Guyton and Hall Physiology Chapter 41 PDF

CHAPTER 41 UNIT VII Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Once oxygen (O2) has diffused from the alveoli into the...

CHAPTER 41 UNIT VII Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Once oxygen (O2) has diffused from the alveoli into the diffusion of O2 between alveolar air and pulmonary pulmonary blood, it is transported to the tissue capillaries blood. The Po2 of the gaseous O2 in the alveolus aver- almost entirely in combination with hemoglobin. The pres- ages 104 mm Hg, whereas the Po2 of the venous blood ence of hemoglobin in the red blood cells allows the blood entering the pulmonary capillary at its arterial end to transport 30 to 100 times as much O2 as could be trans- averages only 40 mm Hg because a large amount ported in the form of dissolved O2 in the water of the blood. of O2 was removed from this blood as it passed through In the body’s tissue cells, O2 reacts with various food- the peripheral tissues. Therefore, the initial pressure stuffs to form large quantities of carbon dioxide (CO2). difference that causes O2 to diffuse into the pulmonary This CO2 enters the tissue capillaries and is transported capillary is 104 − 40 mm Hg, or 64 mm Hg. In the back to the lungs. Carbon dioxide, like O2, also combines graph at the bottom of the figure, the curve shows the with chemical substances in the blood that increase CO2 rapid rise in blood Po2 as the blood passes through transport 15- to 20-fold. the capillary; the blood Po2 rises almost to that of the This chapter presents the physical and chemical prin- alveolar air by the time the blood has moved a third of ciples of O2 and CO2 transport in the blood and tissue the distance through the capillary, becoming almost 104 fluids qualitatively and quantitatively. mm Hg. Uptake of Oxygen by the Pulmonary Blood During TRANSPORT OF OXYGEN FROM THE Exercise. During strenuous exercise, a person’s body LUNGS TO THE BODY TISSUES may require as much as 20 times the normal amount In Chapter 40, we pointed out that gases can move from of oxygen. Also, because of increased cardiac output one point to another by diffusion, and that the cause of during exercise, the time that the blood remains in the this movement is always a partial pressure difference from pulmonary capillary may be reduced to less than one- the first point to the next. Thus, O2 diffuses from the alve- half normal. Yet, because of the great safety factor for oli into the pulmonary capillary blood because the oxygen diffusion of O2 through the pulmonary membrane, the partial pressure (Po2) in the alveoli is greater than the Po2 blood still becomes almost saturated with O2 by the time in the pulmonary capillary blood. In the other tissues of it leaves the pulmonary capillaries. This can be explained the body, a higher Po2 in the capillary blood than in the as follows. tissues causes O2 to diffuse into the surrounding cells. First, in Chapter 40, we pointed out that the diffusing Conversely, when O2 is metabolized in the cells to capacity for O2 increases almost threefold during exer- form CO2, the intracellular CO2 partial pressure (Pco2) cise. This results mainly from increased surface area of rises, causing CO2 to diffuse into the tissue capillaries. capillaries participating in the diffusion and also from a After blood flows to the lungs, the CO2 diffuses out of the more nearly ideal ventilation-perfusion ratio in the upper blood into the alveoli because the Pco2 in the pulmonary part of the lungs. capillary blood is greater than that in the alveoli. Thus, the Second, note in the curve of Figure 41-1 that under transport of O2 and CO2 by the blood depends on both nonexercising conditions, the blood becomes almost diffusion and the flow of blood. We now consider quanti- saturated with O2 by the time it has passed through tatively the factors responsible for these effects. one-third of the pulmonary capillary, and little additional O2 normally enters the blood during the latter two-thirds DIFFUSION OF OXYGEN FROM THE of its transit. That is, the blood normally stays in the lung ALVEOLI TO THE PULMONARY CAPILLARY capillaries about three times as long as needed to cause BLOOD full oxygenation. Therefore, during exercise, even with a The top part of Figure 41-1 shows a pulmonary alveo- shortened time of exposure in the capillaries, the blood lus adjacent to a pulmonary capillary, demonstrating can still become almost fully oxygenated. 