Hyperoxic Stimuli Research Articles

CO2 as an engine for neurofluid flow: Exploring the coupling between vascular reactivity, brain clearance, and changes in tissue properties.

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO2) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO2-induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO2) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes.

Assessing the pulmonary vascular responsiveness to oxygen with proton MRI.

Ventilation-perfusion matching occurs passively and is also actively regulated through hypoxic pulmonary vasoconstriction (HPV). The extent of HPV activity in humans, particularly normal subjects, is uncertain. Current evaluation of HPV assesses changes in ventilation-perfusion relationships/pulmonary vascular resistance with hypoxia and is invasive, or unsuitable for patients because of safety concerns. We used a noninvasive imaging-based approach to quantify the pulmonary vascular response to oxygen as a metric of HPV by measuring perfusion changes between breathing 21% and 30%O2 using arterial spin labeling (ASL) MRI. We hypothesized that the differences between 21% and 30%O2 images reflecting HPV release would be 1) significantly greater than the differences without [Formula: see text] changes (e.g., 21-21% and 30-30%O2) and 2) negatively associated with ventilation-perfusion mismatch. Perfusion was quantified in the right lung in normoxia (baseline), after 15 min of 30% O2 breathing (hyperoxia) and 15 min normoxic recovery (recovery) in healthy subjects (7 M, 7 F; age = 41.4 ± 19.6 yr). Normalized, smoothed, and registered pairs of perfusion images were subtracted and the mean square difference (MSD) was calculated. Separately, regional alveolar ventilation and perfusion were quantified from specific ventilation, proton density, and ASL imaging; the spatial variance of ventilation-perfusion (σ2V̇a/Q̇) distributions was calculated. The O2-responsive MSD was reproducible (R2 = 0.94, P < 0.0001) and greater (0.16 ± 0.06, P < 0.0001) than that from subtracted images collected under the same [Formula: see text] (baseline = 0.09 ± 0.04, hyperoxia = 0.08 ± 0.04, recovery = 0.08 ± 0.03), which were not different from one another (P = 0.2). The O2-responsive MSD was correlated with σ2V̇a/Q̇ (R2 = 0.47, P = 0.007). These data suggest that active HPV optimizes ventilation-perfusion matching in normal subjects. This noninvasive approach could be applied to patients with different disease phenotypes to assess HPV and ventilation-perfusion mismatch.NEW & NOTEWORTHY We developed a new proton MRI method to noninvasively quantify the pulmonary vascular response to oxygen. Using a hyperoxic stimulus to release HPV, we quantified the resulting redistribution of perfusion. The differences between normoxic and hyperoxic images were greater than those between images without [Formula: see text] changes and negatively correlated with ventilation-perfusion mismatch. This suggests that active HPV optimizes ventilation-perfusion matching in normal subjects. This approach is suitable for assessing patients with different disease phenotypes.

The many layers of BOLD. The effect of hypercapnic and hyperoxic stimuli on macro- and micro-vascular compartments quantified by CVR, M, and CBV across cortical depth

Ultra-high field functional magnetic resonance imaging (fMRI) offers the spatial resolution to measure neuronal activity at the scale of cortical layers. However, cortical depth dependent vascularization differences, such as a higher prevalence of macro-vascular compartments near the pial surface, have a confounding effect on depth-resolved blood-oxygen-level dependent (BOLD) fMRI signals. In the current study, we use hypercapnic and hyperoxic breathing conditions to quantify the influence of all venous vascular and micro-vascular compartments on laminar BOLD fMRI, as measured with gradient-echo (GE) and spin-echo (SE) scan sequences, respectively. We find that all venous vascular and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-value parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately two and a half times larger for all venous vascular compartments combined compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in estimates of CBV changes between all venous vascular and micro-vascular compartments, although this relative difference was approximately uniform across cortical depth. Thus, our results suggest that fMRI BOLD signal differences across cortical depth are likely caused by differences in dilation properties between macro- and micro-vascular compartments.

Feasibility of glioblastoma tissue response mapping with physiologic BOLD imaging using precise oxygen and carbon dioxide challenge.

