Effect of alveolar hypoxia on regional pulmonary perfusion

We examined the effects of varying levels of alveolar hypoxia on regional distribution of pulmonary blood flow (QL) in control-ventilated sheep. Regional distribution of QL was measured using 15-micron-diam labeled microspheres during the base-line period and at two levels of hypoxemia (arterial O2 partial pressure 44 and 20 Torr). During the base-line period, regional distribution of QL in the prone position was uniform [14 +/- 4% (SE) of QL/g bloodless dry lung wt in the upper lung and 16 +/- 2% of QL/g in the dependent lung]. During hypoxemia, however, the regional distribution of QL increased in the upper lung (20 +/- 3% of QL/g) while it decreased in the dependent lung (10 +/- 2% of QL/g). The degree of flow distribution was proportional to the severity of hypoxemia. The flow distribution was not associated with significant increases in pulmonary blood flow (2.0 +/- 0.4----2.4 +/- 0.5----2.6 +/- 0.1 l/min) but was associated with increases in mean pulmonary arterial pressure (17.8 +/- 1.3----21.7 +/- 1.1----29.0 +/- 3.8 Torr). Therefore alveolar hypoxia results in a relative increase in regional pulmonary perfusion to the upper lung, which depends on the level of pulmonary hypertension. The increased upper lung perfusion may be due to recruitment in the upper lung or to vasodilation in this region.     

Nonuniform effects of histamine on small pulmonary vessels in cats

In in vivo cat lung, using an X-ray TV system, we analyzed responses in internal diameter (ID), flow velocity, and volume flow of arteries and veins (100-500 microns ID) to histamine (8-15 micrograms/kg iv) under three conditions. With histamine alone, three types of ID response (constriction, dilatation, and no change) occurred in parallel-arranged arteries. Relative frequency and magnitude of constriction were maximum in arteries of 300-400 micron ID, whereas those of dilatation were maximum in arteries of 100-200 micron ID. In veins, relatively uniform constriction occurred. Under H2-blockade, histamine caused greater constriction than that with histamine alone in arteries and veins of 300-500 micron ID. Under beta-blockade, with histamine, ID of all vessels decreased significantly below the ID sizes under the above two conditions, and no dilatation occurred. In two parallel arteries that showed opposite ID changes to histamine, flow velocity increased, but volume flow decreased in a constricted artery while it increased in a dilated one. Those data indicated that, with histamine, qualitatively and quantitatively nonuniform ID response was induced in both parallel- and series-arranged small pulmonary arteries and, in turn, produced heterogeneous flow distribution. Factors to cause the nonuniformity may be partly explained by difference in density of H2- and beta-receptors in vascular walls.     

Effect of regional alveolar hypoxia on permeability pulmonary edema formation in dogs

We studied the effects of regional alveolar hypoxia on permeability pulmonary edema formation. Anesthetized dogs had a bronchial divider placed so that the left lower lobe (LLL) could be ventilated with a hypoxic gas mixture (HGM) while the right lung was continuously ventilated with 100% O2. Bilateral permeability edema was induced with 0.05 ml/kg oleic acid and after 4 h of LLL ventilation with an HGM (n = 9) LLL gross weight was 161 +/- 13 (SE) g compared with 204 +/- 13 (SE) g (P less than 0.05) in the right lower lobe (RLL). Bloodless lobar water and dry weight were also significantly lower in the LLL as compared with the RLL of the study animals. In seven control animals in which the LLL fractional inspired concentration of O2 (FIO2) was 1.0 during permeability edema, there were no differences in gravimetric variables between LLL and RLL. In eight additional animals, pulmonary capillary pressure (Pc), measured by simultaneous occlusion of left pulmonary artery and vein, was not significantly different between LLL FIO2 of 1.0 and 0.05 either before or after pulmonary edema. We conclude that, in the presence of permeability pulmonary edema, regional alveolar hypoxia causes reduction in edema formation. The decreased edema formation during alveolar hypoxia is not due to a reduction in Pc.     

