Effect of peripheral and central alpha-adrenoceptor blockade on cerebral microvascular and blood flow responses to hypoxia.

The purpose of this study was to evaluate the effects of vascular and central alpha-adrenoceptor blockade on cerebral blood flow (CBF) and utilization of brain arteriolar and capillary reserve in conscious rats during normoxia and hypoxia (8% O2 in N2). Animals were divided into three groups and administered either saline, N-methyl chlorpromazine (does not cross the blood-brain barrier), or phenoxybenzamine (crosses the blood-brain barrier) in equipotent doses. Neither agent affected regional CBF and the utilization of brain microvascular reserve during normoxia. CBF increased from 70.9 +/- 2.9 (SEM) ml/min/100 g in the control normoxic group to 123.8 +/- 4.2 ml/min/100 g in control hypoxic animals. In control, hypoxic flow to pons and medulla of the brain was higher than to cortex, hypothalamus or thalamus. The percent of arterioles/mm2 perfused increased from 49.6 +/- 2.0% during control normoxia to 65.6 +/- 3.0% during control hypoxia. The percentage of capillaries/mm2 perfused changed similarly. Hypoxic CBF was increased similarly after administration of N-methyl chlorpromazine or phenoxybenzamine. Administration of N-methyl chlorpromazine or phenoxybenzamine eliminated regional differences in hypoxic CBF and the utilization of arterioles, and did not affect capillary response. There was no difference between the effect of N-methyl chlorpromazine and phenoxybenzamine on cerebral microvascular and blood flow responses to hypoxia. It was concluded that peripheral alpha-adrenoceptors affect the distribution of regional microvascular and blood flow responses to hypoxia, and central alpha-adrenoceptors probably do not participate in this effect.     

Effect of barbitone sodium and thiopental sodium on brain dopamine, noradrenaline, serotonin and 5-hydroxyindoleacetic acid content in Arvicanthis niloticus

The quantitative estimation of total dopamine (DA), noradrenaline (NE), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in the whole brain tissue of normal Nile grass rat, Arvicanthis niloticus, gives and average of 631 +/- 12 ng DA/g, 366 +/- 12 ng NE/g, 617 +/- 15 ng 5-HT/g and 431 +/- 10 ng 5-HIAA/g fresh brain tissue. The effect of barbitone sodium and thiopental sodium on the total DA, NE, 5-HT and 5-HIAA content in the brain tissue of the Nile grass rat, Arvicanthis niloticus, was studied. The total DA, NE, 5-HT and 5-HIAA contents were determined 5 hr after i.p. injection of different doses of barbitone sodium (20, 40 and 80 mg/ml/100 g body wt) and thiopental sodium (5, 10 and 20 mg/ml/100 g body wt). The effect of different time intervals (1, 10, 30 min, 1, 2.5, 5, 8, 16, 24 and 48 hr) on the total brain DA, NE, 5-HT and 5-HIAA content was investigated after i.p. injection of 40 mg of barbitone sodium and 10 mg of thiopental sodium/ml/100 g body wt. Both barbitone sodium and thiopental sodium caused an increase in DA, NE and 5-HT content and a decrease in 5-HIAA content in the brain tissue of Arvicanthis niloticus. The increase in the whole brain contents of DA, NE and 5-HT after the administration of barbitone sodium and thiopental sodium may be due either to inhibition of transmitter release by an action at the monoamine nerve terminal or to effects causing a decrease in nerve impulse flow. On the other hand, the decrease in 5-HIAA may be due to the decrease in the turnover of 5-HT.     

Altered precursor availability and metabolism of monoamines in the brain caused by the injection of physiologic saline to suckling rats: On the reliability of saline “controls” in neurochemical studies