Innovative physiologic MRI development focuses on depiction of heterogenous vascular and metabolic features in glioblastoma. For this feasibility study, we employed blood oxygenation level-dependent (BOLD) MRI with standardized and precise carbon dioxide (CO2) and oxygen (O2) modulation to investigate specific tumor tissue response patterns in patients with newly diagnosed glioblastoma. Seven newly diagnosed untreated patients with suspected glioblastoma were prospectively included to undergo a BOLD study with combined CO2 and O2 standardized protocol. %BOLD signal change/mmHg during hypercapnic, hypoxic, and hyperoxic stimulus was calculated in the whole brain, tumor lesion and segmented volumes of interest (VOI) [contrast-enhancing (CE) - tumor, necrosis and edema] to analyze their tissue response patterns. Quantification of BOLD signal change after gas challenges can be used to identify specific responses to standardized stimuli in glioblastoma patients. Integration of this approach with automatic VOI segmentation grants improved characterization of tumor subzones and edema. Magnitude of BOLD signal change during the 3 stimuli can be visualized at voxel precision through color-coded maps overlayed onto whole brain and identified VOIs. Our preliminary investigation shows good feasibility of BOLD with standardized and precise CO2 and O2 modulation as an emerging physiologic imaging technique to detail specific glioblastoma characteristics. The unique tissue response patterns generated can be further investigated to better detail glioblastoma lesions and gauge treatment response.

Testing Ventilatory Acclimatization to High Altitude using the Hyperoxic Ventilatory Withdrawal Test

Testing the transient hypoxic ventilatory response (HVR) is the most common method utilized for assessing ventilatory acclimatization in the setting of high altitude ascent, as the peripheral chemoreceptors become sensitized to hypoxia with chronic exposure. However, this test requires sophisticated equipment (e.g., gas tanks, feedback controllers) that lacks portability, and may lead to participant discomfort while already hypoxic while at altitude. The transient hyperoxic withdrawal (HVW) test is simple, portable and safe, using a small 100% O2 tank available on most expeditions, and may better assess ventilatory acclimatization when participants are chronically hypoxic in high altitude fieldwork studies. We hypothesized that the HVW would be larger following 7-days of ascent to 4240m while taking acetazolamide (Diamox; i.e., ventilatory stimulant) than an acute hypoxic control group at low altitude, thus having utility in detecting ventilatory acclimatization during ascent to high altitude. Using two separate recruitments, we tested two groups in two contexts. In Part A, we recruited 14 participants to assess the HVW in the context of acute, steady-state hypoxia (~30-min; FIO2 13.5-14%) in a laboratory context (1045m, PATM ~665 mmHg). In Part B, 12 participants were recruited from a large research expedition to high altitude in the Nepal Himalaya, following 7 days of incremental ascent to high altitude (4240m, PATM ~460 mmHg), while taking prophylactic Diamox (125 mg, BID). Participants were instrumented with a mouthpiece and bacteriological filter attached to a calibrated pneumotachometer (to measure inspired ventilation; VI; L/min) and a peripheral pulse oximeter to measure oxygen saturation (SpO2;%). First, while breathing roughly equivalent PIO2 of ~85 mmHg at baseline (BL), both groups were exposed a single tidal breath of 100% O2 from a 50L Douglas bag by switching a three-way valve from room air to hyperoxia. The HVW was quantified as the change (delta) in VI from BL to the smallest instantaneous breath within 20-sec of the hyperoxic stimulus indexed to the change in SpO2 from BL to the peak following the hyperoxic breath, wherever it occurred (i.e., ventilatory response/oxygen change). We found that the HVW values from acute hypoxic participants had a mean of 0.34±0.23 L/min/%, while those who underwent acclimatization to high altitude hypoxia had a significantly larger HVW of 0.53±0.24 L/min/% (P=0.03). Our results suggest that the transient HVW test is a feasible method to detect peripheral chemoreceptor sensitization and ventilatory acclimatization in the context of high altitude ascent.

Quantitative Measurement of Oxygen Extraction Fraction (OEF) Using Respiratory Modulated Perfusion MRI

