Influence of arterial O2 on the susceptibility to posthyperventilation apnea during sleep.

To investigate the contribution of the peripheral chemoreceptors to the susceptibility to posthyperventilation apnea, we evaluated the time course and magnitude of hypocapnia required to produce apnea at different levels of peripheral chemoreceptor activation produced by exposure to three levels of inspired P(O2). We measured the apneic threshold and the apnea latency in nine normal sleeping subjects in response to augmented breaths during normoxia (room air), hypoxia (arterial O2 saturation = 78-80%), and hyperoxia (inspired O2 fraction = 50-52%). Pressure support mechanical ventilation in the assist mode was employed to introduce a single or multiple numbers of consecutive, sigh-like breaths to cause apnea. The apnea latency was measured from the end inspiration of the first augmented breath to the onset of apnea. It was 12.2 +/- 1.1 s during normoxia, which was similar to the lung-to-ear circulation delay of 11.7 s in these subjects. Hypoxia shortened the apnea latency (6.3 +/- 0.8 s; P < 0.05), whereas hyperoxia prolonged it (71.5 +/- 13.8 s; P < 0.01). The apneic threshold end-tidal P(CO2) (Pet(CO2)) was defined as the Pet(CO2)) at the onset of apnea. During hypoxia, the apneic threshold Pet(CO2) was higher (38.9 +/- 1.7 Torr; P < 0.01) compared with normoxia (35.8 +/- 1.1; Torr); during hyperoxia, it was lower (33.0 +/- 0.8 Torr; P < 0.05). Furthermore, the difference between the eupneic Pet(CO2) and apneic threshold Pet(CO2) was smaller during hypoxia (3.0 +/- 1.0 Torr P < 001) and greater during hyperoxia (10.6 +/- 0.8 Torr; P < 0.05) compared with normoxia (8.0 +/- 0.6 Torr). Correspondingly, the hypocapnic ventilatory response to CO2 below the eupneic Pet(CO2) was increased by hypoxia (3.44 +/- 0.63 l.min(-1).Torr(-1); P < 0.05) and decreased by hyperoxia (0.63 +/- 0.04 l.min(-1).Torr(-1); P < 0.05) compared with normoxia (0.79 +/- 0.05 l.min(-1).Torr(-1)). These findings indicate that posthyperventilation apnea is initiated by the peripheral chemoreceptors and that the varying susceptibility to apnea during hypoxia vs. hyperoxia is influenced by the relative activity of these receptors.     

Lung diffusion capacity for nitric oxide and carbon monoxide is impaired similarly following short-term graded exercise.

Study aimed to determine whether short-term graded exercise affects single-breath lung diffusion capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) similarly, and whether the DLNO/DLCO ratios during rest are altered post-exercise compared to pre-exercise. Eleven healthy subjects (age=29+/-6 years; weight=76.6+/-13.2 kg; height=177.9+/-13.2 cm; and maximal oxygen uptake or V(.-)(O(2max) = 52.7 +/- 9.3 ml kg(-1) min(-1))performed simultaneous single-breath DLNO and DLCO measurements at rest (inspired NO concentration=43.2+/-4.1 ppm, inspired CO concentration=0.30%) 15 min before and 2h after a graded exercise test to exhaustion (exercise duration=593+/-135 s). Resting DLNO and DLCO was similarly reduced 2h post-exercise (DLNO=-7.8+/-3.5%, DLCO=-10.3+/-6.9%, and P<0.05) due to reductions in pulmonary capillary blood volume (-11.3+/-9.0%, P<0.05) and membrane diffusing capacity for CO (-7.8+/-3.5%; P<0.05). The change in DLCO was reflected by the change in DLNO post-exercise such that 68% of the variance in the change in DLCO was accounted for by the variance in the change in DLNO (P<0.05). The DLNO/DLCO ratio was not altered post-exercise (5.87+/-0.37) compared to pre-exercise (5.70+/-0.34). We conclude that the decrease in single-breath DLNO and DLCO from pre- to post-exercise is similar, the magnitude of the change in DLCO closely reflects that of the change in DLNO, and single-breath DLNO/DLCO ratios are independent of the timing of measurement suggesting that using NO and CO transfer gases are valid in looking at short-term changes in lung diffusional conductance.     

