книги студ / color atlas of physiology 5th ed[1]. (a. despopoulos et al, thieme 2003)

Binding and Transport of O2 in Blood

Hemoglobin (Hb) is the O2-carrying protein of red blood cells (RBCs) (mol. mass: 64 500 Da). Hb is also involved in CO2 transport and is an important blood pH buffer (!pp. 124 and 138ff.). Hb is a tetramer with 4 subunits (adults: 98%: 2α + 2" = HbA; 2% 2α + 2δ = HbA2), each with its own heme group. Heme consists of porphyrin and Fe(II). Each of the four Fe(II) atoms (each linked with one histidine residue of Hb) binds reversibly with an O2 molecule. This is referred to as oxygenation (not oxidation) of Hb to oxyhemoglobin (OxyHb). The amount of O2 which combines with Hb depends on the partial pressure of O2 (PO2): oxygen dissociation curve (!A, red line). The curve has a sigmoid shape, because initially bound O2 molecules change the conformation of the Hb tetramer (positive cooperativity) and thereby increase hemoglobin-O2 affinity.

When fully saturated with O2, 1 mol of tetrameric Hb combines with 4 mol O2, i.e., 64 500 g of Hb combine with 4 !22.4 L of O2. Thus, 1 g Hb can theoretically transport 1.39 mL O2, or 1.35 mL in vivo (Hüfner number). The total Hb concentration of the blood

([Hb]total) is a mean 150 g/L (!p. 88), corresponding to a maximum O2 concentration of

9.1 mmol/L or an O2 fraction of 0.203 L O2/L blood. This oxygen-carrying capacity is a func-

tion of [Hb]total (!A, yellow and purple curves as compared to the red curve).

The O2 content of blood is virtually equivalent to the amount of O2 bound by Hb since only 1.4% of O2 in blood is dissolved at a PO2 of 13.3 kPa (!A, orange line). The solubility coefficient (αO2), which is 10 µmol ! [L of plasma]– 1 ! kPa– 1, is 22 times smaller

than αCO2 (!p. 126).

Oxygen saturation (SO2) is the fraction of Oxy-Hb relative to [Hb]total, or the ratio of actual O2 concentration/ O2-carrying capacity. At normal PO2 in arterial blood (e.g., PaO2 = 12.6 kPa or 95 mmHg), SO2 will reach a saturation plateau at approx. 0.97, while SO2 will still amount to 0.73 in mixed venous blood (PVO2 = 5.33 kPa or 40 mmHg). The venous SO2 values in different organs can vary greatly (!p. 130).

O2 dissociation is independent of total Hb if plotted as a function of SO2 (!B). Changes in O2 affinity to Hb can then be easily identified as shifting of the O2 dissociation curve. A shift to

the right signifies an affinity decrease, and a shift to the left signifies an affinity increase, resulting in flattening and steepening, respectively, of the initial part of the curve. Shifts to the left are caused by increases in pH (with or without a PCO2 decrease) and/or decreases in PCO2, temperature and 2,3-bisphosphoglyc- erate (BPG; normally 1 mol/mol Hb tetramer). Shifts to the right occur due to decreases in pH and/or increases in PCO2, temperature and 2,3- BPG (!B). The half-saturation pressure (P0.5 or

P50) of O2 (!B, dotted lines) is the PO2 at which SO2 is 0.5 or 50%. The P0.5, which is normally 3.6 kPa or 27 mmHg, is a measure of shifting to

the right (P0.5") or left (P0.5#). Displacement of the O2 dissociation curve due to changes in pH and PCO2 is called the Bohr effect. A shift to the right means that, in the periphery (pH#, PCO2"), larger quantities of O2 can be absorbed from the blood without decreasing the PO2, which is the driving force for O2 diffusion (!B, broken lines). A higher affinity for O2 is then re-established in the pulmonary capillaries (pH", PCO2#). A shift to the left is useful when the PAO2 is decreased (e.g., in altitude hypoxia), a situation where arterial SO2 lies to the left of the SO2 plateau.

Myoglobin is an Fe(II)-containing muscle protein that serves as a short-term storage molecule for O2 (!p. 72). As it is monomeric (no positive cooperativity), its O2 dissociation curve at low PO2 is much steeper than that of HbA (!C). Since the O2 dissociation curve of fetal Hb (2α + 2γ = HbF) is also steeper, SO2 values of 45 to 70% can be reached in the fetal umbilical vein despite the low PO2 (3–4 kPa or 22–30 mmHg) of maternal placental blood. This is sufficient, because the fetal [Hb]total is 180 g/L. The carbon monoxide (CO) dissociation curve is extremely steep. Therefore, even tiny amounts of CO in the respiratory air will dissociate O2 from Hb. This can result in carbon monoxide poisoning (!C). Methemoglobin, Met-Hb (normally 1% of Hb), is formed from Hb by oxidation of Fe(II) to Fe(III) either spontaneously or via exogenous oxidants. Met-Hb cannot combine with O2 (!C). Methemoglobin reductase reduces Fe(III) of Met-Hb back to Fe(II); deficiencies of this enzyme can cause methemoglobinemia, resulting in neonatal anoxia.