521 UNIT VII Respiration Alveolus PO2 = 104 mm Hg Arterial end Venous end of capillary 40 mm Hg of capillary Pulmonary capillary PO2 = 95 mm Hg 23 mm Hg PO2 = 40 mm Hg PO2 = 40 mm Hg PO2 = 104 mm Hg Arterial end Venous end 110 Alveolar oxygen partial pressure Figure 41.3 Diffusion of oxygen from a peripheral tissue capillary to 100 the cells. (PO2 in interstitial fluid = 40 mm Hg; in tissue cells, PCO2 = Blood PO2 (mm Hg) 23 mm Hg.) 90 2 O dP 80 100 Upper limit of infinite blood flow o tion Blo 70 sump Interstitial fluid PO2 (mm Hg) con 80 O 2 60 al ption m sum co n or /4 n 50 al O 2 B 60 rm 1 N o 40 tion ump Figure 41-1 Uptake of oxygen by the pulmonary capillary blood. (Data 40 cons A al O 2 from Milhorn HT Jr, Pulley PE Jr: A theoretical study of pulmonary capil- lary gas exchange and venous admixture. Biophys J 8:337, 1968.) n orm 20 4× C Mixed with pulmonary 0 shunt blood 0 100 200 300 400 500 600 700 100 Blood flow (percent of normal) Systemic venous blood Figure 41-4 Effect of blood flow and rate of oxygen consumption 80 on tissue PO2. PO2 (mm Hg) Pulmonary Systemic Systemic Systemic 60 capillaries arterial capillaries venous blood blood DIFFUSION OF OXYGEN FROM THE 40 PERIPHERAL CAPILLARIES INTO THE TISSUE FLUID 20 When the arterial blood reaches the peripheral tissues, its Po2 in the capillaries is still 95 mm Hg. Yet, as shown 0 in Figure 41-3, the Po2 in the interstitial fluid that sur- Figure 41-2 Changes in PO2 in the pulmonary capillary blood, sys- rounds the tissue cells averages only 40 mm Hg. Thus, temic arterial blood, and systemic capillary blood demonstrating the there is a large initial pressure difference that causes O2 to effect of venous admixture. diffuse rapidly from the capillary blood into the tissues— so rapidly that the capillary Po2 falls almost to equal the TRANSPORT OF OXYGEN IN ARTERIAL 40-mm Hg pressure in the interstitium. Therefore, the BLOOD Po2 of the blood leaving the tissue capillaries and entering About 98% of the blood that enters the left atrium from the systemic veins is also about 40 mm Hg. the lungs has just passed through the alveolar capillaries and has become oxygenated up to a Po2 of about 104 Increasing Blood Flow Raises Interstitial Fluid Po2. If the mm Hg. Another 2% of the blood has passed from the blood flow through a particular tissue is increased, greater aorta through the bronchial circulation, which supplies quantities of O2 are transported into the tissue, and the tissue mainly the deep tissues of the lungs and is not exposed Po2 becomes correspondingly higher. This effect is shown in to lung air. This blood flow is called shunt flow, meaning Figure 41-4. Note that an increase in flow to 400% of normal that blood is shunted past the gas exchange areas. On increases the Po2 from 40 mm Hg (at point A in the figure) leaving the lungs, the Po2 of the shunt blood is approxi- to 66 mm Hg (at point B). However, the upper limit to which mately that of normal systemic venous blood—about 40 the Po2 can rise, even with maximal blood flow, is 95 mm mm Hg. When this blood combines in the pulmonary Hg because this is the O2 pressure in the arterial blood. Con- veins with the oxygenated blood from the alveolar capil- versely, if blood flow through the tissue decreases, the tissue laries, this so-called venous admixture of blood causes Po2 also decreases, as shown at point C. the Po2 of the blood entering the left heart and pumped into the aorta to fall to about 95 mm Hg. These changes Increasing Tissue Metabolism Decreases Interstitial in blood Po2 at different points in the circulatory system Fluid Po2. If the cells use more O2 for metabolism than nor- are shown in Figure 41-2. mal, the interstitial fluid Po2 is reduced. Figure 41-4 also 522  Chapter 41 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids Alveolus PCO2 = 40 mm Hg Arterial end Venous end of capillary 45 mm Hg of capillary Pulmonary capillary PCO2 = 40 mm Hg 46 mm Hg PCO2 = 45 mm Hg PCO2 = 45 mm Hg PCO2 = 40 mm Hg Arterial end Venous end UNIT VII 45 Blood PCO2 (mm Hg) Figure 41-5 Uptake of carbon dioxide by the blood in the tissue cap- 44 illaries. (PCO2 in tissue cells = 46 mm Hg; in interstitial fluid, PCO2 = 45 mm Hg.) 43 42 demonstrates this effect, showing reduced interstitial fluid 41 Po2 when the cellular oxygen consumption is increased Pulmonary capillary blood 40 and increased Po2 when consumption is decreased. Alveolar carbon dioxide partial pressure In summary, tissue Po2 is determined by a balance Figure 41-6 Diffusion of carbon dioxide from the pulmonary blood between (1) the rate of O2 transport to the tissues in the into the alveolus. (Data from Milhorn HT Jr, Pulley PE Jr: A theoretical blood, and (2) the rate at which the O2 is used by the study of pulmonary capillary gas exchange and venous admixture. tissues. Biophys J 8:337, 1968.) DIFFUSION OF OXYGEN