Brain hypoxia preferentially stimulates genioglossal EMG responses to CO2

Although the dominant respiratory response to hypoxia is stimulation of breathing via the peripheral chemoreflex, brain hypoxia may inhibit respiration. We studied the effects of two levels of brain hypoxia without carotid body stimulation, produced by inhalation of CO, on ventilatory (VI) and genioglossal (EMGgg) and diaphragmatic (EMGdi) responses to CO2 rebreathing in awake, unanesthetized goats. Neither delta VI/delta PCO2 nor VI at a PCO2 of 60 Torr was significantly different between the three conditions studied (0%, 25%, and 50% carboxyhemoglobin, HbCO). There were also no significant changes in delta EMGdi/delta PCO2 or EMGdi at a PCO2 of 60 Torr during progressive brain hypoxia. In contrast, delta EMGgg/delta PCO2 and EMGgg at a PCO2 of 60 Torr were significantly increased at 50% HbCO compared with either normoxia or 25% HbCO (P less than 0.05). The PCO2 threshold at which inspiratory EMGgg appeared was also decreased at 50% HbCO (45.6 +/- 2.6 Torr) compared with normoxia (55.0 +/- 1.4 Torr, P less than 0.02) or 25% HbCO (53.4 +/- 1.6 Torr, P less than 0.02). We conclude that moderate brain hypoxia (50% HbCO) in awake, unanesthetized animals results in disproportionate augmentation of EMGgg relative to EMGdi during CO2 rebreathing. This finding is most likely due to hypoxic cortical depression with consequent withdrawal of tonic inhibition of hypoglossal inspiratory activity.     

Ventilatory control during exercise with peripheral chemoreceptor stimulation: hypoxia vs. domperidone

Hypoxia potentiates the ventilatory response to exercise, eliciting a greater decrease in arterial PCO2 (PaCO2) from rest to exercise than in normoxia. The mechanism of this hypoxia-exercise interaction requires intact carotid chemoreceptors. To determine whether carotid chemoreceptor stimulation alone is sufficient to elicit the mechanism without whole body hypoxia, ventilatory responses to treadmill exercise were compared in goats during hyperoxic control conditions, moderate hypoxia (PaO2 = 38-44 Torr), and peripheral chemoreceptor stimulation with the peripheral dopamine D2-receptor antagonist, domperidone (Dom; 0.5 mg/kg iv). Measurements with Dom were made in both hyperoxia (Dom) and hypoxia (Dom/hypoxia). Finally, ventilatory responses to inspired CO2 at rest were compared in each experimental condition because enhanced CO2 chemoreception might be expected to blunt the PaCO2 decrease during exercise. At rest, PaCO2 decreased from control with Dom (-5.0 +/- 0.9 Torr), hypoxia (-4.1 +/- 0.5 Torr), and Dom/hypoxia (-11.1 +/- 1.2 Torr). The PaCO2 decrease from rest to exercise was not significantly different between control (-1.7 +/- 0.6 Torr) and Dom (-1.4 +/- 0.8 Torr) but was significantly greater in hypoxia (-4.3 +/- 0.7 Torr) and Dom/hypoxia (-3.5 +/- 0.9 Torr). The slope of the ventilation vs. CO2 production relationship in exercise increased with Dom (16%), hypoxia (18%), and Dom/hypoxia (68%). Ventilatory responses to inspired CO2 at rest increased from control to Dom (236%) and Dom/hypoxia (295%) and increased in four of five goats in hypoxia (mean 317%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Carotid body excision significantly changes ventilatory control in awake rats

