Hypercapnic Hypoxia Research Articles

Effects of Hypoxia and Hypercapnic Hypoxia on Oxygen Transport and Acid-Base Status in the Atlantic Blue Crab, Callinectes sapidus, During Exercise.

The responses of estuarine invertebrates to hypoxic conditions are well established. However, many studies have investigated hypoxia as an isolated condition despite its frequent co-occurrence with hypercapnia (elevated CO2 ). Although many studies suggest deleterious effects, hypercapnia has been observed to improve blue crab walking performance in hypoxia. To investigate the physiological effects of combined hypercapnic hypoxia, we measured Po2 , pH, [l-lactate], Pco2 , and total O2 in pre- and postbranchial hemolymph sampled from blue crabs during walking exercise. Crabs walked at 8m min-1 on an aquatic treadmill in normoxic (100% air saturation), moderately hypoxic (50%), and severely hypoxic (20%) seawater with and without the addition of hypercapnia (about 2% CO2 ). Respiration was almost completely aerobic in normoxic conditions, with little buildup of lactate. During exercise under severe hypoxia, lactate increased from 1.4 to 11.0mM, indicating a heavy reliance on anaerobic respiration. The O2 saturation of arterial hemocyanin was 47% in severe hypoxia after 120min, significantly lower than in normoxia (80%). However, the addition of hypercapnia significantly increased the percentage saturation of arterial hemocyanin in severe hypoxia to 92% after 120 min of exercise, equivalent to normoxic levels. Hypercapnia in severe hypoxia also caused a marked increase in hemolymph Pco2 (around 1.1kPa), but caused only a minor decrease in pH of 0.1 units. We suggest that the improved O2 saturation at the gills results from a specific effect of molecular CO2 on hemocyanin oxygen binding affinity, which works independently of and counter to the effects of decreased pH.

Stress of the Endoplasmic Reticulum of Neurons in Stroke Can Be Maximally Limited by Combined Exposure to Hypercapnia and Hypoxia.

We studied the expression of chaperone GRP-78 and transcription factor NF-kB during the development of ischemic tolerance of the brain after combined and isolated exposure to hypoxia and hypercapnia. Combined exposure to hypoxia and hypercapnia maximally increased the expression of chaperone GRP-78 and transcription factor NF-kB, while the formation of ischemia-induced tolerance under conditions of hypercapnic hypoxia can be associated with activation of adaptive stress mechanisms in the endoplasmic reticulum. Under these conditions, hypercapnia in combination with hypoxia is a priority factor for activation of GRP-78 and transcription factor NF-kB.

Changes in orexinergic immunoreactivity of the piglet hypothalamus and pons after exposure to chronic postnatal nicotine and intermittent hypercapnic hypoxia.

We recently showed that orexin expression in sudden infant death syndrome (SIDS) infants was reduced by 21% in the hypothalamus and by 40-50% in the pons as compared with controls. Orexin maintains wakefulness/sleeping states, arousal, and rapid eye movement sleep, abnormalities of which have been reported in SIDS. This study examined the effects of two prominent risk factors for SIDS, intermittent hypercapnic hypoxia (IHH) (prone-sleeping) and chronic nicotine exposure (cigarette-smoking), on orexin A (OxA) and orexin B (OxB) expression in piglets. Piglets were randomly assigned to five groups: saline control (n=7), air control (n=7), nicotine [2mg/kg per day (14 days)] (n=7), IHH (6min of 7% O2 /8% CO2 alternating with 6-min periods of breathing air, for four cycles) (n=7), and the combination of nicotine and IHH (N+IHH) (n=7). OxA/OxB expression was quantified in the central tuberal hypothalamus [dorsal medial hypothalamus (DMH), perifornical area (PeF), and lateral hypothalamus], and the dorsal raphe, locus coeruleus of the pons. Nicotine and N+IHH exposures significantly increased: (i) orexin expression in the hypothalamus and pons; and (ii) the total number of neurons in the DMH and PeF. IHH decreased orexin expression in the hypothalamus and pons without changing neuronal numbers. Linear relationships existed between the percentage of orexin-positive neurons and the area of pontine orexin immunoreactivity of control and exposure piglets. These results demonstrate that postnatal nicotine exposure increases the proportion of orexin-positive neurons in the hypothalamus and fibre expression in the pons, and that IHH exposure does not prevent the nicotine-induced increase. Thus, although both nicotine and IHH are risk factors for SIDS, it appears they have opposing effects on OxA and OxB expression, with the IHH exposure closely mimicking what we recently found in SIDS.