FROM 2. Pco2 of the arterial blood entering the tissues, 40 PERIPHERAL CAPILLARIES TO TISSUE CELLS mm Hg; Pco2 of the venous blood leaving the tis- Oxygen is always being used by the cells. Therefore, the sues, 45 mm Hg. Thus, as shown in Figure 41-5, intracellular Po2 in peripheral tissues remains lower than the tissue capillary blood comes almost exactly to the Po2 in peripheral capillaries. Also, in many cases, there equilibrium with the interstitial Pco2 of 45 mm Hg. is considerable physical distance between the capillaries 3. Pco2 of the blood entering the pulmonary capillar- and cells. Therefore, the normal intracellular Po2 ranges ies at the arterial end, 45 mm Hg; Pco2 of the alveo- from as low as 5 mm Hg to as high as 40 mm Hg, averag- lar air, 40 mm Hg. Thus, only a 5 mm Hg pressure ing (by direct measurement in experimental animals) 23 difference causes all the required CO2 diffusion out mm Hg. Because only 1 to 3 mm Hg of O2 pressure is nor- of the pulmonary capillaries into the alveoli. Fur- mally required for full support of the chemical processes thermore, as shown in Figure 41-6, the Pco2 of the that use oxygen in the cell, even this low intracellular Po2 pulmonary capillary blood falls to almost exactly of 23 mm Hg is more than adequate and provides a large equal the alveolar Pco2 of 40 mm Hg before it has safety factor. passed more than about one-third of the distance through the capillaries. This is the same effect that DIFFUSION OF CO2 FROM PERIPHERAL was observed earlier for O2 diffusion, except that it TISSUE CELLS INTO CAPILLARIES AND is in the opposite direction. FROM PULMONARY CAPILLARIES INTO ALVEOLI Effect of Tissue Metabolism and Tissue Blood Flow When O2 is used by the cells, virtually all of it becomes Rate on Interstitial Pco2. Tissue capillary blood flow and CO2, and this transformation increases the intracellular tissue metabolism affect the Pco2 in ways exactly oppo- Pco2; because of this elevated tissue cell Pco2, CO2 dif- site to their effect on tissue Po2. Figure 41-7 shows these fuses from the cells into the capillaries and is then carried effects, as follows: by the blood to the lungs. In the lungs, it diffuses from the 1. A decrease in blood flow from normal (point A) to pulmonary capillaries into the alveoli and is expired. one-quarter normal (point B) increases peripheral tis- Thus, at each point in the gas transport chain, CO2 sue Pco2 from the normal value of 45 mm Hg to an diffuses in the direction exactly opposite to the diffu- elevated level of 60 mm Hg. Conversely, increasing the sion of O2. Yet, there is one major difference between blood flow to six times normal (point C) decreases the diffusion of CO2 and of O2—CO2 can diffuse about 20 interstitial Pco2 from the normal value of 45 to 41 mm times as rapidly as O2. Therefore, the pressure differ- Hg, almost equal to the Pco2 in the arterial blood (40 ences required to cause CO2 diffusion are, in each case, mm Hg) entering the tissue capillaries. far less than the pressure differences required to cause 2. Note also that a 10-fold increase in tissue metabolic O2 diffusion. The CO2 pressures are approximately the rate greatly elevates the interstitial fluid Pco2 at all following: rates of blood flow, whereas decreasing the metabo- 1. Intracellular Pco2, 46 mm Hg; interstitial Pco2, 45 lism to one-quarter normal causes the interstitial mm Hg. Thus, there is only a 1 mm Hg pressure dif- fluid Pco2 to fall to about 41 mm Hg, closely ap- ferential, as shown in Figure 41-5. proaching that of the arterial blood, 40 mm Hg. 523 UNIT VII Respiration 120 20 Oxygen in blood (volumes %) globin Venous blood in exercise 18 ith hemo nd w bo u Normal venous blood 16 Interstitial fluid PCO2 (mm Hg) 100 O2 Normal arterial blood 14 12 80 10 10 × normal metabolism B 8 60 6 A Normal metabolism 4 40 C 2 Lower limit of infinite blood flow 1/4 normal metabolism 0 0 20 40 60 80 100 120 140 20 Pressure of oxygen in blood (PO2) (mm Hg) 0 Figure 41-9 Effect of blood PO2 on the quantity of oxygen bound 0 100 200 300 400 500 600 with hemoglobin in each 100 ml of blood. Blood flow (percent of normal) Figure 41-7 Effect of blood flow and metabolic rate on peripheral demonstrates a progressive increase in the percentage of tissue PCO2. hemoglobin bound with O2 as blood Po2 increases, called 100 20 the percent saturation of hemoglobin. Because the blood 90 18 leaving the lungs and entering the systemic arteries usu- Hemoglobin saturation (%) Oxygenated blood 80 leaving the lungs 16 ally has a Po2 of about 95 mm Hg, it can be seen from 70 14 the dissociation curve that the usual O2 saturation of sys- Volumes (%) 60 12 temic arterial blood averages 97%. Conversely, in normal 50 10 venous blood returning from the peripheral tissues, the 40 Reduced blood returning Po2 is about 40 mm Hg, and the saturation of hemoglobin 8 from tissues averages 75%. 