Background: Measurement of oxygen consumption can give useful information of brain functionality in health and disease. To have a better understanding of normal physiology in all conditions (rest or functional tasks), development of accurate brain oxygen mapping is essential. This mapping could also be a great help in managing pathological conditions with disturbance in oxygen supply. One of the most important hemodynamic parameters of the brain is oxygen extraction fraction (OEF). By development of blood oxygen level dependent magnetic resonance imaging (BOLD MRI) in imaging, several methods have been proposed for measuring this parameter. The latest methods are mostly based on hypercapnic and hyperoxic stimulus. Objectives: Here, we presented a new method with hypercapnic and hyperoxic stimulus and using BOLD and dynamic susceptibility contrast (DSC) perfusion imaging instead of arterial spin labelling (ASL). Materials and Methods: A 3T Siemens Trio Tim Scanner was used for imaging five patients (three males and two females) who were recruited for this experiment. Four set of T1 data, BOLD data and two DSC-perfusions (two injections) were applied to each subject. Gas manipulation was applied while acquiring BOLD data and one of the DSC-perfusion was done in hyperoxic condition. Gas manipulation was a combination of hypercapnic, hyperoxic and normoxic conditions in a total of 13 minutes. The DSC data was analyzed using PMA (ASIST) software to calculate cerebral blood flow (CBF) and using its results with the BOLD data, OEF was calculated by MATLAB coding. All preprocessing was done with the SPM12 (MATLAB). Results: Comparable results were acquired for OEF with previous studies. The mean value of estimated OEF for gray matter (GM), white matter (WM) and whole brain is 0.46, 0.37, and 0.44, respectively which are within the expected range of normal condition. Conclusion: As the proposed method for OEF measurement uses a combination of hyperoxic and hypercapnic stimulus with BOLD and DSC-perfusion imaging, it could be considered the most available one in all MRI scanners and being a voxel wise method, it could give OEF value for any requested ROI.

CAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle

Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.

Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active hypoxic pulmonary vasoconstriction in normoxia.

Hypoxic pulmonary vasoconstriction (HPV) is thought to actively regulate ventilation-perfusion (V̇a/Q̇) matching, reducing perfusion in regions of alveolar hypoxia. We assessed the extent of HPV in the healthy human lung using inhaled nitric oxide (iNO) under inspired oxygen fractions (FiO2 ) of 0.125, 0.21, and 0.30 (a hyperoxic stimulus designed to abolish HPV without the development of atelectasis). Dynamic measures of blood flow were made in a single sagittal slice of the right lung of five healthy male subjects using an arterial spin labeling (ASL) MRI sequence, following a block stimulus pattern (3 × 60 breaths) with 40 ppm iNO administered in the central block. The overall spatial heterogeneity, spatiotemporal variability, and regional pattern of pulmonary blood flow was quantified as a function of condition (FiO2 × iNO state). While spatial heterogeneity did not change significantly with iNO administration or FiO2 , there were statistically significant increases in Global Fluctuation Dispersion, (a marker of spatiotemporal flow variability) when iNO was administered during hypoxia (5.4 percentage point increase, P = 0.003). iNO had an effect on regional blood flow that was FiO2 dependent (P = 0.02), with regional changes in the pattern of blood flow occurring in hypoxia (P = 0.007) and normoxia (P = 0.008) tending to increase flow to dependent lung at the expense of nondependent lung. These findings indicate that inhaled nitric oxide significantly alters the distribution of blood flow in both hypoxic and normoxic healthy subjects, and suggests that some baseline HPV may indeed be present in the normoxic lung.

Heterogeneous sensitivity of cerebral and muscle tissues to acute normobaric hyperoxia at rest

The purpose was to investigate the effects of acute normobaric hyperoxia at rest on cerebral, respiratory and leg muscle oxygenation. Ten healthy men were studied twice in a single-blinded counterbalanced crossover study protocol. On one occasion they breathed air and on the other 100% normobaric O2 for a 2-hour time period. Oxygenated (Δ[O2Hb]), deoxygenated (Δ[HHb]) and total (Δ[tHb]) hemoglobin in the cerebral frontal cortex, and in the intercostal and vastus lateralis muscles were simultaneously monitored with near-infrared spectroscopy. The hyperoxic stimulus promptly increased Δ[O2Hb] (~2μM) and decreased Δ[HHb] (~3.6μM) in the frontal cortex. These cerebral responses were directly and fully countered by resumption of normoxic air breathing. In contrast, Δ[HHb] significantly decreased due to the acute hyperoxic stimulus in both intercostal and vastus lateralis muscles. The temporal changes in muscle oxygenation were slower compared to those in the cerebral area; and they only partially recovered during the 15-min normoxic-recovery period. Acute supplementation of normobaric O2 at rest influences cerebral, leg and respiratory muscle oxygenation of healthy individuals, but not in the same manner. Namely, the frontal cortex seems to be more sensitive to hyperoxia than are the skeletal muscle regions.

