Inspired O2 Tension Research Articles

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea

What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensinII and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea. Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensinII type1 receptor (AT1 R) blockade. Both AT1 R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25eventsh-1 and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O2 tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.

On the mechanisms that limit oxygen uptake during exercise in acute and chronic hypoxia: role of muscle mass

Peak aerobic power in humans (VO2,peak) is markedly affected by inspired O2 tension (FIO2). The question to be answered in this study is what factor plays a major role in the limitation of muscle peak VO2 in hypoxia: arterial O2 partial pressure (Pa,O2) or O2 content (Ca,O2)? Thus, cardiac output (dye dilution with Cardio-green), leg blood flow (thermodilution), intra-arterial blood pressure and femoral arterial-to-venous differences in blood gases were determined in nine lowlanders studied during incremental exercise using a large (two-legged cycle ergometer exercise: Bike) and a small (one-legged knee extension exercise: Knee)muscle mass in normoxia, acute hypoxia (AH) (FIO2 = 0.105) and after 9 weeks of residence at 5260 m (CH). Reducing the size of the active muscle mass blunted by 62% the effect of hypoxia on VO2,peak in AH and abolished completely the effect of hypoxia on VO2,peak after altitude acclimatization. Acclimatization improved Bike peak exercise Pa,O2 from 34 +/- 1 in AH to 45 +/- 1 mmHg in CH(P <0.05) and Knee Pa,O2 from 38 +/- 1 to 55 +/- 2 mmHg(P <0.05). Peak cardiac output and leg blood flow were reduced in hypoxia only during Bike. Acute hypoxia resulted in reduction of systemic O2 delivery (46 and 21%) and leg O2 delivery (47 and 26%) during Bike and Knee, respectively, almost matching the corresponding reduction in VO2,peak. Altitude acclimatization restored fully peak systemic and leg O(2) delivery in CH (2.69 +/- 0.27 and 1.28 +/- 0.11 l min(-1), respectively) to sea level values (2.65 +/- 0.15 and 1.16 +/- 0.11 l min(-1), respectively) during Knee, but not during Bike. During Knee in CH, leg oxygen delivery was similar to normoxia and, therefore, also VO2,peak in spite of a Pa,O2 of 55 mmHg. Reducing the size of the active mass improves pulmonary gas exchange during hypoxic exercise, attenuates the Bohr effect on oxygen uploading at the lungs and preserves sea level convective O2 transport to the active muscles. Thus, the altitude-acclimatized human has potentially a similar exercising capacity as at sea level when the exercise model allows for an adequate oxygen delivery (blood flow x Ca,O2), with only a minor role of Pa,O2 per se, when Pa,O2 is more than 55 mmHg.

Ventilatory acclimatization in awake guinea pigs raised at high altitude

To determine if laboratory strains of guinea pigs bred at sea level (SL) are "pre-adapted" to high altitude (HA), we raised litter-matched weanling Hartley guinea pigs for 4 months at SL, intermediate altitude (IA, 1250 m) or HA (3800 m) and exposed them acutely to 100, 21 and 12% inspired O2 at their respective altitude of residence. Control animals raised at SL were also exposed acutely to 10 and 8% inspired O2. In awake spontaneously breathing guinea pigs raised at SL, resting minute ventilation and tidal volume increased significantly when inspired O2 tension fell below about 60 mm Hg. In guinea pigs raised at IA or HA, ventilation was higher at any given inspired O2 tension in direct relationship to the altitude of residence. Resting hematocrit was also higher in animals raised at HA than at SL. We conclude that the pattern of ventilatory acclimatization to HA exposure in Hartley guinea pigs is similar to that in laboratory rats and human lowlanders; therefore laboratory guinea pigs are not pre-adapted and are suitable animals for the study of adaptation to high altitude.

Arousal and cardiorespiratory responses to hypoxia in Prader-Willi syndrome.

