GABA(A) and GABA(B) receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats.

The aim of this study was to investigate whether GABA(A) and/or GABA(B) receptor-mediated mechanisms contribute to the impaired ventilatory response and reduced maximal aerobic exercise capacity in obese Zucker rats. Ten lean and 10 obese Zucker rats were studied at 12 wk of age. Minute ventilation (Ve), tidal volume (Vt), and breathing frequency (f) during room air breathing and in response to 10 min of hypercapnia (8% CO(2)) and 30 min of hypoxia (10% O(2)) were measured by the barometric method, and peak oxygen consumption (Vo(2 peak)) was measured by an enclosed metabolic treadmill following the randomized blinded subcutaneous administration of equal volumes of DMSO (vehicle), bicuculline (selective GABA(A) receptor antagonist, 1 mg/kg), and phaclofen (selective GABA(B) receptor antagonist, 1 mg/kg). Administration of bicuculline and phaclofen to lean animals had no effect on Ve and Vo(2 peak). Similarly, phaclofen failed to alter Ve and Vo(2 peak) in obese rats, although it did significantly increase f after 5-20 min of hypoxia. In contrast, bicuculline increased Ve and Vt relative to DMSO during room air breathing and after 10-30 min of hypoxic exposure in obese rats, but it did not increase Ve at 5 min of hypoxemia. Bicuculline increased Vo(2 peak) relative to DMSO in obese Zucker rats. We conclude that endogenous GABA acting on GABA(A) receptors can modulate Ve and Vo(2 peak) in obese but not in lean Zucker rats, whereas endogenous GABA acting on GABA(B) receptors modulates f during hypoxia (5-20 min) in obese rats in a very different manner from that when acting on GABA(A) receptors.     

The central effect of 5-hydroxytryptamine, gamma-amino-butyric acid and carbachol on thermoregulation in the neonatal guinea pig.

5-Hydroxytryptamine (10 microgram), gamma-amino-butyric acid (20 microgram) and carbachol (1 microgram) were injected through the soft skull into the lateral cerebral ventricle of guinea pigs aged 2 to 12 days, at the slightly subneutral ambient temperature of 30 degrees C. 5-Hydroxytryptamine (5-HT) produced no immediate change in oxygen consumption, whereas colonic temperature fell rapidly. One hour after injecting 5-HT, when colonic temperature had decreased by about 0.5 degrees C, oxygen consumption increased and after a lag of 30--40 min was followed by an increase in colonic temperature. Gamma-amino-butyric acid (GABA) increased oxygen consumption and colonic temperature after a latency of 30--60 min. Carbachol was followed by an immediate decrease in colonic temperature and oxygen consumption. Colonic temperature was below the pre-injection level throughout the five-hour period of observation.     

Hypoxic initiation of pulmonary hypertension is mediated by serotonin secretion from neuroepithelial bodies in chemodenervated dogs

The purpose of this study was to investigate the stimulatory effect of hypoxia on the secretion of serotonin by neuroepithelial bodies (NEB) as well as to determine the relation between its level and changes in pulmonary arterial pressure (PAP) and also to determinate the effect of serotonin antagonists (pizotifen and methysergide) on the responses of pulmonary and systemic arterial pressures. The experiments were carried out in peripheral chemoreceptor-denervated dogs anesthetized with Na penthabarbital (30 mg/kg i.v.). On the breathing of normoxic and hypoxic (7% O2-93% N2) gas mixtures and on the injection of KCN (80 microg/kg i.v.), PAP, systemic arterial blood pressure (BP), tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) were determined. Also PAP and BP were recorded before and after the injection of pizotifen (0.5 mg/kg i.v.) and methysergide (1 mg/kg i.v.) during normoxic or hypoxic gas mixture breathing. At the end of each experimantal phase, serotonin level, PaO2, PaCO2 and pHa values in blood samples obtained from left ventricle and femoral artery were determined. On the breathing of the hypoxic gas mixture of the chemodenervated dogs, VT, VE and BP significantly decreased (P < 0.001, P < 0.001, P < 0.01). The mean value of PAP and serotonin levels (ventricular and femoral) were found significantly increased when compared with the corresponding normoxic values (P < 0.001, P < 0.05). On the other hand, injection of KCN produced no significant changes in PAP, serotonin levels, BP and respiratory parameters. After the injection of pizotifen, PAP was significantly increased in hypoxia (P < 0.01). After the injection of methysergide, the response of PAP was completely abolished during the breathing of hypoxic gas mixture. The finding of the abolition of response of PAP to hypoxia after the injection of methysergide indicates that serotonin release from NEB may be responsible for the elevation of PAP in hypoxic hypoxia.     