The effect of subcutaneous injections of saline (0.9% NaCl, 10–40 μl/g b. wt) to 5- and 20-day old rats on the concentrations of tyrosine (Tyr) and tryptophan (Trp) in the serum and the brain and on the levels of biogenic amines and their metabolites in the developing brain at 6 h p.i. is described. At day 5 the concentration of Tyr in the blood was decreased (dose-dependent), but the brain concentrations of Tyr and of its amine-metabolites, dopamine (DA), norepinephrine (NE), homovanillic acid (HVA) and dihydroxyphenylacetate (DOPAC) were unaffected. In contrast, in the 20-day old rat, serum Tyr was unaffected by the saline injections, but the Tyr concentration in the brain decreased markedly at the highest saline dose. The concentrations of NE (only at maximum dose) and of DA (independent on the amount of saline injected) were elevated in the brains of saline injected 20-day old rats. The concentrations of Trp and indoles were more affected at day 5 than at day 20: slightly decreased concentration of Trp in the serum but markedly increased concentrations of brain Trp (only at maximum dose), elevated serotonin (5-HT, independent on the amount of saline injected) and 5-hydroxyindoleacetic acid (5-HIAA, at maximum dose) in the brain. If the maximum dose of 40 μl/g body weight was injected to suckling rats repeatedly during the whole suckling period (in 12 h intervals), some effects caused by one single injection of 40 μl/g disappeared (Tyr—depletion in blood or brain, increase in brain NE, DA and Trp), but other additional effects appeared (decreased DA and increased DOPAC, decreased 5-HT and 5-HIAA). The results show that saline injections do cause characteristic, age-dependent alterations of precursor availability as well as of the rate of synthesis and degradation of catecholamine and 5-HT. Repeated treatments have different effects than one single treatment on the precursor availability and the metabolism of monoamines. These alterations must be taken into account if the effects of certain “specific” treatments are compared and discussed in relation to saline “controls”.     

Synaptosomal Uptake and Release of Dopamine in Rat Striatum After Hypoxia

Hypoxia induces alterations of central monoaminergic transmission and of behavior. We studied the effect of hypoxia on adult and newborn rats to obtain more information about long-lasting changes of dopamine (DA) transmission caused by neonatal hypoxia. One single exposure of adult rats to hypoxia leads to short-term alterations of DA uptake: decreased affinity of the uptake carrier to DA (Km, 269.5% versus control) and a sharp increase of Vmax up to 301.4% resulting in an increase of total uptake of DA into the striatum synaptosomes. The K+-evoked DA release decreased to 69.5%. After 1 week of recovery all parameters are normalized. Chronic postnatal hypoxia (postnatal day 2-11) caused long-lasting changes of DA release and uptake opposite to those observed in adult rats. Three months after hypoxia, the K+-stimulated DA release was enhanced (132% of control), and the uptake was reduced due to decreased affinity of the uptake carrier system for the substrate (Km, 187% of control value). In conclusion, the alterations observed after chronic postnatal hypoxia reflect special adaptive processes that are related to the high plasticity of the immature neonatal brain and contribute to an increased DA function in the nigrostriatal system.     

Increased Stimulated Release and Uptake of Dopamine in Nucleus Accumbens After Repeated Cocaine Administration as Measured by In Vivo Voltammetry

Electrically stimulated dopamine (DA) release (overflow) and uptake were measured with in vivo voltammetry in the nucleus accumbens (N ACC) of anesthetized rats that had previously received repeated cocaine treatments. Electrically stimulated DA release was induced by a 10-s stimulation in the medial forebrain bundle (2-ms, 200-microA, biphasic pulses at 100 Hz). DA overflow and uptake were measured with fast chronoamperometry using a Nafion-plated, carbon fiber electrode. Animals given repeated doses of cocaine (10 mg/kg s.c. from day 1 to 5, 20 mg/kg s.c. from day 6 to 10) showed marked increases in DA uptake (5.47 +/- 0.28 vs. 2.93 +/- 0.26 microM/s) and in stimulated DA overflow (27.3 +/- 1.1 vs. 18.9 +/- 1.3 microM) compared with DA uptake and stimulated overflow in saline control animals. The increased uptake was shown to be independent of the increased overflow. Uptake was monitored as a function of stimulation current, and the data were extrapolated to zero stimulation, resulting in calculated rates of uptake of 2.43 and 3.71 microM/s in the control and cocaine-treated groups, respectively. These effects were found to be temporary, as there were no significant differences in stimulated release or uptake between saline control animals and animals given 10 days of cocaine followed by a 10-day abstinence period. These alterations in the N ACC produced by repeated cocaine administration may be a compensatory response to prolonged uptake blockade of synaptic DA.     