Strength of pulmonary vascular response to regional alveolar hypoxia.

Regional alveolar hypoxia in the lung induces regional pulmonary vasoconstriction which diverts blood flow from the hypoxic area. However, the predominant determinant of the distribution of perfusion in the normal erect lung is gravity so that more perfusion occurs at the base than at the apex. To determine the strength of the regional alveolar hypoxic response in diverting flow with or against the gravity gradient a divided tracheal cannula was placed in anesthetized dogs and unilateral alveolar hypoxia created by venilating one lung with nitrogen while ventilating the other lung with oxygen to preserve normal systemic oxygentation. Scintigrams of the distribution of perfusion obtained with intravenous 13-N and the MGH positron camera revealed a 34 and 32 per cent decrease in perfusion to the hypoxic lung in the supine and erect positions and a 26 per cent decrease in the decubitus position with the hypoxic lung dependent (P equal to 0.94 from supine shift), indicating nearly equal vasoconstriction with shift of perfusion away from the hypoxic lung in all positions. Analysis of regional shifts in perfusion revealed an equal vasoconstrictor response from apex to base in the supine position but a greater response in the lower lung zones in the erect position where perfusion was also greatest.     

Effects of hypoxia and hypercapnia on surfactant protein expression proliferation and apoptosis in A549 alveolar epithelial cells

During lung injury alveolar epithelial cells are directly exposed to changes in PO(2) and PCO(2). Integrity of alveolar epithelial type II cells (AECII) is critical in lung injury but the effect of hypoxia and hypercapnia on AECII function, viability and proliferation has not been clearly investigated. Aim of the present work was to determine the direct effect of hypoxia and hypercapnia on surfactant protein expression, proliferation and apoptosis of lung epithelial cells in vitro. A549 alveolar epithelia cells were subjected to hypoxia (1%O(2)-5% CO(2)) or hypercapnia (21% O(2-) 15% CO(2)) and expression of surfactant protein C was measured and compared to normal conditions (21% O(2)- 5% CO(2)). Cell cycle progression and apoptosis were measured by flow cytometric analysis. RESULTS: A549 alveolar epithelial cells produce surfactant proteins, including surfactant protein C, when cultured under normal conditions, which is reduced under hypoxic conditions. Specifically, pro-SpC expression is moderately decreased after 8 h of culture in hypoxia, and is completely attenuated after 48 h. Hypercapnia decreases pro-SpC expression only after 48 h of exposure. Stimulation with TNF-alpha partly reverses pSPC decrease observed under hypoxic and hypercapnic conditions. Hypoxic culture of A549 cells results in progressive arrest of cells in the G1 phase of the cell cycle and increased apoptosis first observed 4 h following exposure and peaking at 24 h. In contrast hypercapnia has no significant effect on alveolar epithelial cell proliferation or apoptosis. CONCLUSIONS: Taken together we can conclude that hypoxia rapidly and severely affects AECII function and viability while hypercapnia has an inhibitory effect on pro-SpC production only after prolonged exposure.     

Effect of regional alveolar hypoxia on gas exchange in dogs

We studied the effects of left lower lobe (LLL) alveolar hypoxia on pulmonary gas exchange in anesthetized dogs using the multiple inert gas elimination technique (MIGET). The left upper lobe was removed, and a bronchial divider was placed. The right lung (RL) was continuously ventilated with 100% O2, and the LLL was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Whole lung and individual LLL and RL ventilation-perfusion (VA/Q) distributions were determined. LLL hypoxia reduced LLL blood flow and increased the perfusion-related indexes of VA/Q heterogeneity, such as the log standard deviation of the perfusion distribution (log SDQ), the retention component of the arterial-alveolar difference area [R(a-A)D], and the retention dispersion index (DISPR*) of the LLL. LLL hypoxia increased blood flow to the RL and reduced the VA/Q heterogeneity of the RL, indicated by significant reductions in log SDQ, R(a-A)D, and DISPR*. In contrast, LLL hypoxia had little effect on gas exchange of the lung when evaluated as a whole. We conclude that flow diversion induced by regional alveolar hypoxia preserves matching of ventilation to perfusion in the whole lung by increasing gas exchange heterogeneity of the hypoxic region and reducing heterogeneity in the normoxic lung.     

