An Analysis of Hypoxia in Sheep Brain using a Mathematical Model

Cerebral blood flow (CBF) increases as arterial oxygen content falls with hypoxic (low PO₂), anemic (low hemoglobin) and carbon monoxide (CO) (high carboxyhemoglobin) hypoxia. Despite a higher arterial PO₂, CO hypoxia provokes a greater increase in CBF than hypoxic hypoxia. We analyzed published data using a compartmental mathematical model to test the hypothesis that differences in PO₂ in tissue, or a closely related vascular compartment, account for the greater response to CO hypoxia. Calculations showed that tissue, but not arteriolar, PO₂ was lower in CO hypoxia because of the increased oxyhemoglobin affinity with CO hypoxia. Analysis of studies in which oxyhemoglobin affinity was changed independently of CO supports the conclusion that changes in tissue PO₂ (or closely related capillary or venular PO₂) are predictive of alterations in CBF. We then sought to determine the role of tissue PO₂ in anemic hypoxia, with no change in arterial and little, if any, change in venous PO₂. Calculations predict a small fall in tissue PO₂ as hematocrit decreases from 55% to 20%. However, calculations show that changes in blood viscosity can account for the increase in CBF in anemic hypoxia over this range of hematocrits. © 1998 Biomedical Engineering Society. PAC98: 8710+e, 8722-q, 8745Ft     

Die Nierenmarkhypoxie: Ein Schlüssel zum Verständnis des akuten Nierenversagens?

Summary The ability to produce a concentrated urine is imposed by a uniquely low ambient oxygen pressure in the renal medulla due to shunt diffusion within the vascular bundles. As the thick ascending limb of Henle's loop (TAL-segment) is able to glycolyse anaerobically, a phase of oxygen deficiency may be bridgespanned. It allows an exceptionally high oxygen extraction of 80% in this area. If oxygen capacity is reduced systematically, which can be effected in the isolated kidney model by using cell free perfusate, a typical pattern of lesions occur in TAL-segments. Segments near vascular bundles remain intact, as they take advantage from a radial oxygen diffusion originating from vascular bundles. The extent of lesions is increasing directed to the inner medulla due to the reduction of oxygen pressure, whereas lesions are not present in the inner medulla itself. Cells of TAL-segments are swelling during oxygen deficiency, when transport work surpasses the available energy necessary due to the luminal fluid inflow. Lesions could be prevented, when oxygen capacity was enhanced by adding erythrocytes or when transport was blocked by furosemide. Swollen cells in TAL-segments however are able to aggravate medullary hypoxia by an outflow block in vivo.Secondly, it can be demonstrated, that oxygen shunt diffusion is not only present in renal medulla but also within renal cortex especially as a preglomerular diffusion shunt for blood gases. Thus PCO₂ has been measured to be 65 mmHg in the outermost cortical zone and thereby some 20 mmHg higher than renal venous blood. Our own measurements of the PO₂ at superficial glomeruli in vivo using MWF-rats demonstrate values as low as 42–46 mmHg at average and a simultaneously measured arterial PO₂ of 90 mmHg in systemic blood. This represents a markedly higher desaturation of hemoglobin than found in renal venous blood. This unexpected high preglomerular shuntdiffusion is likely localized within interlobular vessels, where thinwalled arteries and veins exhibiting the wall structure of capillaries are generally in close contact. Following this concept, PO₂ of the superficial cortical zone is low and the PO₂ of the juxtamedullary cortical zone is not far from arterial PO₂. Plasmaskimming may modify O₂-pressure as well as O₂-capacity within the different cortical zones. These results may explain, why proximal tubules within the renal cortex — which exhibit a low enzymatic activity to glycolyse anaerobically compared to TAL-segments — develop lesions very rapidly under ischemic or hypoxic conditions or when the demand of energy for transport work cannot be produced aerobically. This becomes evident especially within areas of oxygen deficiency at the outer stripe of outer medulla, where predominantly P₃-segments in the interbundle area are involved however much less TAL-segments. This may also explain, that the production of erythropoietin is localized within the renal cortex and outer stripe of outer medulla, as oxygen deficiency can be measured effectively in this area. The common error, that oxygen supply of the kidney is abundant, must be revised: it is at the brink of oxygen deficiency in the case of renal medulla and at shortage also for renal cortex.     