Amino Acid Content of Nerve Endings (Synaptosomes) in Different Regions of Brain: Effects of Gabaculine and Isonicotinic Acid Hydrazide

Abstract: The amino acid content of synaptosomes was determined in six regions of rat brain, and in all regions the five predominant amino acids were glutamate, glutamine, aspartate, taurine, and GABA (γ-aminobutyrate). However, the proportions of the individual amino acids varied considerably from one region to another, the GABA content being particularly high and the taurine content low in synaptosomes from the diencephalon and mesencephalon. Administration of isonicotinic acid hydrazide to rats lowered the synaptosomal GABA level by similar amounts in all brain regions, but the administration of gabaculine resulted in a particularly long-acting elevation in GABA levels in the nerve endings of the diencephalon and mesencephalon. The possibility is raised that the high GABA levels in the nerve terminals of the diencephalon may be involved in the gabaculine-induced lowering of the body temperature of the rats. A constancy in the amount of the synaptosomal pool of "aspartate + glutamate + glutamine + GABA" was observed despite large changes in the relative amounts of the four amino acids brought about by gabaculine.     

Acute alterations in stroke volume during exercise at 3,100 m altitude.

Following 3 weeks exposure to an altitude of 3,100 m, the cardiac output response to upright submaximal exercise was examined in 3 healthy subjects breathing ambient air and breathing 60% oxygen. The procedure allowed acute alteration of the 2 conditions within a single testing period of 30 min, 60% oxygen breathing either preceding or following breathing ambient air. Cardiac output was also measured in two of the subjects during maximal exercise under these two conditions. Administration of the high oxygen inspirate during exercise had little effect on the level of cardiac output but resulted in an immediate bradycardia and a dramatic increase of approximately 16% in stroke volume. Stroke volumes during maximal exercise were also increased by approximately 10% by the administration of high oxygen. It is suggested that the condition of decreases exercise stroke volume which develops with chronic exposure to altitude may be largely the result of diminished myocardial contractility stemming from a condition of myocardial hypoxia.     

Individual specifics of oxygen consumption by the human organism in hypoxia

Influence of hypoxia on a human organism was studied with the help of hypoxic gas mixtures (HGM) in the first series with 14 % content of oxygen in nitrogen (n = 6), in the second one--with 12 % (n = 10) in the third one--with 8 % (n = 14). Hypoxic exposition in all the series was 25 min. In 6 subjects engaged in all the 3 series, physical working capacity was assessed in two-step test on a veloergometer. In all the 3 series, oxygen consumption by the organism some time after the start of the hypoxic action exceeded the background normnoxic level. Maximal value of this excess on the average was the highest in HGM-12 series--40 +/- 12 %. Maximal increase of the respiration and central blood circulation velocity was the highest in HGM-8 series, 90 +/- 24 and 25 +/- 16 % respectively. Analysis of the EEG parameters, oxygen saturation and rheoencephalographic data indicates the probability of the cerebral metabolic rate of oxygen during hypoxia to beein normal (in most subjects) and even increased (in some subjects). In 3 subjects of 6, whose physical working capacity was assessed, maximal increase of oxygen consumption was observed in HGM-8 series--105 +/- 34 %. Their physical working capacity was higher than of those subjects, who showed maximal increase of oxygen consumption in HGM-12 series. Analysis of increase in oxygen consumption (paradoxical under hypoxic conditions) doesn't allow to ascribe it wholly to an increase of the respiration and central blood circulation. Obviously, the increase of oxygen and energy expenditures for biochemical adaptation to hypoxia, which has common features with adaptation to physical activity plays an important role under hypoxia.     

