoxia ∆15.2±6.7 vs. ∆25.6±6.7L/min, P=0.007; hypercapnic hypoxia ∆28.8±9.3 vs. ∆39.9±12.5L/min, P=0.004). MAP responses were similar in women and men (hypercapnic hyperoxia ∆10±2 vs. ∆23±2mmHg, P=0.35; hypercapnic hypoxia ∆16±3 vs. ∆25±3mmHg, P=0.35).In summary, young women have greater MSNA response to central chemoreflex activation than young men, which explains their augmented sympathetic response to combined central and peripheral chemoreflex activation. Future studies should determine the effect of menopause on these sex‐differences in the sympathetic neurocirculatory responses to chemoreflex activation.