Respiratory mechanics in adult rats hypercapnic in the neonatal period

Because chronic hypoxia in the neonatal period has long-term effects on the mechanical properties of the respiratory system (S. Okubo and J. P. Mortola, J. Appl. Physiol. 66: 1772-1778, 1989), we asked whether similar effects would occur after neonatal exposure to hypercapnia. Three groups of rats were used. The first was exposed to 7% CO2 in normoxia from day 1 to 7 after birth and then returned to normocapnia (NB-CO2). The second was exposed to the same level and duration of hypercapnia from day 36 to 42, i.e., approximately 2 wk after weaning (AD-CO2). The third was raised in normoxia and normocapnia (control). At approximately 50 days, i.e., 1-2 wk after puberty, the passive mechanical properties of the respiratory system, lung, and chest were measured during artificial ventilation in the anesthetized and paralyzed animal. No differences were observed between AD-CO2 and control. NB-CO2 had higher compliance of the lung (approximately +40%) and respiratory system (+32%) than control or AD-CO2. Average values of resistance of the total respiratory system, lung, and chest wall were consistently lower in NB-CO2 than in control and AD-CO2, although the magnitude and statistical significance of the decrease depended on the method of measurement. In a separate group of NB-CO2, lung compliance was measured during spontaneous breathing, and it averaged 34% more than in control. The exponential constant of the deflation quasi-static pressure-volume curve of the liquid-filled lungs was also significantly higher than in control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Compliance of the respiratory system in newborn and adult rats after gestation in hypoxia

We hypothesized that hypoxia during gestation modifies the compliance of the respiratory system of newborn and adult rats. Pregnant rats were placed in a hypobaric chamber at an inspired oxygen pressure of 86 mmHg (equivalent to 12% O₂ in normobaria) from day 4 of gestation until day 2 post-partum. Three- day-old rat pups were smaller than controls, with higher hematocrit; the lungs were also small, with less protein and DNA content. The pressure (x-axis)-volume (y-axis) curve of the respiratory system was displaced to the right of the control curve, and the compliance of the respiratory system, measured on the inflation or deflation limb of the pressure-volume curve, was decreased by ∼20–25%, depending upon the normalization procedure (per body mass or per dry lung weight). In 50-day-old rats exposed to hypoxia during gestation, body weight, hematocrit, lung mass and DNA content were normal; the compliance of the respiratory system, measured at ventilation frequencies between 20 cpm and 100 cpm, was higher than in controls by ∼20%. It is concluded that the effects of prenatal hypoxia on the compliance of the respiratory system can vary with age. In the rat the process of alveolar formation initiates postnatally. Hence, in the newborn the effects of the prenatal hypoxia on the compliance of the respiratory system are likely to be dominated by the hypoxic pulmonary hypoplasia and hypertension, which decrease the compliance of the respiratory system. In the adult, the effects of the decreased alveolar formation are the prevailing ones, increasing the compliance of the respiratory system. Accepted: 3 January 2000     

Tyrosine hydroxylase expression and activity in the rat brain: differential regulation after long-term intermittent or sustained hypoxia.

Tyrosine hydroxylase, a hypoxia-regulated gene, may be involved in tissue adaptation to hypoxia. Intermittent hypoxia, a characteristic feature of sleep apnea, leads to significant memory deficits, as well as to cortex and hippocampal apoptosis that are absent after sustained hypoxia. To examine the hypothesis that sustained and intermittent hypoxia induce different catecholaminergic responses, changes in tyrosine hydroxylase mRNA, protein expression, and activity were compared in various brain regions of male rats exposed for 6 h, 1 day, 3 days, and 7 days to sustained hypoxia (10% O(2)), intermittent hypoxia (alternating room air and 10% O(2)), or normoxia. Tyrosine hydroxylase activity, measured at 7 days, increased in the cortex as follows: sustained > intermittent > normoxia. Furthermore, activity decreased in the brain stem and was unchanged in other brain regions of sustained hypoxia-exposed rats, as well as in all regions from animals exposed to intermittent hypoxia, suggesting stimulus-specific and heterotopic catecholamine regulation. In the cortex, tyrosine hydroxylase mRNA expression was increased, whereas protein expression remained unchanged. In addition, significant differences in the time course of cortical Ser(40) tyrosine hydroxylase phosphorylation were present in the cortex, suggesting that intermittent and sustained hypoxia-induced enzymatic activity differences are related to different phosphorylation patterns. We conclude that long-term hypoxia induces site-specific changes in tyrosine hydroxylase activity and that intermittent hypoxia elicits reduced tyrosine hydroxylase recruitment and phosphorylation compared with sustained hypoxia. Such changes may not only account for differences in enzyme activity but also suggest that, with differential regional brain susceptibility to hypoxia, recruitment of different mechanisms in response to hypoxia will elicit region-specific modulation of catecholamine response.     