Ventilatory responses to peripheral chemoreceptor stimuli are absent in patients with Prader-Willi syndrome (PWS) during wakefulness. Because arousal from sleep after rapidly developing hypoxia may require intact peripheral chemoreceptor function, we hypothesized that blunted hypoxic arousal responses during sleep Stage 3/4 would be present in PWS. Thirteen patients with PWS (mean age, 23.4 +/- 3.7 +/- SEM yr; 46% male; body mass index [BMI], 28.9 +/- 1.6 kg/m2) and 11 matched control subjects (mean age 28.0 +/- 5.4 yr; 54% male; BMI, 28.8 +/- 3.1 kg/m2) were studied. An abrupt decrease in inspired O2 tension to 80 mm Hg was introduced until arousal occurred or for a maximum of 3 min. One of the 13 patients with PWS and seven of the 11 control subjects were aroused by the hypoxic challenge (p < 0.02). During hypoxia, heart rate increased by 9 +/- 2% in the PWS group versus 22 +/- 4% in the control group (p < 0.005). Respiratory rate did not change in the PWS group (4 +/- 2%; p = NS), but it increased by 13 +/- 2% in the control group (p < 0.02). We conclude that abnormal arousal and cardiorespiratory responses to hypoxia are frequent in PWS. We postulate that intact peripheral chemoreceptor function is an important component underlying arousal mechanisms to rapidly developing hypoxia during sleep.

Hypoxic bronchodilation.

Recent advances in computed tomographic imaging provide a unique method to serially and directly visualize acute physiological response in the lung. To directly investigate the airway response to hypoxia, high-resolution computed tomographic scans of the lungs of eight intact anesthetized minipigs were serially repeated before, during, and after ventilation with a hypoxic gas mixture (inspired fraction of O2 congruent to 0.07). This approach demonstrated an acute reversible 56 +/- 8% (SE) dilation in large airways (greater than 2 mm diam) and a 90 +/- 15% dilation in small airways (less than 1.99 mm diam) with decreased inspired O2 tension. Of the airways studied, 70 of 76 dilated. Hypoxic bronchodilation may interact with hypoxic pulmonary vasoconstriction in the fundamental physiological process of ventilation-perfusion matching in the lung.

Effects of glucose on hypoxic vasoconstriction in isolated ferret lungs

To characterize the effects of glucose on the pulmonary vascular response to anoxia and hypoxia, isolated ferret lungs were ventilated with 28% O2 and 5% CO2 and perfused at constant flow (100 ml.kg-1.min-1). Perfusate glucose concentrations were allowed to fall spontaneously to less than 1 mM (low glucose) or were controlled at 5-6 mM (normal glucose) or 12-17 mM (high glucose). At 60, 120, and 180 min of perfusion, the inspired O2 tension (PIO2) was reduced to 0, 10, or 30 Torr for 30 min, and vasomotor responses were quantified by continuous measurement of pulmonary arterial pressure. At PIO2 of 0 Torr, the response consisted of an early phase of transient intense vasoconstriction and a late phase of sustained slight vasoconstriction. High glucose markedly potentiated the magnitude of late-phase vasoconstriction with each successive anoxic exposure. This effect was not reproduced in normal glucose lungs and was not caused by a change in perfusate osmolarity, an action on blood cells, or an altered ability of pulmonary vascular smooth muscle to contract. At PIO2 of 10 Torr, high glucose not only potentiated late-phase vasoconstriction but also slowed the onset of early-phase vasoconstriction. At PIO2 of 30 Torr, high glucose had no effect on vasomotor responses, which were characterized by a slowly developing sustained vasoconstriction. Our results suggest that the vascular response of isolated ferret lungs to severe hypoxia consisted of separate early and late phases of vasoconstriction. This biphasic response may have resulted from two distinct vasoconstrictor mechanisms or from modulation of a single vasoconstrictor mechanism by a secondary vasodilator influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Does leukotriene C4 mediate hypoxic vasoconstriction in isolated ferret lungs?

