Blood HbO<Subscript>2</Subscript> and HbCO<Subscript>2</Subscript> Dissociation Curves at Varied O<Subscript>2</Subscript>, CO<Subscript>2</Subscript>, pH, 2,3-DPG and Temperature Levels

New mathematical model equations for O₂ and CO₂ saturations of hemoglobin (S_HbO2 and S_HbCO2) are developed here from the equilibrium binding of O₂ and CO₂ with hemoglobin inside RBCs. They are in the form of an invertible Hill-type equation with the apparent Hill coefficients _KHbO2 and K_HbCO2 in the expressions for S_HbO2 and S_HbCO2 dependent on the levels of O₂ and CO₂ partial pressures (P_O2 and P_CO2), pH, 2,3-DPG concentration, and temperature in blood. The invertibility of these new equations allows P_O2 and P_CO2 to be computed efficiently from S_HbO2 and S_HbCO2 and vice-versa. The oxyhemoglobin (HbO₂) and carbamino-hemoglobin (HbCO₂) dissociation curves computed from these equations are in good agreement with the published experimental and theoretical curves in the literature. The model solutions describe that, at standard physiological conditions, the hemoglobin is about 97.2% saturated by O₂ and the amino group of hemoglobin is about 13.1% saturated by CO₂. The O₂ and CO₂ content in whole blood are also calculated here from the gas solubilities, hematocrits, and the new formulas for S_HbO2 and S_HbCO2. Because of the mathematical simplicity and invertibility, these new formulas can be conveniently used in the modeling of simultaneous transport and exchange of O₂ and CO₂ in the alveoli-blood and blood-tissue exchange systems.     

<Emphasis Type="Italic">V</Emphasis>O<Subscript>2</Subscript>max during successive maximal efforts

The concept of VO₂max has been a defining paradigm in exercise physiology for >75 years. Within the last decade, this concept has been both challenged and defended. The purpose of this study was to test the concept of VO₂max by comparing VO₂ during a second exercise bout following a preliminary maximal effort exercise bout. The study had two parts. In Study #1, physically active non-athletes performed incremental cycle exercise. After 1-min recovery, a second bout was performed at a higher power output. In Study #2, competitive runners performed incremental treadmill exercise and, after 3-min recovery, a second bout at a higher speed. In Study #1 the highest VO₂ (bout 1 vs. bout 2) was not significantly different (3.95 ± 0.75 vs. 4.06 ± 0.75 l min⁻¹). Maximal heart rate was not different (179 ± 14 vs. 180 ± 13 bpm) although maximal V _E was higher in the second bout (141 ± 36 vs. 151 ± 34 l min⁻¹). In Study #2 the highest VO₂ (bout 1 vs. bout 2) was not significantly different (4.09 ± 0.97 vs. 4.03 ± 1.16 l min⁻¹), nor was maximal heart rate (184 + 6 vs. 181 ± 10 bpm) or maximal V _E (126 ± 29 vs. 126 ± 34 l min⁻¹). The results support the concept that the highest VO₂ during a maximal incremental exercise bout is unlikely to change during a subsequent exercise bout, despite higher muscular power output. As such, the results support the “classical” view of VO₂max.     

Mitochondrial coupling in humans: assessment of the P/O<Subscript>2</Subscript> ratio at the onset of calf exercise

Coupling of oxidation to ATP synthesis (P/O₂ ratio) is a critical step in the conversion of carbon substrates to fuel (ATP) for cellular activity. The ability to quantitatively assess mitochondrial coupling in vivo can be a valuable tool for basic research and clinical purposes. At the onset of a square wave moderate exercise, the ratio between absolute amount of phosphocreatine split and O₂ deficit (corrected for the amount of O₂ released from the body O₂ stores and in the absence of lactate production), is the mirror image of the P/O₂ ratio. To calculate this value, cardiac output whole body O₂ uptake O₂ deficit and high-energy phosphates concentration (by ³¹P-NMR spectroscopy) in the calf muscles were measured on nine healthy volunteers at rest and during moderate intensity plantar flexion exercise (3.44 ± 0.73 W per unit active muscle mass). and increased (from 4.68 ± 1.56 to 5.83 ± 1.59 l min⁻¹ and from 0.28 ± 0.05 to 0.48 ± 0.09 l min⁻¹, respectively), while phosphocreatine (PCr) concentration decreased significantly (22 ± 6%) from rest to steady-state exercise. For each volunteer, “gross” was corrected for the individual changes in the venous blood O₂ stores yielding the “net” . Resting PCr concentration was estimated from the appropriate spectroscopy data. The so calculated P/O₂ ratio amounted on average to 4.24 ± 0.13 and was, in all nine subjects, very close to the literature values obtained directly on intact skeletal muscle. This unfolds the prospect of a non-invasive tool to quantitatively study mitochondrial coupling in vivo.     