Life-long consequences of postnatal normoxia exposure in rats raised at high altitude

We tested the hypothesis that exposure of high-altitude (HA) rats to a period of postnatal normoxia has long-term consequences on the ventilatory and hematological acclimatization in adults. Male and female HA rats (3,600 m, Po(2) ? 100 Torr; La Paz, Bolivia) were exposed to normal room air [HA control (HACont)] or enriched oxygen (32% O(2); Po(2) ? 160 Torr) from 1 day before to 15 days after birth [HA postnatal normoxia (HApNorm)]. Hematocrit and hemoglobin values were assessed at 2, 12, and 32 wk of age. Cardiac and lung morphology were assessed at 12 wk by measuring right ventricular hypertrophy (pulmonary hypertension index) and lung air space-to-tissue ratio (indicative of alveolarization). Respiratory parameters under baseline conditions and in response to 32% O(2) for 10 min (relieving the ambient hypoxic stimulus) were measured by whole body plethysmography at 12 wk. Finally, we performed a survival analysis up to 600 days of age. Compared with HACont, HApNorm rats had reduced hematocrit and hemoglobin levels at all ages (both sexes); reduced right ventricular hypertrophy (both sexes); lower air space-to-tissue ratio in the lungs (males only); reduced CO(2) production rate, but higher oxygen uptake (males only); and similar respiratory frequency, tidal volume, and minute ventilation. When breathing 32% O(2), HApNorm male rats had a stronger decrease of minute ventilation than HACont. HApNorm rats had a marked tendency toward longer survival throughout the study. We conclude that exposure to ambient hypoxia during postnatal development in HA rats has deleterious consequences on acclimatization to hypoxia as adults.     

Influence of acidosis and hypoxia on liver ischemia and reperfusion injury in an in vivo rat model.

The contribution of acidosis to the development of reperfusion injury is controversial. In this study, we examined the effects of respiratory acidosis and hypoxia in a frequently used in vivo liver ischemia and reperfusion (I/R) injury rat model. Rats were anesthetized with intraperitoneal anesthetics and subjected to partial liver ischemia (70%) for 60 min and subsequent reperfusion for 90 min under the following conditions: 1) no acidosis and normoxia, maintained by controlled ventilation; 2) acidosis and normoxia, maintained by passive supply with oxygen; 3) no acidosis and hypoxia, maintained by bicarbonate administration without respiratory support; and 4) acidosis and hypoxia, i.e., without respiratory support or pH correction. Changes in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured as parameters of hepatocellular injury, and bile secretion was monitored. AST and ALT levels were lowest in the ventilated rats and highest in the bicarbonate-treated rats. No differences in bile secretion were found between groups. Our results suggest that respiratory acidosis significantly enhanced liver I/R injury under normoxic conditions, whereas respiratory acidosis significantly reduced liver I/R injury under hypoxic conditions.     

Effects of hypoxia and cold acclimation on thermoregulation in the rat.