To evaluate leukotriene (LT) C4 as a mediator of hypoxic pulmonary vasoconstriction, we examined the effects of FPL55712, a putative LT antagonist, and indomethacin, a cyclooxygenase inhibitor, on vasopressor responses to LTC4 and hypoxia (inspired O2 tension = 25 Torr) in isolated ferret lungs perfused with a constant flow (50 ml.kg-1.min-1). Pulmonary arterial injections of LTC4 caused dose-related increases in pulmonary arterial pressure during perfusion with physiological salt solution containing Ficoll (4 g/dl). FPL55712 caused concentration-related inhibition of the pressor response to LTC4 (0.6 micrograms). Although 10 micrograms/ml FPL55712 inhibited the LTC4 pressor response by 61%, it did not alter the response to hypoxia. At 100 microgram/ml, FPL55712 inhibited the responses to LTC4 and hypoxia by 73 and 71%, respectively, but also attenuated the vasoconstrictor responses to prostaglandin F2 alpha (78% at 8 micrograms), phenylephrine (68% at 100 micrograms), and KCl (51% at 40 mM). At 0.5 microgram/ml, indomethacin significantly attenuated the pressor response to arachidonic acid but did not alter responses to LTC4 or hypoxia. These results suggest that in isolated ferret lungs 1) the vasoconstrictor response to LTC4 did not depend on release of cyclooxygenase products and 2) LTC4 did not mediate hypoxic vasoconstriction.

1765 THE EFFECTS OF INDOMETHACIN ON THE HYPOXIC VASOPRESSOR RESPONSE IN ISOLATED LUNGS OF NEWBORN LAMBS

Previous studies suggest that pulmonary prostaglandin metabolism and action change during the newborn period. Indomethacin, a cyclo–oxygenase inhibitor, increases pulmonary artery pressure (Ppa) in perinatal animals. However, indomethacin has no effect on hypoxic and normoxic Ppa in the isolated perfused lungs of 2-3 month old lambs. This study examined the effects of indomethacin on the steady state pulmonary vascular response to graded hypoxia in isolated perfused lungs of 2-4 day old lambs. Lungs were randomly exposed to 3 levels of hypoxia and returned to an inspired O2 tension (PiO2) of 200 torr after each hypoxic stimulus. The mean Ppa +/- SE (torr) at flow = 50 ml/kg·min for control (C) and indomethacin (I) groups were:In both groups hypoxia (50 and 30) caused an increase in Ppa and vasodilation occurred at 0. Indomethacin enhanced the pressor response (P<.05). Moreover we noted that, in the C group after a first hypoxic exposure, subsequent hypoxic responses were blunted in comparison with the I group (p<.05). These results suggest that, in isolated lungs of 2-4 day old lambs, an initial hypoxic pressor response caused the release of a dilator prostaglandin which attenuated subsequent responses.

Adenosine and hypoxic pulmonary vasodilation.

We have previously shown that after exposure to an inspired O2 tension less than 25 Torr, isolated lungs perfused with autologous blood exhibit vasoconstriction followed by dilation. Because adenosine has been implicated as a mediator of hypoxic vasodilation in the systemic circulation and because the concentration of adenosine in the lung has been shown to increase with hypoxia, we tested the hypothesis that adenosine is the mediator of hypoxic pulmonary vasodilation. We first confirmed that adenosine was a vasodilator in isolated lungs of adult male ferrets. Next we added the enzyme adenosine deaminase (ADase), which inactivates adenosine by converting it to inosine, to the perfusate before exposure to one of two levels of hypoxia [inspiratory PO2 (PIO2) 18 or 0 Torr]. In comparison with untreated lungs, the time course of pulmonary arterial pressure at constant flow in lungs treated with ADase (24 mg protein or 6,000 U) was not different; however, when the vessels were constricted at PIO2 25 Torr, ADase prevented vasodilator responses to adenosine administered into either the perfusate or the airways, indicating penetration of active ADase into the interstitium. Unless adenosine released endogenously into the interstitium during hypoxia was somehow protected from the ADase which reached the interstitium, these results indicate that hypoxic pulmonary vasodilation was not mediated by adenosine.

Effect of puberty and estradiol on hypoxic vasomotor response in isolated sheep lungs.