Internal (Tissue) Respiration, Hypoxia

O2 diffuses from peripheral blood to adjacent tissues and CO2 in the opposite direction (!pp. 20ff. and 106). Since CO2 diffuses much faster (!p. 120), O2 diffusion is the limiting factor. Sufficient O2 delivery is ensured by a dense capillary network with a gas exchange area of about 1000 m2. The diffusion distance

(!R in A) is only 10–25 µm. The driving force for diffusion is the difference in partial pressures of oxygen ( PO2) in capillary blood and mitochondria, where the PO2 must not fall below 0.1 kPa !1 mmHg. Since PO2 decreases with distance parallel and perpendicular to the course of capillaries, the O2 supply to cells at the venous end far away from the capillaries (large R) is lowest, as shown using Krogh’s cylinder model (!A1). Since these cells are also the first to be affected by oxygen deficiency (hypoxia), this is sometimes called the “lethal corner” (!A2).

Using Fick’s principle (!p. . 106), oxygen consumption of a given organ, VO2 (in L/min), is calculated as.the difference between the arterial supply (Q ! [O2.]a) and non-utilized. venous O2 volume/time (Q ! [O2]v), where Q is rate of blood flow in the organ (L/min) and [O2] is the

To meet increased O2 demands, Q can therefore be increased by vasodilatation in the organ in question and/or by raising the oxygen extrac-

EO2 varies according to the type and function of the organ under resting conditions: skin 0.04 (4%), kidney 0.07; brain, liver and resting skeletal muscle ca. 0.3, myocardium 0.6. The EO2 of muscle during strenuous exercise can rise to 0.9. Skeletal muscle can therefore meet increased O2 demands by raising the EO2 (0.3 0.9), as can myocardial tissue to a much smaller extent (!p. 210).

Hypoxia. An abnormally reduced O2 supply to tissue is classified as follows:

1. Hypoxic hypoxia (!A2, B1): an insufficient O2 supply reaches the blood due, for ex-

ample, to decreased atmospheric PO2 at high altitudes (!p. 136), reduced alveolar ventilation, or impaired alveolar gas exchange.

2.Anemic hypoxia (!B2): reduced O2-car- rying capacity of blood (!p. 128), e.g., due to decreased total Hb in iron deficiency anemia (!p. 90).

3.Stagnant or ischemic hypoxia (!B3): in-

sufficient O2 reaches. the tissue due to reduced blood flow (Q"). The cause can be systemic (e.g., heart failure) or local (e.g., obstructed artery). The reduction of blood flow must be

compensated for by a rise in EO2 to maintain an adequate O2 delivery (see Eq. 5.7). This is not the case in hypoxic and anemic hypoxia. The influx and efflux of substrates and metabolites is also impaired in stagnant hypoxia. Anaerobic glycolysis (!p. 72) is therefore of little help because neither the uptake of glucose nor the discharge of H+ ions dissociated from lactic acid is possible.

4.Hypoxia can also occur when the diffusion distance is increased due to tissue thickening without a corresponding increase in the number of blood capillaries. This results in an insufficient blood supply to

cells lying outside the O2 supply radius (R) of the Krogh cylinder (!A).

5.Histotoxic or cytotoxic hypoxia occurs due to im-

paired utilization of O2 by the tissues despite a sufficient supply of O2 in the mitochondria, as observed in cyanide poisoning. Cyanide (HCN) blocks oxidative cellular metabolism by inhibiting cytochromoxidase.

Brain tissue is extremely susceptible to hypoxia, which can cause critical damage since dead nerve cells generally cannot be replaced. Anoxia, or a total lack of oxygen, can occur due to heart or respiratory failure. The cerebral survival time is thus the limiting factor for overall survival. Unconsciousness occurs after only 15 s of anoxia, and irreparable brain damage occurs if anoxia lasts for more than 3 min or so.