Acute hypoxia influence on cardio-respiratory system and new possibilities of pharmacological prophylactics of hypoxia in experiment

Cardiorespiratory system activities have been studied on rats in experiment after oral introduction of the new selenium-containing metal-complex substance πQ1983 in dose 100 mg/kg before and under action of acute hypercapnic hypoxia (AH + Hc). The substance was introduced 90 min. before (incubation period) placement of animals into hypoxic chambers with 1.0 L free volume. During each experiment as well as during AH+Hc an electrical activity of myocardium (ECG) and respiration curves called pneumobarogramm (PBG) were recorded simultaneously. It has been established that the substance πQ1983 made cardiodepressive effect and decreases parameters of lungs ventilation in animals. According to ECG and PBG dynamics, rats protected by the substance demonstrated a high resistance level to the aroused acute hypoxia with hypercapnia, that expressed by weakening of early reactions from cardiorespiratory system under hypercapnia action, and by twice longer life span of animals in hypoxic experiment.

T2* and T1 assessment of abdominal tissue response to graded hypoxia and hypercapnia using a controlled gas mixing circuit for small animals.

To characterize T2* and T1 relaxation time response to a wide spectrum of gas challenges in extracranial tissues of healthy rats. A range of graded gas mixtures (hyperoxia, hypercapnia, hypoxia, and hypercapnic hypoxia) were delivered through a controlled gas-mixing circuit to mechanically ventilated and intubated rats. Quantitative magnetic resonance imaging (MRI) was performed on a 3T clinical scanner; T2* and T1 maps were computed to determine tissue response in the liver, kidney cortex, and paraspinal muscles. Heart rate and blood oxygen saturation (SaO2 ) were measured through a rodent oximeter and physiological monitor. T2* decreases consistent with lowered SaO2 measurements were observed for hypercapnia and hypoxia, but decreases were significant only in liver and kidney cortex (P < 0.05) for >10% CO2 and <15% O2 , with the new gas stimulus, hypercapnic hypoxia, producing the greatest T2* decrease. Hyperoxia-related T2* increases were accompanied by negligible increases in SaO2 . T1 generally increased, if at all, in the liver and decreased in the kidney. Significance was observed (P < 0.05) only in kidney for >90% O2 and >5% CO2 . T2* and T1 provide complementary roles for evaluating extracranial tissue response to a broad range of gas challenges. Based on both measured and known physiological responses, our results are consistent with T2* as a sensitive marker of blood oxygen saturation and T1 as a weak marker of blood volume changes. J. Magn. Reson. Imaging 2016;44:305-316.

Curcumin alleviates brain edema by lowering AQP4 expression levels in a rat model of hypoxia-hypercapnia-induced brain damage.

The present study aimed to investigate the therapeutic effects of curcumin (CU) against brain edema in a rat model of hypoxia-hypercapnia (HH)-induced brain damage (HHBD). Male Sprague-Dawley rats were divided into five groups, including a control group and four treatment groups. The rats in the control group were raised under normal laboratory conditions and were injected with water, whereas the rats in the treatment groups were exposed to a low O2/high CO2 environment simulating HH conditions, and were injected with water, CU, dimethyl sulfoxide (solvent control) or monosialoganglioside GM1. After 2 weeks, the morphological characteristics of the brain tissues were analyzed using optical and electron microscopy. In addition, aquaporin (AQP)-4 protein expression levels in brain tissue samples were analyzed using streptavidin-biotin complex immunohistochemistry and western blotting, and mRNA expression levels were detected using reverse transcription-quantitative polymerase chain reaction. Severe brain edema, tissue structure disruption and increased AQP4 expression levels were detected in the brain tissues of the HH rats. Conversely, the rats treated with CU or GM1 exhibited attenuated HHBD-induced brain edema and tissue structure disruption, and decreased mRNA and protein expression levels of AQP4. The results of the present study suggested that CU treatment was able to attenuate HHBD-induced brain edema by downregulating the expression levels of AQP4 in a rat model. Therefore, CU may be considered a potential therapeutic drug for the treatment of patients with brain edema.