Effect of N-acetyl-cysteine and hyperoxia on erythropoietin production

Previous studies in healthy subjects have shown an increase in erythropoietin (EPO) production after administration of N-acetyl-cysteine (NAC). These authors hypothesized that NAC increases intracellular reduced glutathione, decreasing reactive oxygen species and enabling EPO production. We investigated if EPO production could be stimulated with a single dose of NAC, after 90min of pure oxygen breathing. Thirty-eight healthy volunteers were randomized into either the control (C) group or the NAC group, which received 600mg NAC PO dissolved in a glass of orange juice, 60min before breathing 15L/min of 100% normobaric oxygen. Orange juice was administered to both groups. Blood samples for EPO measurement were taken at T0, before the orange juice administration, and T1, T2, T3 and T4, respectively, 8, 24, 32 and 48h after the orange juice. The EPO concentrations of the NAC group decreased significantly at T1, followed by a significant increase compared to baseline, which was obvious until T4. The EPO concentrations of the C group did not show any significant variations. In this study, a significant increase of EPO production was observed after a short-term hyperoxic stimulus only when preceded with the administration of a single dose of NAC.

Detecting blood oxygen level‐dependent (BOLD) contrast in the breast

To develop a robust technique for detecting blood oxygenation level-dependent (BOLD) contrast in the human breast and to evaluate the signal in healthy and malignant breast. The design of this study focused on determining the optimal pulse sequence and stimulus for detecting BOLD contrast in the breast. For this study a single-shot fast spin echo (SSFSE) sequence was compared to a gradient echo (GRE) pulse sequence. Also, several hyperoxic stimuli were tested on 15 healthy volunteers to determine the best stimulus for inducing BOLD contrast in the breast: air interleaved with carbogen (95% O(2), 5% CO(2)), air interleaved with oxygen, and oxygen interleaved with carbogen. The stimulus with the most consistent results among the healthy population was tested on three breast cancer patients. An SSFSE pulse sequence produced improved BOLD contrast results in the breast compared to a GRE pulse sequence. Oxygen interleaved with carbogen yielded the most consistent results in the healthy population. BOLD contrast in healthy glandular breast tissue positively correlates with carbogen and malignant tissue mostly negatively correlates to carbogen. BOLD contrast can consistently be detected in the breast using a robust protocol. This methodology may be used in the future as a noninvasive method for evaluating tumor oxygenation.

Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons

Breathing hyperbaric oxygen (HBO) is common practice in hyperbaric and diving medicine. The benefits of breathing HBO, however, are limited by the risk of central nervous system O2 toxicity, which presents as seizures. We tested the hypothesis that excitability increases in CA1 neurons of the rat hippocampal slice (400 microm) over a continuum of hyperoxia that spans normobaric and hyperbaric pressures. Amplitude changes of the orthodromic population spike were used to assess neuronal O2 sensitivity before, during, and following exposure to 0, 0.6, 0.95 (control), 2.84, and 4.54 atmospheres absolute (ATA) O2. Polarographic O2 electrodes were used to measure tissue slice PO2 (PtO2). In 0.95 ATA O2, core PtO2 at 200 microm deep was 115±16 Torr (mean±SE). Increasing O2 to 2.84 and 4.54 ATA increased core PtO2 to 1,222±77 and 2,037±157 Torr, respectively. HBO increased the orthodromic population spike amplitude and usually induced hyperexcitability (i.e., secondary population spikes) and, in addition, a long-lasting potentiation of the orthodromic population spike that we have termed "oxygen-induced potentiation" (OxIP). Exposure to 0.60 ATA O2 and hypoxia (0.00 ATA) decreased core PtO2 to 84±6 and 20±4 Torr, respectively, and abolished the orthodromic response. Reoxygenation from 0.0 or 0.6 ATA O2, however, usually produced a response similar to that of HBO: hyperexcitability and activation of OxIP. We conclude that CA1 neurons exhibit increased excitability and neural plasticity over a broad range of PtO2, which can be activated by a single, hyperoxic stimulus. We postulate that transient acute hyperoxia stimulus, whether caused by breathing HBO or reoxygenation following hypoxia (e.g., disordered breathing), is a powerful stimulant for orthodromic activity and neural plasticity in the CA1 hippocampus.