Effects of Hypoxia on the Activities of Noradrenergic and Dopaminergic Neurons in the Rat Brain

The effects of hypoxia (10% O2, 90% N2) on the content, biosynthesis, and turnover of noradrenaline (NA) and 3,4-dihydroxyphenylethylamine (dopamine, DA) in the rat brain were examined. Up to 24 h following exposure to hypoxia, NA content in the whole brain was decreased, whereas DA content remained unchanged. The accumulation of 3,4-dihydroxyphenylalanine (DOPA) after central decarboxylase inhibition was decreased. The turnover rate of DA after synthesis inhibition was markedly decreased up to 8 h and returned to the control level within 24 h. In contrast, the turnover rate of NA was all but unchanged, except for a 4-h exposure. The 2-h exposure to the hypoxic environment resulted in a significant decrease in NA content and DOPA accumulation in all brain regions tested, but no significant change was observed in DA content. The turnover rate of DA was remarkably decreased in all brain regions tested, whereas the rate of NA was slightly decreased only in the cerebral cortex and hippocampus. These results suggest that although hypoxia decreases the biosynthesis of both NA and DA, the effects of oxygen depletion on the functional activities of NA neurons differ considerably from those of DA neurons: Only in the cerebral cortex and hippocampus are the NA neurons slightly sensitive to hypoxia, whereas the DA neurons are most sensitive in all brain regions.     

Activation of rat liver branched-chain 2-oxo acid dehydrogenase in vivo by glucagon and adrenaline.

The activity of liver branched-chain 2-oxo acid dehydrogenase complex was measured in rats fed on low-protein diets and given adrenaline, glucagon, insulin or dibutyryl cyclic AMP in vivo. Administration of glucagon or adrenaline (200 micrograms/100 g body wt.) resulted in a 4-fold increase in the percentage of active complex. As with glucagon and adrenaline, treatment of rats with cyclic AMP (5 mg/100 g body wt.) resulted in marked activation of branched-chain 2-oxo acid dehydrogenase. Insulin administration (1 unit/100 g body wt.) also resulted in activation of enzyme; however, these effects were less than those observed with glucagon and adrenaline. In contrast with the results obtained with low-protein-fed rats, administration of adrenaline (200 micrograms/100 g body wt.) to rats fed with an adequate amount of protein resulted in only a modest (14%) increase in the activity of the complex. The extent to which these hormones activate branched-chain 2-oxo acid dehydrogenase appears to be correlated with their ability to stimulate amino acid uptake into liver.     

Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity.

Reflexes arising from the carotid bodies may play an important role in cardiorespiratory changes evoked by chronic intermittent hypoxia (CIH). In the present study, we examined whether CIH affects the hypoxic sensing ability of the carotid bodies and, if so, by what mechanisms. Experiments were performed on adult male rats (Sprague-Dawley, 250-300 g) exposed to two paradigms of CIH for 10 days: 1) multiple exposures to short durations of intermittent hypoxia per day (SDIH; 15 s of 5% O(2) + 5 min of 21% O(2), 9 episodes/h, 8 h/day) and 2) single exposure to longer durations of intermittent hypoxia per day [LDIH; 4 h of hypobaric hypoxia (0.4 atm/day) + 20 h of normoxia]. Carotid body sensory response to graded isocapnic hypoxia was examined in both groups of animals under anesthetized conditions. Hypoxic sensory response was significantly enhanced in SDIH but not in LDIH animals. Similar enhancement in hypoxic sensory response was also elicited in ex vivo carotid bodies from SDIH animals, suggesting that the effects were not secondary to cardiovascular changes. SDIH, however, had no significant effect on the hypercapnic sensory response. The effects of SDIH on the hypoxic sensory response completely reversed after SDIH animals were placed in a normoxic environment for an additional 10 days. Previous treatment with systemic administration of O(2)(-)* radical scavenger prevented SDIH-induced augmentation of the hypoxic sensory response. These results demonstrate that SDIH but not LDIH results in selective augmentation of the hypoxic response of the carotid body and O(2)(-)* radicals play an important role in SDIH-induced sensitization of the carotid body.     

Chronic hypoxia in development selectively alters the activities of key enzymes of glucose oxidative metabolism in brain regions

