Systemic Arterial Oxygen Tension Research Articles

A method for volumetric retinal tissue oxygen tension imaging

ABSTRACTPurpose: Inadequate retinal oxygenation occurs in many vision-threatening retinal diseases, including diabetic retinopathy, retinal vascular occlusions, and age-related macular degeneration. Therefore, techniques that assess retinal oxygenation are necessary to understand retinal physiology in health and disease. The purpose of the current study is to report a method for the three-dimensional (3D) imaging of retinal tissue oxygen tension (tPO2) in rats.Methods: Imaging was performed in Long Evans pigmented rats under systemic normoxia (N = 6) or hypoxia (N = 3). A vertical laser line was horizontally scanned on the retina and a series of optical section phase-delayed phosphorescence images were acquired. From these images, phosphorescence volumes at each phase delay were constructed and a 3D retinal tPO2 volume was generated. Retinal tPO2 volumes were quantitatively analyzed by generating retinal depth profiles of mean tPO2 (MtPO2) and the spatial variation of tPO2 (SVtPO2). The effects of systemic condition (normoxia/hypoxia) and retinal depth on MtPO2 and SVtPO2 were determined by mixed linear model.Results: Each 3D retinal tPO2 volume was approximately 500 × 750 × 200 μm (horizontal × vertical × depth) and consisted of 45 en face tPO2 images through the retinal depth. MtPO2 at the chorioretinal interface was significantly correlated with systemic arterial oxygen tension (P = 0.007; N = 9). There were significant effects of both systemic condition and retinal depth on MtPO2 and SVtPO2, such that both were lower under hypoxia than normoxia and higher in the outer retina than inner retina (P < 0.001).Conclusion: For the first time, 3D imaging of retinal tPO2 was demonstrated, with potential future application for assessment of physiological alterations in animal models of retinal diseases.

Femoral growth plate is sensitive to loss of cardiac shunt in the American alligator

Longitudinal growth rate (LGR) has been shown to correlate with calcified cartilage column height (CCC) in the growth plates of birds. In order to infer limb bone growth patterns in non‐avian dinosaurs, this correlation needs to be documented in crocodilians. We tested the LGR‐CCC correlation in femora of juvenile alligators raised for two years under laboratory conditions, and injected with fluorochrome dyes (alizarin, calcein). Some alligators were constrained to in‐series circulation by left aortic ablation (n=24), whereas sham‐operated controls retained in‐parallel circulation (n=36). Animals either remained sedentary or were subjected to rigorous walking or swimming exercise (n=20). We found CCC correlated with LGR and was significantly augmented (+36%) in alligators with in‐series circulation compared to those with in‐parallel circulation. Exhaustive exercise reduced thickness (−15%) of the distal, but not proximal, growth plate, suggesting local effect of biomechanic loading. We propose loss of the pulmonary bypass shunt results in higher systemic arterial oxygen tension, which allows for greater oxygen diffusion distance through the growth plate. Among archosaur ancestors, thicker growth plates may have appeared concurrently with the origin of in‐series circulation, and thus set the stage for later acquisition of fast growth and endothermic metabolism. Supported by NSF IOB 04445680 to JWH.

Oxygen tension and gradient measurements in the retinal microvasculature of rats

Oxygen delivery from the retinal vasculature plays a crucial role in maintaining normal retinal metabolic function. Therefore, measurements of retinal vascular oxygen tension (PO(2)) and PO(2) longitudinal gradients (gPO(2)) along retinal blood vessels may help gain fundamental knowledge of retinal physiology and pathological processes. Three-dimensional retinal vascular PO(2) maps were generated in rats by optical section phosphorescence lifetime imaging. A major retinal artery and vein pair, and a smaller blood vessel (microvessel) between them were segmented, and PO(2) along each blood vessel was measured. In each blood vessel, an average PO(2) (mPO(2)) was calculated, and gPO(2) was determined by linear regression analysis. Reproducibility of measurements was assessed by calculating intraclass correlation coefficient (ICC) of repeated measurements. The correlations of mPO(2) and gPO(2) measurements with systemic arterial oxygen tension (P(a)O(2)) and carbon dioxide tension (P(a)CO(2)) was determined. Measurements of mPO(2) and gPO(2) in retinal arteries, microvessels and veins were reproducible (ICC > 0.86; p < 0.01; N = 8), except for retinal arterial gPO(2). Retinal arterial, microvessel and venous mPO(2) were 41 ± 8, 32 ± 8 and 25 ± 7mmHg, respectively (mean ± SD; N = 27). Retinal arterial mPO(2) was correlated with P(a)O(2) and P(a)CO(2) (R > 0.44; p < 0.03), while retinal microvessel and venous mPO(2) were only correlated with P(a)CO(2) (R > 0.68; p < 0.01). Retinal microvessel gPO(2) (-3.8 ± 1.5mmHg/100μm) was significantly steeper (more negative) than venous gPO(2) (0.02 ± 0.43mmHg/100μm) (p < 0.01; N = 27), and neither were significantly correlated with P(a)O(2) or P(a)CO(2). Quantitative measurement of mPO(2) and gPO(2) in the retinal microvasculature was demonstrated. A significant decrease in PO(2) was observed along most retinal microvessels, indicative of substantial oxygen extraction by the retinal tissue. This method has the potential to help elucidate retinal microvascular oxygen transport in health and disease.