We previously reported that in isolated lungs from 6-mo-old sheep acute hypoxia caused a greater vasoconstrictor response in males than in females but that this response in castrated males was not different from noncastrated males. To determine whether a gender difference exists before puberty, we compared the steady-state stimulus-response relationship of the pulmonary circulation to graded hypoxia in isolated perfused lungs of juvenile 2-mo-old male and female sheep. The flow-resistive properties of the pulmonary vessels were assessed by pressure-flow curves generated over a wide range of flows (0-150 ml X min-1 X kg-1) at six different levels of inspired O2 tension (PIO2) between 200 and 0 Torr. The stimulus-response relationship, quantified by plotting the pulmonary arterial pressure at a flow of 50 ml X min-1 X kg-1 against PIO2 was the same in juvenile male and female sheep lungs. Furthermore, the responses of juvenile sheep were not different from those of 6-mo-old males and were greater than those of 6-mo-old females. Treatment with 17 beta-estradiol (10-20 mg im) 2-5 days prior to perfusion significantly attenuated the response in the lungs from both 2-mo-old female and 6-mo-old castrated male sheep. We conclude that the gender difference in the hypoxic stimulus-response relationship observed in isolated lungs from 6-mo-old sheep arises from attenuation in the female at the time of puberty. This attenuation may be mediated by estradiol.

Hypoxia alters blood coagulation during acute decompression in humans.

Acute decompression is associated with a shortening of the activated partial thromboplastin time (aPTT). This study was performed to examine whether this change in aPTT results from hypoxia or hypobaria. We exposed healthy adults on three separate occasions to 2 h of 1) hypoxic hypobaria (410 Torr, n = 5), 2) hypoxic normobaria (fractional inspired O2 tension = 0.11, n = 4), or 3) normoxic hypobaria (410 Torr breathing supplemental O2, n = 5). The aPTT shortened during hypoxic hypobaria and hypoxic normobaria (P less than 0.05) but was unchanged during normoxic hypobaria. The prothrombin and thrombin times, hematocrit, and concentrations of fibrinogen, total plasma protein, and fibrinogen-fibrin fragment E were unchanged. During hypoxic hypobaria biologic levels of prekallikrein, high-molecular-weight kininogen, and factors XII, XI, X, VII, V, and II were unchanged, but procoagulant VIII (VIII:C) increased 50% without an increase in VIII-related antigen levels (VIIIR:Ag). Fibrin monomer was not detected in any group. In one subject who became ill after 1.5 h of hypoxic normobaria aPTT shortened by 10 s; the platelet count decreased by 93,000/mm3; VIII:C increased fivefold, but VIIIR:Ag only increased three-fold. We conclude that it is the hypoxia which shortens aPTT during acute decompression to 410 Torr and speculate that it results from an increase in plasma VIII:C-like activity.

Modification of Chemical Toxicity by Selenium Deficiency

Modification of Chemical Toxicity by Selenium Deficiency. Burk, R.F. and Lane, J.M. (1983). Fundam. Appl. Toxicol. 3: 218–221. Selenium deficiency causes a number of hepatic metabolic alterations in the rat which could lead to changes in chemical toxicity. It causes a decrease in glutathione peroxidase activity, an increase in glutathione S-transferase activity, and an increase in the rate of glutathione synthesis. The hepatotoxicities of three compounds which bind to glutathione S-transferase; iodipamide, acetaminophen, and aflatoxin B1, are decreased by selenium deficiency. The toxicity of redox cycling compounds is generally increased by selenium deficiency and is accompanied by evidence of lipid peroxidation. Thus, nitrofurantoin (100 mg/kg) causes renal tubular necrosis in selenium-deficient rats but not in controls. Selenium-deficient rats are much more sensitive to diquat toxicity than are controls. Lethality of diquat in selenium-deficient rats appears to be causally linked to lipid peroxidation. Lethality of diquat in control rats is not linked to lipid peroxidation. The effect of selenium does not appear to be mediated by glutathione peroxidase, however, indicating that selenium has another oxidant defense function. Another interesting observation made was that increases in inspired O2 tension decreased ethane production (lipid peroxidation) in selenium-deficient and in control rats given diquat. Thus, O2 appears to prevent diquat-induced lipid peroxidation.

