The respiratory function of blood in elderly and old age and the factors that determine it

Indices of pulmonary gas exchange, blood gases, the oxyhemoglobin dissociation curve, and intraerythrocytic metabolic parameters were analyzed in 62 apparently healthy elderly and senile subjects (60–92 years old) and 18 young healthy subjects (19–30 years old). PaO₂ was found to decrease in elderly and senile subjects. Arterial hypoxemia in old age is caused by an increase in the alveoloarterial PO₂ gradient, primarily as a result of the malcoordination of pulmonary ventilation and blood flow. A rightward compensatory shift of the oxyhemoglobin dissociation curve was observed, which was due to facilitated oxygen release in tissues owing to a pH decrease in erythrocytes (the Bohr effect). However, the facilitated oxygen release by oxyhemoglobin cannot compensate for the effect of factors deteriorating oxygen supply delivery to tissues, observed with aging, which is confirmed by the decrease in the partial pressure of oxygen in the venous blood of elderly and senile people, reflecting PO₂ in tissues.     

Comparison of hematologic parameters in normal and streptozotocin-induced diabetic rats.

Hematologic values are compared for normal and streptozotocin-induced diabetic rats after 6 weeks of induced diabetes. Most hematologic parameters were the same in the two groups except for blood glucose, glycated hemoglobin, and 2,3 diphosphoglycerate, all of which were elevated in the streptozotocin group. However the P50 (the PO2 at which the oxygen-carrying capacity of blood is 50% of maximal) remained normal. We hypothesize that a left shift in the oxyhemoglobin dissociation curve caused by the glycation of a small percentage of the hemoglobin is compensated by elevation in the 2,3-diphosphoglycerate which returns the P50 to normal values. This compensatory mechanism also occurs in some stages of human diabetes.     

The in vitro Effect of a Magnetic Field on the Oxygen-Transport Function and the Gaseous Transmitter System in Blood

The effect of an alternating magnetic field with a magnetic flux density of 150 mT on the blood oxygen-transport function was studied. In vitro exposure of blood cells was performed following a 10-day series of in vivo exposure of the rat tail artery in combination with administration of chemical compounds that affect the formation of gaseous transmitters. In vitro exposure to a magnetic field changed the oxygen-transport function of the blood, as observed by a greater decrease in the affinity of hemoglobin for oxygen and an increase in the concentration of gaseous transmitters (nitric oxide and hydrogen sulfide). In animals to which nitroglycerin and sodium hydrosulfide were administered exposure to a magnetic field caused a shift in the oxyhemoglobin dissociation curve to the right; this effect was absent when a nonselective inhibitor of the NO synthase enzyme or an irreversible inhibitor of the cystathionine γ-lyase enzyme was added. These results suggest that the magnetic field affects the oxygen-binding properties of the blood by modifying intra-erythrocyte mechanisms that involve gaseous transmitters.     

Involvement of oxygen-depending processes in the pathogenesis of hepatic reperfusion injury

The disbalance between reactive oxygen species generation and antioxidant defensive factors importantly contributes in the development of hepatic reperfusion damage. Changes in blood oxygen transport during hepatic ischemia/reperfusion are involved in its development. Ischemia-induced oxyhemoglobin dissociation curve shift rightwards also exists during the hepatic reperfusion and thereby may facilitate the free radical attacks against the liver. The least disorders in blood oxygen transport, prooxidant-antioxidant balance and hepatic morpho-functional state were observed during the postischemic period under the conditions of moderate hypoxia. The protective effect of L-arginine during the hepatic ischemia-reperfusion may be partially due to the changed hemoglobin function and thereby tissue oxygen delivery and to the keeping of body prooxidant-antioxidant balance. The development of new pharmacological tools to modify the blood oxygen transport and generate the optimal nitric oxide amounts may be a promising strategy for correction of reperfusion injury.     