Different Concentrations of Notoginsenoside Rg1 Attenuate Hypoxic and Hypercapnia Pulmonary Hypertension by Reducing the Expression of ERK in Rat PASMCs

Pulmonary arterial hypertension (PAH) is a serious disease which is characterized by increased vascular resistance and pressure. We have previously hypothesized that panax notoginseng saponins (PNS) might attenuate pulmonary vasoconstriction under hypoxia and hypercapnia condition. This study aims to investigate the effect of notoginsenoside R g1 , a main ingredient of PNS, with various concentrations (8, 40, 100 mg/L, respectively) on extracellular signal regulated kinase (ERK1/2) signaling pathway in pulmonary arterial smooth muscle cells (PASMCs). In addition, PASMCs were randomly divided into six groups: SD rat under normoxic condition as control group (N group), hypoxia hypercapnia group (H group), DMSO control group (HD group), R g1 -treatment groups (R gL R gM and R gH group). Western-blot and RT-PCR were used to test the expression of p-ERK protein and the expression of ERK1 mRNA and ERK2 mRNA. This study provided the evidence that the expression of p-ERK protein and the expression of ERK1 mRNA and ERK2 mRNA in HD group and H group were obviously higher than that in N group (P < 0.01), Whereas the level of ERK1/2 mRNA in R g1 -treatment groups was significantly lower than that in HD group and H group (P < 0.01), and the proper concentration of R g1 is 40 mg/L. These results suggested that notoginsenoside R g1 can attenuate pulmonary vasoconstriction which may lead to HHPV through reducing the expression of ERK1/2.

The effects of hypercapnia on the West Coast rock lobster (Jasus lalandii) through acute exposure to decreased seawater pH — Physiological and biochemical responses

The cold water palinurid Jasus lalandii (“West Coast rock lobster”) is a commercially important crustacean in South Africa and Namibia and inhabits the Benguela Current Eastern Boundary System. This habitat is characterised by strong upwelling events in summer and algal blooms with their subsequent decay in autumn. Upwelling can lead to acute hypercapnia whereas the algal decay is associated with acute hypercapnic hypoxia. Both types of hypercapnic events could become more frequent and severe in the future due to ongoing climate change. The aim of the present study was, however, to study the capability and mechanisms of response in J. lalandii to hypercapnia exclusively. Accordingly, the following research questions were formulated: 1) To what extent is haemocyanin oxygen-binding affinity of adult J. lalandii pH-sensitive? 2) Can adult male J. lalandii respond swiftly to drastic changes in pH? 3) What physiological mechanisms facilitate a potential response to a drastically declining pH, i.e. acute hypercapnia? These questions were answered by analysing 1) the pH sensitivity of the haemocyanin's oxygen binding properties and 2) in vivo changes in the acid–base balance of adult J. lalandii during acute exposure to hypercapnia (pH7.4). Results showed the following: 1) Haemocyanin displays a strong Bohr shift (whole haemolymph: ΔlogP50/ΔpH=−1.17; dialysed haemolymph: ΔlogP50/ΔpH=−0.84) in response to lowering of pH. 2) Acute hypercapnia leads to a decline in extracellular pH within the initial 1.5h of exposure. 3) Thereafter, active compensation becomes apparent as the bicarbonate levels start to increase, with complete compensation reached after 5h of exposure (+2.3mmoll−1; +48%). 3) This bicarbonate increase is reversed when returning lobsters to normocapnia (pH7.9). 4) Levels of molecular modulators of haemocyanin oxygen affinity (Ca2+, Mg2+ and l-lactate) do not change during acute exposure to hypercapnia.Our results show the capability of adult J. lalandii to rapidly and fully compensate the experienced extracellular acidosis, protecting oxygen carrying capacity of haemocyanin and ensuring an outward gradient of CO2. The West Coast rock lobster is therefore well equipped for its habitat where these hypercapnic events are known to occur frequently.