Contribution of environmental factors in development of hyperbaric bradycardia.

Bradycardia has been observed in animals and humans upon exposure to various hyperbaric environments. However, the relative contribution of ambient pressure, gas density, inert gas species, and inspired O2 tension has not been defined. By means of cutaneous ECG leads, the heart rates of unanesthetized rats were recorded and compared in 11 separate thermo-neutral environments. Ambient pressures applied were 1, 3, and 10 ATA, O2 partial pressure PO2 ranged from 140 to 1,590 Torr, and gas densities were varied from 0.40 to 11.45 g/l, utilizing either N2-O2 or He-O2 mixtures. The exposure heart rates were averaged over a 30-min period and compared with a preceding control value obtained in 1 ATA normoxic He or N2. Significant bradycardia was associated with hyperoxia in environments containing either He or N2, with a magnitude proportional to log PO2. On the other hand, under normoxic conditions bradycardia was not observed despite the similar density, pressure, and inert gas components. It is concluded that hyperoxia is the most important variable of those considered in the development of hyperbaric bradycardia.

Recovery from hyperoxic depression of pulmonary 5-hydroxytryptamine clearance: effect of inspired O2 tension.

The present study evaluated the effect of inspired O2 tension\((PI_{O_2 } )\) on the extent and rapidity of recovery from hyperoxic depression of pulmonary 5-hydroxytryptamine (5-HT) clearance. Rats were exposed to either 100% O2 at 4 atm absolute (ATA) or 6% O2 at 4 ATA (controls) for 60 min and then transferred to chambers containing either compressed air at 3.5 ATA or compressed air, 30% O2 or 70% O2 at 1 ATA for recovery. 5-HT clearance by the isolated, perfused lung was measured after 1, 4 or 24 h recovery. Clearances by the lungs of nonexposed rats and control rats were indistinguishable. In contrast, 5-HT clearances by the lungs of rats exposed to 100% O2 at 4 ATA (hyperbaric O2; HBO) were markedly depressed 1 h after exposure (P < 0.001 vs. controls). In HBO-exposed rats breathing compressed air or 30% O2 at 1 ATA during the recovery period, depressed 5-HT clearances seen 1 h after exposure returned to control levels 4 h following exposure. In HBO-exposed rats breathing 70% O2 at 1 ATA or compressed air at 3.5 ATA during recovery, 5-HT clearance remained significantly depressed (P < 0.02) 24 h after exposure. These results (1) confirm that depression of pulmonary 5-HT clearance is a reversible alteration of lung function in the rat due to high partial pressures of inspired O2, (2) indicate that the extent and rate of reversibility is dependent upon postexposure\(PI_{O_2 } \), and (3) suggest that repair of hyperoxic lung damage may occur rapidly and completely while the animal is breathing an elevated, nontoxic O2 tension (i.e., 30% O2 at 1 ATA).