ERYTHROPOIETIN ENHANCES OXYGENATION IN CRITICALLY PERFUSED TISSUE THROUGH MODULATION OF NITRIC OXIDE SYNTHASE

The aim of this study was to investigate the effect of human recombinant erythropoietin (EPO) on the microcirculation and oxygenation of critically ischemic tissue and to elucidate the role of endothelial NO synthase in EPO-mediated tissue protection. Island flaps were dissected from the back skin of anesthetized male Syrian golden hamsters including a critically ischemic, hypoxic area that was perfused via a collateralized vasculature. Before ischemia, animals received an injection of epoetin beta at a dose of 5,000 U/kg body weight with (n = 7) or without (n = 7) blocking NO synthase by 30 mg/kg body weight L-NAME (Nomega-nitro-L-arginine methyl ester hydrochloride). Saline-treated animals served as control (n = 7). Ischemic tissue damage was characterized by severe hypoperfusion and inflammation, hypoxia, and accumulation of apoptotic cell nuclei after 5 h of collateralization. Erythropoietin pretreatment increased arteriolar and venular blood flow by 33% and 37%, respectively (P < 0.05), and attenuated leukocytic inflammation by approximately 75% (P < 0.05). Furthermore, partial tissue oxygen tension in the ischemic tissue increased from 8.2 to 15.8 mmHg (P < 0.05), which was paralleled by a 21% increased density of patent capillaries (P < 0.05) and a 50% reduced apoptotic cell count (P < 0.05). The improved microcirculation and oxygenation were associated with a 2.2-fold (P < 0.05) increase of endothelial NO synthase protein expression. Of interest, L-NAME completely abolished all the beneficial effects of EPO pretreatment. Our study demonstrates that, in critically ischemic and hypoxic collateralized tissue, EPO pretreatment improves tissue perfusion and oxygenation in vivo. This effect may be attributed to NO-dependent vasodilative effects and anti-inflammatory actions on the altered vascular endothelium.

Effects of Arginine Vasopressin on Oxygenation and Haemodynamics during One-Lung Ventilation in an Animal Model

In a case of arterial hypotension during one-lung ventilation, haemodynamic support may be required to maintain adequate mean arterial pressure. Arginine vasopressin, a potent systemic vasoconstrictor with limited effects on the pulmonary artery pressure, has not been studied in this setting. Twelve female pigs were anaesthetised and ventilated and arterial, central venous and pulmonary artery catheters were inserted. A left-sided double lumen tube was placed via tracheostomy and one-lung ventilation was initiated. The animals were in the left lateral position, with the left lung ventilated and right lung collapsed. Respiratory and haemodynamic values were recorded before and during a continuous infusion of arginine vasopressin sufficient to double the mean arterial pressure. The arginine vasopressin caused a decrease in cardiac output (3.8+/-1.1 vs. 2.7+/-0.7 l/min, P <0.001) and mixed-venous oxygen tension (39.1+/-5.8 vs. 34.4+/-5 mmHg, P=0.003). Pulmonary artery pressure was unchanged (24+/-2 vs. 24+/-3 mmHg, P=0.682). There was no effect of the arginine vasopressin on arterial oxygen tension (226+/-106 vs. 231+/-118 mmHg, P=0.745). However, there was a significant decrease in shunt fraction (28.3+/-6.2 vs. 24.3+/-7.8%, P=0.043) and a significant proportional increase in perfusion of the ventilated lung (78.8+/-9.5 vs. 85.5+/-7.9%, P=0.036). In our animal model of one-lung ventilation, doubling mean arterial pressure by infusion of arginine vasopressin significantly affected global haemodynamics, but had no influence on systemic arterial oxygen tension.

Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury

Hypoxic pulmonary vasoconstriction (HPV) preserves systemic arterial oxygenation during lung injury by diverting blood flow away from poorly ventilated lung regions. Ventilator-induced lung injury (VILI) is characterized by pulmonary inflammation, lung edema, and impaired HPV leading to systemic hypoxemia. Studying mice congenitally deficient in inducible nitric oxide synthase (NOS2) and wild-type mice treated with a selective NOS2 inhibitor, L-N(6)-(1-iminoethyl)lysine (L-NIL), we investigated the contribution of NOS2 to the impairment of HPV in anesthetized mice subjected to 6 h of either high tidal volume (HV(T)) or low tidal volume (LV(T)) ventilation. HPV was estimated by measuring the changes of left lung pulmonary vascular resistance (LPVR) in response to left mainstem bronchus occlusion (LMBO). LMBO increased the LPVR similarly in wild-type, NOS2(-/-), and wild-type mice treated with L-NIL 30 min before commencing 6 h of LV(T) ventilation (96% +/- 30%, 103% +/- 33%, and 80% +/- 16%, respectively, means +/- SD). HPV was impaired in wild-type mice subjected to 6 h of HV(T) ventilation (23% +/- 16%). In contrast, HPV was preserved after 6 h of HV(T) ventilation in NOS2(-/-) and wild-type mice treated with L-NIL either 30 min before or 6 h after commencing HV(T) ventilation (66% +/- 22%, 82% +/- 29%, and 85% +/- 16%, respectively). After 6 h of HV(T) ventilation and LMBO, systemic arterial oxygen tension was higher in NOS2(-/-) than in wild-type mice (192 +/- 11 vs. 171 +/- 17 mmHg; P < 0.05). We conclude that either congenital NOS2 deficiency or selective inhibition of NOS2 protects mice from the impairment of HPV occurring after 6 h of HV(T) ventilation.

Tissue oxygen tension and blood-flow changes in rat incisor pulp with graded systemic hyperoxia

The role of oxygen in the regulation of the pulpal microcirculation is unknown. This investigation is aimed to measure tissue oxygen tension and blood-flow changes in the pulp of rat lower incisors during graded systemic hyperoxia, and to determine the response of the pulpal vasculature to various oxygen tensions. Twenty-four Sprague–Dawley rats were anaesthetized and artificially ventilated with the appropriate gas mixture. Recessed oxygen-sensitive microelectrodes were used to measure pulpal tissue oxygen tension via a small access cavity filled with saline on the labial surface of the incisor. A laser Doppler flowmeter was used to record pulpal blood-flow. Inspired oxygen was increased stepwise from 20 to 100% in 20% steps. Systemic blood-gas concentrations were measured at each step. Systemic arterial oxygen tension at 100% oxygen ventilation reached 481.2±30.7% of the baseline at 20% oxygen breathing ( n=21). Pulpal tissue oxygen tension did not change significantly whereas pulpal blood-flow fell dose-dependently to 74.6±5.0% at 100% oxygen ventilation ( n=21). Systemic hyperoxia, therefore, induces a significant reduction in pulpal blood-flow whereas pulpal tissue oxygen tension remains relatively stable, indicating an oxygen-dependent local regulatory mechanism.

Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model.

Tumor necrosis factor alpha (TNF-alpha) activity, platelet and neutrophil degranulation and margination, and increased vascular permeability are central to the pathophysiology of endotoxin-mediated acute lung injury. Nonanticoagulant activities of low molecular weight heparin (LMWH) include solubilization of the TNF-alpha receptor protein, inhibition of neutrophil adhesion, and regulation of thromboxane B2 (TXB2) biosynthesis. In this study, we evaluated the ability of LMWH to modulate TNF-alpha and TXB2 activity during endotoxemia and the subsequent effects on pulmonary hemodynamics. Domestic pigs 8-10 weeks old were anesthetized and catheterized for standard cardiopulmonary measurements and the lungs harvested for cuff:vessel ratio, myeloperoxidase activity, and permeability index. Pigs were randomly assigned to one of four groups: lipopolysaccharide (LPS) (n = 6), given .5 microg/kg/h Escherichia coli LPS intravenously for 6 h; saline control (n = 5); LMWH (n = 5), given .5 mg/kg LMWH for 30 min, followed by .5 mg/kg/h; and LMWH + LPS (same dosages, n = 6). Administration of LPS resulted in increased plasma TNF-alpha and TXB2 activity; increased pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen tension; decreased systemic arterial oxygen tension; and pulmonary edema. The cardiopulmonary parameters for the LMWH-treated pigs did not differ from those of the saline-treated control pigs. Pretreatment with LMWH attenuated the LPS-mediated TNF-alpha and TXB2 activity and attenuated LPS-mediated pulmonary hypertension, hypoxemia and neutrophil emigration, and edema formation. In conclusion, the data show that the protective effects of LMWH in this model of acute lung injury are associated with altered neutrophil adhesion and TNF-alpha and thromboxane activity.