The immature brain is more resistant to hypoxia/ischemia than the mature brain. Although chronic hypoxia can induce adaptive-changes on the developing brain, the mechanisms underlying such adaptive changes are poorly understood. To further elucidate some of the adaptive changes during postnatal hypoxia, we determined the activities of four enzymes of glucose oxidative metabolism in eight brain regions of hypoxic and normoxic rats. Litters of Sprague-Dawley rats were put into the hypoxic chamber (oxygen level maintained at 9.5%) with their dams starting on day 3 postnatal (P3). Age-matched normoxic rats were use as control animals. In P10 hypoxic rats, lactate dehydrogenase (LDH) activity in cerebral cortex, striatum, olfactory bulb, hippocampus, hypothalamus, pons and medulla, and cerebellum was significantly increased (by 100%–370%) compared to those in P10 normoxic rats. In P10 hypoxic rats, hexokinase (HK) activity in hypothalamus, hippocampus, olfactory bulb, midbrain, and cerebral cortex was significantly decreased (by 15%–30%). Neither -ketoglutarate dehydrogenase complex (KGDHC, which is believed to have an important role in the regulation of the tricarboxylic acid [TCA] cycle flux) nor citrate synthase (CS) activity was significantly decreased in the eight regions of P10 hypoxic rats compared to those in P10 normoxic rats. In P30 hypoxic rats, LDH activity was only increased in striatum (by 19%), whereas HK activity was only significantly decreased (by 30%) in this region. However, KGDHC activity was significantly decreased in olfactory bulb, hippocampus, hypothalamus, cerebral cortex, and cerebellum (by 20%–40%) in P30 hypoxic rats compared to those in P30 normoxic rats. Similarly, CS activity was decreased, but only in olfactory bulb, hypothalamus, and midbrain (by 9%–21%) in P30 hypoxic rats. Our results suggest that at least some of the mechanisms underlying the hypoxia-induced changes in activities of glycolytic enzymes implicate the upregulation of HIF-1. Moreover, our observation that chronic postnatal hypoxia induces differential effects on brain glycolytic and TCA cycle enzymes may have pathophysiological implications (e.g., decreased in energy metabolism) in childhood diseases (e.g., sudden infant death syndrome) in which hypoxia plays a role.     

The effect of acute ethanol treatment on rates of oxygen uptake, ethanol oxidation and gluconeogenesis in isolated rat hepatocytes.

In hepatocytes isolated from fed rats, acute ethanol pretreatment (at a dose of 5.0 g/kg body wt.) did not change rates of O2 uptake. In cells from starved animals, acute ethanol pretreatment increased O2 uptake by 17-29%. The increased O2 uptake in hepatocytes from starved rats was not accompanied by increased rates of ethanol oxidation, but was accompanied by increased rates of gluconeogenesis under some conditions. The provision of ethanol (10 mM) as a substrate to cells from fed or starved rats decreased O2 uptake in the absence of other substrates or in the presence of lactate, and increased it in the presence of pyruvate or lactate and pyruvate. The results of this study show that the acute effects of ethanol on liver O2 uptake are dependent on the physiological state of the liver. Previously reported large (2-fold) increases in O2 uptake after acute ethanol pretreatment may have been an artefact owing to low control uptake rates (approximately 1.8 micromol/min per g wet wt. of cells) in the liver preparation used. The ATP contents (2.4-2.6 micromol/g wet wt. of cells) and rates of O2 uptake (2.5-5.0 micromol/min per g wet wt. of cells) of cells used in the present study were the same as values reported under conditions close to those in vivo. Therefore the increase in O2 uptake in cells from starved rats after acute ethanol pretreatment is likely to be of physiological significance.     

Quercetin as a prophylactic measure against high altitude cerebral edema

The present study was undertaken to elucidate the intervention of quercetin against high altitude cerebral edema (HACE) using male Sprague Dawley rats as an animal model. This study was also programmed to compare and correlate the effect of both quercetin (flavonoid) and dexamethasone (steroid) against HACE. Six groups of animals were designed for this experiment, (I) normoxia, (II) hypoxia (25,000ft, 24h), (III) normoxia+quercetin (50mg/kg body wt), (IV) normoxia+dexamethasone (4mg/kg body wt), (V) hypoxia+quercetin (50mg/kg body wt), (VI) hypoxia+dexamethasone (4mg/kg body wt). Quercetin at 50mg/kg body wt, orally 1h prior to hypoxia exposure, was considered as the optimum dose, due to a significant reduction in the level of brain water content and cerebral transvascular leakage (P<0.001), as compared to control (24h hypoxia). Dexamethasone was administered at 4mg/kg body wt, orally, 1h prior to hypoxia exposure. Both drugs (quercetin and dexamethasone) could efficiently reduce the hypoxia-induced hematological changes. Quercetin was observed to be a more potent antioxidative and anti-inflammatory agent. It blocks nuclear factor kappa-beta (NFκB) more significantly (P<0.05) than the dexamethasone-administered hypoxia-exposed rats. Histopathological findings demonstrate the absence of an edema and inflammation in the brain sections of quercetin-administered hypoxia-exposed rats. The present study reveals quercetin to be a potent drug against HACE, as it efficiently attenuates inflammation as well as cerebral edema formation without any side effects of steroid therapy (dexamethasone).     