The effects of hypoxia (inspired O2 fraction = 0.12) on thermoregulation and on the different sources of thermogenesis were studied in rats before and after periods of 1-4 wk of cold acclimation. Measurements of metabolic rate (VO2) and body temperature (Tb) were made at 5-min intervals, and shivering activity was recorded continuously in groups of rats subjected to three protocols. In protocol 1, rats were exposed to normoxia to an ambient temperature (Ta) of 5 degrees C for 2 h. In protocol 2, at Ta of 5 degrees C, rats were exposed for 30 min to normoxia, then for 45 min to hypoxia, and finally for 30 min to normoxia. In protocol 3, in the non-cold-acclimated (NCA) rats, Ta was decreased from 30 to 5 degrees C in steps of 5 degrees C and of 30-min duration while in cold-acclimated (CA) rats at 5 degrees C for 4-wk, Ta was increased from 5 to 30 degrees C in steps of 5 degrees C and of 30-min duration. Recordings were made in normoxia and in hypoxia on different days in the same animals. The results showed that 1) in NCA rats, cold exposure in normoxia induced increases in VO2 and shivering that were proportional to the decrease in Ta; 2) in CA rats in normoxia, for a given Ta, VO2 and Tb were higher than in NCA rats, whereas shivering was generally lower; and 3) in both NCA and CA rats, hypoxia induced a transient decrease in shivering and a sustained decrease in nonshivering thermogenesis associated with a marked decrease in Tb that was about the same in NCA and CA rats. We speculate that hypoxia acts on Tb control to produce a general inhibition of thermogenesis. Nonshivering thermogenesis is markedly sensitive to hypoxia, especially demonstrable in CA rats; a recovery or even an increase in shivering can compensate for the decrease in nonshivering thermogenesis.     

Dynamics of breathing in the hypoxic awake lamb

Newborn mammals respond to hypoxia with an immediate hyperventilation that is rapidly dampened. Changes in mechanical properties of the respiratory system during hypoxia have been considered an important reason for this fall in minute ventilation (VE). We have studied the dynamic mechanical behavior of the respiratory system in eight unanesthetized intact newborn lambs (mean age 2 days) during normoxia and hypoxia (FIO2 = 0.08). Mouth pressure (P), airflow (V), and volume (V) were recorded while lambs were breathing through a leak-proof face mask and a pneumotachograph. Active compliance (C') and resistance (R') of the respiratory system were computed from P developed during an inspiratory effort against airway closure at end expiration and V and V of the preceding breaths. Tidal expiratory V-V curves were analyzed to estimate the elevation in functional residual capacity (FRC) over resting volume (Vr). After hypoxia, there was an immediate increase in VE in the first 2 min, from 0.49 to 1.13 l.kg-1.min-1, followed by a rapid decrease to 0.80. After 8 min of hypoxia, C' was unchanged. The inspiratory R' decreased during hypoxia, probably reflecting a drop in inspiratory laryngeal resistance. The expiratory V-V curves during hypoxia showed considerable braking, often with a double peak in expiratory V. This pattern was only occasionally seen during normoxia. In animals with a linear segment of the expiratory V-V curves the FRC-Vr difference could be calculated and averaged 1.93 ml/kg during normoxia and 3.47 during hypoxia. The recoil P of the respiratory system at end expiration was 0.75 cmH2O during normoxia vs. 1.63 cmH2O during hypoxia (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of perinatal hypoxia on pentylenetetrazol-induced seizures in developing rats

The effects of perinatal hypoxia on susceptibility to seizures due to a single dose (55 mg/kg, i.p.) of pentylenetetrazol (PTZ) were examined, in 15-, 20-, 30-, 60- and 90 to 120-day-old rats. The rats exposed to hypoxia at 10 days of age and the unexposed controls showed similar developmental changes in the types of seizures, ictal electro-encephalograms and severity scores, the last being lowest at 30 days of age. However, the susceptibility to seizures induced by PTZ, which was measured by the mean number of generalized convulsions (GCs) as well as a mean duration of the 1st GC and severity score, was more enhanced in the rats exposed to perinatal hypoxia than in the control group at every age. The present study suggests that hypoxia in rats results in greater seizure susceptibility throughout the developmental period.     

Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia.