Response of newborn lambs to CO-induced hypoxia

This study was undertaken to measure the neonate's response to CO-induced hypoxia in the first 10 days of life. CO breathing was used to induce hypoxia because CO causes tissue hypoxia with no or minimal chemoreceptor stimulation. An inspired gas mixture of 0.25 to 0.5% CO in air was used to raise the blood carboxyhemoglobin (HbCO) progressively from 0 to 60% over approximately 20 min. The study, conducted in awake conscious lambs aged 2 and 10 days, consisted in measuring the response of ventilation and the change in arterial blood gases during the rise of HbCO. The results showed that the 2- and 10-day-old lambs tolerated very high HbCO levels without an increase in minute ventilation (VE) and without metabolic acidosis. At both ages, HbCO caused no VE change until HbCO levels rose to between 45 and 50% after which the VE change was exponential in some animals but minimal in others. The VE change was brought about by a rise in tidal volume and respiratory frequency. During the period of maturation from 2 to 10 days, there was a small shift to the right in the VE-HbCO response. In the 10-day-old lambs the VE response to high HbCO was greater than that of the 2-day-olds because of the lambs' higher respiratory frequency response. Six of the 10-day-old lambs but only two of the 2-day-old lambs showed a hypoxic tachypnea to HbCO of 55-65%. None of the lambs developed periodic breathing, dysrhythmic breathing, or recurrent apneas with an HbCO level as high as 60%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of changes in arterial oxygen content on circulation and physical performance.

To evaluate the effect of different levels of arterial oxygen content on hemodynamic parameters during exercise nine subjects performed submaximal bicycle or treadmill exercise and maximal treadmill exercise under three different experimental conditions: 1) breathing room air (control); 2) breathing 50% oxygen (hyperoxia); 3) after rebreathing a carbon monoxide gas mixture (hypoxia). Maximal oxygen consumption (Vo2 max) was significantly higher in hyperoxia (4.99 1/min) and significantly lower in hypoxia (3.80 1/min) than in the control experiment (4.43 1/min). Physical performance changes in parallel with Vo2 max. Maximal cardiac output (Qmax) was similar in hyperoxia as in control but was significantly lower in hypoxia mainly due to a decreased stroke volume. A correlation was found between Vo2 max and transported oxygen, i.e., Cao2 times Amax, thus suggesting that central circulation is an important limiting factor for human maximal aerobic power. During submaximal work HR was decreased in hyperoxia and increased in hypoxia. Corresponding Q values were unchanged except for a reduction during high submaximal exercise in hyperoxia.     

The Effect of Acute Hypoxia on Synaptosomes from Rat Brain

Abstract: Synaptosomes have been isolated from the brains of nonanesthetized and nembutal-anesthetized rats subjected to 30 min hypoxia induced by breathing 7% oxygen in nitrogen. The respiratory rate was depressed in synaptosomes from starved hypoxic animals but was not significantly different from the respective control values in preparations from fed hypoxic animals, anesthetized animals, and hypoxic nonanesthetized animals allowed to recover from the hypoxic episode by 60 min of normoxic conditions. Observations are also reported concerning the levels of various metabolites in the synaptosomes isolated from the brains of the same groups of animals. It is suggested that hypoxia results in damage to the synaptosomal and/or mitochondrial membrane, which modifies substrate oxidation in the mitochondria and decreases availability of reducing equivalents for the respiratory chain. Results obtained on afflicted and recovered animals indicate that synaptosomal preparations provide a useful model for the study of hypoxic damage.     

The oxygen delivery response to acute hypoxia during incremental knee extension exercise differs in active and trained males

Background

It is well known that hypoxic exercise in healthy individuals increases limb blood flow, leg oxygen extraction and limb vascular conductance during knee extension exercise. However, the effect of hypoxia on cardiac output, and total vascular conductance is less clear. Furthermore, the oxygen delivery response to hypoxic exercise in well trained individuals is not well known. Therefore our aim was to determine the cardiac output (Doppler echocardiography), vascular conductance, limb blood flow (Doppler echocardiography) and muscle oxygenation response during hypoxic knee extension in normally active and endurance-trained males.