Cumulative effects of repetitive intermittent hypercapnic hypoxia on orexin in the developing piglet hypothalamus

Orexin neuropeptides (OxA and OxB) and their receptors (OX1R and OX2R) are involved in maintenance of sleep and wakefulness, and are regulated by various environmental stimuli. We studied piglets, in the early neonatal period, exposed to 48-min of intermittent hypercapnic hypoxia (IHH; 7% O2/8% CO2) alternating with air. Three groups of 13–14 day-old piglets with IHH exposure of 1-day (1D-IHH) (n=7), 2-days (2D-IHH) (n=7) and 4-days (4D-IHH) (n=8) were compared to controls (exposed only to air, n=8). Immunoreactivity of OxA and OxB was studied in the piglet hypothalamic regions of the dorsomedial hypothalamus (DMH), perifornical area (PeF) and lateral hypothalamic area (LH). Results showed that after 1D- and 2D-IHH, total OxA and OxB expression decreased by 20% (p≤0.005) and 40% (p<0.001), respectively. After 4D-IHH, the decrease in OxA and OxB was 50% (p<0.001). These findings indicate that a chronic IHH exposure induces greater changes in orexin neuropeptide expression than an acute 1-day exposure in the hypothalamus. This may be causally related to the dysregulation of sleep.

Plasticity in breathing and arterial blood pressure following acute intermittent hypercapnic hypoxia in infant rat pups with a partial loss of 5-HT neurons.

The role of serotonin (5-HT) neurons in cardiovascular responses to acute intermittent hypoxia (AIH) has not been studied in the neonatal period. We hypothesized that a partial loss of 5-HT neurons would reduce arterial blood pressure (BP) at rest, increase the fall in BP during hypoxia, and reduce the long-term facilitation of breathing (vLTF) and BP following AIH. We exposed 2-wk-old, 5,7-dihydroxytryptamine-treated and controls to AIH (10% O2; n = 13 control, 14 treated), acute intermittent hypercapnia (5% CO2; n = 12 and 11), or acute intermittent hypercapnic hypoxia (AIHH; 10% O2, 5% CO2; n = 15 and 17). We gave five 5-min challenges of AIH and acute intermittent hypercapnia, and twenty ∼20-s challenges of AIHH to mimic sleep apnea. Systolic BP (sBP), diastolic BP, mean arterial pressure, heart rate (HR), ventilation (V̇e), and metabolic rate (V̇o2) were continuously monitored. 5,7-Dihydroxytryptamine induced an ∼35% loss of 5-HT neurons from the medullary raphe. Compared with controls, pups deficient in 5-HT neurons had reduced resting sBP (∼6 mmHg), mean arterial pressure (∼5 mmHg), and HR (56 beats/min), and experienced a reduced drop in BP during hypoxia. AIHH induced vLTF in both groups, reflected in increased V̇e and V̇e/V̇o2, and decreased arterial Pco2. The sBP of pups deficient in 5-HT neurons, but not controls, was increased 1 h following AIHH. Our data suggest that a relatively small loss of 5-HT neurons compromises resting BP and HR, but has no influence on ventilatory plasticity induced by AIHH. AIHH may be useful for reversing cardiorespiratory defects related to partial 5-HT system dysfunction.

Proliferative and Synthetic Activity of Nerve Cells after Combined or Individual Exposure to Hypoxia and Hypercapnia.

We compared synthetic and proliferative activity of brain cells in rats exposed hypoxia, hypercapnia, or both prior to experimental focal stroke. The mean number of nucleolus organizer regions in penumbra neurons did not change after normobaric hypoxia, but increased after permissive hypercapnia or hypercapnic hypoxia. These data attest to activation of proliferative and synthetic functions in nerve cells, which plays an important role in the neuroprotective mechanisms under conditions of combined exposure to hypoxia and hypercapnia.

The effect of prenatal maternal infection on respiratory function in mouse offspring: evidence for enhanced chemosensitivity.