Assessment of Ventilatory Response to Hypoxia Methods and Interpretation

Study of the ventilatory response to hypoxia in man is contributing important information concerning the physiology of ventilatory control and providing new insights concerning the pathogenesis of respiratory failure. Assessment of ventilatory responses to hypoxia in man may be carried out using a variety of procedures. Most commonly, such responses are measured under conditions in which arterial carbon dioxide tension remains unchanged so that the response of ventilation to hypoxia may be examined independent of inhibiting effects which hyperventilation-induced hypoeapnia would have on such a response. Several techniques are used, but methods employed generally fit into one of four categories. Steady-state techniques involve measurement of ventilation during stepwise decrement of inspired O2 tension where each step is of several minutes' duration. 1 Cormack RS Cunningham DJC Gee JBL The effect of carbon dioxide on the respiratory response to want of oxygen in man.. Quart J Exp Physiol. 1957; 42: 303 Crossref PubMed Scopus (57) Google Scholar Second is the technique of progressive hypoxia. Because the ventilatory response to hypoxia has a relatively short time constant of approximately 18 seconds, the ventilatory response can be described as a continuous function while the oxygen tension of the gas being breathed is gradually lowered. 2 Weil JV Byrne-Quinn E Sodal IE et al. Hypoxic ventilatory drive in normal man.. J Clin Invest. 1970; 49: 1061 Crossref PubMed Scopus (296) Google Scholar This technique yields data comparable to steady-state method. 3 Kronenberg R Hamilton FN Gabel R et al. Comparison of three methods for quantitating respiratory response to hypoxia in man.. Respiration Physiol. 1972; 16: 109 Crossref PubMed Scopus (72) Google Scholar There is concern that these first two methods entail relatively persistent hypoxia which may in time result in depression of ventilation. Hence, a number of investigators have used a third technique—rapid tests involving hypoxic periods lasting no more than a few breaths. The increase in tidal volume of subsequent breaths is used to gauge the response. 4 Dejours P Labrousse Y Raynaud J et al. Etude du stimulus gaz carbonique de la ventilation chez l'homme.. J Physiol. 1958; 50: 239 Google Scholar These latter tests in general suffer from the disadvantage that the stimulus is so rapidly changing and so transient that its precise magnitude cannot be accurately assessed. In addition, the response is also fleeting and it is not certain that the response has become fully developed. Although some investigators have shown reasonably good agreement between transient and steady-state results, 5 Edelman NH Epstein PE Lahiri S et al. Ventilatory responses to transient hypoxia and hypercapnia in man.. Respir Physiol. 1973; 17: 302 Crossref PubMed Scopus (115) Google Scholar transient tests are generally considered less quantitatively rigorous. A fourth method for measuring hypoxic responses depends upon the fact that hypoxia augments the ventilatory response to hypercapnia. The ventilatory response to carbon dioxide is measured at high and low oxygen tensions 6 Nielsen M Smith H Studies on the regulation of respiration in acute hypoxia.. Acta Physiol Scand. 1951; 24: 293 Crossref Scopus (168) Google Scholar , 7 Lloyd BB Jukes MGM Cunningham DJC The relation between alveolar oxygen pressure and the respiratory response to carbon dioxide in man.. Quart J Exp Physiol. 1958; 43: 214 Crossref PubMed Scopus (134) Google Scholar and the change in slope of the hypercapnic response is used as a measure of the hypoxic drive.

Survival of mice in absence of inert gas.

Summary1) Mice were maintained for 51 days in an atmosphere of oxygen at total pressure of 197 mm Hg. This provides a normal inspired O2 tension. CO2 and N2 pressures in the ambient atmosphere did not exceed 5 mm Hg for either gas. 2) Under these conditions animals usually did not encounter any difficulties. Several litters were born and in one case young were conceived, born and raised in virtual absence of inert gas. However, in several cases animals died within 48 hours after being subjected to this environment. Once past this period Only mechanical failure of the apparatus terminated these experiments. It is suggested that pulmonary atelectasis was responsible for these early deaths.

Attempt to demonstrate the distribution component of the alveolar-arterial oxygen pressure difference

Under normal conditions, the alveolar-arterial oxygen pressure difference (A-a difference) is believed to be due primarily to two causes, venous admixture (shunt component) and variation in ventilation-perfusion ratios (distribution component). In order to assess quantitatively the role played by the latter factor, the difference in O2 tension between end-tidal air and arterial blood was measured in anesthetized dogs under two conditions: a) at normal ambient pressure (Pb = 747 mm Hg), breathing air; b) at low ambient pressure (Pb = 192 mm Hg), breathing 100% O2. The essential feature of this procedure is that, while the inspired O2 tension is identical in both conditions, there is no nitrogen in the gas inspired at low ambient pressure. Theoretical analysis indicates that, if all or part of the A-a difference measured under condition a is due to a variation in ventilation-perfusion ratios, then this difference must be significantly reduced under condition b. Such a decrease in the A-a difference should provide an index of the magnitude of the distribution component. However, in our experiment, the A-a difference was found to be the same in both conditions. Therefore, our results do not support the hypothesis that there exists a large distribution component of alveolar-arterial difference. Submitted on October 21, 1959