Seasonal variability of sialo-glycoconjugates in the brain of the Djungarian hamster (Phodopus sungorus)

The influence of season, photoperiod and ambient temperature on the content of proteins, sialo-glycoproteins and gangliosides and on the composition of gangliosides of three different brain regions (cortex, cerebellum and basalbrain) of the Djungarian dwarf hamster (Phodopus sungorus) had been investigated. Concomittantly changes in body wt and fur colouration were recorded. Dwarf hamsters living under natural photoperiod and ambient temperature conditions ("outside") showed a distinct annual cycle in body wt (summer: about 45 g; winter: about 25 g) and fur colouration (summer: dark grey; winter: whitish). Among the three brain regions the mean concentration of proteins ranged between 120 and 155 mg protein/g wet wt. The sialo-glycoprotein content varied between 260 and 410 micrograms NeuAc/g wet wt, and that of gangliosides between 800 and 1650 micrograms NeuAc/g wet wt. Seasonal fluctuations were not found. The composition of brain gangliosides remained uninfluenced throughout the year in the cerebellum, whereas seasonal variations were observed in cortex and basalbrain. Consequently the concentration ratio of the two major mammalian ganglioside fractions GD1a vs GT1b remained almost stable in cerebellum (0.3). In contrast to this the seasonal values of cortex and basalbrain changed from 0.6 and 0.8 in winter to 0.7 and 1.1 in summer. This indicated a higher polarity of the gangliosides in these brain regions during cold adaptation. The results are discussed with regard to modulatory functions of neuronal gangliosides for the process of synaptic transmission during seasonal adaptation.     

Proline promotes decrease in glutamate uptake in slices of cerebral cortex and hippocampus of rats

In the present study we first investigated the in vitro and in vivo effects of proline on glutamate uptake in the cerebral cortex and hippocampus slices of rats. The action of alpha-tocopherol and/or ascorbic acid on the effects elicited by administration of proline was also evaluated. For in vitro studies, proline (30.0 microM and 1.0 mM) was added to the incubation medium. For acute administration, 29-day-old rats received one subcutaneous injection of proline (18.2 micromol/g body weight) or saline (control) and were sacrificed 1 h later. Results showed that addition of proline in the assay (in vitro studies) reduces glutamate uptake in both cerebral structures. Administration of proline (in vivo studies) reduces glutamate uptake in the cerebral cortex, but not in the hippocampal slices of rats. In another set of experiments, 22-day-old rats were pretreated for one week with daily administration of alpha-tocopherol (40 mg/kg) or ascorbic acid (100 mg/kg) or with both vitamins. Twelve hours after the last vitamins injection, rats received a single injection of proline or saline and were killed 1 h later. Pretreatment with alpha-tocopherol and/or ascorbic acid did not prevent the effect of proline administration on glutamate uptake. alpha-Tocopherol plus ascorbic acid prevented the inhibitory effect of acute hyperprolinemia on Na(+),K(+) -ATPase activity in the cerebral cortex of 29-day-old rats. The data indicate that the effect of proline on reduction of glutamate uptake and Na(+),K(+) -ATPase activity may be, at least in part, involved in the brain dysfunction observed in hyperprolinemic patients.     

Influence of Prenatal Hypoxia on Brain Development: Effects on Body Weight, Brain Weight, DNA, Protein, Acetylcholinesterase, 3-Quinuclidinyl Benzilate Binding, and In Vivo Incorporation of [14C]Lysine into Subcellular Fractions