Systemic maternal inflammation is implicated in preterm birth and bronchopulmonary dysplasia (BPD) and may induce morbidities including reduced pulmonary function, sleep-disordered breathing, and cardiovascular disorders. Here we test the hypothesis that antenatal maternal inflammation per se causes altered alveolar development and increased chemoreflex sensitivity that persists beyond infancy. Pregnant C57BL/6 mice were administered lipopolysaccharide (LPS) (150 μg/kg ip) to induce maternal inflammation or saline (SHAM) at embryonic day 16 (randomized). Pups were weighed daily. On days 7, 28, and 60 (D07, D28, and D60), unrestrained wholebody plethysmography quantified ventilation and chemoreflex responses to hypoxia (10%), hypercapnia (7%), and asphyxia (hypoxic hypercapnia). Lungs were harvested to quantify alveolar number, size, and septal thickness. LPS pups had reduced baseline ventilation per unit bodyweight (∼40%, P < 0.001) vs. SHAM. LPS increased ventilatory responses to hypoxia (D07: 66% vs. 28% increase in ventilation; P < 0.001) hypercapnia (170% vs. 88%; P < 0.001), and asphyxia (249% vs. 154%; P < 0.001); hypersensitive hypoxic responsiveness persisted until D60 (P < 0.001). LPS also increased apnea frequency (P < 0.01). LPS caused thicker alveolar septae (D07, P < 0.001), diminished alveolar number (D28, P < 0.001) vs. SHAM, but effects were minimal by D60. Pups delivered from mothers exposed to antenatal inflammation exhibit deficits in lung structure and hypersensitive responses to respiratory stimuli that persist beyond the newborn period. Antenatal inflammation may contribute to impaired gas exchange and unstable breathing in newborn infants and adversely affect long-term health.

Differences in respiratory changes and Fos expression in the ventrolateral medulla of rats exposed to hypoxia, hypercapnia, and hypercapnic hypoxia

Respiratory responses to hypoxia and/or hypercapnia, and their relationship to neural activity in the ventrolateral medulla (VLM), which includes the respiratory center, have not yet been elucidated in detail. We herein examined respiratory responses during exposure of 10% O2 (hypoxia), 10% CO2 (hypercapnia), and 10% O2–10% CO2 (hypercapnic hypoxia) using plethysmography. In addition to recording respiration, Fos expressions were examined in the VLM of the rat exposed to each gas to analyze neural activity. Respiratory frequency was increased in rats exposed to hypoxia, and Fos-positive neurons were observed in the caudal VLM (cVLM) and medial VLM (mVLM). Tidal volume was increased in rats exposed to hypercapnia, and Fos-positive neurons were observed in the rostral VLM (rVLM) includes the retrotrapezoid nucleus (RTN) and mVLM. Tidal volume was enhanced in rats exposed to hypercapnic hypoxia, similar to that in hypercapnia-exposed rats, and Fos-positive neurons were observed in the entire region of the VLM. In the mVLM and cVLM, double immunofluorescence showed Fos-immunoreactive nerve cells were also immunoreactive to dopamine β-hydroxylase, the marker for A1/C1 catecholaminergic neuron. These results suggested that hypoxia and hypercapnia modulated rhythmogenic microcircuits in the mVLM via A1/C1 neurons and the RTN, respectively.

Comparative ventilatory strategies of acclimated rats and burrowing plateau pika (Ochotona curzoniae) in response to hypoxic–hypercapnia

The objective of this study was to compare the different ventilatory strategies that help in coping with hypoxic–hypercapnia environment among two species: use acclimated rats and plateau pikas (Ochotona curzoniae) that live in Tibetan plateaus, and have been well adjusted to high altitude. Arterial blood samples taken at 4100m of elevation in acclimatized rats and adapted pikas revealed inter-species differences with lower hemoglobin and hematocrit and higher blood pH in pikas. A linear and significant increase in minute ventilation was observed in pikas, which help them to cope with hypoxic–hypercapnia. Pikas also displayed a high inspiratory drive and an invariant respiratory timing regardless of the conditions. Biochemical analysis revealed that N-methyl-D-aspartate receptor (NMDA) receptor gene and nNOS gene are highly conserved between rats and pikas, however pikas have higher expression of NMDA receptors and nNOS compared to rats at the brainstem level. Taken together, these results suggest that pikas have developed a specific ventilatory pattern supported by a modification of the NMDA/NO ventilatory central pathways to survive in extreme conditions imposed on the Tibetan plateaus. These physiological adaptive strategies help in maintaining a better blood oxygenation despite high CO2 concentration in burrows at high altitude.