Cyanosis is a bluish discoloration of the skin, lips, nails, etc. due to excessive arterial deoxyhemoglobin ("50 g/L). Cyanosis is a sign of hypoxia in individuals with normal or only moderately reduced total Hb levels. When total Hb is extremely low, O2 deficiencies (anemic hypoxia) can be life-threatening, even in the absence of cyanosis. Cyanosis can occur in absence of significant hypoxia when the Hb level is elevated.

Effects of High Altitude on Respiration

At sea level, the average barometric pressure (PB) !101 kPa (760 mmHg), the O2 fraction in ambient air (FIO2) is 0.209, and the inspiratory partial pressure of O2 (PIO2) !21 kPa (!p. 106). However, PB decreases with increasing altitude (h, in km):

This results in a drop in PIO2 (!A, column 1), alveolar PO2 (PAO2) and arterial PO2 (PaO2). The PAO2 at sea level is about 13 kPa (!A, column 2). PAO2 is an important measure of oxygen supply. If the PAO2 falls below a critical level (ca. 4.7 kPa = 35 mmHg), hypoxia (!p. 130) and impairment of cerebral function will occur. The critical PAO2 would be reached at heights of about 4000 m above sea level during normal ventilation (!A, dotted line in column 2). However, the low PaO2 triggers chemosensors

ventilation (!A, column 4). As a result, larger volumes of CO2 are exhaled, and the PACO2 and PaCO2 decrease (see below). As described by the alveolar gas equation,

(!pp. 120 and 228), any fall in PACO2 will lead to a rise in the PAO2. O2 deficiency ventilation stops the PAO2 from becoming critical up to altitudes of about 7000 m (altitude gain, !A).

The maximal increase in ventilation (!3 " resting rate) during acute O2 deficiency is relatively small compared to the increase (!10 times the resting rate) during strenuous physical exercise at normal altitudes (!p. 74, C3) because increased ventilation at high altitudes reduces the PaCO2 (= hyperventilation, !p. 108), resulting in the development of respiratory alkalosis (!p. 144). Central chemosensors (!p. 132) then emit signals to lower the respiratory drive, thereby counteracting the signals from O2 chemosensors to increase the respiratory drive. As the mountain climber adapts, respiratory alkalosis is compensated for by increased renal excretion of HCO3– (!p. 144). This helps return the pH of the blood toward normal, and the O2 deficiencyrelated increase in respiratory drive can now

prevail. Stimulation of O2 chemosensors at high altitudes also leads to an increase in the heart rate and a corresponding increase in cardiac output, thereby increasing the O2 supply to the tissues.

High altitude also stimulates erythropoiesis (!p. 88ff.). Prolonged exposure to high altitudes increases the hematocrit levels, although this is limited by the corresponding rise in blood viscosity (!pp. 92, 188).

Breathing oxygen from pressurized O2 cylinders is necessary for survival at altitudes above 7000 m, where PIO2 is almost as high as the barometric pressure PB (!A, column 3). The critical PAO2 level now occurs at an altitude of about 12 km with normal ventilation, and at about 14 km with increased ventilation. Modern long-distance planes fly slightly below this altitude to ensure that the passengers can survive with an oxygen mask in case the cabin pressure drops unexpectedly.

Survival at altitudes above 14 km is not possible without pressurized chambers or pressurized suits like those used in space travel. Otherwise, the body fluids would begin to boil at altitudes of 20 km or so (!A), where PB is lower than water vapor pressure at body temperature (37 #C).

Oxygen Toxicity

Hyperoxia occurs when PIO2 is above normal ($22 kPa or 165 mmHg) due to an increased O2 fraction (oxygen therapy) or to an overall pressure increase with a normal O2 fraction (e.g. in diving, !p. 134). The degree of O2 toxicity depends on the PIO2 level (critical: ca. 40 kPa or 300 mmHg) and duration of hyperoxia. Lung dysfunction (!p. 118, surfactant deficiency) occurs when a PIO2 of about 70 kPa (525 mmHg) persists for several days or 200 kPa (1500 mmHg) for 3–6 hours. Lung dysfunction initially manifests as coughing and painful breathing. Seizures and unconsciousness occur at PIO2 levels above 220 kPa (1650 mmHg), e.g., when diving at a depth of about 100 m using pressurized air.

Newborns will go blind if exposed to PIO2 levels much greater than 40 kPa (300 mmHg) for long periods of time (e.g., in an incubator), because the vitreous body then opacifies.

(km)Altitude 18

16

14

12

10

8

6

4

2

0

Boiling point of body fluids at 37°C

Maximum altitude

when breathing O2

Increased ventilation

when breathing O2

Maximum altitude when breathing air

Increased ventilation when breathing air

Inspiratory pressures

1

Barometric pressure

PIO2 when breathing O2

PIO2 when breathing air