Inhibitory effects of repeated hyperoxia on breathing in newborn mice.

Brief oxygen therapy is commonly used for resuscitation at birth or prevention of hypoxaemia before procedures during the neonatal period. However, O(2) may severely depress breathing, especially when administered repeatedly. The aim of the present study was to test the effects of repeated hyperoxia on breathing control in newborn mice. A total of 97 Swiss mouse pups were assigned to O(2) or air on post-natal day 0, 1 or 2. Each pup in the O(2) group was subjected to four hyperoxic tests (100% O(2) for 3 min followed by 12 min normoxia), whereas pups in the air group were maintained in normoxia. Breathing variables were measured using flow-through barometric plethysmography. O(2) significantly decreased minute ventilation as seen in a decrease in respiratory rate. This decrease became significantly larger with repeated exposure and ranged -17- -26% for all ages combined. Furthermore, hyperoxia increased total apnoea duration, as compared with the baseline value. In newborn mice, repeated hyperoxia increasingly depressed breathing. This finding further supports a need for stringent control of oxygen therapy, most notably repeated oxygen administration in the neonatal period for premature newborn infants and those carried to term.     

Effects of hyperoxia on ventilatory and metabolic rates of newborn mice

Newborn mammals of medium or large sized species have ventilatory rates, expressed per kg body weight, larger than adults of corresponding size, while newborns of the smallest species do not. We hypothesized that the oxygen consumption of the smallest newborns is limited by the supply of oxygen and reasoned that if this were the case, an increase in Po2 of the inspired air should decrease their ventilation/oxygen consumption (VE/Vo2) ratio. We exposed 1-2 days old newborn mice for 5 min to 21% O2 in N2 or 100% O2, then measured their breathing pattern, by flow plethysmography, and Vo2 with an isovolume closed system. During hyperoxia the VE/Vo2 ratio dropped in average 36%, since VE decreased in 14 out of 18 animals and Vo2 increased in all the animals tested. The drop in VE was due to a prolongation of the expiratory time, with no changes in inspiratory time or tidal volume. During expiration, interruptions of the expiratory flow and tendency to maintain the lung inflated, a characteristic of neonatal respiration, were more pronounced with 100% O2 than 21% O2 breathing. We conclude that the resting metabolic rate of newborn mice is limited by the supply of oxygen; when Po2 is raised, metabolism increases and ventilatory rate decreases in favor of a breathing pattern aimed to preserve lung volume elevated.     

Retinal blood flow during hyperoxia in humans revisited: concerted results using different measurement techniques

Retinal vasculature shows pronounced vasoconstriction in response to hyperoxia, which appears to be related to the constant oxygen demand of the retina. However, the exact amount of blood flow reduction and the exact time course of this phenomenon are still a matter of debate. We set out to investigate the retinal response to hyperoxia using innovative techniques for the assessment of retinal hemodynamics. In a total of 48 healthy volunteers we studied the effect of 100% O(2) breathing on retinal blood flow using two methods. Red blood cell movement in larger retinal veins was quantified with combined laser Doppler velocimetry and retinal vessel size measurement. Retinal white blood cell movement was quantified with the blue field entoptic technique. The time course of retinal vasoconstriction in response to hyperoxia was assessed by continuous vessel size determination using the Zeiss retinal vessel analyzer. The response to hyperoxia as measured with combined laser Doppler velocimetry and vessel size measurement was almost twice as high as that observed with the blue field technique. Vasoconstriction in response to 100% O(2) breathing occurred within the first 5 min and no counterregulatory or adaptive mechanisms were observed. Based on these results we hypothesize that hyperoxia-induced vasoconstriction differentially affects red and white blood cell movement in the human retina. This hypothesis is based on the complex interactions between red and white blood cells in microcirculation, which have been described in detail for other vascular beds.     