Previous studies suggest that carotid body responses to long-term changes in environmental oxygen differ between neonates and adults. In the present study we tested the hypothesis that the effects of chronic intermittent hypoxia (CIH) on the carotid body differ between neonates and adult rats. Experiments were performed on neonatal (1-10 days) and adult (6-8 wk) males exposed either to CIH (9 episodes/h; 8 h/day) or to normoxia. Sensory activity was recorded from ex vivo carotid bodies. CIH augmented the hypoxic sensory response (HSR) in both groups. The magnitude of CIH-evoked hypoxic sensitization was significantly greater in neonates than in adults. Seventy-two episodes of CIH were sufficient to evoke hypoxic sensitization in neonates, whereas as many as 720 CIH episodes were required in adults, suggesting that neonatal carotid bodies are more sensitive to CIH than adult carotid bodies. CIH-induced hypoxic sensitization was reversed in adult rats after reexposure to 10 days of normoxia, whereas the effects of neonatal CIH persisted into adult life (2 mo). Acute intermittent hypoxia (IH) evoked sensory long-term facilitation of the carotid body activity (sensory LTF, i.e., increased baseline neural activity following acute IH) in CIH-exposed adults but not in neonates. The effects of CIH were associated with hyperplasia of glomus cells in neonatal but not in adult carotid bodies. These observations demonstrate that responses to CIH differ between neonates and adults with regard to the magnitude of sensitization of HSR, susceptibility to CIH, induction of sensory LTF, reversibility of the responses, and morphological remodeling of the chemoreceptor tissue.     

Postnatal intermittent hypoxia alters baroreflex function in adult rats

Chronic perinatal intermittent hypoxia (IH) could have long-term cardiovascular effects by altering baroreflex function. To examine this hypothesis, we exposed rats (n = 6/group) for postnatal days 1-30 or prenatal embryonic days 5-21 to IH (8% ambient O2 for 90 s after 90 s of 21% of O2, 12 h/day) or to normoxia (control). Baroreflex sensitivity (BRS) and cardiac chronotropic responses were examined in anesthetized animals 3.5-5 mo later by infusing phenylephrine or sodium nitroprusside (6-12 microg/min iv, 1-2 min) during normoxia and after 18 min of acute IH (IHA). In controls after IHA, baroreflex gain was 42% (P < 0.05) less than during normoxia. BRS in the postnatal IH group during normoxia was approximately 50% less than in control rats and similar to controls after IHA. The heart rate response to phenylephrine in the IH group was also less than in controls (P < 0.05) and was not changed by IHA. BRS and heart rate responses in the prenatal IH group were similar to the normoxic control group. Vagal efferent projections to atrial ganglia neurons in rats after postnatal IH (n = 4) were examined by injecting tracer into the left nucleus ambiguous. After 35 days of postnatal IH, basket ending density was reduced by 17% (P < 0.001) and vagal axon varicose contacts by 56% (P < 0.001) compared with controls. We conclude that reduction of vagal efferent projections in cardiac ganglia could be a cause of long-term modifications in baroreflex function.     

Postnatal development of the denervated lung in normoxia, hypoxia, or hyperoxia.

We asked whether lung innervation was essential for the normal postnatal development of the lung in conditions of normoxia, hypoxia, or hyperoxia. Litters of newborn rats were assigned to a normoxic [inspired oxygen partial pressure (PIO2) = 150 Torr, eight litters], hypoxic (PIO2 = 100 Torr, nine litters), or hyperoxic (PIO2 = 360 Torr, nine litters) group. Each litter consisted of 12 pups. Two days after birth, one-third of the litter had the vagus and sympathetic trunk cut in the neck on the left side [left denervated (L)], one-third was denervated on the right side (R), and one-third was sham-operated (S). From day 3, all pups were exposed to the designed PIO2, until day 8 or days 21-22. Almost all rats, whether S, R, or L, survived in normoxia and hyperoxia, whereas in hypoxia survival at day 22 of R and L was approximately 60-65%. Body growth was the same in S, R, and L and less in hypoxia than in normoxia or hyperoxia. At days 8 and 22, hematocrit and hemoglobin concentration, heart and lung dry and wet weights, and lung DNA content did not differ among S, R, and L, whether the pups were raised in normoxia, hypoxia, or hyperoxia. At days 21-22, aerobic metabolism and breathing pattern, both measured during air breathing, as well as compliance of isolated lungs, were also similar among S, R, and L for each of the conditions in which the pups were raised.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of neonatal hypoxia on the development of hepatic lipase in the rat