Disequilibrium Between Alveolar and End-Pulmonary-Capillary O<Subscript>2</Subscript> Tension in Altitude Hypoxia and Respiratory Disease: An Update of a Mathematical Model of Human Respiration at Altitude

We have previously formulated and validated a mathematical model specifically designed to describe human respiratory behavior at altitude. In that model, we assumed equality of alveolar and end-pulmonary-capillary oxygen tensions. However, this equality may not hold true during rapid and prolonged changes to high altitudes producing severe hypoxia as can occur in aircraft cabin decompressions and in some respiratory diseases. We currently investigate this possibility by modifying our previous model to include the dynamics of oxygen exchange across the pulmonary capillary. The updated model was validated against limited experimental data on ventilation and gas tensions in various altitude-decompression scenarios. The updated model predicts that during rapid and sustained decompressions to high altitudes the disequilibrium of gas tensions between alveolar gas and capillary blood could be 10 Torr, or larger. Neglecting this effect underestimates the severity of a decompression and its potential to produce unconsciousness and subsequent brain damage. In light of these results, we also examined the effect of this disequilibrium on the diminished oxygen diffusion capacity that can occur in some respiratory diseases. We found that decreases in diffusion capacity which would have minimal effects at sea level produced significant disequilibrium of gas tensions and a large fall in hemoglobin oxygen saturation at a cabin altitude of 4000–8000 ft. As demonstrated, this new model could serve as an important tool to examine the important physiological consequences of decompression scenarios in aircraft and the pathophysiological situations in which the equilibrium of gas tensions along the pulmonary capillary are particularly critical.     

Analysis of Oxygen Transport to Hepatocytes in a Flat-Plate Microchannel Bioreactor

Oxygen transfer to cultured hepatocytes in microchannel parallel-plate bioreactors with and without an internal membrane oxygenator was investigated with a mathematical model and the results were corroborated with fluorescence imaging experiments. The consumption of oxygen by hepatocytes was assumed to follow Michaelis–Menten kinetics. Our simulations indicate that under conditions of low Péclet (Pe) number (<80) and fixed Damkohler number (=0.14, corresponding to rat hepatocytes) the cells are hypoxic in the bioreactor without an internal membrane oxygenator. Under the same conditions, the bioreactor with an internal membrane oxygenator can avoid cell hypoxia by appropriate selection of membrane Sherwood number and/or the gas phase oxygen partial pressure, thus providing greater control of cell oxygenation. At high Pe, both bioreactors are well oxygenated. Experimentally determined oxygen concentrations within the bioreactors were in good qualitative agreement with model predictions. At low Pe, cell surface oxygen depletion was predicted from analytically derived criteria. Hepatocytes with oxygen dependent functional heterogeneity may exhibit optimal function in the bioreactor with the internal membrane oxygenator. © 2001 Biomedical Engineering Society.PAC01: 8717Aa, 8780-y     

Central circulatory and peripheral O<Subscript>2</Subscript> extraction changes as interactive facilitators of pulmonary O<Subscript>2</Subscript> uptake during a repeated high-intensity exercise protocol in humans

It has frequently been demonstrated that prior high-intensity exercise facilitates pulmonary oxygen uptake response at the onset of subsequent identical exercise. To clarify the roles of central O₂ delivery and/or peripheral O₂ extraction in determining this phenomenon, we investigated the relative contributions of cardiac output (CO) and arteriovenous O₂ content difference to the transient during repeated bouts of high-intensity knee extension (KE) exercise. Nine healthy subjects volunteered to participate in this study. The protocol consisted of two consecutive 6-min KE exercise bouts in a supine position (work rate 70–75% of peak power) separated by 6 min of rest. Throughout the protocol, continuous-wave Doppler ultrasound was used to measure beat-by-beat CO (i.e., via simultaneous measurement of stroke volume and the diameter of the arterial aorta). The phase II response was significantly faster and the slow component (phase III) was significantly attenuated during the second KE bout compared to the first. This was a result of increased CO during the first 30 s of exercise: CO contributing to 100 and 56% of the speeding at 10 and 30 s, respectively. After this, the contribution of became increasingly more predominant: being responsible to an estimated 64% of the speeding at 90 s, which rose to 100% by 180 s. This suggests that, while both CO and clearly interact to determine the response, the speeding of kinetics by prior high-intensity KE exercise is predominantly attributable to increases in .     