Mechanism of the antihypoxic action of zinc compounds

It was established in experimental normobaric and hypobaric hypoxia and hemic hypoxia induced by carbon monoxide poisoning that zinc compounds administered in a dose of 0.15 mA/kg have a marked prophylactic protective effect. The mechanism of action of zinc compounds consists in changes of oxygen transport blood function. It was shown that interaction of the hemoglobin molecule with zinc ion brings about an increase in Hb affinity for O2 (the left drive of the oxyhemoglobin dissociation curve), a reduction in cooperative interaction of hemoglobin subunits, and a relative decrease in hemoglobin affinity for carbon monoxide. The leading defence mechanism against hypoxic hypoxia is the left drive, the mechanism of defence against carbon monoxide protection consists in the lowering of the "hem-hem" cooperation and of the relative hemoglobin affinity for carbon monoxide.     

CO2 dissociation curves of oxygenated whole blood obtained at rest and in exercise

In vitro CO2 dissociation curves for oxygenated whole blood were determined in 19 healthy male subjects at rest and during submaximal and maximal bicycle work. Hemoglobin concentration and blood lactate increased with increasing work load and accordingly buffer value of the whole blood increased while bicarbonate and Base Excess (BE) decreased, resulting in a downward shift of the CO2 dissociation curve during exercise. Despite the marked increase in buffer values of the blood, the slopes of the CO2 dissociation curves during exercise were found to be about the same as those obtained at rest. It was inferred that the increasing effect of increased buffer value, on the dissociation slope, was essentially compensated by the decreasing effect of diminished bicarbonate content. The advantages of this relatively constant CO2 dissociation slope for the indirect measurement of cardiac output by the Fick principle are discussed.     

Oxyhemoglobin dissociation curve as expo-exponential paradigm of asymmetric sigmoid function.

From the assumption that the fractional increase of HbO₂ as a function of pO₂ is proportional to HbO₂, and that the proportionality coefficient of that relation decreases exponentially with pO₂, an equation can be derived that gives an excellent fit to the full range of the oxyhemoglobin dissociation curve. To generate this asymmetric sigmoid curve, only one rate constant is required. In addition, the initial and final conditions specify an intermediate constant B, the “shift factor” that determines the horizontal displacement of the curve. The rate constant K specifies the rate of change of the specific rate of increase of HbO₂ with respect to O₂. Governing the slope of the curve, K decreases as temperature and acidity increase, while the B factor remains constant. For Hb in solution, B decreases with decrease of concentration, but K appears to be unchanged. The expo-exponential constants provide convenient specification of the full course and position of the oxyhemoglobin dissociation curve.     

Effect of thyroxine on the hemoglobin affinity to oxygen and 2,3-diphosphoglycerate level in rat erythrocytes

Affinity of hemoglobin to oxygen was studied in rat erythrocytes under conditions of intraperitoneal administration of thyroxin in a dose of 0.4 mg per 100 g of animal weight each 24 h for five days. A significant right shift of the oxyhemoglobin dissociation curve is observed only on the 6th day simultaneously with the increase of the 2,3-diphosphoglycerate level in erythrocytes in the period under study. The results obtained from the study of the thyroxin effect on the respiratory function of hemoglobin permit recommending it as an antihypoxant.     

In vitro manipulation of 2,3-diphosphoglycerate levels in acid-citrate-dextrose blood with steroids

Erythrocyte 2, 3-DPG content has a marked effect on the oxyhemoglobin dissociation curve and is known to decrease in ACD stored blood. This study revealed the effect of various steroids on the level of 2, 3-DPG. Hydrocortisone sodium succinate and methylprednisolone sodium succinate were found to increase the levels of 2, 3-DPG in 3, 10, and 13 day old ACD stored blood during incubation. Hydrocortisone sodium succinate was more effective than methylprednisolone sodium succinate in increasing the level of 2, 3-DPG. In three day old blood the increased 2, 3-DPG approached the lower limits of normal values.     