Retinal arteriolar vascular reactivity to incremental changes in hyperoxic stimuli during isocapnia

Abstract Purpose To determine the relationship between the magnitude of retinal arteriolar vascular reactivity and incremental changes in hyperoxic stimuli whilst maintaining isocapnia. Methods Twelve healthy, young adults (mean age 27 years, SD 4) participated in a gas protocol consisting of 4 phases at varying fractional expired oxygen levels (FeO2): baseline (15%), hyperoxia I (40%), hyperoxia II (65%), and recovery (15%). End‐tidal carbon dioxide (ETCO2) was maintained at isocapnia throughout the experiment. Retinal arteriolar diameter, blood velocity, and blood flow were assessed non‐invasively using the Canon Laser Blood Flowmeter during each of these phases. Results Repeated measures ANOVA showed that there were significant influences of incremental changes in FeO2 on retinal arteriolar diameter (p&lt;0.0001), blood velocity (p&lt;0.0001), and blood flow (p&lt;0.0001). Paired t‐tests of these retinal hemodynamic parameters during each phase in the gas sequence showed they were significantly different (p&lt;0.05) from each other, with the exception of baseline and recovery values. Incremental increases in FeO2 caused a linear decrease in group mean arteriolar diameter (R2 = 1, p = 0.002), group mean blood velocity (R2 = 0.9968, p = 0.04), and group mean blood flow (R2 = 0.9982, p= 0.03). Conclusion Isocapnic hyperoxia elicits vasoconstriction and the reduction of retinal arteriolar diameter, velocity and blood flow in a dose‐dependent manner over the range of FeO2 explored in this study. Commercial interest

Clinical aspects of Clara cell 10-kDa protein/ uteroglobin (secretoglobin 1A1).

Clara cell 10-kDa protein (CC10)/ uteroglobin (UG) is a nonglycoprotein with a molecular mass of 16 kilodaltons, which is produced by mucosal epithelial cells in the lung (Clara cells), uterus and prostate. Like other low molecular weigh proteins it is catabolized in renal proximal tubules. Structurally it is a homodimer of subunits of 70 amino acids covalently bound in an antiparallel manner. It belongs to secretogobin (SCGB) family and is assigned as subgroup 1A1. The function of the protein so far elucidated is immunoregulatory and anti-inflammatory in innate immunity. The knockout mouse of UG gene resulted in aggravation of inflammation by allergic and hyperoxic stimuli. It also showed very similar pathological features with human IgA nephropathy. The value is changed in the lung fluid and serum of various inflammatory and allergic lung diseases. Several kinds of single nucleotide polymorphisms (SNPs) in human CC10/UG gene were recently discovered; Adenine allele accumulation in G38A SNP has possible association with asthma and IgA nephropathy, being paralleled with disease severity of IgA nephropathy. Its expression is enhanced by some transcriptional factors induced by cytokines such as interferon-gamma. For cancer cells, the protein functions as an antagonist of neoplastic phenotype. CC10/UG forms one of intra- and intercellular regulators involved in inflammation and malignant transformation in the respiratory and urogenital fields.

State-dependent regulation of cortical blood flow and respiration in hamsters: response to hypercapnia during arousal from hibernation.

Hibernation is characterised by a global reduction of metabolism, body temperature and blood flow, while arousal from hibernation is achieved by the reversal of these processes. Our experiments were performed on Syrian hamsters that had been chronically implanted with a cortical thermocouple and an optical fibre over the contralateral cortex, and acutely implanted with thermocouples in the rectal, cheek pouch and interscapular brown adipose tissue (BAT). Measurements revealed large thermal gradients in the body of the arousing animals. Maximum whole-body metabolic rate, which was 2.4 times normal cenothermic resting metabolic rate, coincided not with rectal temperature but more closely with respiratory rate (RR) or BAT temperature. Regional cortical blood flow (rCBF), as measured by laser-Doppler flowmetry, changed in parallel with whole-body metabolic rate, peaking at 3.8 times the normal cenothermic resting levels, when rectal temperature was 15 degrees C. When BAT temperature was less than 25 degrees C, RR, rCBF and heart rate (HR) were decreased by breathing hypercapnic gas, but these parameters were unresponsive to hyperoxic gases. At cenothermia the RR and rCBF of anaesthetised hamsters was increased by exposure to hypercapnic gases. Exposure to hyperoxic gas decreased RR but had no effect on rCBF. The mechanisms regulating rCBF, HR and RR exhibit state-dependent sensitivities to hypercapnic and hyperoxic stimuli. The large increase in rCBF observed during arousal implies that cerebral autoregulation is temporarily suspended and suggests that hamsters effectively use endogenous mechanisms to minimise the pathology normally associated with dramatic increases in rCBF.

Oxygen measurements in brain stem slices exposed to normobaric hyperoxia and hyperbaric oxygen.