Identification of <Emphasis Type="Italic">I</Emphasis><Subscript>Kr</Subscript> Kinetics and Drug Binding in Native Myocytes

Determining the effect of a compound on I _Kr is a standard screen for drug safety. Often the effect is described using a single IC₅₀ value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of I _Kr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on I _Kr. I _Kr was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from −70 to −20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published I _Kr Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on I _Kr I–V relation and I _Kr inactivation. The method produced models that quantitatively reproduce both the control I _Kr kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC₅₀ method. Although the method was developed for I _Kr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Effect of Nanodisperse Ferrite Cobalt (CoFe<Subscript>2</Subscript>O<Subscript>4</Subscript>) Particles on Contractile Reactions in Guinea Pigs Airways

The effect of nanopowder CoFe₂O₄ on contractile responses of smooth-muscle segments of guinea pigs airways was studied by mechanography. Both in vivo inhalation of nanopowder aerosol or in vitro application of nanopowder to isolated airway segments increased the amplitude of contractile responses to histamine and potentiated the dilatory reaction to adrenergic salbutamol.     

Effects of Autoregulation and CO<Subscript>2</Subscript> Reactivity on Cerebral Oxygen Transport

Both autoregulation and CO₂ reactivity are known to have significant effects on cerebral blood flow and thus on the transport of oxygen through the vasculature. In this paper, a previous model of the autoregulation of blood flow in the cerebral vasculature is expanded to include the dynamic behavior of oxygen transport through binding with hemoglobin. The model is used to predict the transfer functions for both oxyhemoglobin and deoxyhemoglobin in response to fluctuations in arterial blood pressure and arterial CO₂ concentration. It is shown that only six additional nondimensional groups are required in addition to the five that were previously found to characterize the cerebral blood flow response. A resonant frequency in the pressure-oxyhemoglobin transfer function is found to occur in the region of 0.1 Hz, which is a frequency of considerable physiological interest. The model predictions are compared with results from the published literature of phase angle at this frequency, showing that the effects of changes in breathing rate can significantly alter the inferred phase dynamics between blood pressure and hemoglobin. The question of whether dynamic cerebral autoregulation is affected under conditions of stenosis or stroke is then examined.     

Pathways for the bradykinin B<Subscript>1</Subscript> receptor-mediated diabetic hyperalgesia in mice

Objective: Experimental evidence has shown that the bradykinin B₁ receptor (BKB₁-R) is involved in the development of hyperalgesia associated with diabetes since specific BKB₁-R antagonists significantly inhibited the hyperalgesic activity observed in streptozotocin (STZ)-mice in thermal nociceptive tests.Materials and methods: The involvement of the nitric oxide (NO), the substance P (SP) and the calcitonin gene-related peptide (CGRP) pathways in mediating BKB₁-R-induced hyperalgesia was evaluated. Diabetes was induced in male CD-1 mice by injecting STZ (200 mg/kg; i.p.). Nociception was assessed using the hot plate and tail immersion tests, one week following the injection of STZ.Results: The nitric oxide synthase (NOS) inhibitors (L-NNA, 20 mg/kg; L-NMMA, 30 mg/kg and AGUA, 50 mg/kg; i.p.), the SP antagonists (sendide and L-732,138, 100 g/kg; i.v.) and the CGRP antagonist (hCGRP8-37, 100 g/kg; i.v.) significantly attenuated the hyperalgesic activity and also reversed the potentiating effect of the BKB₁- R agonist, DBK on diabetic hyperalgesia in STZ-mice.Conclusions: These results support the involvement of BKB₁-R in the development of diabetic hyperalgesia in STZ-mice through activation of the NO, SP and CGRP pathways.Received 5 December 2003; returned for revision 21 January 2004; returned for final revision 24 May 2004; accepted by N. Boughton-Smith 15 July 2004     

Anti-oxidative effects of the biennial flower of <Emphasis Type="Italic">Panax notoginseng</Emphasis> against H<Subscript>2</Subscript>O<Subscript>2</Subscript>-induced cytotoxicity in cultured PC12 cells

Background  

Radix notoginseng is used in Chinese medicine to improve blood circulation and clotting; however, the pharmacological activities of other parts of Panax notoginseng have yet to be explored. The present study reports the anti-oxidative effects of various parts of Panax notoginseng.     