Lung vascular cell proliferation in hyperoxic pulmonary hypertension and on return to air: [3H]thymidine pulse-labeling of intimal, medial, and adventitial cells in microvessels and at the hilum

The labeling index (LI) of lung vascular intimal (endothelial and precursor smooth muscle, medial (smooth muscle), and adventitial cells (fibroblasts) was in the normal rat and in the rat with pulmonary hypertension caused by breathing high oxygen (87% O2 at normobaric pressure). Cell labeling was assessed during hyperoxia (Days 1, 4, 7, 10, and 28), at the start and end of weaning hyperoxia-adapted rats to air (Days 29 and 35), and 1, 2, and 4 wk after return to breathing air after hyperoxia and weaning (Days 42, 49, and 63). Bursts of intimal, medial, and adventitial cell proliferation different in their timing and extent contribute to lung vascular wall remodelling in these injuries. The Ll of the microvascular fibroblast increased most on Day 4 of hyperoxia (20-fold); it persisted above the normal rate throughout hyperoxia and was high at the start of weaning (greater than 1- less than 2-fold). Two weeks after return to breathing air, it again increased (less than 1-fold). The Ll of the microvascular endothelial cell increased most on Day 7 of hyperoxia (10-fold); it also persisted above the normal rate throughout hyperoxia and at the start of weaning (greater than 2- less than 3-fold) and increased again 2 wk after return to breathing air (6-fold). Labeled precursor cells were not present in the normal lung: they were present on Days 4 and 7 of hyperoxia but not at any other time, including weaning and return to breathing air.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperoxic ventilatory responses of high altitude acclimatized cats

We have examined the effect of steady-state hyperoxia on the ventilation of sea level (SL) cats and cats acclimatized to simulated high altitude (HA) at 5500 m for three weeks. Three groups of cats were studied. In group I, the ventilatory responses to 10%, 21% and 100% O2 were studied at SL, and after acclimatization to HA, the ventilatory responses to 10% and 100% O2 were measured. In group II the ventilatory responses and femoral artery and superior sagittal sinus blood gases were measured in two sets of cats, one at SL and one at HA, during exposure to the gases outlined in group I. In group III, we examined the effect of chronic vagotomy on the ventilatory responses to the gas mixtures outlined in group I. Breathing 100% O2 at SL had no significant effect on ventilation, tidal volume, respiratory frequency, or cerebral blood flow (inferred from the cerebral veno-arterial CO2 difference). Ventilation was constant in the HA acclimatized cats while breathing 10% and 100% O2, but the ventilatory pattern changed dramatically during hyperoxia: respiratory frequency increased and tidal volume fell. Breathing 100% O2 was associated with changes in CBF, and venous PCO2 that might be expected to stimulate ventilation, but the change in ventilatory pattern suggests to us that hyperoxic disinhibition of central respiratory processes (which were modified by HA acclimatization) is the mechanism whereby ventilation is sustained during hyperoxia at HA. After vagotomy at HA, ventilation remained constant while breathing 100% O2, but the changes in respiratory pattern were no longer apparent. Therefore, vagal afferents seems to have a role in determining the pattern, but not necessarily the absolute level, of ventilation during hyperoxia. Cats vagotomized at SL prior to HA exposure did not show any evidence of HA ventilatory acclimatization; thus, the vagi may also play a heretofore unrecognized role in the process of acclimatization.     

Concentration-dependent vasoconstrictive effect of hyperoxia on hypercarbia-dilated retinal arterioles

BACKGROUND/AIMS: The relative effects of simultaneously administered oxygen and carbon dioxide on vascular resistance are unknown. The purpose of the study was to investigate the independent effect of oxygen partial pressure on hypercarbia-induced vasodilation in the retinal arterioles. METHODS: Twelve young healthy volunteers participated in the study. End-tidal partial pressure of carbon dioxide was raised 23% from the baseline (i.e. air) at normoxia and then maintained constant while end-tidal partial pressure of oxygen (PETO(2)) was raised in a stepwise incremental fashion. Retinal vessel diameter and blood velocity were measured in the superior-temporal arteriole using the Canon Laser Blood Flowmeter. RESULTS: Hypercarbia resulted in a 16% increase in blood velocity and a 22% increase in blood flow (p<0.05). At maximal hyperoxia (group mean PETO(2) of 556 mm Hg) vessel diameter, blood velocity and flow were reduced by 9%, 22% and 36%, respectively, relative to baseline (p<0.001). CONCLUSION: The concentration-dependent vasoconstrictive effect of oxygen in retinal arterioles was quantified for the first time by implementing precise control of end-tidal concentrations of CO(2) and O(2). Oxygen-induced vasoconstriction is sufficiently potent to offset and reverse hypercarbia-induced vasodilation.     