30 6 20 4 Maximum Amount of Oxygen That Can Combine 10 2 With the Hemoglobin of the Blood. The blood of a 0 0 normal person contains about 15 grams of hemoglobin 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 Pressure of oxygen in blood (PO2) (mm Hg) in each 100 ml of blood, and each gram of hemoglobin can bind with a maximum of 1.34 ml of O2 (1.39 ml when Figure 41-8 Oxygen-hemoglobin dissociation curve. the hemoglobin is chemically pure, but impurities such as methemoglobin reduce this). Therefore, 15 times 1.34 ROLE OF HEMOGLOBIN IN OXYGEN equals 20.1, which means that on average, the 15 grams of TRANSPORT hemoglobin in 100 ml of blood can combine with a total of about 20 ml of O2 if the hemoglobin is 100% saturated. Normally, about 97% of the oxygen transported from the This is usually expressed as 20 volume percent. The O2- lungs to the tissues is carried in chemical combination with hemoglobin dissociation curve for the normal person can hemoglobin in the red blood cells. The remaining 3% is also be expressed in terms of volume percent of O2, as transported in the dissolved state in the water of the plasma shown by the far right scale in Figure 41-8, instead of per- and blood cells. Thus, under normal conditions, oxygen is cent saturation of hemoglobin. carried to the tissues almost entirely by hemoglobin. Amount of Oxygen Released From Hemoglobin Reversible Combination of O2 With When Systemic Arterial Blood Flows Through Tis- Hemoglobin sues. The total quantity of O2 bound with hemoglobin in The chemistry of hemoglobin is presented in Chapter 33, normal systemic arterial blood, which is 97% saturated, is where we pointed out that the O2 molecule combines about 19.4 ml/100 ml of blood, as shown in Figure 41-9. loosely and reversibly with the heme portion of hemoglo- On passing through the tissue capillaries, this amount is bin. When Po2 is high, as in the pulmonary capillaries, reduced, on average, to 14.4 ml (Po2 of 40 mm Hg, 75% O2 binds with hemoglobin, but when Po2 is low, as in the saturated hemoglobin). Thus, under normal conditions, tissue capillaries, O2 is released from hemoglobin. This is about 5 ml of O2 are transported from the lungs to the tis- the basis for almost all O2 transport from the lungs to the sues by each 100 ml of blood flow. tissues. Transport of Oxygen Is Markedly Increased During Oxygen-Hemoglobin Dissociation Curve. Figure 41-8 Strenuous Exercise. During heavy exercise, the muscle shows the O2-hemoglobin dissociation curve, which cells use O2 at a rapid rate, which in extreme cases can 524  Chapter 41 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids cause the muscle interstitial fluid Po2 to fall from the nor- the decreased Po2. That is, a very small fall in Po2 causes mal 40 mm Hg to as low as 15 mm Hg. At this low pres- large amounts of extra O2 to be released from hemoglo- sure, only 4.4 ml of O2 remains bound with the hemo- bin. Thus, hemoglobin in the blood automatically delivers globin in each 100 ml of blood, as shown in Figure 41-9. O2 to the tissues at a pressure that is held rather tightly Thus, 19.4 − 4.4 ml, or 15 ml, is the quantity of O2 that is between about 15 and 40 mm Hg. UNIT VII actually delivered to the tissues by each 100 ml of blood flow, meaning that three times as much O2 as normal is When Atmospheric Oxygen Concentration Changes delivered in each volume of blood that passes through Markedly, the Buffer Effect of Hemoglobin Still Main- the tissues. Keep in mind that the cardiac output can in- tains Almost Constant Tissue Po2. The normal Po2 crease to six to seven times normal in well-trained mara- in the alveoli is about 104 mm Hg, but as one ascends thon runners. Thus, multiplying the increase in cardiac a mountain or ascends in an airplane, the Po2 can easily output (6- to 7-fold) by the increase in O2 transport in fall to less than half this amount. Alternatively, when one each volume of blood (3-fold) gives a 20-fold increase in enters areas of compressed air, such as deep in the sea or O2 transport to the tissues. We will see later in the chap- in pressurized chambers, the Po2 may rise to 10 times this ter that several other factors facilitate delivery of O2 into level. Even so, the tissue Po2 changes little. muscles during exercise, so muscle tissue Po2 often falls It can be seen from the oxygen-hemoglobin dissociation just slightly below normal, even during very strenuous curve in Figure 41-8 that when the