Increases in plasma lipids occur during hypoxia in suckling but not in weaned rats and may result from altered hepatic enzyme activity. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Hypoxia led to an increase in hepatic lipid content in the suckling rat only. Hepatic lipase was decreased to approximately 45% of control in 7-day-old rats exposed to hypoxia but not in hypoxic 35-day-old rats. Hypoxic suckling rats also had a 50% reduction in lactate dehydrogenase activity, whereas transaminase activity and CYP1A and CYP3A protein content were not different between hypoxic and normoxic groups. Additional rats were studied 7 and 14 days after recovery from hypoxic exposure from birth to 7 days of age; hepatic lipase activity had recovered to 85% by 7 days and to 100% by 14 days in the rats previously exposed to hypoxia. Administration of dexamethasone to neonatal rats to simulate the hyperglucocorticoid state found in hypoxic 7-day-old rats led to a moderate decrease ( approximately 75% of control) in hepatic lipases. Developmentally, in the normoxic state, hepatic lipases increased rapidly after birth and reached levels more than twofold that of the newborn by 7 days of age. Hypoxia delays the maturation of hepatic lipases. We suggest that the decrease in hepatic lipase activity contributes to hyperlipemia in the hypoxic newborn rats.     

Intermittent hypoxia attenuates ischemia／reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2／Bax expression

Intermittent hypoxia has been shown to provide myocardial protection against ishemiaJreperfusion-induced injury.Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion.Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins,Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion,enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group.Ischemia/reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion,expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts comparedwith normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reducemyocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl-2/Bax, especially in membrane fraction.     

Effect of neonatal hypoxia on leptin, insulin, growth hormone and body composition in the rat.

The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone).     

Hypercapnic and hypoxic ventilatory responses in long-term streptozotocin-diabetic rats during conscious and pentobarbital-induced anesthetic states

To clarify the diabetes mellitus (DM)-associated changes in the respiratory neuronal control system, acute ventilatory responses to progressively increasing hypercapnia (6%) and hypoxia (10%) were compared between normal (N) and streptozotocin (60 mg/kg, i.v.) -DM rats for a long period up to 28 weeks. The same comparison was conducted during the anesthetic state induced with pentobarbital (35 mg/kg, i.p.). During the conscious state, basic ventilatory parameters, such as respiratory rate, tidal volume and minute ventilation, were not impaired in DM rats, but ventilatory responses to hypercapnia and hypoxia were reduced significantly at 16 weeks and later after streptozotocin injection. The reduced responses in DM rats were not recovered by insulin treatment (5-6 U/body, s.c., daily). During the anesthetic state, both hypoxic and hypercapnic responses were depressed more intensely in N rats than in DM rats, resulting in an equivalent level of the response in the two groups. The present study demonstrated that ventilatory responses to hypercapnia and hypoxia were reduced in a long-term DM condition. This may be derived from the impairment of the peripheral and central chemosensitivity. The reduction in ventilatory responses was exaggerated during the anesthetic state.     