Effect of sodium nitroprusside on hemoglobin oxygen binding properties of the blood during hepatic ischemia-reperfusion in rabbits

The parameters of blood oxygen transport were determined in rabbits during the hepatic ischemia/reperfusion (HIR) with or without sodium nitroprusside (SNP) administration. Hepatic ischemia was induced for 30 min by a. hepatica propria clamping, reperfusion lasted 120 min. Indices of blood oxygen transport (hemoglobin-oxygen affinity index (p50), pO2, pH, pCO2, HCO3-, TCO2, ABE, etc.) and nitrite/nitrate (NO(x)) amounts were measured in blood during HIR. Animals were subdivided into two groups: 1st group--HIR; 2nd--HIR plus SNP infusion (SNP, Sigma, i.v. 10 mcmol/kg). The experiments had shown that HIR led to significant acidic changes in the acid-base balance and high blood p50. The SNP infusion in the 2nd group led to less changing in the p50 values during HIR which were accompanied with high NO(x) levels. We conclude that oxyhemoglobin dissociation curve shift leftwards after SNP administration promotes the maintenance liver during ischemia-reperfusion.     

Blood oxygen transport in rats under hypothermia combined with modification of the L-Arginine-NO pathway.

Nitric oxide (NO) has high affinity to heme and by interaction with oxyhemoglobin (HbO2) is converted into nitrate to form methemoglobin (MetHb) as a side product. In combining with deoxy-Hb NO yields a stable molecule of nitrosyl-hemoglobin (HbFe(II)NO) that can further be converted into nitrate and hemoglobin (Hb). In addition, Hb was shown to transport NO in a form of S-nitrosohemoglobin (SNO-Hb). These features of the Hb and NO interaction are important for blood oxygen transport including hemoglobin-oxygen affinity (HOA). The present investigation was aimed to study the blood oxygen transport indices (pO2, pCO2, pH, HOA, etc.) in rats under hypothermia combined with a modification of L-arginine-NO pathway. To modify the L-arginine-NO pathway, rats were administered with N(G)-nitro-L-arginine methyl ester (L-NAME), L-arginine, or sodium nitroprusside (SNP) intravenously before cooling. A substantial impairment of oxygen delivery and development of hypoxia, with an important contribution of HOA into the latter accompanied the deep hypothermia in rats. All the experimental groups developed metabolic acidosis, less pronounced in rats treated with L-arginine only. In the experiments with a modification of the L-arginine-NO pathway, an enhanced cold resistance, attenuated oxygen deficiency, and a weaker oxyhemoglobin dissociation curve (ODC) shift leftwards were observed only after the administration of L-arginine. Neither SNP nor L-NAME had not any protective effects. L-Arginine lowered the value of standard P50 (pO2, corresponding to 50% Hb saturation with oxygen at 37 degrees C, pH 7.4, and pCO2 = 40 mmHg). The actual P50 (at actual pH, pCO2 and temperature) decreased by approximately 15 mmHg and was significantly higher than that under hypothermia without the drug treatment (21.03 +/- 0.35 vs 17.45 +/- 0.60 mmHg). NO also can contribute to this system through different mechanisms (HOA modification, vascular tone regulation, peroxynitrite formation, and effects).     

The flow of sickle-cell blood in the capillaries.

Oxygen tension levels and red cell velocities for the flow of sickle-cell blood in the capillaries are determined by using the Krogh model for oxygen transport and lubrication theory for the cell motion. The coupling and interaction between these arises from the red cell compliance, which is assumed to vary with the oxygen concentration. Microsieving data is used to establish an upper bound for this relationship. Calculations are carried out for a range of capillary sizes, taking into account the rightward shift of the oxyhemoglobin dissociation curve and the reduced hematocrit of sickle-cell blood, and are compared to, as a base case, the flow of normal blood under normal pressure gradient. The results indicate that under normal pressure gradients the oxygen tensions and cell velocities for sickle blood are considerably higher than for normal blood, thus acting against the tendency for cells to sickle, or significantly change their rheological properties, in the capillaries. Under reduced pressure gradients, however, the concentrations and velocities drop dramatically, adding to the likelihood of such shape or flow property changes.     