Combined Effects of Intermittent Hyperoxia and Intermittent Hypercapnic Hypoxia on Respiratory Control

We previously observed that chronic intermittent hyperoxia attenuates the hypoxic ventilatory response (HVR) in neonatal rats. In clinical situations, however, intermittent hyperoxia alternates with bouts of hypercapnic hypoxia. In the present study, we exposed rats from birth through 14 days of age to one of three treatments: control (21% O2/0% CO2), intermittent hypercapnic hypoxia (10% O2/6% CO2, 5 episodes h‐1; I21/10), or intermittent hyperoxia + hypercapnic hypoxia (30% O2/0% CO2 to 10% O2/6% CO2, 5 episodes h‐1; I30/10). I30/10 rats exhibited slightly greater baseline ventilation than controls (measured by head‐body plethysmography) at P14, but this corresponded to a greater resting metabolic rate (in both I30/10 and I21/10 vs. controls). Although I21/10 and I30/10 treatments reduced single‐unit carotid chemoafferent responses to hypoxia (measured in vitro), the HVR was not different from that of control rats in either of these groups. Similarly, I21/10 and I30/10 treatments did not alter the hypercapnic ventilatory response. I21/10 and I30/10 rats had larger mass‐specific dry lung weight compared to controls, while continuous hyperoxia (60% O2) decreased lung size. Our results suggest that intermittent hypercapnic hypoxia counteracts the effects of intermittent hyperoxia, either by presenting an opposing stimulus (e.g., carotid body activation vs. inhibition) or by eliciting a more prominent plastic response.

5‐HT 1A Receptors in the Caudal Nucleus Tractus Solitarii Mediate Arousal to Hypoxic Hypercapnia in Male Rats

Serotonin (5-HT) neurons of the caudal raphe, 5-HT1A receptors of the caudal nucleus tractus solitarii (cNTS), and sinoaortic afferents contribute to sympathoexcitatory compensation from hemorrhage in unanesthetized rats. Here, we examined the role of the peripheral chemoreflex in 5-HT-dependent compensation, by testing whether acidosis similar to that seen in hemorrhage was sufficient to activate 5-HT neurons of the caudal raphe, and whether 5-HT1A receptors in the cNTS contributed to peripheral chemoreflex responses during acidosis. Hypoxic hypercapnia (10% O2/5% CO2), but not hypercapnia alone, increased c-Fos expression in 5-HT neurons of the caudal raphe (P<0.01). Short hairpin RNA-mediated knockdown of 5-HT1A receptors in the cNTS (n=13) did not produce consistent effects on ventilation during hypoxic hypercapnia compared to rats treated with a scrambled shRNA (n=15). Instead, 5-HT1A knockdown attenuated intermittent bouts of high frequency ventilation (sniffing) normally expressed during exposure to hypoxic hypercapnia (4.9 ± 1.1 vs 11.2 ± 2.4% of a 45 minute exposure, P< 0.05). Accordingly, cumulative breaths during gas exposure was reduced by 5-HT1A knockdown in the cNTS (2173 ± 520 vs 3887± 1312 breaths/45 min, log transformed P<0.001). The data support the hypothesis that peripheral chemoreflex activation augments the ability of a central chemoreflex stimulus to activate 5-HT neurons of the caudal raphe. In turn, activation of 5-HT1A receptors in the cNTS contributes to arousal as indicated by sniffing. Thus, we conclude that 5-HT1A receptors in the cNTS serve to promote arousal when both peripheral and central chemoreceptors are activated simultaneously, and may thereby promote sympathoexcitation during blood loss.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges.

Hypoventilation is a defining feature of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), a rare respiratory and autonomic disorder. This chronic hypoventilation has been explained as the result of dysfunctional chemosensory control circuits, possibly affecting peripheral afferent input, central integration, or efferent motor control. However, chemosensory function has never been quantified in a cohort of ROHHAD patients. Therefore, the purpose of this study was to assess the response to awake ventilatory challenge testing in children and adolescents with ROHHAD. The ventilatory, cardiovascular and cerebrovascular responses in 25 distinct comprehensive physiological recordings from seven unique ROHHAD patients to three different gas mixtures were analyzed at breath-to-breath and beat-to-beat resolution as absolute measures, as change from baseline, or with derived metrics. Physiologic measures were recorded during a 3-min baseline period of room air, a 3-min gas exposure (of 100% O2; 95% O2, 5% CO2; or 14% O2, 7% CO2 balanced with N2), and a 3-min recovery period. An additional hypoxic challenge was conducted which consisted of either five or seven tidal breaths of 100% N2. While ROHHAD cases showed a diminished VT and inspiratory drive response to hypoxic hypercapnia and absent behavioral awareness of the physiologic compromise, most ventilatory, cardiovascular, and cerebrovascular measures were similar to those of previously published controls using an identical protocol, suggesting a mild chemosensory deficit. Nonetheless, the high mortality rate, comorbidity and physiological fragility of patients with ROHHAD demand continued clinical vigilance.