alveolar Po2 is decreased exercise. to as low as 60 mm Hg, the arterial hemoglobin is still 89% saturated with O2—only 8% below the normal saturation of Utilization Coefficient. The percentage of the blood that 97%. Furthermore, the tissues still remove about 5 ml of O2 gives up its O2 as it passes through the tissue capillaries from each 100 ml of blood passing through the tissues. To is called the utilization coefficient. The normal value for remove this O2, the Po2 of the venous blood falls to 35 mm this is about 25%, as is evident from the preceding discus- Hg—only 5 mm Hg below the normal value of 40 mm Hg. sion—that is, 25% of the oxygenated hemoglobin gives its Thus, the tissue Po2 hardly changes, despite the marked fall O2 to the tissues. During strenuous exercise, the utiliza- in alveolar Po2 from 104 to 60 mm Hg. tion coefficient in the entire body can increase to 75% to Conversely, when the alveolar Po2 rises as high as 500 85%. In local tissue areas where blood flow is extremely mm Hg, the maximum O2 saturation of hemoglobin can slow or the metabolic rate is very high, utilization coef- never rise above 100%, which is only 3% above the normal ficients approaching 100% have been recorded—that is, level of 97%. Only a small amount of additional O2 dis- essentially all the O2 is given to the tissues. solves in the fluid of the blood, as will be discussed subse- quently. Then, when the blood passes through the tissue Hemoglobin “Buffers” Tissue Po2 capillaries and loses several milliliters of O2 to the tissues, Although hemoglobin is necessary for the transport of O2 this reduces the Po2 of the capillary blood to a value only to the tissues, it performs another function essential to a few milliliters higher than the normal 40 mm Hg. Con- life. This is its function as a tissue oxygen buffer system. sequently, the level of alveolar O2 may vary greatly—from That is, the hemoglobin in the blood is mainly respon- 60 to more than 500 mm Hg Po2—and still the Po2 in sible for stabilizing the Po2 in the tissues, which can be the peripheral tissues does not vary more than a few mil- explained as follows. liliters from normal, demonstrating beautifully the tissue “oxygen buffer” function of the blood hemoglobin system. Hemoglobin Helps Maintain Nearly Constant Po2 in the Tissues. Under basal conditions, the tissues re- quire about 5 ml of O2 from each 100 ml of blood pass- Factors That Shift the Oxygen- ing through the tissue capillaries. Referring to the O2- Hemoglobin Dissociation Curve—Their hemoglobin dissociation curve in Figure 41-9, note that Importance for Oxygen Transport for the normal 5 ml of O2 to be released per 100 ml of The O2-hemoglobin dissociation curves of Figures 41-8 blood flow, the Po2 must fall to about 40 mm Hg. There- and 41-9 are for normal average blood. However, several fore, the tissue Po2 normally cannot rise above this 40 factors can displace the dissociation curve in one direction mm Hg level because, if it did, the amount of O2 needed or the other, as shown in Figure 41-10. This figure shows by the tissues would not be released from the hemoglobin. that when the blood becomes slightly acidic, with the pH In this way, the hemoglobin normally sets an upper limit decreasing from the normal value of 7.4 to 7.2, the O2- on the Po2 in the tissues at about 40 mm Hg. hemoglobin dissociation curve shifts, on average, about 15% Conversely, during heavy exercise, extra amounts of to the right. Conversely, an increase in pH from the normal O2 (as much as 20 times normal) must be delivered from 7.4 to 7.6 shifts the curve a similar amount to the left. the hemoglobin to the tissues. However, this delivery of In addition to pH changes, several other factors are known extra O2 can be achieved with little further decrease in tis- to shift the curve. Three of these, which shift the curve to sue Po2 because of (1) the steep slope of the dissociation the right are the following: (1) increased CO2 concentra- curve, and (2) the increase in tissue blood flow caused by tion; (2) increased blood temperature; and (3) increased 525 UNIT VII Respiration the quantity of BPG in the blood increases considerably, 100 thus shifting the O2-hemoglobin dissociation curve even 90 Hemoglobin saturation (%) farther to the right. This shift causes O2 to be released to 80 70 the tissues at as much as 10 mm Hg higher tissue O2 pres- 7.6 pH sure than would be the case without this increased BPG. 7.4 60 7.2 50 Therefore, under some conditions, the BPG mechanism 40 Shift to right: 30 (1) Increased hydrogen ions can be important for adaptation to hypoxia, especially to 20 (2) Increased CO2 hypoxia caused by poor