The role of the oxygen-binding properties of the blood in maintaining pro-oxidant-antioxidant equilibrium in the body]

Tissue pro-oxidant generation under standard conditions is equilibrated with the activity of intra- and extracellular antioxidants; thus some optimal level of pro-oxidant-antioxidant balance is created. Oxygen-dependent nature of lipid peroxidation processes implicates its complex multilevel regulatory system, where systemic mechanisms may dominate upon the intracellular ones. This suggests a necessity in the investigation of body oxygen transport not only in terms of the requirements of energetic metabolism in electron acceptor but also as a physiological mechanism for antioxidant defense and, in general, as the mechanism involved in a maintenance of pro-oxidant-antioxidant balance. The hemoglobin-oxygen affinity has a special place in a complex antioxidant system hierarchy, because it determines the condition of oxygen diffusion to tissues and ultimately the value of tissue pO2. The blood oxygen-binding properties under different hyperthermic states with or without a correction of hemoglobin-oxygen affinity and L-arginine-NO pathway were shown to be involved into a complex integration with elements of different functional systems and to play an important role in complex physiologic mechanisms for the maintenance of pro-oxidant-antioxidant balance. The oxyhemoglobin dissociation curve shift leftwards may have an adaptive effect under conditions of low oxygen utilization because of limitation of oxygen fraction spent on a free radical generation and the following initiation of lipid peroxidation processes.     

A mathematical model for the computation of the oxygen dissociation curve in human blood

The mathematical relations developed by various researchers for the oxygen dissociation curve are reviewed. Using well-known mechanisms of chemical kinetics of various species in the blood, we have developed a mathematical formula to compute the oxygen dissociation curve in the blood showing its dependence on the pH and PCO2. The functional form, proposed here, is much simpler in comparison to those available in the literature for use in the mathematical modelling of O2 transport in the pulmonary and systemic circulations. In the process, the well-known Hill's equation has been generalized showing an explicit dependence on PCO2 and pH. It is shown that the oxygen dissociation curve computed from our comparatively simpler equation, fits in fairly well with the documented data and shows realistic shift with PCO2 and pH.     

Variations of the sensitivity of the human body to a stable hypoxic stimulus

The individual, age-related, and professional variations of the sensitivity to a stable hypoxic stimulus have been studied in healthy male subjects. Hypoxia was induced using the method of rebreathing with modifications. An algorithm have been suggested for detecting the point when the oxygen saturation level of blood oxyhemoglobin started to decrease in comparison with the initial value upon gradual reduction of the gas in the inhaled air. We have found that age-related differences in the oxyhemoglobin saturation with oxygen under the conditions of hypoxia were nonsignificant in subjects at the ages from 21 to 50 years. At the same time, the average sensitivity to hypoxia in the subjects performing their professional duties in a modified atmosphere (hyperoxia) was lower than in those of the conventional professions.     

Nitric oxide effect on the hemoglobin-oxygen affinity.

The biological roles of nitric oxide (NO)-hemoglobin (Hb) derivatives are obscure. It is proposed that NO can function as an allosteric regulator of hemoglobin oxygen-binding properties. We aimed to estimate the effects of NO donors and NO-synthase substrate (L-arginine) on hemoglobin-oxygen affinity (HOA) in experiments in vitro with the various ratios between NO formed and Hb and various oxygen pressures. HOA index (p50), blood pH, plasma and red blood cell (RBC) concentrations of nitrite/nitrate and methemoglobin amounts were measured after the experiments. In our experiments, blood incubation with NO donors (glyceryltrinitrate, molsidomine, sodium nitroprusside, S-nitrosocysteine) or NO-synthase substrate (L-arginine) did not change HOA even at NO:Hb ratio of 1:1. At the same time our results showed that oxygenated blood incubation with S-nitrosocysteine induced an oxyhemoglobin dissociation curve shift leftwards. This indicates a leading role of met-Hb in a modification of Hb oxygen-binding properties. However other NO-modified forms of hemoglobin (S-nitroso- and nitrosylhemoglobin) also may be involved in the regulation of HOA. The results obtained indicate that nitric oxide can be the allosteric effector of hemoglobin, increasing or decreasing its oxygen affinity - possibly, through the generation of different NO-Hb derivatives.     