Treatment of persistent pulmonary hypertension in the newborn lamb by inhaled nitric oxide

We previously showed that fetal lambs whose ductus arteriosus is ligated prenatally will have persistent pulmonary hypertension at birth. We investigated the effect of inhaled nitric oxide on the pulmonary circulation in this animal model. The ductus arteriosus of six fetal lambs was ligated at 126 days of gestation. The lambs were delivered and studied at 136 days of gestation. Mechanical ventilation was maintained at a fraction of inspired oxygen of 0.80. Nitric oxide gas was administered at five different concentrations (6, 12, 25, 50, and 100 ppm) for 5-minute periods separated by 10-minute periods of ventilation without nitric oxide. Inhaled nitric oxide caused dose-dependent decreases in pulmonary arterial pressure and vascular resistance and dose-dependent increases in pulmonary blood flow without affecting systemic arterial pressure. Thus pulmonary arterial pressure decreased from equal to aortic pressure to less than aortic pressure. At the highest dose, mean pulmonary arterial pressure decreased by 27% +/- 2%, pulmonary blood flow increased by 86% +/- 6%, and pulmonary vascular resistance decreased by 59% +/- 4%. Nitric oxide also caused dose-dependent increases in systemic arterial oxygen tension and in the saturation of hemoglobin with oxygen. Partial pressure of arterial oxygen increased from 43 +/- 16 mm Hg at baseline to 185 +/- 72 mm Hg at the highest dose; saturation increased from 74% +/- 8% to 96% +/- 2%. In our model of persistent pulmonary hypertension of the newborn, inhaled nitric oxide selectively dilates the pulmonary circulation, thereby improving systemic arterial oxygenation. Nitric oxide is a promising new treatment of persistent pulmonary hypertension of the newborn.

Effect of nifedipine on physiologic shunting and oxygenation in chronic obstructive pulmonary disease

purpose: To assess changes in physiologic shunting and oxygenation following short-term treatment with nifedipine in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. patients and methods: Changes in pulmonary vascular pressure, pulmonary vascular resistance, venous admixture, and systemic arterial oxygen tension following sublingual administration of 20 mg of nifedipine were studied in 18 patients (13 men, 5 women; mean age of 59.7 [SD 7.2] years) using Swan-Ganz catheterization. These patients had a mean peak expiratory flow rate of 112 (SD 27) L/min (mean 22.2 [SD 12.2]% of predicted value), mean forced expiratory volume in 1 second (FEV 1) of 0.84 (SD 0.23) L (mean 31.2 [SD 8.5]% of predicted value), mean FEV 1/forced vital capacity ratio of 31.6 (SD 4.5), and mean carbon monoxide diffusing capacity of 6.8 (SD 1.96) mmol/min/kPa. results: There was a significant decrease in mean pulmonary vascular resistance (562 to 371 dyne sec.cm −5) and a significant reduction in the mean pulmonary arterial pressure (mean 32.8 to 23.6 mm Hg). Pulmonary venous admixture, however, increased significantly from the baseline mean of 44.6% (SD 16.1) to a mean of 56% (SD 15.6), and the mean arterial oxygen tension decreased from 5.8 (SD 1.3) kPa to 4.5 (SD 0.8) kPa at 60 minutes following drug administration (p < 0.001). conclusion: The role of nifedipine in the treatment of pulmonary hypertension secondary to chronic bronchitis may be limited because of its deleterious effect on venous admixture.

The mechanical effects of expiratory airflow limitation on cardiac performance in cystic fibrosis.