Methods

Ten normally active and nine endurance-trained males (VO_2max = 46.1 and 65.5 mL/kg/min, respectively) performed 2 leg knee extension at 25, 50, 75 and 100% of their maximum intensity in both normoxic and hypoxic conditions (FIO₂ = 15%; randomized order). Results were analyzed with a 2-way mixed model ANOVA (group × intensity).

Results

The main finding was that in normally active individuals hypoxic sub-maximal exercise (25 – 75% of maximum intensity) brought about a 3 fold increase in limb blood flow but decreased stroke volume compared to normoxia. In the trained group there were no significant changes in stroke volume, cardiac output and limb blood flow at sub-maximal intensities (compared to normoxia). During maximal intensity hypoxic exercise limb blood flow increased approximately 300 mL/min compared to maximal intensity normoxic exercise.

Conclusion

Cardiorespiratory fitness likely influences the oxygen delivery response to hypoxic exercise both at a systemic and limb level. The increase in limb blood flow during maximal exercise in hypoxia (both active and trained individuals) suggests a hypoxic stimulus that is not present in normoxic conditions.

     

Partitioning of respiration between the gills and air-breathing organ in response to aquatic hypoxia and exercise in the pacific tarpon, Megalops cyprinoides

The evolution of air-breathing organs (ABOs) is associated not only with hypoxic environments but also with activity. This investigation examines the effects of hypoxia and exercise on the partitioning of aquatic and aerial oxygen uptake in the Pacific tarpon. The two-species cosmopolitan genus Megalops is unique among teleosts in using swim bladder ABOs in the pelagic marine environment. Small fish (58-620 g) were swum at two sustainable speeds in a circulating flume respirometer in which dissolved oxygen was controlled. For fish swimming at 0.11 m s(-1) in normoxia (Po2 = 21 kPa), there was practically no air breathing, and gill oxygen uptake was 1.53 mL kg(-0.67) min(-1). Air breathing occurred at 0.5 breaths min(-1) in hypoxia (8 kPa) at this speed, when the gills and ABOs accounted for 0.71 and 0.57 mL kg(-0.67) min(-1), respectively. At 0.22 m s(-1) in normoxia, breathing occurred at 0.1 breaths min(-1), and gill and ABO oxygen uptake were 2.08 and 0.08 mL kg(-0.67) min(-1), respectively. In hypoxia and 0.22 m s(-1), breathing increased to 0.6 breaths min(-1), and gill and ABO oxygen uptake were 1.39 and 1.28 mL kg(-0.67) min(-1), respectively. Aquatic hypoxia was therefore the primary stimulus for air breathing under the limited conditions of this study, but exercise augmented oxygen uptake by the ABOs, particularly in hypoxic water.     

Effect of hypobaric air, oxygen, heliox (50:50), or heliox (80:20) breathing on air bubbles in adipose tissue.

The fate of bubbles formed in tissues during decompression to altitude after diving or due to accidental loss of cabin pressure during flight has only been indirectly inferred from theoretical modeling and clinical observations with noninvasive bubble-measuring techniques of intravascular bubbles. In this report we visually followed the in vivo resolution of micro-air bubbles injected into adipose tissue of anesthetized rats decompressed from 101.3 kPa to and held at 71 kPa corresponding to approximately 2.750 m above sea level, while the rats breathed air, oxygen, heliox (50:50), or heliox (80:20). During air breathing, bubbles initially grew for 30-80 min, after which they remained stable or began to shrink slowly. Oxygen breathing caused an initial growth of all bubbles for 15-85 min, after which they shrank until they disappeared from view. Bubble growth was significantly greater during breathing of oxygen compared with air and heliox breathing mixtures. During heliox (50:50) breathing, bubbles initially grew for 5-30 min, from which point they shrank until they disappeared from view. After a shift to heliox (80:20) breathing, some bubbles grew slightly for 20-30 min, then shrank until they disappeared from view. Bubble disappearance was significantly faster during breathing of oxygen and heliox mixtures compared with air. In conclusion, the present results show that oxygen breathing at 71 kPa promotes bubble growth in lipid tissue, and it is possible that breathing of heliox may be beneficial in treating decompression sickness during flight.     