Erythrocyte 2,3-DPG,PO250% and available O2 during the early post-natal fall in hemoglobin in rabbits

Erythrocyte 2,3-DPG, PO₂50%, whole blood hemoglobin and available O₂, and fixed acid Bohr effect were studied during the first 10 days after birth in rapidly growing suckling rabbits. The post-natal fall in hemoglobin concentration was accompanied by a marked rise in erythrocyte 2,3-DPG and a gradual increase in PO₂50%. The rise in PO₂50% was sufficient to keep the available O₂ of the blood unchanged throughout the observation period. The observations show that a 2,3-DPG mediated rise in PO₂50% very effectively contributes to maintenance of adequate tissue oxygenation during the post-natal fall in hemoglobin. The rise in 2,3-DPG and PO₂50% may be due to the ordinary hypoxia-induced shift to the right of the hemoglobin O₂ dissociation curve, as observed under other circumstances when blood hemoglobin is rapidly reduced, but the very marked rise in 2,3-DPG and the very low Δ PO₂50%/Δ 2,3-DPG ratio suggest that the rise may as well be due to hypoxia independent, pre-programmed processes. The fixed acid Bohr effect was essentially the same in newborn and adult rabbits, and was uninfluenced by large variations in 2,3-DPG.     

Transmural Oxygen Tension Gradients in Rat Cerebral Cortex Arterioles

Modified needle oxygen microelectrodes and vital microscopy were used to measure transmural oxygen tension gradients (PO₂) in pial arterioles with lumen diameters of 20–90  μm. A relationship between the magnitude of the transmural PO₂ gradient and arteriole wall tone was found: in control conditions, PO₂ gradients were 1.17 ± 0.06 mmHg/μm (n  = 40), while in conditions of arteriolar wall dilation the transmural PO₂ gradient decreased to 0.68 ± 0.04 mmHg/μm (p  <  0.001, n  = 38). These data provide the first measurements of transmural PO₂ gradients in pial arterioles of different calibers at different levels of vascular tone and have fundamental importance for assessing the role of arterial microvessels in tissue oxygen supply processes. The results obtained here provide evidence that oxygen consumption by the vessel wall is within the range characteristic of enveloping tissues and that oxygen consumption by the endothelial cell layer probably has no significant effect on the magnitude of the transmural PO₂ gradient. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 4, pp. 394–405, April, 2008.     

The Influence of Acute Normovolemic Anemia on Cerebral Blood Flow and Oxygen Consumption of Anesthetized Rats

The influence of acute normovolemic anemia on cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMR_O2) was studied in normocapnic rats under nitrous oxide anaesthesia. The arterial hemoglobin content was reduced to values of about 12, 9, 6 and 3 g.(100 ml)^-1 by arterial bleeding and substitution with equal volumes of homologous plasma. The CBF increased in proportion to the reduction in hemoglobin content to reach values of 500–600 per cent of normal at extreme degrees of anemia, but CMR_O2 remained unchanged. Cerebral venous P_O2 and oxygen saturation did not decrease below normal values, indicating that tissue hypoxia did not develop. However, since the increase in CBF at hemoglobin concentrations of below 9 g ^. (100 ml)^-1 was far in excess of that expected from the decrease in viscosity the results indicate that dilatation of cerebral resistance vessels occurred. This dilatation, which was obviously related to the fall in arterial oxygen content, cannot be explained by any of the current theories proposed to explain cerebral hyperemia in hypoxia.     