Validity of criteria for establishing maximal O<Subscript>2</Subscript> uptake during ramp exercise tests

The incremental or ramp exercise test to the limit of tolerance has become a popular test for determination of maximal O₂ uptake However, many subjects do not evidence a definitive plateau of the -work rate relationship on this test and secondary criteria based upon respiratory exchange ratio (RER), maximal heart rate (HR_max) or blood [lactate] have been adopted to provide confidence in the measured We hypothesized that verification of using these variables is fundamentally flawed in that their use could either allow underestimation of (if, for any reason, a test were ended at a sub-maximal ), or alternatively preclude subjects from recording a valid Eight healthy male subjects completed a ramp exercise test (at 20 W/min) to the limit of tolerance on an electrically braked cycle ergometer during which pulmonary gas exchange was measured breath-by-breath and blood [lactate] was determined every 90 s. Using the most widely used criterion values of RER (1.10 and 1.15), as determined during the ramp test (4.03 ± 0.10 l/min) could be undermeasured by 27% (2.97 ± 0.24 l/min) and 16% (3.41 ± 0.15 l/min), respectively (both P < 0.05). The criteria of HR_max (age predicted HR_max ± 10 b/min) and blood [lactate] (≥8 mM) were untenable because they resulted in rejection of 3/8 and 6/8 of the subjects, most of whom (5/8) had demonstrated a plateau of at These findings provide a clear mandate for rejecting these secondary criteria as a means of validating on ramp exercise tests.     

Biotransformation of ginsenosides Rb<Subscript>1</Subscript>, Rg<Subscript>3</Subscript> and Rh<Subscript>2</Subscript> in rat gastrointestinal tracts

Background  

Ginsenosides such as Rb₁, Rg₃ and Rh₂ are major bioactive components of Panax ginseng. This in vivo study investigates the metabolic pathways of ginsenosides Rb₁, Rg₃ and Rh₂ orally administered to rats.     

Influence of training status and exercise modality on pulmonary O<Subscript>2</Subscript> uptake kinetics in pubertal girls

The influence of training status on the oxygen uptake ( [(V)\dot]\textO ₂ \dot{V}{\text{O}}_{ 2} ) response to heavy intensity exercise in pubertal girls has not previously been investigated. We hypothesised that whilst training status-related adaptations would be evident in the [(V)\dot]\textO ₂ \dot{V}{\text{O}}_{ 2} , heart rate (HR) and deoxyhaemoglobin ([HHb]) kinetics of pubertal swimmers during both lower and upper body exercise, they would be more pronounced during upper body exercise. Eight swim-trained (T; 14.2 ± 0.7 years) and eight untrained (UT; 14.5 ± 1.3 years) girls completed a number of constant-work-rate transitions on cycle and upper body ergometers at 40% of the difference between the gas exchange threshold and peak [(V)\dot]\textO ₂ \dot{V}{\text{O}}_{ 2} . The phase II [(V)\dot]\textO ₂ \dot{V}{\text{O}}_{ 2} time constant (τ) was significantly shorter in the trained girls during both cycle (T: 21 ± 6 vs. UT: 35 ± 11 s; P < 0.01) and upper body exercise (T: 29 ± 8 vs. UT: 44 ± 8 s; P < 0.01). The [(V)\dot]\textO ₂ \dot{V}{\text{O}}_{ 2} slow component was not influenced by training status. The [HHb] τ was significantly shorter in the trained girls during both cycle (T: 12 ± 2 vs. UT: 20 ± 6 s; P < 0.01) and upper body exercise (T: 13 ± 3 vs. UT: 21 ± 7 s; P < 0.01), as was the HR τ (cycle, T: 36 ± 5 vs. UT: 53 ± 9 s; upper body, T: 32 ± 3 vs. UT: 43 ± 2; P < 0.01). This study suggests that both central and peripheral factors contribute to the faster [(V)\dot]\textO ₂ \dot{V}{\text{O}}_{ 2} kinetics in the trained girls and that differences are evident in both lower and upper body exercise.     

Effect of prostaglandins E<Subscript>2</Subscript> and D<Subscript>2</Subscript> on presynaptic NMDA receptors in rat cerebral cortex

We studied the effect of prostaglandins on presynaptic NMDA receptors. Prostaglandin E₂ inhibited NMDA-induced ⁴⁵Ca²⁺ uptake by synaptosomes in low concentrations (IC₅₀ ∼10 μM), but potentiated it in higher concentrations. Prostaglandin D₂ increased ⁴⁵Ca²⁺ uptake by synaptosomes during stimulation of NMDA receptors. Our results indicate that prostaglandins D₂ and E₂ modulate function of presynaptic NMDA receptors. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 9, pp. 271–273, September, 2007     

Effect of NO-generating compound NaNO<Subscript>2</Subscript> on ultrastructure of synaptic vesicles of glutamatergic synapses