Cutaneous and gill O2 uptake in the European eel (Anguilla anguilla L.) in relation to ambient PO2, 10-400 Torr

The partition of O2 uptake between gills and skin was examined in the freshwater eel (Anguilla anguilla L.) at ambient PO2 ranging from hyperoxia (PO2 = 400 Torr) to severe hypoxia (PO2 = 10 Torr), using a technique of open-flow respirometry. All the expired water was collected, and the ventilatory flow and the mixed expired water PO2 were directly measured. The ventilatory water flow decreased moderately in hyperoxia, increased markedly between normoxia and 40 Torr, and below 40 Torr, hyperventilation was gradually reduced. Between PO2 400 and 70 Torr, the total O2 uptake was constant and the skin O2 uptake was lower than gill O2 uptake (32% of total uptake in normoxia). Between 70 and 10 Torr, the skin contribution to the total O2 uptake progressively increased, and was higher than gill O2 uptake in severe hypoxia. A possible facilitation of cutaneous O2 uptake in hypoxia is discussed from estimates of the O2 diffusing capacity of the skin.     

Hyperoxic and hyperbaric-induced cardioprotection: role of nitric oxide synthase 3

OBJECTIVE: The relative contributions of the fraction of inspired oxygen (FIO2) and atmospheric pressure (ATM) to cardioprotection are unknown. We determined whether the product of FIO2 x ATM (oxygen partial pressure) controls the extent of hyperoxic+hyperbaric-induced cardioprotection and involves activation of nitric oxide synthase (NOS). METHODS: Adult Sprague Dawley rats (n = 10/gp) were treated for 1 h with (1) normoxia+normobaria (21% O2 at 1 ATM), (2) hyperoxia+normobaria (100% O2 at 1 ATM), (3) normoxia+hyperbaria (21% O2 at 2 ATM) and (4) hyperoxia+hyperbaria (100% O2 at 2 ATM). RESULTS: Infarct size following 25 min ischemia and 180 min reperfusion was decreased following hyperoxia+normobaria and normoxia+hyperbaria compared with normoxia+normobaria and further decreased following hyperoxia+hyperbaria treatment. l-NAME (200 microM) reversed the cardioprotective effects of hyperoxia+hyperbaria. Nitrite plus nitrate content was increased 2.2-fold in rats treated with normoxia+hyperbaria and hyperoxia+hyperbaria. NOS3 protein increased 1.2-fold and association of hsp90 with NOS3 four-fold in hyperoxic+hyperbaric rats. CONCLUSIONS: Cardioprotection conferred by hyperoxia+hyperbaria is directly dependent on oxygen availability and mediated by NOS.     

Transcutaneous measurement of the partial pressure of the oxygen. Theoretical bases and hemodynamic significance

Transcutaneous measurement using a modified Clark type electrode actually measures the amount of oxygen diffusing through the skin, i.e. the transcutaneous oxygen flow (tc O2). The latter depends on arterial partial oxygen pressure, local blood flow, diffusion of oxygen in tissues and local oxygen consumption. In this study, tc O2, cutaneous blood flow (133-xenon) and pedal systolic blood pressure were measured simultaneously on the foot. In normal subjects, there was a good correlation between tc O2, perfusion pressure (r = 0.89) and local blood flow (r = 0.77). Tc O2 passively depends on perfusion pressure, because local heating induced an inhibition of vasomotricity. In patients with severe ischemia (stages 3 and 4), there was a lack of correlation between local blood flow measured by 133-xenon clearance and tc O2. This may be explained by variations of partition coefficient from patient to patient, which introduce a bias in blood flow calculation. Furthermore, tc O2 may constitute an index of nutritional blood flow, while 133-xenon clearance measures total blood flow.     