tissue blood flow. 10 (3) Increased temperature (4) Increased BPG 0 Rightward Shift of the Oxygen- Hemoglobin Dissociation Curve During Exercise 0 10 20 30 40 50 60 70 80 90 100110 120 130 140 During exercise, several factors shift the dissociation curve Pressure of oxygen in blood (PO2) (mm Hg) considerably to the right, thus delivering extra amounts of Figure 41-10 Shift of the oxygen-hemoglobin dissociation curve to O2 to the active, exercising muscle fibers. The exercising the right caused by an increase in H+ concentration (decrease in pH). muscles, in turn, release large quantities of CO2; this and BPG, 2,3-Biphosphoglycerate. several other acids released by the muscles increase the H+ concentration in the muscle capillary blood. In addition, the temperature of the muscle often rises 2° to 3°C, which 2,3-biphosphoglycerate (BPG), a metabolically important can increase O2 delivery to the muscle fibers even more. All phosphate compound present in the blood in different con- these factors act together to shift the oxygen-hemoglobin centrations under different metabolic conditions. dissociation curve of the muscle capillary blood consider- ably to the right. This rightward shift of the curve forces O2 Increased Delivery of Oxygen to Tissues to be released from blood hemoglobin to the muscle at Po2 When CO2 and H+ Shift the Oxygen- levels as great as 40 mm Hg, even when 70% of the O2 has Hemoglobin Dissociation Curve—the already been removed from the hemoglobin. Then, in the Bohr Effect lungs, the shift occurs in the opposite direction, allowing extra amounts of O2 to be picked up from alveoli. A shift of the oxygen-hemoglobin dissociation curve to the right in response to increases in blood CO2 and H+ levels has a significant effect by enhancing the release METABOLIC USE OF OXYGEN BY CELLS of O2 from the blood in the tissues and enhancing oxy- Effect of Intracellular Po2 on Oxygen Usage Rate. genation of the blood in the lungs. This is called the Bohr Only a minute level of O2 pressure is required in the cells effect, which can be explained as follows. As the blood for normal intracellular chemical reactions to take place. passes through the tissues, CO2 diffuses from tissue cells The reason for this phenomenon is that the respiratory into the blood. This diffusion increases the blood Pco2, enzyme systems of the cell, discussed in Chapter 68, have which in turn raises blood H2CO3 (carbonic acid) and been configured so that when the cellular Po2 is more than H+ concentration. These effects shift the O2-hemoglobin 1 mm Hg, O2 availability is no longer a limiting factor in dissociation curve to the right and downward, as shown the rates of the chemical reactions. Instead, the main lim- in Figure 41-10, forcing O2 away from the hemoglobin iting factor is the concentration of adenosine diphosphate and therefore delivering increased amounts of O2 to the (ADP) in the cells. This effect is demonstrated in Figure tissues. 41-11, which shows the relationship between intracellu- Exactly the opposite effects occur in the lungs, where lar Po2 and the O2 usage rate at different concentrations CO2 diffuses from the blood into alveoli. This diffusion of ADP. Note that whenever the intracellular Po2 is above reduces blood Pco2 and H+ concentration, shifting the 1 mm Hg, O2 usage rate becomes constant for any given O2-hemoglobin dissociation curve to the left and upward. concentration of ADP in the cell. Conversely, when the Therefore, the quantity of O2 that binds with the hemo- ADP concentration is altered, the rate of O2 usage chang- globin at any given alveolar Po2 becomes considerably es in proportion to the change in ADP concentration. increased, thus allowing greater O2 transport to the As explained in Chapter 3, when adenosine triphos- tissues. phate (ATP) is used in the cells to provide energy, it is converted into ADP. The increasing concentration Effect of BPG to Cause Rightward of ADP increases metabolic usage of O2 as it combines Shift of the Oxygen-Hemoglobin with the various cell nutrients, releasing energy that Dissociation Curve reconverts the ADP back to ATP. Under normal operating The normal BPG in the blood always keeps the O2- conditions, the rate of O2 usage by the cells is controlled hemoglobin dissociation curve shifted slightly to the right. ultimately by the rate of energy expenditure within the In hypoxic conditions that last longer than a few hours, cells—that is, by the rate at which ADP is formed from ATP. 526  Chapter 41 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids ADP = 11/2 normal 100 1.5 90 Hemoglobin saturation (%) 80 (unormal resting level) 70 UNIT VII ADP = Normal