Ultrastructure of synaptic vesicles in axon terminals of granule cells from isolated cerebellum of Rana temporaria frogs under the influence of NO-generating compound NaNO₂ in various concentrations and electrical stimulation was evaluated by the method of electron microscopy. NO-generating compound in low concentration induced translocation of synaptic vesicles and formation of small clusters. The size and structure of synaptic vesicles remained unchanged under these conditions. Increasing the concentration of NaNO₂ led to swelling of synaptic vesicles, formation of arranged heaps from individual vesicles or fusion of their content. Electrical stimulation of the cerebellum in the presence of NaNO₂ increased damage to synaptic vesicles. These experimental data model some stages observed in stroke. The formation of clusters from synaptic vesicles is a compensatory and adaptive response maintaining the structure of synaptic vesicles and protecting neurons from high concentrations of glutamate. Glutamate produces a toxic effect on nerve cells and glial cells of the cerebellum under pathological conditions, which is accompanied by impairment of signal transduction from presynaptic to postsynaptic neurons. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 146, No. 7, pp. 13–17, July, 2008     

Longitudinal changes in haemoglobin mass and <Emphasis Type="Italic">V</Emphasis>O<Subscript>2max</Subscript> in adolescents

This study assessed the relationship between haemoglobin mass (Hb_mass) and maximum oxygen consumption (VO_2max) in adolescents over 1 year. Twenty-three subjects (11–15 years) participated; 12 undertook ~12 months of cycle training (cyclists) and 11 were sedentary (controls). Hb_mass and VO_2max were measured approximately every 3 months. At baseline there was a high correlation (r = 0.82, P < 0.0001) between relative VO_2max (ml kg⁻¹ min⁻¹) and relative Hb_mass (g kg⁻¹). During 12 months there was a significant increase in relative VO_2max of the cyclists but not the controls; however, there was no corresponding increase in relative Hb_mass of either group. The correlation between percent changes in relative VO_2max and relative Hb_mass was not significant for cyclists (r = 0.31, P = 0.33) or controls (r = 0.42, P = 0.19). Training does not increase relative Hb_mass in adolescents consistent with a strong hereditary role for Hb_mass and VO_2max. Hb_mass may be used to identify adolescents who have a high VO_2max.     

Immunosuppressive Effects of Multipotent Mesenchymal Stromal Cells in Cultures with Different O<Subscript>2</Subscript> Content in the Medium

We studied the effects of multipotent mesenchymal stromal cells isolated from the adipose tissue on proliferation and viability of immunocompetent cells at different concentration of O₂ (5 and 20%) in culture medium. It was shown that co-culturing with multipotent mesenchymal stromal cells 3-fold reduced proliferative index of phytohemagglutinin-activated lymphocytes, while their viability remained unchanged and did not depend on partial oxygen pressure in the medium. These findings suggest that low O₂ concentration in tissues will not affect immunosuppressive properties of multipotent mesenchymal stromal cells, which is very important for their application in regenerative medicine.     

Skeletal muscle StO<Subscript>2</Subscript> kinetics are slowed during low work rate calf exercise in peripheral arterial disease

The time course of muscle oxygen desaturation (StO₂ kinetics) following exercise onset reflects the dynamic interaction between muscle blood flow and muscle oxygen consumption. In patients with peripheral arterial disease (PAD), muscle StO₂ kinetics are slowed during walking exercise; potentially reflecting altered muscle oxygen consumption relative to blood flow. This study evaluated whether StO₂ kinetics measured using near infrared spectroscopy (NIRS) would be slowed in PAD during low work rate calf exercise compared with healthy subjects under conditions in which blood flow did not differ. Eight subjects with PAD and eight controls performed 3 min of calf exercise at 5, 10, 30, and 50% of maximal voluntary contraction (MVC). Calf blood flow responses were measured by plethysmography. Power outputs were similar between groups for all work rates. In PAD, the time constants of StO₂ kinetics were significantly slower than controls during 5% MVC (13.5 ± 1.7 vs. 6.9 ± 1.2 s, P < 0.05) and 10% MVC work rates (14.5 ± 2.7 vs. 6.8 ± 1.1 s, P < 0.05). Blood flow assessed when exercise was interrupted after 30 s did not differ between PAD and control subjects at these work rates. In contrast, the StO₂ time constants were not different between groups during 30 and 50% MVC work rates, where blood flow responses in PAD subjects were lower as compared with controls. Thus in PAD, the slowed StO₂ kinetic responses under conditions of unimpaired calf blood flow reflect slowed muscle oxygen consumption in PAD skeletal muscle during low work rate plantar flexion exercise as compared with healthy skeletal muscle.