Oxygen transport properties of blood in two different bovine breeds

1. The whole oxygen dissociation curve of oxyhemoglobin has been determined in double-muscled cattle of the Belgian White Blue breed and in Friesian cattle of different body weight. 2. In calves, P50 values are low and DPG level is high (4-20 mumol/g Hb). 3. P50 values of 25 +/- 1.4 mm Hg (mean +/- SD) and a level of DPG less than 1.5 mumol/g Hb have been found in animals weighing more than 80 kg. 4. Effects of temperature and pH on the oxygen dissociation curve have been measured at all levels of saturation. The temperature coefficient (dlog P50/dT) and the Bohr effect expressed as dlog P50/dpH were 0.017 and -0.40, respectively. 5. Hematocrit, hemoglobin concentrations and oxygen capacity of hemoglobin have been measured. 6. No difference between both breeds has been observed. 7. These data can be used to correct measured values of oxygen tension for temperature and pH and to measure oxygen content of blood in cattle.     

M?ssbauer study of red blood cells from patients with erythremia

Red blood cell samples from several patients with erythremia have been studied by M?ssbauer spectroscopy. Quadrupole splitting and isomer shift for oxyhemoglobin from erythremic red blood cells and those of oxyhemoglobin from normal ones differ slightly, while these hyperfine parameters for deoxyhemoglobins are the same. An additional component in M?ssbauer spectra of red blood cell samples was observed in some cases of erythremia. It is proposed that this component is related to ferritin-like iron and its content ranged from 13-15% to 5-7%.     

Effects and post-effects of two-hour exhausting exercise on composition and gas transport functions of blood

Eleven male sport students (age 23.3 +/- 1.7 years) exercised for 2 h on a bicycle ergometer (60 rpm), the braking force of which was regulated to yield a constant pulse rate (156 +/- 3 min-1). Before, at end of, and 3 and 6 h after exercise blood was sampled from a cubital vein and an earlobe for measurement of hemoglobin (Hb) concentration, hematocrit (Hct) value, osmolality (Osm), plasma protein (Prot), sodium (Na+), potassium (K+), inorganic phosphate (Pi), and lactate (Lac) concentrations, red cell 2,3-diphosphoglycerate (DPG) and adenosin triphosphate (ATP) concentrations, acid base status and half saturation pressure (P50) of the oxygen dissociation curve. At end of exercise [Hb], Hct, [Prot], Osm, [K+], [Pi] and [Lac] were significantly elevated, pH in ear lobe (+ 0.04) and venous blood (+ 0.08) was also increased by both respiratory and nonrespiratory effects (BE + 1.4 mmol/l). The oxygen dissociation curve showed an unexplained slight right shift (standard P50 + 0.19 kPa). During the post-exercise period most parameters approximated to control values after only 3 h. [Prot] and especially [Pi], however, remained elevated while [DPG] slightly rose during the post-exercise period. It is suggested that these changes are first signs of adaptation to exercise, perhaps caused by endocrine stimulation.     

High hemoglobin affinity to oxygen and its relationships with lipid peroxidation during fever

The effects of high hemoglobin-oxygen affinity (HOA) on rectal temperature and lipid free radical oxidation were investigated in red blood cells, heart, liver and kidneys of male rats during fever. Fever was induced by intraperitoneal injection of Salmonella typhi lipopolysaccharide (LPS; 5.0 mg kg(-1)). HOA was increased by addition of 0.5% sodium cyanate to drinking water for eight weeks. HOA modification (actual half-saturation oxygen pressure, P50act, decreased to 23.3+/-0.7 vs. 31.6+/-0.7 Torr in control; p < 0.001) weakened a febrile response: rise of temperature after 4 hours was 0.79+/-0.2 degrees C vs. 1.38+/-0.1 degrees C in rats with normal HOA (p < 0.05). In red cells and tissues of rats with normal HOA, concentrations of conjugated dienes and Schiff bases increased during fever, and alpha-tocopherol level and catalase activity decreased. Rats with increased HOA had an inverse pattern of such changes. Changes in rectal temperature and markers of free radical oxidation correlated with a shift of oxyhemoglobin dissociation curve leftwards. The present results indicate that the intentional increment of HOA may substantially diminish lipid peroxidation activity, increase the body antioxidant content during fever and decrease the febrile response on LPS.