High capacity for extracellular acid-base regulation in the air-breathing fish Pangasianodon hypophthalmus.

The evolution of accessory air-breathing structures is typically associated with reduction of the gills, although branchial ion transport remains pivotal for acid-base and ion regulation. Therefore, air-breathing fishes are believed to have a low capacity for extracellular pH regulation during a respiratory acidosis. In the present study, we investigated acid-base regulation during hypercapnia in the air-breathing fish Pangasianodon hypophthalmus in normoxic and hypoxic water at 28-30°C. Contrary to previous studies, we show that this air-breathing fish has a pronounced ability to regulate extracellular pH (pHe) during hypercapnia, with complete metabolic compensation of pHe within 72 h of exposure to hypoxic hypercapnia with CO2 levels above 34 mmHg. The high capacity for pHe regulation relies on a pronounced ability to increase levels of HCO3(-) in the plasma. Our study illustrates the diversity in the physiology of air-breathing fishes, such that generalizations across phylogenies may be difficult.

Combined Exposure to Hypercapnia and Hypoxia Provides Its Maximum Neuroprotective Effect During Focal Ischemic Injury in the Brain

In the present research, we compared the neuroprotective efficiency of combined and isolated exposure to hypoxia and hypercapnia preceding focal cerebral ischemic injury in rats. The study was conducted to verify the hypothesis of a possible increase in normobaric hypoxia (NbH; 90 mm Hg) efficiency when combined with permissive hypercapnia (PH; 50 mm Hg). The rats from the test groups were subjected to a 15-fold exposure to NbH (90 mm Hg) and/or PH (50 mm Hg). After the 15th exposure, cerebral ischemic injury was induced by photochemical thrombosis. Seventy-two hours later, neurologic deficit was determined on the Neurological Severity Score scale and by the rotarod test, and the volume of cerebral infarction was measured after focal photochemical thrombosis. The neurologic deficit decreased most efficiently in rats that underwent PH and hypercapnic hypoxia (HH) exposure, whereas NbH had no impact on the neurologic status of the animals. On the contrary, motor coordination disturbances were minimal during exposure to hypoxia and HH. All respiratory interventions reduced the cerebral ischemic infarction volume in rats. The smallest infarction volumes were registered in the area of photochemical thrombosis in rats from the hypercapnic-hypoxic impact group, whereas exposure to NbH or PH did not show any cross difference. The impact of PH has greater neuroprotective potential compared with NbH. Thus, we can assume that hypercapnia is a predominant factor in providing neuroprotection in combination with hypoxia.

Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats.

Brainstem hypoperfusion is a major excitant of sympathetic activity triggering hypertension, but the exact mechanisms involved remain incompletely understood. A major source of excitatory drive to preganglionic sympathetic neurons originates from the ongoing activity of premotor neurons in the rostral ventrolateral medulla (RVLM sympathetic premotor neurons). The chemosensitivity profile of physiologically characterized RVLM sympathetic premotor neurons during hypoxia and hypercapnia remains unclear. We examined whether physiologically characterized RVLM sympathetic premotor neurons can sense brainstem ischaemia intrinsically. We addressed this issue in a unique in situ arterially perfused preparation before and after a complete blockade of fast excitatory and inhibitory synaptic transmission. During hypercapnic hypoxia, respiratory modulation of RVLM sympathetic premotor neurons was lost, but tonic firing of most RVLM sympathetic premotor neurons was elevated. After blockade of fast excitatory and inhibitory synaptic transmission, RVLM sympathetic premotor neurons continued to fire and exhibited an excitatory firing response to hypoxia but not hypercapnia. This study suggests that RVLM sympathetic premotor neurons can sustain high levels of neuronal discharge when oxygen is scarce. The intrinsic ability of RVLM sympathetic premotor neurons to maintain responsivity to brainstem hypoxia is an important mechanism ensuring adequate arterial pressure, essential for maintaining cerebral perfusion in the face of depressed ventilation and/or high cerebral vascular resistance.