Abstract: The influence of prenatal hypoxia on subsequent brain development in the young rat was investigated by examining body and brain weight, cerebral cortex wet weight, protein and DNA concentrations, acetylcholinesterase (AChE) activity, 3-quinuclidinyl benzilate (QNB)-binding levels, the relative amounts of protein in various subcellular fractions, and the in vivo incorporation of [¹⁴C]lysine into the protein of homogenate and subcellular fractions. Exposure of pregnant females to a mild hypoxia (9.1% Os, 10 h per day for the 9-11 days preceding birth) resulted in a reduced body weight in the pups at days 1 and 5 after birth; total cortical DNA was reduced but brain weight and protein content were unaffected, leading to a higher protein/DNA ratio in prenatally hypoxic pups. By 10 days of age these differences between prenatally hypoxic and control animals were no longer apparent. There were no differences between prenatally hypoxic and control animals in AChE and QNB binding per milligram cortex protein. The relative amount of synaptic membrane protein from the cerebral cortex was reduced at day 1 in prenatally hypoxic animals and the synaptic membrane fraction showed a higher level of incorporation of [¹⁴C]lysine on days 1, 5, and 10. The developmental profile of [¹⁴C]lysine incorporation showed a peak on day 10 which was higher in prenatally hypoxic rats. By 46 days after birth little difference could be found between prenatally hypoxic and control animals.     

Chronic hypoxia abolishes posthypoxia frequency decline in the anesthetized rat

In anesthetized rats, increases in phrenic nerve amplitude and frequency during brief periods of hypoxia are followed by a reduction in phrenic nerve burst frequency [posthypoxia frequency decline (PHFD)]. We investigated the effects of chronic exposure to hypoxia on PHFD and on peripheral and central O2-sensing mechanisms. In Inactin-anesthetized (100 mg/kg) Sprague-Dawley rats, phrenic nerve discharge and arterial pressure responses to 10 s N2 inhalation were recorded after exposure to hypoxia (10 +/- 0.5% O2) for 6-14 days. Compared with rats maintained at normoxia, PHFD was abolished in chronic hypoxic rats. Because of inhibition of PHFD, the increased phrenic burst frequency and amplitude after N2 inhalation persisted for 1.8-2.8 times longer in chronic hypoxic (70 s) compared with normoxic (25-40 s) rats (P < 0.05). After acute bilateral carotid body denervation, N2 inhalation produced a short depression of phrenic nerve discharge in both chronic hypoxic and normoxic rats. However, the degree and duration of depression of phrenic nerve discharge was smaller in chronic hypoxic compared with normoxic rats (P < 0.05). We conclude that after exposure to chronic hypoxia, a reduction in PHFD contributes to an increased duration of the acute hypoxic ventilatory response in anesthetized rats. Furthermore, after exposure to chronic hypoxia, the central network responsible for respiration is more resistant to the depressant effects of acute hypoxia in anesthetized rats.     

Exercise delays the hypoxic thermal response in rats.

Exercise exacerbates acute mountain sickness. In infants and small mammals, hypoxia elicits a decrease in body temperature (Tb) [hypoxic thermal response (HTR)], which may protect against hypoxic tissue damage. We postulated that exercise would counteract the HTR and promote hypoxic tissue damage. Tb was measured by telemetry in rats (n = 28) exercising or sedentary in either normoxia or hypoxia (10% O2, 24 h) at 25 degrees C ambient temperature (Ta). After 24 h of normoxia, rats walked at 10 m/min on a treadmill (30 min exercise, 30 min rest) for 6 h followed by 18 h of rest in either hypoxia or normoxia. Exercising normoxic rats increased Tb ( degrees C) vs. baseline (39.68 +/- 0.99 vs. 38.90 +/- 0.95, mean +/- SD, P < 0.05) and vs. sedentary normoxic rats (38.0 +/- 0.09, P < 0.05). Sedentary hypoxic rats decreased Tb (36.15 +/- 0.97 vs. 38.0 +/- 0.36, P < 0.05) whereas Tb was maintained in the exercising hypoxic rats during the initial 6 h of exercise (37.61 +/- 0.55 vs. 37.72 +/- 1.25, not significant). After exercise, Tb in hypoxic rats reached a nadir similar to that in sedentary hypoxic rats (35.05 +/- 1.69 vs. 35.03 +/- 1.32, respectively). Tb reached its nadir significantly later in exercising hypoxic vs. sedentary hypoxic rats (10.51 +/- 1.61 vs. 5.36 +/- 1.83 h, respectively; P = 0.002). Significantly greater histopathological damage and water contents were observed in brain and lungs in the exercising hypoxic vs. sedentary hypoxic and normoxic rats. Thus exercise early in hypoxia delays but does not prevent the HTR. Counteracting the HTR early in hypoxia by exercise exacerbates brain and lung damage and edema in the absence of ischemia.     