We determined the effects of carotid body excision (CBX) on eupneic ventilation and the ventilatory responses to acute hypoxia, hyperoxia, and chronic hypoxia in unanesthetized rats. Arterial PCO2 (PaCO2) and calculated minute alveolar ventilation to minute metabolic CO2 production (VA/VCO2) ratio were used to determine the ventilatory responses. The effects of CBX and sham operation were compared with intact controls (PaCO2 = 40.0 +/- 0.1 Torr, mean +/- 95% confidence limits, and VA/VCO2 = 21.6 +/- 0.1). CBX rats showed 1) chronic hypoventilation with respiratory acidosis, which was maintained for at least 75 days after surgery (PaCO2 = 48.4 +/- 1.1 Torr and VA/VCO2 = 17.9 +/- 0.4), 2) hyperventilation in response to acute hyperoxia vs. hypoventilation in intact rats, 3) an attenuated increase in VA/VCO2 in acute hypoxemia (arterial PO2 approximately equal to 49 Torr), which was 31% of the 8.7 +/- 0.3 increase in VA/VCO2 observed in control rats, 4) no ventilatory acclimatization between 1 and 24 h hypoxia, whereas intact rats had a further 7.5 +/- 1.5 increase in VA/VCO2, 5) a decreased PaCO2 upon acute restoration of normoxia after 24 h hypoxia in contrast to an increased PaCO2 in controls. We conclude that in rats carotid body chemoreceptors are essential to maintain normal eupneic ventilation and to the process of ventilatory acclimatization to chronic hypoxia.     

Ventilatory effects and interactions with change in PaO2 in awake goats.

We utilized selective carotid body (CB) perfusion while changing inspired O2 fraction in arterial isocapnia to characterize the non-CB chemoreceptor ventilatory response to changes in arterial PO2 (PaO2) in awake goats and to define the effect of varying levels of CB PO2 on this response. Systemic hyperoxia (PaO2 greater than 400 Torr) significantly increased inspired ventilation (VI) and tidal volume (VT) in goats during CB normoxia, and systemic hypoxia (PaO2 = 29 Torr) significantly increased VI and respiratory frequency in these goats. CB hypoxia (CB PO2 = 34 Torr) in systemic normoxia significantly increased VI, VT, and VT/TI; the ventilatory effects of CB hypoxia were not significantly altered by varying systemic PaO2. We conclude that ventilation is stimulated by systemic hypoxia and hyperoxia in CB normoxia and that this ventilatory response to changes in systemic O2 affects the CB O2 response in an additive manner.     

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)     

Effects of altitude acclimatization on pulmonary gas exchange during exercise

Pulmonary gas exchange was studied in eight normal subjects both before and after 2 wk of altitude acclimatization at 3,800 m (12,470 ft, barometric pressure = 484 Torr). Respiratory and multiple inert gas tensions, ventilation, cardiac output (Q), and hemoglobin concentration were measured at rest and during three levels of constant-load cycle exercise during both normoxia [inspired PO2 (PIO2) = 148 Torr] and normobaric hypoxia (PIO2 = 91 Torr). After acclimatization, the measured alveolar-arterial PO2 difference (A-aPO2) for any given work rate decreased (P less than 0.02). The largest reductions were observed during the highest work rates and were 24.8 +/- 1.4 to 19.7 +/- 0.8 Torr (normoxia) and 22.0 +/- 1.1 to 19.4 +/- 0.7 Torr (hypoxia). This could not be explained by changes in ventilation-perfusion inequality or estimated O2 diffusing capacity, which were unaffected by acclimatization. However, Q for any given work rate was significantly decreased (P less than 0.001) after acclimatization. We suggest that the reduction in A-aPO2 after acclimatization is a result of more nearly complete alveolar/end-capillary diffusion equilibration on the basis of a longer pulmonary capillary transit time.     

Pulmonary gas exchange during exercise in highly trained cyclists with arterial hypoxemia.