Elevated diaphragm electromyogram during neonatal hypoxic ventilatory depression

Diaphragmatic electromyogram (EMG) was obtained in eight 48-h-old unanesthetized monkeys while breathing air and then either of two different hypoxic gas mixtures (12 or 8% O2 in N2) for 5 min. Minute ventilation (VI) rose significantly above control levels by 1 min of hypoxemia while animals were breathing either of the hypoxic gas mixtures as tidal volume (VT) and slope and rate moving average EMG increased. The relative gains in VI were associated with comparable increases in diaphragmatic neural activity per minute (EMG/min = peak EMG X frequency) during this early phase of hypoxemia. VI subsequently fell to control levels (inspired O2 fraction = 12%, arterial PO2 = 23 +/- 3 Torr) or significantly below (inspired O2 fraction = 8%, arterial PO2 = 18 +/- 0.4 Torr) by 5 min of hypoxemia, secondary to changes in VT. Despite the decline in VI, slope and rate moving average EMG, and EMG/min remained statistically above control values by 5 min of hypoxemia, although there was a trend for EMG/min to decrease slightly from the 1-min peak response. These findings demonstrate that hypoxic-induced depression of neural input to the diaphragm is not independently responsible for the biphasic nature of the newborn ventilatory response, although it cannot be ruled out as a contributor. The fall in inspiratory volumes despite constant elevated EMG activity suggests the presence of a change in respiratory mechanics and/or an impairment in diaphragmatic contractile function without offsetting neural compensatory activity.     

Effects of Argon on Oxygen Consumption in Humans during Physical Exercise under Hypoxic Conditions

An increase in oxygen consumption was observed in healthy male subjects breathing argon-containing gas mixtures during physical exercise. According to a detailed analysis of the methodology and calculations, this effect exceeded the possible errors in the measurements. It was proposed that argon has a catalytic effect on the kinetics of oxygen consumption as an attempt to explain two of its known effects, i.e., an increase in oxygen consumption in human subjects breathing moderately hypoxic gas mixtures and an increase in the survival rates observed previously for rats in acute hypoxia.     

Effects of the differentiating agents sodium butyrate and N-methylformamide on the oxygen enhancement ratio of human colon tumor cells

We have previously shown that chronic adaptation of human tumor cells to the differentiation-inducing agents N-methylformamide (NMF) and sodium butyrate (NAB) increases the sensitivity of oxic cells to graded single doses of X rays. These studies were carried out to define the sensitivity of hypoxic cells after adaptation. Clone A colon tumor cells were grown for three passages in medium containing 170 mM NMF or 2 mM NAB and irradiated in suspension culture, after gassing with either oxygen (60 min) or ultrapure nitrogen (90 min), and complete survival curves were generated. Using the linear-quadratic equation to describe the data, it was found that NMF and NAB produced increased X-ray killing of hypoxic cells. At the 10% level of survival, the dose-modifying factors were about 1.20 and 1.25 for NMF- and NAB-adapted hypoxic cells, respectively, as compared to hypoxic control cells. However, since both oxic and hypoxic cells exhibited increased sensitivity after NMF and NAB adaptation, there was no major change in the oxygen enhancement ratio.     

Radiation protection of mice with hypoxic gas mixtures after administration of anti-hypoxic agents

It is shown that such substances as gutimine, antizol and mexamine increases the resistance of animals to short-term breathing of gas mixtures containing 6 and 5% oxygen. Even if some of them decrease the degree of radioprotective effect of hypoxia, they afford the possibility to safe use of breathing mixtures with lower oxygen content than endured by intact animals, with the resulting increase in radioprotection. Thus the antihypoxic substances can be tested during hypoxiradiotherapy of human tumors.     