Pulmonary vascular responses to hypoxia and hyperoxia in healthy volunteers and COPD patients measured by electrical impedance tomography

BACKGROUND: Electrical impedance tomography (EIT) is a noninvasive imaging technique using impedance to visualize and measure blood volume changes. STUDY OBJECTIVE: To examine the validity of EIT in the measurement of hypoxic pulmonary vasoconstriction (HPV) and hyperoxic pulmonary vasodilation in healthy volunteers and COPD patients. PARTICIPANTS: Group 1 consisted of seven healthy volunteers (mean age, 46 years; age range, 36 to 53 years). Group 2 comprised six clinically stable COPD patients (mean age, 65 years; age range, 50 to 74 years). INTERVENTIONS: EIT measurements were performed in healthy subjects while they were breathing room air, 14% oxygen (ie, hypoxia), and 100% oxygen (ie, hyperoxia) through a mouthpiece. Maximal impedance change during systole (DeltaZsys) was used as a measure of pulmonary perfusion-related impedance changes. Stroke volume (SV) was measured by means of MRI. In the COPD group, EIT and SV also were determined, but only in room air and under hyperoxic conditions. RESULTS: The data were statistically compared to data for the room air baseline condition. In the volunteers, the mean (+/- SD) DeltaZsys for the group was 352 +/- 53 arbitrary units (AU) while breathing room air, 309 +/- 75 AU in hypoxia (p < 0.05), and 341 +/- 69 AU in hyperoxia (not significant [NS]). The mean MRI-measured SV was 83 +/- 21 mL while breathing room air, 90 +/- 29) mL in hypoxia (NS), and 94 +/- 19 mL in hyperoxia (p < 0.05). In the COPD patients, the mean DeltaZsys for this group was 222 +/- 84 AU while breathing room air and 255 +/- 83 AU in hyperoxia (p < 0.05). In this group, the SV was 59 +/- 16 mL while breathing room air and 61 +/- 13 mL in hyperoxia (NS). Thus, the volunteer EIT response to hypoxia is not caused by decreased SV, because SV did not show a significant decrease. Similarly, in COPD patients the EIT response to hyperoxia is not caused by increased SV, because SV showed only a minor change. CONCLUSION: EIT can detect blood volume changes due to HPV noninvasively in healthy subjects and hyperoxic vasodilation in COPD patients.     

Ventilatory and metabolic responses to acute hyperoxia in newborns.

Hyperoxia has previously been found to increase metabolic rate (oxygen consumption [VO2] and CO2 production [VCO2]) in newborn mammals. We asked whether the same occurs in the newborn infant. Breathing pattern was measured in 25 full-term infants, 1 to 2 days of age, from the spirometric record obtained with a pneumotachograph attached to a face mask. Concentrations of O2 and CO2 were continuously measured at the mouth; VO2 and VCO2 were computed as the product of VE and the difference between inspired and expired concentration of the respective gases, 5 min of air (FIO2 = 0.21) and 5 min of O2 (FIO2 = 1). A bias flow through the mask and pneumotachograph delivered the inspired gas and eliminated the effects of the instrumental dead space. In neither case did measurements at 1 min significantly differ from those taken at 5 min. In hyperoxia VE increased in 22 of the 25 infants, in average +18% (p less than 0.001, paired two-tailed t test). Because of a rise in tidal volume (+35%, p less than 0.001) and a decrease in breathing rate (-11%, p less than 0.005) alveolar ventilation (VA) increased by about 58% (p less than 0.001). VO2 and VCO2 increased by 25% and 17%, respectively (p less than 0.001). The rise in VO2 was too large to be explained by the greater respiratory work of the hyperventilation, whereas that of VCO2 was not large enough to fully explain the increase in VA. We conclude that in newborn humans, as in other newborn species, the normoxic metabolic rate seems to be limited by the availability of O2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxygen regulation of tumor perfusion by S-nitrosohemoglobin reveals a pressor activity of nitric oxide