Early postnatal chronic intermittent hypoxia modifies hypoxic respiratory responses and long-term phrenic facilitation in adult rats

Acute isocapnic intermittent hypoxia elicits time-dependent, serotonin-dependent enhancement of phrenic motor output in anesthetized rats (phrenic long-term facilitation, pLTF). In adult rats, pLTF is enhanced by chronic intermittent hypoxia (CIH). To test the hypothesis that early postnatal CIH induces persistent modifications of ventilation and pLTF, we exposed male Sprague-Dawley rat pups on their first day of life to a CIH profile consisting of alternating room air and 10% oxygen every 90 s for 30 days during daylight hours (RAIH) or to comparable exposures consisting of room air throughout (RARA). One month after cessation of CIH, respiratory responses were recorded using whole body plethysmography, and integrated phrenic nerve activity was recorded in urethane-anesthetized, vagotomized, paralyzed, and ventilated rats at baseline and after exposures to three 5-min hypoxic episodes [inspired O2 fraction (FiO2)=0.11] separated by 5 min of hyperoxia (FiO2=0.5). RAIH rats displayed greater normoxic ventilation and also increased burst frequency compared with RARA rats (P<0.01). Ventilatory responses to hypoxia and short-term phrenic responses during acute hypoxic challenges were reduced in RAIH rats (P<0.01). Although pLTF was present in both RAIH and RARA rats, it was diminished in RAIH rats (minute activity: 74+/-2% in RARA vs. 55+/-5% in RAIH at 60 min; P<0.01). Thus we conclude that early postnatal CIH modifies normoxic and hypoxic ventilatory and phrenic responses that persist at 1 mo after cessation of CIH (i.e., metaplasticity) and markedly differ from previously reported increased neural plasticity changes induced by CIH in adult rats.     

Dexamethasone prevents transport inhibition by hypoxia in rat lung and alveolar epithelial cells by stimulating activity and expression of Na+-K+-ATPase and epithelial Na+ channels

Hypoxia inhibits Na and lung fluid reabsorption, which contributes to the formation of pulmonary edema. We tested whether dexamethasone prevents hypoxia-induced inhibition of reabsorption by stimulation of alveolar Na transport. Fluid reabsorption, transport activity, and expression of Na transporters were measured in hypoxia-exposed rats and in primary alveolar type II (ATII) cells. Rats were treated with dexamethasone (DEX; 2 mg/kg) on 3 consecutive days and exposed to 10% O(2) on the 2nd and 3rd day of treatment to measure hypoxia effects on reabsorption of fluid instilled into lungs. ATII cells were treated with DEX (1 muM) for 3 days before exposure to hypoxia (1.5% O(2)). In normoxic rats, DEX induced a twofold increase in alveolar fluid clearance. Hypoxia decreased reabsorption (-30%) by decreasing its amiloride-sensitive component; pretreatment with DEX prevented the hypoxia-induced inhibition. DEX increased short-circuit currents (ISC) of ATII monolayers in normoxia and blunted hypoxic transport inhibition by increasing the capacity of Na(+)-K(+)-ATPase and epithelial Na(+) channels (ENaC) and amiloride-sensitive ISC. DEX slightly increased the mRNA of alpha- and gamma-ENaC in whole rat lung. In ATII cells from DEX-treated rats, mRNA of alpha(1)-Na(+)-K(+)-ATPase and alpha-ENaC increased in normoxia and hypoxia, and gamma-ENaC was increased in normoxia only. DEX stimulated the mRNA expression of alpha(1)-Na(+)-K(+)-ATPase and alpha-, beta-, and gamma-ENaC of A549 cells in normoxia and hypoxia (1.5% O(2)) when DEX treatment was begun before or during hypoxic exposure. These results indicate that DEX prevents inhibition of alveolar reabsorption by hypoxia and stimulates the expression of Na transporters even when it is applied in hypoxia.     

Changes in macrovessel pulmonary blood flow distribution following chronic hypoxia: assessed using synchrotron radiation microangiography.