Affinity of hemoglobin for oxygen and prooxidant-antioxidant equilibrium after administration of lipopolysaccharide during correction of the L-arginine—NO pathway

Effects of correction of the L-arginine—NO pathway on the fever reaction, oxygen transport function of the blood, and prooxidant-antioxidant equilibrium in rats injected intramuscularly with lipopolysaccharide were studied. pH, Pco₂, Po₂, and the index of hemoglobin oxygen affinity (p50) were measured in mixed venous blood. Levels of Schiff bases, α-tocopherol, and catalase activity were determined in erythrocytes and in the liver, kidneys, and heart. NO synthase inhibitor attenuated the fever reaction and decreased p50 to 28.89±0.83 mm Hg (in rats administered with lipopolysaccharide, p50 was 34.21±1.63 mm Hg). The increase in the content of Schiff bases and the exhaustion of the antioxidant system in erythrocytes and tissues were less pronounced in rats injected with the NO synthase inhibitor than in animals receiving lipopolysaccharide only. Various parameters of the prooxidant-antioxidant equilibrium correlated with p50. Thus, hemoglobin oxygen affinity and NO are important factors involved in the maintenance of the prooxidant-antioxidant equilibrium in the body. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 6, pp. 616–619, June, 1999     

Carbon monoxide (CO) and hydrogen sulfide (H2S) in hypoxic sensing by the carotid body

Carotid bodies are sensory organs for monitoring arterial blood oxygen (O₂) levels, and the ensuing reflexes maintain cardio-respiratory homeostasis during hypoxia. This article provides a brief update of the role of carbon monoxide (CO) and hydrogen sulfide (H₂S) in hypoxic sensing by the carotid body. Glomus cells, the primary site of O₂ sensing in the carotid body express heme oxygenase-2 (HO-2), a CO catalyzing enzyme. HO-2 is a heme containing enzyme and has high affinity for O₂. Hypoxia inhibits HO-2 activity and reduces CO generation. Pharmacological and genetic approaches suggest that CO inhibits carotid body sensory activity. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO. Glomus cells also express cystathionine γ-lyase (CSE), an H₂S generating enzyme. Exogenous application of H₂S donors, like hypoxia, stimulate the carotid body activity and CSE knockout mice exhibit severely impaired sensory excitation by hypoxia, suggesting that CSE catalyzed H₂S is an excitatory gas messenger. Hypoxia increases H₂S generation in the carotid body, and this response was attenuated or absent in CSE knockout mice. HO inhibitor increased and CO donor inhibited H₂S generation. It is proposed that carotid body response to hypoxia requires interactions between HO-2–CO and CSE–H₂S systems.     

Cardiac output,arterial and mixed-venous O2 saturation,and blood O2 dissociation curve in growing rats adapted to a simulated altitude of 3500 m

Summary In rats adapted to a simulated altitude of 3500 m cardiac output measured at hypoxia by the direct Fick principle was significantly lower than in the control animals (mean values 54.3 ml/min and 69.8 ml/min, resp.). The decrease of cardiac output was accompanied by an increase of arterio-venous O₂ difference and a decrease of stroke volume in the adapted rats. It is suggested that the decrease of cardiac output might be related to the increase of hematocrit. The adapted rats also showed higher arterial and mixed-venous O₂ content (both at hypoxia) and increased O₂ capacity. Arterial O₂ saturation of the animals previously exposed to simulated high altitude hypoxia was significantly higher (67.3% as against 61.2% in the controls). The standard O₂ dissociation curve showed lower oxygen affinity in the blood of the adapted animals but no physiological advantage concerning the transport of O₂ to the tissues was found. In another group of animals the Bohr factor was estimated and no difference was found between rat and human blood.     