In erythrocytes, S-nitrosohemoglobin (SNO-Hb) arises from S-nitrosylation of oxygenated hemoglobin (Hb). It has been shown that SNO-Hb behaves as a nitric oxide (NO) donor at low oxygen tensions. This property, in combination with oxygen transport capacity, suggests that SNO-Hb may have unique potential to reoxygenate hypoxic tissues. The present study was designed to test the idea that the allosteric properties of SNO-Hb could be manipulated to enhance oxygen delivery in a hypoxic tumor. Using Laser Doppler flowmetry, we showed that SNO-Hb infusion to animals breathing 21% O2 reduced tumor perfusion without affecting blood pressure and heart rate. Raising the pO2 (100% O2) slowed the release of NO bioactivity from SNO-Hb (ie, prolonged the plasma half-life of the SNO in Hb), preserved tumor perfusion, and raised the blood pressure. In contrast, native Hb reduced both tumor perfusion and heart rate independently of the oxygen concentration of the inhaled gas, and did not elicit hypertensive effects. Window chamber (to image tumor arteriolar reactivity in vivo) and hemodynamic measurements indicated that the preservation of tissue perfusion by micromolar concentrations of SNO-Hb is a composite effect created by reduced peripheral vascular resistance and direct inhibition of the baroreceptor reflex, leading to increased blood pressure. Overall, these results indicate that the properties of SNO-Hb are attributable to allosteric control of NO release by oxygen in central as well as peripheral issues.     

Effects of high arterial oxygen tension on function, blood flow distribution, and metabolism in ischemic myocardium.

BACKGROUND. Although oxygen inhalation therapy has long been used in the treatment of acute myocardial ischemia, experimental evidence that increased arterial PO2 has any beneficial effect in the absence of hypoxemia is equivocal. In this study, we used a swine model of subendocardial myocardial ischemia to determine the effects of arterial hyperoxia on regional myocardial contractile function (sonomicrometry), myocardial blood flow distribution (microspheres), and regional myocardial glycolytic metabolism (carbon isotope-labeled substrates). METHODS AND RESULTS. In 10 domestic swine, the left anterior descending coronary artery was cannulated and flow to this artery was strictly controlled via a roller pump in the perfusion circuit. Arterial PO2 was controlled by manipulating inspired oxygen concentration (FIO2). Low-flow myocardial ischemia was induced by reducing pump flow to 50% of the control value, which diminished regional endocardial systolic shortening to 30-50% of normal. After a 15-minute period of flow stability, each animal was exposed in randomized order to two additional 15-minute experimental periods: coronary normoxia (PO2 = 90-110 mm Hg) and coronary hyperoxia (PO2 greater than 400 mm Hg). At each level of oxygenation, we measured regional myocardial function, regional myocardial blood flow and metabolism, and hemodynamic indexes of myocardial oxygen demand. Myocardial ischemia during normoxia reduced systolic shortening to 10.9 +/- 5.3% in the ischemic zone. Hyperoxia increased ischemic zone systolic shortening substantially to 15.2 +/- 4.6%. During myocardial ischemia, endocardial blood flow was decreased to 0.26 +/- 0.06 ml.g-1.min-1 in the ischemic zone. During hyperoxia, endocardial blood flow rose to 0.34 +/- 0.10 ml.g-1.m-1. The endocardial: epicardial flow ratio was 0.45 +/- 0.18 in the initial ischemia period and rose to 0.61 +/- 0.23 in the hyperoxic period. Myocardial ischemia increased regional uptake of glucose, conversion of glucose to released lactate, and net myocardial lactate release. In the ischemic myocardium, coronary hyperoxia decreased both chemically measured lactate production and isotopically measured lactate release and decreased glucose extraction and the conversion of glucose to lactate. CONCLUSIONS. These data demonstrate for the first time that increasing arterial PO2 to high levels during acute low-flow myocardial ischemia improves both function and flow distribution in the ischemic myocardium and decreases glycolytic metabolism in the ischemic zone. The degree of improvement in contractile function (5% absolute increase in systolic shortening or 25% change normalized to preischemic values) is consistent with the observed increase in subendocardial blood flow.     