The influence of altered lung mechanics on cardiac performance in cystic fibrosis (CF) was examined in an analysis of cardiorespiratory performance during exercise. The stroke volume (SV) response to exercise, derived from an indirect Fick (CO2) determination of cardiac output during submaximal steady-state exercise served as the index of cardiac performance. The relationship between exercising SV and forced expiratory volume in one second (FEV1), inspiratory duty cycle during exercise (Tl/Ttot) and exercising systemic arterial oxygen tension (PaO2) was examined in 15 studies involving 11 individuals with CF. The subjects were 12 to 25 yr of age and the FEV1 ranged from 15 to 72% predicted. Although a relationship existed between the SV expressed as a percentage of the mean predicted from height and gender (SV%) and PaO2 (r = 0.61, p less than 0.02), a more striking relationship was noted between SV% and either FEV1 or Tl/Ttot (r = 0.79 and 0.73, p less than 0.002). A multiple regression analysis of SV% identified an element of the relationship between FEV1 or Tl/Ttot and cardiac performance which was distinct from the influence of the coexisting hypoxia (p less than or equal to 0.05). The limitation in the SV response to exercise was noted to be in part reversible, coincident with an improvement in ventilatory mechanics that had occurred in 2 of the 4 persons in whom repeated studies were available. These observations suggest that in individuals with CF and a moderately severe degree of expiratory airflow limitation, there is a mechanical element of cardiopulmonary interdependence.

Hemodynamic effects of inhaled terbutaline in congestive heart failure patients without lung disease: Beneficial cardiotonic and vasodilator beta-agonist properties evaluated by ventricular catheterization and radionuclide angiography

To evaluate the hemodynamic effects of the beta-adrenergic receptor agonist, terbutaline sulfate, when given by inhalation in ventricular dysfunction, 0.5 mg of the agent was given by nebulizer to 13 patients with congestive heart failure (nine coronary heart disease and four with idiopathic cardiomyopathy). Data were obtained before and 10 and 30 minutes post inhalation, by right heart catheterization and by gated equilibrium radionuclide ventriculography. All patients responded with increased cardiac output (3.5 to 4.3 L/min, p < 0.01) and stroke volume (40 to 49 ml, p < 0.01) without change in heart rate. Decreases occurred in peripheral vascular resistance (1924 to 1443 dsc −5, p < 0.01), left ventricular filling pressure (21 to 15 mm Hg, p < 0.01), and systemic arterial oxygen tension (81 to 72 mm Hg, p < 0.05). Both left and right ventricular ejection fractions rose (0.24 to 0.38 and 0.36 to 0.51, both p < 0.01) with concomitant declines in blventricular end-diastolic volumes. All variables indicated changed rapidly at 10 minutes post inhalation and returned to control levels by 30 minutes after the agent. Thus moderate inhaled doses of terbutaline produce prompt, potent, and transient salutary hemodynamic effects due to its peripheral vasodilator and cardiotonic properties, without untoward arrhythmogenic or anginal provoking influences in the present study.

15-methylation augments the cardiovascular effects of prostaglandin F 2α

Intramuscular injection of the 15-methyl analogue of prostaglandin F 2α (15-me-PGF 2α) is being used to initiate second trimester abortion. The natural prostaglandin F 2α (PGF 2α) is a known pulmonary pressor agent but there is little information about the cardiovascular effects of the analogue. Consequently, we compared the hemodynamic responses to the two forms in twenty-three anesthetized dogs. Given I.M. or I.V. 15-me-PGF 2α produced a greater and more sustained rise in pulmonary arterial pressure than PG F 2α. Intramuscular 15-me-PGF 2α also elicited a more prolonged increase in pulmonary vascular resistance than prostaglandin F 2α given I.M. or I.V. The methyl analogue (I.M. or I.V.) causes a greater initial fall in systemic arterial oxygen tension and cardiac output, and a greater increase in systemic resistance than I.M. PG F 2α Breathlessness seen during abortion induced by prostaglandin F 2α or its methyl analogue may be caused by acute pulmonary hypertension in addition to bronchoconstriction.

The effect of differences in static airway pressures between two lungs in experimentatl unilateral hypoxia-hypercarbia.

Animals with separately but synchronously ventilated lungs were subjected to a period of unilateral hypoxia-hypercarbia, after which airway pressures were unilaterally increased for 20 seconds, either in the hypoxic-hypercarbic lung or the oxygen-breathing lung during the performance of perfusion scans using xenon-133. Blood flow to the lung ventilated with the hypoxic-hypercarbic gas mixture was at first reduced, as was systemic arterial oxygen tension whereas calculated venous admixture was markedly increased. When the airway pressure in the hypoxic-hypercarbic lung was increased above that of the oxygen-ventilated lung by 15 or 25 cm H2O, perfusion of the hypoxic-hypercarbic lung was further reduced, resulting in diminution of calculated venous admixture and increased arterial oxygen tension. Pulmonary arterial pressure increased slightly. When airway pressure in the oxygen-breathing lung was increased above that of the hypoxic-hypercarbic lung to the same degree, perfusion of the hypoxic-hypercarbic l...