The causes of exercise-induced hypoxemia (EIH) remain unclear. We studied the mechanisms of EIH in highly trained cyclists. Five subjects had no significant change from resting arterial PO(2) (Pa(O(2)); 92.1 +/- 2.6 Torr) during maximal exercise (C), and seven subjects (E) had a >10-Torr reduction in Pa(O(2)) (81.7 +/- 4.5 Torr). Later, they were studied at rest and during various exercise intensities by using the multiple inert gas elimination technique in normoxia and hypoxia (13.2% O(2)). During normoxia at 90% peak O(2) consumption, Pa(O(2)) was lower in E compared with C (87 +/- 4 vs. 97 +/- 6 Torr, P < 0.001) and alveolar-to-arterial O(2) tension difference (A-aDO(2)) was greater (33 +/- 4 vs. 23 +/- 1 Torr, P < 0. 001). Diffusion limitation accounted for 23 (E) and 13 Torr (C) of the A-aDO(2) (P < 0.01). There were no significant differences between groups in arterial PCO(2) (Pa(CO(2))) or ventilation-perfusion (VA/Q) inequality as measured by the log SD of the perfusion distribution (logSD(Q)). Stepwise multiple linear regression revealed that lung O(2) diffusing capacity (DL(O(2))), logSD(Q), and Pa(CO(2)) each accounted for approximately 30% of the variance in Pa(O(2)) (r = 0.95, P < 0.001). These data suggest that EIH has a multifactorial etiology related to DL(O(2)), VA/Q inequality, and ventilation.     

PO2 modulation of paraquat-induced microvascular injury in isolated dog lungs

We determined the effects of paraquat (PQ) concentrations ranging from 10(-3) to 10(-2) M and three levels of venous PO2 [hypoxia (41 +/- 3 Torr), normoxia (147 +/- 8 Torr), and hyperoxia (444 +/- 17 Torr)] in the presence of 4 x 10(-3) M PQ on microvascular permeability in isolated blood-perfused dog lungs. Capillary filtration coefficient (Kf,c) increased and isogravimetric capillary pressure (Pc,i) decreased 3 h after perfusion with 10(-2) M PQ (n = 7) and 5 h after perfusion with 4 x 10(-3) M PQ (n = 6) but not with 10(-3) M PQ (n = 4). In hyperoxic lungs perfused with 4 x 10(-3) M PQ, Kf,c increased to nine times the base-line value 5 h after PQ [0.15 +/- 0.01 to 1.35 +/- 0.25 (SE) ml.min-1.cmH2O-1.100 g-1]. Pc,i significantly decreased from a base-line value of 9.4 +/- 0.2 to 7.1 +/- 0.4 cmH2O at 3 h. In hypoxic lungs perfused with 4 x 10(-3) M PQ (n = 5), Pc,i and Kf,c changes were not significantly different from those in normoxic lungs treated with PQ. Thus both hyperoxia and an increased dose of PQ shortened the latent period and increased the severity of the PQ-induced microvascular permeability lesion, but hypoxia failed to prevent the PQ damage.     

Intermittent hypoxia induces phrenic long-term facilitation in carotid-denervated rats.

Episodic hypoxia elicits a long-lasting augmentation of phrenic inspiratory activity known as long-term facilitation (LTF). We investigated the respective contributions of carotid chemoafferent neuron activation and hypoxia to the expression of LTF in urethane-anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats. One hour after three 5-min isocapnic hypoxic episodes [arterial Po(2) (Pa(O(2))) = 40 +/- 5 Torr], integrated phrenic burst amplitude was greater than baseline in both carotid-denervated (n = 8) and sham-operated (n = 7) rats (P < 0.05), indicating LTF. LTF was reduced in carotid-denervated rats relative to sham (P < 0.05). In this and previous studies, rats were ventilated with hyperoxic gas mixtures (inspired oxygen fraction = 0.5) under baseline conditions. To determine whether episodic hyperoxia induces LTF, phrenic activity was recorded under normoxic (Pa(O(2)) = 90-100 Torr) conditions before and after three 5-min episodes of isocapnic hypoxia (Pa(O(2)) = 40 +/- 5 Torr; n = 6) or hyperoxia (Pa(O(2)) > 470 Torr; n = 6). Phrenic burst amplitude was greater than baseline 1 h after episodic hypoxia (P < 0.05), but episodic hyperoxia had no detectable effect. These data suggest that hypoxia per se initiates LTF independently from carotid chemoafferent neuron activation, perhaps through direct central nervous system effects.     