Diaphragmatic and ventilatory responses to alveolar hypoxia and hypercapnia in conscious kittens.

Ventilation and electromyographic (EMG) activity of the diaphragm were recorded in unanesthetized kittens 2 and 10 wk of age during normoxia, hypercapnia (2 and 4% CO2), and hypoxia (12 and 10% O2). We measured integrated diaphragmatic EMG activity at end inspiration (DIAI) and end expiration (DIAE); the difference (DIAI-E), which represents the phasic change of the diaphragmatic activity, was considered responsible for a given tidal volume (VT). During hypercapnia, the 2-wk-old kittens increased minute ventilation (V) by increases in both VT and respiratory frequency (f), whereas the 10-wk-old kittens increased V primarily by an increase in VT. At both ages, DIAI and DIAI-E increased during hypercapnia, whereas DIAE did not change significantly. During hypoxia, in the young kittens, V and VT decreased while f increased markedly; in the older kittens, V, VT, and f did not change significantly. In kittens of both ages, DIAI increased during hypoxia; because diaphragmatic activity persisted into expiration, DIAE also increased. DIAI-E, as well as VT, was decreased in the young kittens, whereas in the older ones DIAI-E was slightly increased despite an unchanged VT. Finally, the ventilatory and diaphragmatic response to hypoxia changes with maturation in contrast to the response to hypercapnia. It is concluded that 1) the hypoxia-induced reduction of VT may result from prolongation of diaphragmatic activity into expiration, inasmuch as it induces a reduction of the phasic change of the diaphragmatic activity, and 2) because DIAI-E indirectly reflects central inspiratory output, a central mechanism should be involved in the reduced VT and V in response to hypoxia in newborns.     

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance

Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45-65 Torr), and hypercapnia (PCO2 55-80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.     

阿斯匹林对大鼠在低O2高CO2下肺动脉高压的作用

目的：研究阿斯匹林(ASA)对慢性低O2高CO2性肺动脉高压的抑制作用。方法：将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2 阿斯匹林组。用光镜、放射免疫等方法,观察各组大鼠肺动脉平均压(mPAP)、颈动脉平均压(mCAP)、肺细小动脉显微结构、血浆和肺匀浆TXB2及6-keto-PGF1α含量的变化。结果：①低O2高CO2组mPAP比正常组显著增高,ASA组的mPAP比低O2高CO2组显著降低,3组间mCAP比较差异无显著性。②光镜下低O2高CO2组与正常组相比,肺细小动脉管壁面积／管总面积(WA／TA)和肺细小动脉中膜厚度(PAMT)均显著增高。ASA组WA／TA和PAMT显著降低。③低O2高CO2组血浆和肺匀浆TXB2、6-keto-PGF1α浓度以及TXB2／6-keto-PGF1α比正常组显著增高,而ASA组与低O2高CO2组相比显著降低。结论：ASA有抑制慢性低O2高CO2性肺动脉高压和肺血管重构的作用。     