Cardiovascular effects of breathing 95 percent oxygen in children with congenital heart disease

The hemodynamic effects of breathing 95% oxygen were evaluated in 26 children with congenital heart disease. Aortic, pulmonary arterial, right atrial, and pulmonary arterial wedge pressure, aortic and pulmonary artery oxygen saturation, and blood gas, cardiac index, and heart rate were measured in room air and after each patient had breathed 95 % oxygen for 10 (n = 26) and 20 (n = 5) minutes. Measurements were repeated with the patient again breathing room air for 10 (n = 11) and 20 (n = 6) minutes. After 10 minutes of 95% oxygen, arterial partial pressure of oxygen increased from 85 ± 13 to 420 ± 89 torr (p < 0.001). Aortic mean pressure increased from 80 ± 10 to 83 ± 10 mm Hg (p < 0.01), and systemic vascular resistance increased from 20 ± 7 to 26 ± 8 U (p < 0.001). The cardiac index decreased by 21 % from 3.96 ± 0.94 to 3.12 ± 0.74 liters/min/m² (p < 0.001) and the stroke index decreased by 11% (p < 0.001). A 23% decrease in oxygen consumption (p < 0.001) was observed, and oxygen transport decreased from 763 ± 179 to 600 ± 161 ml O₂/min/m² (p < 0.001). Cardiac index, stroke index, and systemic vascular resistance did not return to normal until 20 minutes after cessation of oxygen breathing. To determine whether reflex bradycardia is responsible for these oxygen-induced hemodynamic changes, heart rate was kept constant by atrial pacing in a second group of 5 patients. In these children, significant decreases in cardiac index, stroke index, and oxygen consumption, and increases in systemic vascular resistance also occurred with 95% oxygen. Thus, in children with acyanotic congenital heart disease, hyperoxia increases aortic pressure and systemic vascular resistance and decreases cardiac index, stroke index, oxygen consumption, and oxygen transport.     

Pulmonary oxygen toxicity: increased microvascular permeability to protein in unanesthetized lambs

To study transvascular filtration of fluid and microvascular permeability to protein in the lung during prolonged hyperoxia, we measured lung lymph flow, protein transport, and simultaneous pulmonary vascular pressures of six lambs breathing 100 percent O2 for five days. Lymph flow doubled, protein flow increased by 131 percent, and radioactive tracer studies demonstrated a clearcut increase in pulmonary microvascular permeability to protein after five days of continuous O2 breathing.     

Helium-hyperoxia, exercise, and respiratory mechanics in chronic obstructive pulmonary disease

RATIONALE: Hyperoxia and normoxic helium independently reduce dynamic hyperinflation and improve the exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). Combining these gases could have an additive effect on dynamic hyperinflation and a greater impact on respiratory mechanics and exercise tolerance. OBJECTIVE: To investigate whether helium-hyperoxia improves the exercise tolerance and respiratory mechanics of patients with COPD. METHODS: Ten males with COPD (FEV(1) = 47 +/- 17%pred [mean +/- SD]) performed randomized constant-load cycling at 60% of maximal work rate breathing air, hyperoxia (40% O(2), 60% N(2)), normoxic helium (21% O(2), 79% He), or helium-hyperoxia (40% O(2), 60% He). MEASUREMENTS: Exercise time, inspiratory capacity (IC), work of breathing, and exertional symptoms were measured with each gas. RESULTS: Compared with air (9.4 +/- 5.2 min), exercise time was increased with hyperoxia (17.8 +/- 5.8 min) and normoxic helium (16.7 +/- 9.1 min) but the improvement with helium-hyperoxia (26.3 +/- 10.6 min) was greater than both these gases (p = 0.019 and p = 0.007, respectively). At an isotime during exercise, all three gases reduced dyspnea and both helium mixtures increased IC and tidal volume. Only helium-hyperoxia significantly reduced the resistive work of breathing (15.8 +/- 4.2 vs. 10.1 +/- 4.1 L . cm H(2)O(-1)) and the work to overcome intrinsic positive end-expiratory pressure (7.7 +/- 1.9 vs. 3.6 +/- 2.1 L . cm H(2)O(-1)). At symptom limitation, tidal volume remained augmented with both helium mixtures, but IC and the work of breathing were unchanged compared with air. CONCLUSION: Combining helium and hyperoxia delays dynamic hyperinflation and improves respiratory mechanics, which translates into added improvements in exercise tolerance for patients with COPD.     