resting level Rate of oxygen usage 60 1.0 50 40 30 ADP = 1/2 normal 0.5 20 10 0 0 0.1 0.2 0.3 0.4 0 Gas pressure of carbon monoxide (mm Hg) 0 1 2 3 4 Figure 41-12 Carbon monoxide–hemoglobin dissociation curve. Intracellular PO2 (mm Hg) Note the extremely low carbon monoxide pressures at which carbon monoxide combines with hemoglobin. Figure 41-11 Effect of intracellular adenosine diphosphate (ADP) and PO2 on rate of oxygen usage by the cells. Note that as long as the intracellular PO2 remains above 1 mm Hg, the controlling factor blood flow. This value compares with almost 5 ml of O2 for the rate of oxygen usage is the intracellular concentration of ADP. transported by the red blood cell hemoglobin. Therefore, the amount of O2 transported to the tissues in the dissolved state is normally slight, only about 3% of the total, as com- Effect of Diffusion Distance From the Capillary to the pared with 97% transported by the hemoglobin. Cell on Oxygen Usage. Tissue cells are seldom more than During strenuous exercise, when hemoglobin release of 50 micrometers away from a capillary, and O2 normally O2 to the tissues increases by another 3-fold, the relative can diffuse readily enough from the capillary to the cell quantity of O2 transported in the dissolved state falls to as to supply all the required amounts of O2 for metabolism. little as 1.5%. However, if a person breathes O2 at very high However, occasionally, cells are located farther from the alveolar Po2 levels, the amount transported in the dissolved capillaries, and the rate of O2 diffusion to these cells can state can become much greater, sometimes so much so that become so low that intracellular Po2 falls below the critical a serious excess of O2 occurs in the tissues, and so-called O2 level required to maintain maximal intracellular metabo- poisoning ensues. This condition often leads to brain con- lism. Thus, under these conditions, O2 usage by the cells vulsions and even death, as discussed in detail in Chapter is diffusion-limited and is no longer determined by the 45 in relation to the high-pressure breathing of O2 among deep-sea divers. amount of ADP formed in the cells. However, this situation almost never occurs, except in pathological states. Combination of Hemoglobin With Carbon Monoxide—Displacement of O2 Effect of Blood Flow on Metabolic Use of Oxygen. Carbon monoxide (CO) combines with hemoglobin at the The total amount of O2 available each minute for use in same point on the hemoglobin molecule as O2; it can therefore any given tissue is determined by (1) the quantity of O2 displace O2 from the hemoglobin and decrease the O2 carrying that can be transported to the tissue in each 100 ml of capacity of blood. Furthermore, it binds with about 250 times blood, and (2) the rate of blood flow. If blood flow rate as much tenacity as O2, which is demonstrated by the CO- falls to zero, the amount of available O2 also falls to zero. hemoglobin dissociation curve in Figure 41-12. This curve Thus, there are times when blood flow rate through a tis- is almost identical to the O2-hemoglobin dissociation curve except that the CO partial pressures, shown on the abscissa, sue can be so low that tissue Po2 falls below the critical are at a level 1⁄250 of those for the O2-hemoglobin dissociation 1 mm Hg required for intracellular metabolism. Under curve of Figure 41-8. Therefore, a CO partial pressure of only these conditions, the rate of tissue usage of O2 is blood 0.4 mm Hg in the alveoli, 1⁄250 that of normal alveolar O2 (100 flow–limited. Neither diffusion-limited nor blood flow– mm Hg Po2), allows the CO to compete equally with the O2 limited oxygen states can continue for long, however, be- for combination with the hemoglobin and causes 50% of the cause the cells receive less O2 than is required to continue hemoglobin in the blood to become bound with CO instead of the life of the cells. with O2. Therefore, a CO pressure of only 0.6 mm Hg (a vol- ume concentration < one part/1000 in air) can be lethal. Transport of Oxygen in the Dissolved State Even though the O2 content of blood is greatly reduced At the normal arterial Po2 of 95 mm Hg, about 0.29 ml of in CO poisoning, the Po2 of the blood may be normal. O2 is dissolved in every 100 ml of water in the blood, and This situation makes exposure to CO especially dangerous when the Po2 of the blood falls to the normal 40 mm Hg in because the blood is bright red, and there are no obvious the tissue capillaries, only 0.12 ml of O2 remains dissolved. signs of hypoxemia, such as a bluish color of the fingertips In other words, 0.17 ml of O2 is normally transported in or lips (cyanosis). Also, Po2 