Interactions of nitric oxide and oxygen in cytotoxicity: proliferation and antioxidant enzyme activities of endothelial cells in culture

Nitric oxide (NO) shows cytotoxicity, and its reaction products with reactive oxygen species, such as peroxynitrite, are potentially more toxic. To examine the role of O2 in the NO toxicity, we have examined the proliferation of cultured human umbilical vein endothelial cells in the presence or absence of NO donor, ((Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-++ +ium-1,2-diolate) (DETA-NONOate) (100-500 microM), under normoxia (air), hypoxia (< 0.04% O2) or hyperoxia (88-94% O2). It was found that the dose dependency on NONOate was little affected by the ambient O2 concentration, showing no apparent synergism between the two treatments. We have also examined the effects of exogenous NO under normoxia and hyperoxia on the cellular activities of antioxidant enzymes involved in the H2O2 elimination, since many of them are known to be inhibited by NO or peroxynitrite in vitro. Under normoxia DETA-NONOate (500 microM) caused 25% decrease in catalase activity and 30% increases in glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in 24h. Under hyperoxia NO caused about 25% decreases in activities of catalase, glutathione reductase and glucose-6-phosphate dehydrogenase. The H2O2 removal rate by NO-treated cells was computed on the mathematical model for the enzyme system. It was concluded that the cellular antioxidant function is little affected by NO under normoxia but that it is partially impaired when the cells are exposed to NO under hyperoxia.     

Cerebral oxygen availability by NIR spectroscopy during transient hypoxia in humans

The effects of mild hypoxia on brain oxyhemoglobin, cytochrome a,a3 redox status, and cerebral blood volume were studied using near-infrared spectroscopy in eight healthy volunteers. Incremental hypoxia reaching 70% arterial O2 saturation was produced in normocapnia [end-tidal PCO2 (PETCO2) 36.9 +/- 2.6 to 34.9 +/- 3.4 Torr] or hypocapnia (PETCO2 32.8 +/- 0.6 to 23.7 +/- 0.6 Torr) by an 8-min rebreathing technique and regulation of inspired CO2. Normocapnic hypoxia was characterized by progressive reductions in arterial PO2 (PaO2, 89.1 +/- 3.5 to 34.1 +/- 0.1 Torr) with stable PETCO2, arterial PCO2 (PaCO2), and arterial pH and resulted in increases in heart rate (35%) systolic blood pressure (14%), and minute ventilation (5-fold). Hypocapnic hypoxia resulted in progressively decreasing PaO2 (100.2 +/- 3.6 to 28.9 +/- 0.1 Torr), with progressive reduction in PaCO2 (39.0 +/- 1.6 to 27.3 +/- 1.9 Torr), and an increase in arterial pH (7.41 +/- 0.02 to 7.53 +/- 0.03), heart rate (61%), and ventilation (3-fold). In the brain, hypoxia resulted in a steady decline of cerebral oxyhemoglobin content and a decrease in oxidized cytochrome a,a3. Significantly greater loss of oxidized cytochrome a,a3 occurred for a given decrease in oxyhemoglobin during hypocapnic hypoxia relative to normocapnic hypoxia. Total blood volume response during hypoxia also was significantly attenuated by hypocapnia, because the increase in volume was only half that of normocapnic subjects. We conclude that cytochrome a,a3 oxidation level in vivo decreases at mild levels of hypoxia. PaCO is an important determinant of brain oxygenation, because it modulates ventilatory, cardiovascular, and cerebral O2 delivery responses to hypoxia.     

N omega-nitro-L-arginine influences cerebral metabolism in awake sheep.