Almitrine in low dose potentiates vasoconstrictor responses of isolated rat lungs to moderate hypoxia

To test whether the effect of almitrine on hypoxic pulmonary vasoconstriction was dose-dependent, two series of experiments were performed on isolated rat lungs perfused with constant flow of blood. In the first series, the effects of different doses of almitrine on perfusion pressure were measured. Baseline perfusion pressure was not changed by solvent or by 0.25 micrograms.ml-1 almitrine, but it was increased by 0.5 and 2.0 micrograms.ml-1 almitrine. The increase in perfusion pressure in response to 10 min ventilation with hypoxic gas mixture (5% O2) was significantly (p less than 0.05) higher after 0.25 micrograms.ml-1 almitrine (12.0 +/- 0.8 torr) than before addition of the drug (5.43 +/- 1.8 torr). Responses to hypoxia were insignificant after higher doses (0.5 and 2.0 micrograms.ml-1) of almitrine. In the second series of experiments the responses to varying degrees of hypoxia were measured after administration of one dose of almitrine (0.25 micrograms.ml-1). Almitrine, compared to solvent alone, significantly altered the shape of the dose-response curve to hypoxia. Increases in perfusion pressure in response to moderate degrees of hypoxia were potentiated (10% O2: 8.7 +/- 1.8 torr after almitrine, 2.1 +/- 0.6 torr after solvent, p less than 0.05), whereas responses to severe hypoxia (3% O2) were not changed by almitrine. Reactivity to angiotensin II was decreased by 0.25 micrograms.ml-1 almitrine. We conclude that almitrine in low but not in high dose augments pulmonary vasoconstriction induced by mild degrees of hypoxia.     

Regional alveolar gas composition and lung function in sheep.

The influence of regional alveolar oxygen and carbon dioxide tensions on the distribution of lung blood flow and gas exchange was studied in unanaesthetised sheep. Right apical lobe (RAL) hypoxia, induced by administering nitrogen or nitrogen/oxygen mixtures to the lobe, stimulated a prompt, graded and well sustained reduction in lobar blood flow. Maximum hypoxia was accompanied by an approximate 65% reduction in perfusion, a significant fall in RAL carbon dioxide tension and output, a reversal of lobar oxygen flux and an average 13 Torr fall in arterial oxygen tension. The reduction in perfusion and gas exchange persisted in the face of elevated systemic oxygen tensions produced by giving pure oxygen instead of air to the remainder of the lung (RL). Mild RAL hypercapnia potentiated the hypoxia-induced change in perfusion and gas exchange. During lobar hypoxia RL blood flow and gas exchange increased to maintain total pulmonary gas exchange at an essentially constant level. RAL hyperoxia did not significantly alter the distribution of perfusion or gas exchange.     

Preservation of hypoxic pulmonary pressor response in canine pneumococcal pneumonia.

To determine the role of hypoxic pulmonary vasoconstriction in pneumococcal pneumonia, hemodynamic measurements were made in 16 dogs before, and within 36 hours after, intrapulmonary administration of type III pneumococcus. Ten dogs with one lobe or more of pneumonia increased their pulmonary vascular resistances and slightly decreased their arterial O2 tensions. Hypoxia increased and hyperoxia decreased their pulmonary vascular resistances. During O2 breathing, arterial PO2 was less during than before the pneumonia and increased when pulmonary perfusion was diverted away from the diseased lung. In 2 dogs breathing air, forcing the cardiac output through the diseased lung caused an increase in vascular resistance that could clearly be reduced by O2 breathing. In 5 dogs, lung mast cell counts showed no decrease in the lobes with pneumonia. In pneumococcal pneumonia, the hypoxic pulmonary pressor mechanism serves to decrease blood flow to the diseased lobes and, thus, to maintain the arterial PO2. Lung mast cells could participate in this response.     

Angiotensin II type 2 receptors and nitric oxide sustain oxygenation in the clipped kidney of early Goldblatt hypertensive rats

Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O(2)) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (Po(2)) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (N(G)-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical Po(2) of clipped kidneys was significantly lower than contralateral kidneys (35+/-1 versus 51+/-1 mm Hg; n=40 each). ACEI lowered renal venous Po(2), cortical Po(2), renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and N(G)-nitro-L-arginine methyl ester, but not candesartan, reduced the Po(2) of clipped kidneys and blocked the fall in Po(2) with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.