Separate effects of low carbon dioxide and low oxygen content on rat brain monoamine metabolism during hypoxemia

Awake, adult male rats (some with chronically indwelling femoral artery catheters) were exposed for up to 7 days to one of three environments: a) normoxia (PIO2 = 155 Torr), b) hypoxic hypocapnia (PIO2 = 90 Torr), and c) hypoxic normocapnia (PIO2 = 73 Torr, PICO2 = 32 Torr), and arterial blood gas and acid-base status were documented. After 1 hour to 7 days, rats were sacrificed, and the time courses of the brain levels and turnovers of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine or 5HT) were determined in each condition. The transient decrease in monoamine levels seen on exposure to acute hypoxia was absent if normocapnia was maintained; 7 days hypoxia with or without hypocapnia resulted in increased monoamine levels. Normocapnia also prevented an immediate, sustained decrease in 5HT turnover and a delayed decrease in DA turnover which were observed in hypoxic hypocapnia. A delayed increase in 5HT turnover appeared to be due to hypoxia independent of PaCO2. Therefore, the initial, transient loss of mental acuity and some ventilatory adaptations observed during prolonged hypoxia may be a result of the decrease in PaCO2 rather than the decreased oxygen concentration.     

AMPA glutamate receptors and respiratory control in the developing rat: anatomic and pharmacological aspects

The developmental role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) glutamate receptors in respiratory regulation remains undefined. To study this issue, minute ventilation (V(E)) was measured in 5-, 10-, and 15-day-old intact freely behaving rat pups using whole body plethysmography during room air (RA), hypercapnic (5% CO(2)), and hypoxic (10% O(2)) conditions, both before and after administration of the non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3, 4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX; 10 mg/kg ip). In all age groups, V(E) during RA was unaffected by NBQX, despite reductions in breathing frequency (f) induced by increases in both inspiratory and expiratory duration. During hypoxia and hypercapnia, V(E) increases were similar in both NBQX and control conditions in all age groups. However, tidal volume was greater and f lower after NBQX. To determine if AMPA receptor-positive neurons are recruited during hypoxia, immunostaining for AMPA receptor (GluR2/3) and c-fos colabeling was performed in caudal brain stem sections after exposing rat pups at postnatal ages 2, 5, 10, and 20 days, and adult rats to room air or 10% O(2) for 3 h. GluR2/3 expression increased with postnatal age in the nucleus of the solitary tract (NTS) and hypoglossal nucleus, whereas a biphasic pattern emerged for the nucleus ambiguus (NA). c-fos expression was enhanced by hypoxia at all postnatal ages in the NTS and NA and also demonstrated a clear maturational pattern. However, colocalization of GluR2/3 and c-fos was not affected by hypoxia. We conclude that AMPA glutamate receptor expression in the caudal brain stem is developmentally regulated. Furthermore, the role of non-NMDA receptors in respiratory control of conscious neonatal rats appears to be limited to modest, albeit significant, regulation of breathing pattern.     

Effects of whole body microwave exposure on the rat brain contents of biogenic amines.

The effects of whole body microwave exposure on the central nervous system (CNS) of the rat were investigated. Rats weighing from 250 to 320 g were exposed for 1 h to whole body microwave with a frequency of 2450 MHz at power densities of 5 and 10 mW.cm-2 at an ambient temperature of 21-23 degrees C. The rectal temperatures of the rats were measured just before and after microwave exposure and mono-amines and their metabolites in various discrete brain regions were determined after microwave exposure. Microwave exposure at power densities of 5 and 10 mW.cm-2 increased the mean rectal temperature by 2.3 degrees C and 3.4 degrees C, respectively. The noradrenaline content in the hypothalamus was significantly reduced after microwave exposure at a power density of 10 mW.cm-2. There were no differences in the dopamine (DA) content of any region of the brain between microwave exposed rats and control rats. The dihydroxyphenyl acetic acid (DOPAC) content, the main metabolite of DA, was significantly increased in the pons plus medulla oblongata only at a power density of 10 mW.cm-2. The DA turnover rates, the DOPAC:DA ratio, in the striatum and cerebral cortex were significantly increased only at a power density of 10 mW.cm-2. The serotonin (5-hydroxytryptamine, 5-HT) content in all regions of the brain of microwave exposed rats was not different from that of the control rats. The 5-hydroxyindoleacetic acid (5-HIAA) content in the cerebral cortex of microwave exposed rats was significantly increased at power densities of 5 and 10 mW.cm-2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 +/- 3 mmHg in hypoxic controls, 24 +/- 1 mmHg in Batimastat-treated hypoxic rats, and 16 +/- 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.