The effect of O2 and CO2 on the dive behavior and heart rate of lesser scaup ducks (Aythya affinis): quantification of the critical that initiates a diving bradycardia

Lesser scaup ducks were trained to dive for short and long durations following exposure to various gas concentrations to determine the influence of oxygen (O₂) and carbon dioxide (CO₂) on diving behavior and heart rate. Compared with normoxia, hyperoxia (50% O₂) significantly increased the duration of long dives, whereas severe hypoxia (9% O₂) significantly decreased the duration of both short and long dives. Hypercapnia (5% CO₂) had no effect on dive duration. Surface intervals were not significantly altered by the oxygen treatments, but significantly increased following CO₂ exposure. Heart rate during diving was unaffected by hyperoxia and hypercapnia, but gradually declined in long dives after severe hypoxia. Thus, our results suggest that during the majority of dives, O₂ and CO₂ levels in lesser scaup ducks are managed through changes in diving behavior without any major cardiovascular adjustments, but below a threshold Pa_O2, a bradycardia is evoked to conserve the remaining oxygen for hypoxia sensitive tissues. A model of oxygen store utilization during voluntary diving was developed to estimate the critical Pa_O2 below which bradycardia is initiated (≈26 mmHg) and predicted that this critical Pa_O2 would be reached 19 s into a dive after exposure to severe hypoxia, which corresponded exactly with the time of initiation of bradycardia in the severe hypoxia trials.     

Role of glycolysis in the maintenance of the energy-synthesizing function of hepatocytes from rats adapted and nonadapted to hypoxia at different oxygen concentrations

It is demonstrated that the lactate-Po₂ dependence is the same in hepatocytes of rats with high and low resistance to hypoxia and does not correlate with phasic changes in the ATP concentration in the 890–50 μM O₂ region. Strong activation of lactate formation against the background of ATP decrease indicates that glycolysis is not the major mechanism determining the steady-state ATP level in the cell and affecting the ATP-Po₂ relationship in a wide range of oxygen concentrations. The intensity of glycolysis in hepatocytes of rats with high resistance to hypoxia is markedly increased after periodic adaptation to hypoxia but remains practically unchanged in the hepatocytes of low-resistance rats. This indicates that fundamentally different compensatory mechanisms are involved in this process in the liver of high- and low-resistance rats. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 1, pp. 28–32, January, 1995     

Blood glucose,gas exchange,and hematological parameters in rats with experimental diabetes mellitus after carotid glomectomy

In glomectomized rats with denervated sinus carotid reflexogenic zones as compared with sham-operated controls, the diabetogenic action of streptozotocin was manifested by more pronounced changes in several hematological parameters, including marked elevation of blood glucose and reductions of oxygen consumption, the respiratory quotient, blood hemoglobin concentration, the hematocrit, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. These findings attest that the carotid sinus receptors play an important functional role in producing the symptom complex of diabetes mellitus. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N^no 11, pp. 454–456, November, 1995 Presented by N. A. Agadzhanyan, Member of the Russian Academy of Medical Sciences     

Effect of hypoxia on arterial and venous blood levels of oxygen,carbon dioxide,hydrogen ions and lactate during incremental forearm exercise

Summary The purpose of the present study was to investigate whether, in humans, hypoxia results in an elevated lactate production from exercising skeletal muscle. Under conditions of both hypoxia [inspired oxygen fraction (F_IO₂): 11.10%] and normoxia (F_IO₂: 20.94%), incremental exercise of a forearm was performed. The exercise intensity was increased every minute by 1.6 kg·m·min^–1 until exhaustion. During the incremental exercise the partial pressure of oxygen (PO₂) and carbon dioxide (PCO₂), oxygen saturation (SO₂), pH and lactate concentration [HLa] of five subjects, were measured repeatedly in blood from the brachial artery and deep veins from muscles in the forearm of both the active and inactive sides. The hypoxia (arterial SO₂ approximately 70%) resulted in (1) the difference in [HLa] in venous blood from active muscle (values during exercise — resting value) often being more than twice that for normoxia, (2) a significantly greater difference in venous-arterial (v-a) [HLa] for the exercising muscle compared to normoxia, and (3) a difference in v-a [HLa] for non-exercising muscle that was slightly negative during normoxia and more so with hypoxia. These studies suggest that lower O₂ availability to the exercising muscle results in increased lactate production.     