Effects of hypercapnia and hypoxia on abdominal expiratory nerve activity

We examined the effects of progressive hypercapnia and hypoxia on the efferent neural activity in a whole abdominal expiratory nerve (medial branch of the cranial iliohypogastric nerve (L1) in anesthetized, paralyzed dogs. To eliminate effects of phasic lung and chest-wall movements on expiratory activity, studies were performed in the absence of breathing movements. Progressive hyperoxic hypercapnia and isocapnic hypoxia were produced in the paralyzed animals by allowing 3-5 min of apnea to follow mechanical ventilation with 100% O2 or 35% O2 in N2, respectively; during hypoxia, isocapnia was maintained by intravenous infusion of tris(hydroxymethyl)aminomethane buffer at a predetermined rate. To quantify abdominal expiratory activity, mean abdominal nerve activity in a nerve burst was computed by integrating the abdominal neurogram and dividing by the duration of the nerve burst. Hypercapnia and hypoxia both increased mean abdominal nerve activity and decreased expiratory duration. In contrast to the ramplike phrenic neurogram, the abdominal neurogram consisted of three phases: an initial rising phase, a plateau phase in which abdominal nerve activity was approximately constant, and a terminal declining phase in which the activity returned to the base-line level. The height of this plateau phase and the rates of rise and decline of abdominal nerve activity all increased with increasing hypercapnia and hypoxia. We conclude that, with proprioceptive inputs constant, both hypercapnia and hypoxia are excitatory to abdominal expiratory neural activity.     

Effects of hypoxia and hypercapnia on nonnutritive swallowing in newborn lambs.

The aim of the present study was to investigate the effect of hypercapnia and hypoxia on apnea and nonnutritive swallowing (NNS) frequency, as well as on the coordination between NNS and phases of the respiratory cycle in newborn lambs, while taking into account the potential effects of states of alertness. Six lambs were chronically instrumented for recording electroencephalogram, eye movements, diaphragm and thyroarytenoid muscle (a glottal adductor) activity, nasal airflow, and electrocardiogram. Polysomnographic recordings were performed in nonsedated lambs exposed to air (control), 10% O(2), and 5% CO(2) in a random order at 3, 4, and 5 days of age. Although hypercapnia decreased apnea frequency in wakefulness and active sleep (P = 0.002 vs. air and hypoxia), hypoxia had no significant effect on apnea. In addition, although hypercapnia increased NNS frequency during wakefulness and quiet sleep (P < 0.005 vs. air and hypoxia), hypoxia tended to decrease NNS frequency. Finally, only hypercapnia altered NNS-breathing coordination by increasing NNS at the transition from inspiration to expiration (ie-type NNS; P < 0.001 vs. air and hypoxia). In conclusion, whereas hypercapnia increases overall NNS frequency by specifically increasing ie-type NNS, hypoxia has the inverse tendency. Results were identical in all three states of alertness.     

Effects of hypoxia on vertebrate blood vessels

Hypoxia contracts mammalian respiratory vessels and increases vascular resistance in respiratory tissues of many vertebrates. In systemic vessels these responses vary, hypoxia relaxes mammalian vessels and contracts systemic arteries from cyclostomes. It has been proposed that hypoxic vasoconstriction in cyclostome systemic arteries is the antecedent to mammalian hypoxic pulmonary vasoconstriction, however, phylogenetic characterization of hypoxic responses is lacking. In this study, we characterized the hypoxic response of isolated systemic and respiratory vessels from a variety of vertebrates using standard myography. Pre-gill/respiratory (ventral aorta, afferent branchial artery, pulmonary artery) and post-gill/systemic (dorsal and thoracic aortas, efferent branchial artery) from lamprey (Petromyzon marinus), sandbar shark (Carcharhinus plumbeus), yellowfin tuna (Thunnus albacares), American bullfrog (Rana catesbeiana), American alligator (Alligator mississippiensis), Pekin duck (Anas platyrhynchos domesticus), chicken (Gallus domesticus) and rat (Rattus norvegicus) were exposed to hypoxia at rest or during pre-stimulation (elevated extracellular potassium, epinephrine or norepinephrine). Hypoxia produced a relaxation or transient contraction followed by relaxation in all pre-gill vessels, except for contraction in lamprey, and vasoconstriction or tri-phasic constriction-dilation-constriction in all pulmonary vessels. Hypoxia contracted systemic vessels from all animals except shark and rat and in pre-contracted rat aortas it produced a transient contraction followed by relaxation. These results show that while the classic "systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction" may occur in the microcirculation, the hypoxic response of the vertebrate macrocirculation is quite variable. These findings also suggest that hypoxic vasoconstriction is a phylogenetically ancient response.