Lactate accumulation during incremental exercise with varied inspired oxygen fractions

Six subjects pedaled a stationary cycle ergometer to exhaustion on three separate occasions while breathing gas mixtures of 17, 21, or 60% O2 in N2. Each subject rode for 3 min at work rates of 60, 90, 105 W, followed by 15-W increases every 3 min until exhaustion. Inspired and expired gas fractions, ventilation (V), heart rate, and blood lactate were measured. O2 uptake (VO2) and CO2 output (VCO2) were calculated for the last minute of each work rate; blood samples were drawn during the last 5 s. "Break points" for lactate, V, VCO2, V/VO2, and expired oxygen fraction (FEO2) were mathematically determined. VO2 was not significantly different at any work rate among the three different conditions. Nor did maximal VO2 differ significantly among the three treatments (P greater than 0.05). Lactate concentrations were significantly lower during hyperoxia and significantly higher during hypoxia compared with normoxia. Lactate values at exhaustion were not significantly different among the three treatments. Four subjects were able to work for a longer period of time during hyperoxic breathing. The variations in lactate accumulation as reported in this study cannot be explained on the basis of differences in VO2. The results of this research lend support to the hypothesis that differences in the performance of subjects breathing altered fractions of inspired oxygen may be caused by differences in lactate (or H+) accumulation.     

Cardiorespiratory effects of respiratory protective devices during exercise in well-trained men

The effects of a filtering device, an air-line breathing apparatus and a self-contained breathing apparatus ( SCBA ) on pulmonary ventilation, oxygen consumption and heart rate were studied in 12 well-trained firemen aged 21-35 years. Their average maximal oxygen consumption (VO2 max) was 64.9 ml X min-1 X kg-1. Sequential tests without and with the respirator were performed on a treadmill. The continuous test contained five components, each of which lasted 5 min: sitting at rest, walking at 20%, 40%, and 60% of the individual VO2 max, and recovery sitting. During the higher submaximal work levels and recovery, ventilation, heart rate, and oxygen consumption in particular increased more with respirators than without them. At the highest work level the increments in oxygen consumption caused by the respirators were 13%, (8.7 ml X min-1 X kg-1), 7% (4.4 ml X min-1 X kg-1), and 20% (12.7 ml X min-1 X kg-1) of VO2 max. All three respirators hampered respiration, resulting in hypoventilation. The additional effort of breathing and the weight of the apparatus (15 kg with the SCBA ) increased the subjects' cardiorespiratory strain so clearly that the need for rest periods and the individual's work capacity when the respirators are worn must be carefully considered, particularly with the SCBA .     

THE EFFECT ON GABA METABOLISM IN BRAIN OF ISONICOTINIC ACID HYDRAZIDE AND PYRIDOXINE AS A FUNCTION OF TIME AFTER ADMINISTRATION

—The effect of intramuscularly administered INH on brain levels of GABA in chicks was dependent on the amount injected. A subconvulsant dose of INH (1·1 mmol/kg) produced a slow steady decline in the level of GABA, whereas a convulsant dose (2·19 mmol/kg) brought about a sequential fall and rise in GABA level. This sequence of events reflected changes in the relative activities of GAD and GABA-T brought about by the hydrazide. The administration of pyridoxine together with the INH (2·19 mmol/kg) prevented the onset of seizures and lessened the effect of the INH on GABA levels and GAD activity but not on GABA-T activity. The possibility that a deranged GABA metabolism is responsible for hydrazide-induced seizures is discussed.     

Individual characteristics of external respiration during intermittent normobaric hypoxia

Correlation and regression relationships between the indices of the body responsiveness to hypoxic impacts and initial individual values of indices of the respiratory system and heart activity were studied in a group of subjects during three repeated cycles of breathing alternately a hypoxic gas mixture (11 vol % O₂) for 5 min and normal air for 5 min. A steady negative correlation between the most important regulatory indicator, the increase in the CO₂ content of the lungs, and its initial level in individual subjects was found. This may determine the known “normalizing” curative and prophylactic effects of intermittent normobaric hypoxia on the gas transport system of the body. A correlation between the individual increase in the CO₂ content of the lungs in response to hypoxia and changes in the heart rate and initial inhalation rate and depth, rather than oxygen consumption by the body, was found.