We previously reported (J Appl Physiol 89: 807-822, 2000) that < or =10 min of hyperbaric oxygen (HBO(2); < or = 2,468 Torr) stimulates solitary complex neurons. To better define the hyperoxic stimulus, we measured PO(2) in the solitary complex of 300-microm-thick rat medullary slices, using polarographic carbon fiber microelectrodes, during perfusion with media having PO(2) values ranging from 156 to 2,468 Torr. Under control conditions, slices equilibrated with 95% O(2) at barometric pressure of 1 atmospheres absolute had minimum PO(2) values at their centers (291 +/- 20 Torr) that were approximately 10-fold greater than PO(2) values measured in the intact central nervous system (10-34 Torr). During HBO(2), PO(2) increased at the center of the slice from 616 +/- 16 to 1,517 +/- 15 Torr. Tissue oxygen consumption tended to decrease at medium PO(2) or = 1,675 Torr to levels not different from values measured at PO(2) found in all media in metabolically poisoned slices (2-deoxy-D-glucose and antimycin A). We conclude that control medium used in most brain slice studies is hyperoxic at normobaric pressure. During HBO(2), slice PO(2) increases to levels that appear to reduce metabolism.

Hyperoxia and Recovery from Hypoxia Alter Collagen in Peripheral Pulmonary Arteries Similarly

Chronic hypoxia causes pulmonary hypertension, the mechanism of which includes altered collagen metabolism in the pulmonary vascular wall. This chronic hypoxic pulmonary hypertension is gradually reversible upon reoxygenation. The return to air after the adjustment to chronic hypoxia resembles in some aspects a hyperoxic stimulus and we hypothesize that the changes of extracellular matrix proteins in peripheral pulmonary arteries may be similar. Therefore, we studied the exposure to moderate chronic hyperoxia (FiO2 = 0.35, 3 weeks) in rats and compared its effects on the rat pulmonary vasculature to the effects of recovery (3 weeks) from chronic hypoxia (FiO2 = 0.1, 3 weeks). Chronically hypoxic rats had pulmonary hypertension (Pap = 26±3 mm Hg, controls 16±1 mm Hg) and right ventricular hypertrophy. Pulmonary arterial blood pressure and right ventricle weight normalized after 3 weeks of recovery in air (Pap = 19±1 mm Hg). The rats exposed to moderate chronic hyperoxia also did not have pulmonary hypertension (Pap = 18±1 mm Hg, controls 17±1 mm Hg). Collagenous proteins isolated from the peripheral pulmonary arteries (100-300 mm) were studied using polyacrylamide gel electrophoresis. A dominant low molecular weight peptide (approx. 76 kD) was found in hypoxic rats. The proportion of this peptide decreases significantly in the course of recovery in air. In addition, another larger peptide doublet was found in rats recovering from chronic hypoxia. It was localized in polyacrylamide gels close to the zone of a2 chain of collagen type I. It was bound to anticollagen type I antibodies. An identically localized peptide was found in rats exposed to moderate chronic hyperoxia. The apparent molecular weight of this collagen fraction suggests that it is a product of collagen type I cleavage by a rodent-type interstitial collagenase (MMP-13). We conclude that chronic moderate hyperoxia and recovery from chronic hypoxia have a similar effect on collagenous proteins of the peripheral pulmonary arterial wall.

Ventilatory responses to hypercapnia and hypoxia following chronic hypercapnia in the rat

This study investigated the effects of an 18 week exposure to 10% CO 2 in air on minute ventilation ( V ̇ E ), breathing pattern and the chemoresponiveness of rats to hypoxic and hyperoxic stimuli. We found that V ̇ E remained elevated over the 18 weeks. Nonetheless, the breathing pattern changed significantly. Tidal volume increased and the durations of inspiration and the total cycle decreased. After the sustained hypercapnia the mean Pa CO 2 was 72.0±5.1 (S.D.) mmHg. Every 6 weeks the chemoresponiveness of the CO 2-exposed rats was tested by an acute exposure sequentially to room air, then a 6% O 2, 10% CO 2 and 84% N 2 gas mixture, and finally a 90% O 2 in 10% CO 2 mixture. On either room air or the hyperoxic–hypercapnic mixture V ̇ E fell to its pre-hypercapnic level. On the hypoxic–hypercapnic mixture V ̇ E increased significantly. These results demonstrate that the initial stimulating effect of 10% CO 2 on V ̇ E persisted for the entire 18 weeks without altering hypoxic or hyperoxic ventilatory responses.