Phrenic artery blood flow under loaded respiration

Acute experiments on anesthetized cats with additional resistive loads to inspiration and/or expiration revealed adequate changes in vascular bed resistance and blood flow rate in the phrenic artery. The increase in the phrenic artery blood flow during airflow resistive loading by 30–40 mm H₂O was similar to the, changes previously found for inspiration of gas mixtures containing 5% O₂ and 5% CO₂. Minute ventilation increased 2 times under hypoxia and 3.5 times under hypercapnia. This index did not change under additional loading. Translated fromByulleten' Eksperimental'noi Biologii I Meditsiny, Vol. 125, No. 1, pp. 18–22, January, 1998.     

Relationship between hemoglobin affinity for oxygen and lipid peroxidation in fever

Hemoglobin affinity for oxygen (P₅₀ parameter) and the content of malonic dialdehyde (MDA), Schiff's bases, and diene conjugates in the plasma and red cell mass were examined in mixed venous blood of rabbits with pyrogenal fever. Correlation regression analysis of the tested parameters showed that reduction of the actual affinity of hemoglobin for oxygen is conducive to activation of free-radical processes. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 118, N ^o 7, pp. 27–30, July, 1994 Presented by K. V. Sudakov, Member of the Russian Academy of Medical Sciences     

Ultrastructure of the glomus cells in the carotid body of chronically hypoxic rats: With special reference to the similarity of amphibian glomus cells

The ultrastructural characteristics of the glomus cells in the rat carotid body exposed to extremely long-term hypoxia (10–12 weeks) were investigated. The glomus cells could be classified into four distinct types according to the shape of dense-cored vesicles in the glomus cell cytoplasm: (1) small vesicle cells (SVCs, 50 nm in mean diameter), (2) large vesicle cells (LVCs, 80 nm in mean diameter), (3) dilated eccentric vesicle cells (EVCs, 400–800 nm in diameter), and (4) mixed vesicle cells (MVCs, large and eccentric vesicles). Many clusters of glomus cells were found to contain all four categories of cell types. The appearance of EVCs was a unique and common characteristic of glomus cells in this long-term hypoxia model. We also noted other ultrastructural features with chronic hypoxia which are characteristic of the amphibian carotid labyrinth glomus cells: (1) incomplete covering of glomus cells with the supporting cell missing over a wide area, (2) long thin cytoplasmic projections in the intervascular stroma, and (3) intimate apposition of the glomus cells and pericytes (g-p connection), endothelial cells (g-e connection), plasma cells, and fibrocytes. Because arterial PO₂ is generally low in amphibia, these may be general features of hypoxic adaptation and facilitate both uptake of oxygen from blood and release of catecholamine into the blood. The g-p and g-e connections may take part in the regulation of the microcirculation in the enlarged carotid body. © 1993 Wiley-Liss Inc.     

Changes in the mesenteric microcirculation of rats with acute hypoxic hypoxia

Hypoxia was induced in rats by administration of a gas mixture corresponding to the composition of the atmosphere at an altitude of 6000 m above sea level. Mesenteric arteries and veins measuring from 9 to 43 in diameter were studied. Their diameter and the pressure and velocity of the blood flow in them were measured. The arterial microvessels were dilated in hypoxia. Their diameter was increased by the greatest amount (by 3–5 ) during the first 3–5 min of administration of the gas mixture. The blood pressure and velocity of blood flow in these vessels were reduced throughout the experiment.Department of Normal Physiology, Abu Ali ibn-Sina Tadjik Medical Institute, Dushanbe. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 3, pp. 277–279, March, 1976.     