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide (NO). An inhibitor of NO formation, N omega-nitro-L-arginine (LNA, 100 micrograms/kg i.v.), was given to conscious sheep (n = 6) during normoxia and again in hypocapnic hypoxia (arterial PO2 approximately 38 Torr). Blood samples were obtained from the aorta and sagittal sinus, and cerebral blood flow (CBF) was measured with 15-microns radiolabeled microspheres. During normoxia, LNA elevated (P < 0.05) mean arterial pressure from 82 +/- 3 to 88 +/- 2 (SE) mmHg and cerebral perfusion pressure (CPP) from 72 +/- 3 to 79 +/- 3 mmHg, CBF was unchanged, and cerebral lactate release (CLR) rose temporarily from 0.0 +/- 1.9 to 13.3 +/- 8.7 mumol.min-1 x 100 g-1 (P < 0.05). The glucose-O2 index declined (P < 0.05) from 1.67 +/- 0.16 to 1.03 +/- 0.4 mumol.min-1 x 100 g-1. Hypoxia increased CBF from 59.9 +/- 5.4 to 122.5 +/- 17.5 ml.min-1 x 100 g-1 and the glucose-O2 index from 1.75 +/- 0.43 to 2.49 +/- 0.52 mumol.min-1 x 100 g-1 and decreased brain CO2 output, brain respiratory quotient, and CPP (all P < 0.05), while cerebral O2 uptake, CLR, and CPP were unchanged. LNA given during hypoxia decreased CBF to 77.7 +/- 11.8 ml.min-1 x 100 g-1 and cerebral O2 uptake from 154 +/- 22 to 105.2 +/- 12.4 mumol.min-1 x 100 g-1 and further elevated mean arterial pressure to 98 +/- 2 mmHg (all P < 0.05), CLR was unchanged, and, surprisingly, brain CO2 output and respiratory quotient were reduced dramatically to negative values (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Does cerebral oxygen delivery limit incremental exercise performance?

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal Pco(2) (Pet(CO(2))) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which Pet(CO(2)) was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower Pet(CO(2)) (40 Torr) from ～75 to 100% W(peak) to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping Pet(CO(2)) at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping Pet(CO(2)) at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (～40%) and improved cerebral hemoglobin oxygenation (～15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (～15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO(2)-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.     

Selected contribution: chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans.

The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal PO2 (PET(O2)) = 55 Torr and end-tidal PCO2 (PET(CO2)) = eucapnia; 2) poikilocapnic hypoxia, with PET(O2) = 55 Torr and PET(CO2) = uncontrolled; and 3) air-breathing control. The ventilatory response to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of PET(CO2): 1.5 and 10 Torr above the normal resting value. PET(O2) was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases in combined Gp + Gc (26%, P < 0.05), Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in chemosensitivity to CO2 within the peripheral chemoreflex.     

Pulmonary venous pressure increases during alveolar hypoxia in isolated lungs of newborn pigs.

The purpose of this study was to determine whether pulmonary venous pressure increases during alveolar hypoxia in lungs of newborn pigs. We isolated and perfused with blood the lungs from seven newborn pigs, 6-7 days old. We maintained blood flow constant at 50 ml.min-1.kg-1 and continuously monitored pulmonary arterial and left atrial pressures. Using the micropuncture technique, we measured pressures in 10 to 60-microns-diam venules during inflation with normoxic (21% O2-69-74% N2-5-10% CO2) and hypoxic (90-95% N2-5-10% CO2) gas mixtures. PO2 was 142 +/- 21 Torr during normoxia and 20 +/- 4 Torr during hypoxia. During micropuncture we inflated the lungs to a constant airway pressure of 5 cmH2O and kept left atrial pressure greater than airway pressure (zone 3). During hypoxia, pulmonary arterial pressure increased by 69 +/- 24% and pressure in small venules increased by 40 +/- 23%. These results are similar to those obtained with newborn lambs and ferrets but differ from results with newborn rabbits. The site of hypoxic vasoconstriction in newborn lungs is species dependent.     