Structural and functional changes of the pulmonary circulation, particularly during the pathogenesis of pulmonary arterial hypertension (PAH), remain to be fully elucidated. In this study, we utilized monochromatic synchrotron radiation (SR) microangiography to assess changes in pulmonary arteriole blood flow in the intact-chest rat after 4 wk of chronic hypoxia. Sprague-Dawley rats were exposed to normoxia (N-rats) or chronic hypoxia (10% O(2); CH-rats) for 28 days. Rats were anesthetized, and microangiography was performed on the left lung to assess 1) the branching distribution of pulmonary arteriole blood flow (internal diameter >80 microm) and 2) dynamic changes in vessel lumen diameter during acute hypoxic (8% O(2) for 4 min) pulmonary vasoconstriction (HPV) before and after beta-adrenoceptor blockade (2 mg/kg i.v. propranolol). Using SR angiography, we observed that the number of opaque third- and fourth-generation vessels (100-300 microm) for CH-rats was significantly fewer than the number for N-rats. The magnitude of HPV was not different between CH-rats and N-rats. Beta-adrenoceptor blockade accentuated the HPV in 200- to 300-microm vessels for CH-rats, but even more so in N-rats. However, in CH-rats, beta-adrenoceptor blockade also accentuated the HPV in 100- to 200-microm vessels. In summary, we utilized SR to assess gross blood flow changes and functional changes (i.e., HPV) of the pulmonary circulation in PAH. These results highlight the benefits of SR for assessing pulmonary circulatory pathology. Of particular importance, future use of SR will provide an effective method for assessing potential therapeutic treatments for PAH.     

Chronic intermittent hypoxia reduces ventilatory long-term facilitation and enhances apnea frequency in newborn rats

Ventilatory long-term facilitation (LTF; defined as gradual increase of minute ventilation following repeated hypoxic exposures) is well described in adult mammals and is hypothesized to be a protective mechanism against apnea. In newborns, LTF is absent during the first postnatal days, but its precise developmental pattern is unknown. Accordingly, this study describes this pattern of postnatal development. Additionally, we tested the hypothesis that chronic intermittent hypoxia (CIH) from birth alters this development. LTF was estimated in vivo using whole body plethysmography by exposing rat pups at postnatal days 1, 4, and 10 (P1, P4, and P10) to 10 brief hypoxic cycles (nadir 5% O2) and respiratory recordings during the following 2 h (recovery, 21% O2). Under these conditions, ventilatory LTF (gradual increase of minute ventilation during recovery) was clearly expressed in P10 rats but not in P1 and P4. In a second series of experiments, rat pups were exposed to CIH during the first 10 postnatal days (6 brief cyclic exposures at 5% O2 every 6 min followed by 1 h under normoxia, 24 h a day). Compared with P10 control rats, CIH enhanced hypoxic ventilatory response (estimated during the hypoxic cycles) specifically in male rat pups. Ventilatory LTF was drastically reduced in P10 rats exposed to CIH, which was associated with higher apnea frequency during recovery. We conclude that CIH from birth enhances hypoxic chemoreflex and disrupts LTF development, thus likely contributing to increase apnea frequency.     

Disodium cromoglycate attenuates hypoxia induced enlargement of end-expiratory lung volume in rats

Mechanism responsible for the enlargement of end-expiratory lung volume (EELV) induced by chronic hypoxia remains unclear. The fact that the increase in EELV persists after return to normoxia suggests involvement of morphological changes. Because hypoxia has been also shown to activate lung mast cells, we speculated that they could play in the mechanism increasing EELV similar role as in vessel remodeling in hypoxic pulmonary hypertension (HPH). We, therefore, tested an effect of mast cells degranulation blocker disodium cromoglycate (DSCG) on hypoxia induced EELV enlargement. Ventilatory parameters, EELV and right to left heart weight ratio (RV/LV+S) were measured in male Wistar rats. The experimental group (H+DSCG) was exposed to 3 weeks of normobaric hypoxia and treated with DSCG during the first four days of hypoxia, control group was exposed to hypoxia only (H), two others were kept in normoxia as non-treated (N) and treated (N+DSCG) groups. DSCG treatment significantly attenuated the EELV enlargement (H+DSCG = 6.1+/-0.8; H = 9.2+/-0.9; ml +/-SE) together with the increase in minute ventilation (H + DSCG = 190+/-8; H = 273 +/- 10; ml/min +/- SE) and RV/LV + S (H + DSCG = 0.39 +/- 0.03; H = 0.50 +/- 0.06).