Gas exchange and hemodynamics after total blood replacement by a solution of purified hemoglobin

Complete exchange replacement of the blood (to a hematocrit index of 1–3%) by a 7–8% solution of human hemoglobin, purified completely from stroma and procoagulant activity, was carried out in cats. The Hb solution is able to transport O₂ and can support life of the completely exsanguinated animal for a certain length of time (up to 2–6 h). It readily takes up O₂ in the lungs and gives up O₂ in the tissues, but to a much lesser degree than Hb incorporated in erythrocytes. The Hb solution can also maintain the basic indices of the hemodynamics for a certain time.Laboratory of Pathological Physiology, Central Institute of Hematology and Blood Transfusion, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 10, pp. 402–405, October, 1977.     

Sensitivity of the respiratory system to oxygen in cats with activated GABAergic brain structures

Activation of the GABAergic system in pentobarbital-anesthetized random-bred male and female cats by intravenous injection of GABA agonist (sodium oxybutyrate or phenibut) increases the contribution of oxygen to the regulation of respiration. Hypoxia stimulates, while hyperoxia inhibits pulmonary ventilation in cats regardless of whether their breathing is of the periodic apneustic or “machinelike” type. Their respiratory response to hypoxia and hyperoxia is more pronounced than that observed before sodium oxybutyrate of phenibut injection. It is shown that respiratory reactions to these stimuli after administration of the agonists are due not to concomitant changes in the systemic hemodynamics but rather to decreased contribution of carbon dioxide to the regulation of respiration and low oxygen tension in arterial blood. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 123, No. 3, pp. 264–268, March, 1997     

Respiratory response of malignant and placental cells to changes in oxygen concentration

Malignant cells and foetal tissues are exposed to low oxygen partial pressure (pO₂) in situ due to the limited supply of oxygenated blood. Whether these cells have adapted to low pO₂ or live under constant constraint is not clear. Herein, we compared the respiratory responses of different malignant cell types, maternal and foetal placental leucocytes, and benign cells by incubating them under a gradient of pO₂, from saturation to hypoxia, in a high resolution respirometer. The malignant cells and foetal leucocytes showed higher rates of mitochondrial oxygen uptake compared to the benign cells and maternal leucocytes, respectively. On the other hand, the mitochondrial oxygen uptake rates of the hypoxia adapted cells declined faster than the other cell types during the onset of hypoxia, probably suggesting conformance of aerobic metabolism to the local oxygen concentration. The O₂ consumption rate per million cells (JO₂) of the malignant cells declined only when the O₂ concentration ([O₂]) decreased to values ≤10 μM. On the other hand, the JO₂ of the benign cells declined with the decrease in [O₂] from 200 to 40 μM and ≤10 μM. In the [O₂] ranges outside these values the JO₂ remained constant regardless of the decline of [O₂] in the medium. The JO₂ of foetal leucocytes and malignant cells responded to the change in [O₂] in a similar manner, and may indicate comparable mechanisms of adaptation to hypoxia.     

Differences in brain and liver blood flow during and after acute blood loss in rats with different resistance to circulatory hypoxia

Variations of blood flow and vascular resistance in the common carotid arteries and of blood flow in the hepatic artery and portal vein are examined during and after acute massive blood loss in rats with low and high resistance to circulatory hypoxia. In rats with low resistance, arterial pressure and the rates of cerebral and hepatic blood macro- and microflow, which have decreased during blood loss, continued to fall during the posthemorrhagic period. After cessation of bleeding, a transient arterial pressure rise to 70 mm Hg is observed in rats with high resistance, while the blood flow via carotid arteries increases to 65% of its initial value, being maintained at this level throughout the period of changes in carotid vascular resistance; intrinsic hepatic arterial blood flow increases to 115% of baseline value, while the portal vein blood flow and hepatic microflow increase to 75%. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 123, No. 3, pp. 253–257, March, 1997