Pulmonary diffusing capacity for nitric oxide during exercise in morbid obesity

Morbidly obese individuals may have altered pulmonary diffusion during exercise. The purpose of this study was to examine pulmonary diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) during exercise in these subjects. Ten morbidly obese subjects (age = 38 +/- 9 years, BMI = 47 +/- 7 kg/m(2), peak oxygen consumption or VO(2peak) = 2.4 +/- 0.4 l/min) and nine nonobese controls (age = 41 +/- 9 years, BMI = 23 +/- 2 kg/m(2), VO(2peak) = 2.6 +/- 0.9 l/min) participated in two sessions: the first measured resting O(2) and VO(2peak) for determination of wattage equating to 40, 75, and 90% oxygen uptake reserve (VO(2)R). The second session measured pulmonary diffusion from single-breath maneuvers of 5 s each, as well as heart rate (HR) and VO(2) over three workloads. DLNO, DLCO, and pulmonary capillary blood volume were larger in obese compared to nonobese groups (P 0.10). The morbidly obese have increased pulmonary diffusion per unit increase in VA compared with nonobese controls which may be due to a lower rise in VA per unit increase in VO(2) in the obese during exercise.     

Chronic intermittent hypoxia increases the CO2 reserve in sleeping dogs.

We hypothesized that chronic intermittent hypoxia (CIH) would induce a predisposition to apnea in response to induced hypocapnia. To test this, we used pressure support ventilation to quantify the difference in end-tidal partial pressure of CO(2) (Pet(CO(2))) between eupnea and the apneic threshold ("CO(2) reserve") as an index of the propensity for apnea and unstable breathing during sleep, both before and following up to 3-wk exposure to chronic intermittent hypoxia in dogs. CIH consisted of 25 s of Pet(O(2)) = 35-40 Torr followed by 35 s of normoxia, and this pattern was repeated 60 times/h, 7-8 h/day for 3 wk. The CO(2) reserve was determined during non-rapid eye movement sleep in normoxia 14-16 h after the most recent hypoxic exposure. Contrary to our hypothesis, the slope of the ventilatory response to CO(2) below eupnea progressively decreased during CIH (control, 1.36 +/- 0.18; week 2, 0.94 +/- 0.12; week 3, 0.73 +/- 0.05 l.min(-1).Torr(-1), P < 0.05). This resulted in a significant increase in the CO(2) reserve relative to control (P < 0.05) following both 2 and 3 wk of CIH (control, 2.6 +/- 0.6; week 2, 3.7 +/- 0.8; week 3, 4.5 +/- 0.9 Torr). CIH also 1) caused no change in eupneic, air breathing Pa(CO(2)); 2) increased the slope of the ventilatory response to hypercapnia after 2 wk but not after 3 wk compared with control; and 3) had no effect on the ventilatory response to hypoxia. We conclude that 3-wk CIH reduced the sensitivity of the ventilatory response to transient hypocapnia and thereby increased the CO(2) reserve, i.e., the propensity for apnea was reduced.     

Effect of hyperoxia on substrate utilization during intense submaximal exercise

Six trained males [mean maximal O2 uptake (VO2max) = 66 ml X kg-1 X min-1] performed 30 min of cycling (mean = 76.8% VO2max) during normoxia (21.35 +/- 0.16% O2) and hyperoxia (61.34 +/- 1.0% O2). Values for VO2, CO2 output (VCO2), minute ventilation (VE), respiratory exchange ratio (RER), venous lactate, glycerol, free fatty acids, glucose, and alanine were obtained before, during, and after the exercise bout to investigate the possibility that a substrate shift is responsible for the previously observed enhanced performance and decreased RER during exercise with hyperoxia. VO2, free fatty acids, glucose, and alanine values were not significantly different in hyperoxia compared with normoxia. VCO2, RER, VE, and glycerol and lactate levels were all lower during hyperoxia. These results are interpreted to support the possibility of a substrate shift during hyperoxia.