is not reduced, and the feed- the dissolved state to the tissues by each 100 ml of arterial back mechanism that usually stimulates an increased res- 527 UNIT VII Respiration Capillary The amount of CO2 dissolved in the fluid of the blood at 45 mm Hg is about 2.7 ml/dl (2.7 volume percent). The Red blood cell amount dissolved at 40 mm Hg is about 2.4 ml, or a dif- ference of 0.3 ml. Therefore, only about 0.3 ml of CO2 is Hgb – CO2 Cell transported in the dissolved form by each 100 ml of blood Carbonic Hgb flow. This is about 7% of all the CO2 normally transported. anhydrase + H2CO3 H2O + CO2 CO2 CO2 Transport of CO2 in the Form of HCO3– + H+ Bicarbonate Ion + H2O Hgb Cl CO2 Carbonic Anhydrase Catalyzes the Reaction of CO2 H2O Hgb – H + With Water in Red Blood Cells. The dissolved CO2 in CO2 transported as: the blood reacts with water to form carbonic acid. This re- Cl 1. CO2 = 7% HCO3– action would occur much too slowly to be of importance 2. Hgb − CO2 = 23% Plasma 3. HCO3– = 70% were it not for the fact that there is an enzyme called carbonic anhydrase inside the red blood cells, which Figure 41-13 Transport of carbon dioxide in the blood. Hgb, Hemo- catalyzes the reaction between CO2 and water and ac- globin. celerates its reaction rate by about 5000-fold. Therefore, instead of requiring many seconds or minutes to occur, piration rate in response to lack of O2 (usually reflected by as is true in the plasma, the reaction occurs so rapidly in a low Po2) is absent. Because the brain is one of the first red blood cells that it reaches almost complete equilib- organs affected by lack of oxygen, the person may become rium within a small fraction of a second. This phenom- disoriented and unconscious before becoming aware of the enon allows tremendous amounts of CO2 to react with danger. the red blood cell water, even before the blood leaves the A patient severely poisoned with CO can be treated by tissue capillaries. administering pure O2 because O2 at high alveolar pressure can displace CO rapidly from its combination with hemo- Dissociation of Carbonic Acid Into Bicarbonate and globin. The patient can also benefit from simultaneous ad- ministration of 5% CO2 because this strongly stimulates the Hydrogen Ions. In another fraction of a second, the car- respiratory center, which increases alveolar ventilation and bonic acid formed in red cells (H2CO3) dissociates into reduces alveolar CO. With intensive O2 and CO2 therapy, H+ and bicarbonate ions (H+ and HCO3−). Most of the H+ CO can be removed from the blood as much as 10 times as ions then combine with hemoglobin in the red blood cells rapidly as without therapy. because the hemoglobin protein is a powerful acid–base buffer. In turn, many of the HCO3− ions diffuse from the red blood cells into the plasma while chloride ions diffuse TRANSPORT OF CO2 IN BLOOD into the red blood cells to take their place. This diffusion Transport of CO2 by the blood is not nearly as prob- is made possible by the presence of a special bicarbonate- lematical as transport of O2 is because even in the most chloride carrier protein in the red blood cell membrane abnormal conditions, CO2 can usually be transported in that shuttles these two ions in opposite directions at rapid far greater quantities than can O2. However, the amount velocities. Thus, the chloride content of venous red blood of CO2 in the blood has a lot to do with the acid–base cells is greater than that of arterial red blood cells, a phe- balance of the body fluids, which is discussed in Chapter nomenon called the chloride shift. 31. Under normal resting conditions, an average of 4 ml of The reversible combination of CO2 with water in red CO2 are transported from the tissues to the lungs in each blood cells under the influence of carbonic anhydrase 100 ml of blood. accounts for about 70% of the CO2 transported from the tissues to the lungs. Thus, this means of transporting CO2 CHEMICAL FORMS IN WHICH CO2 IS is the most important. Indeed, when a carbonic anhy- TRANSPORTED drase inhibitor (e.g., acetazolamide) is administered to an To begin the process of CO2 transport, CO2 diffuses out animal to block the action of carbonic anhydrase in the of the tissue cells in the dissolved molecular CO2 form. red blood cells, CO2 transport from the tissues becomes On entering the tissue capillaries, the CO2 initiates a so poor that the tissue Pco2 may rise to 80 mm Hg instead host of almost instantaneous physical and chemical reac- of the normal 45 mm Hg. tions, shown in Figure 41-13, which are essential for CO2 transport. Transport of CO2 in Combination With Hemoglobin and Plasma Proteins—Carbaminohemoglobin. In ad- Transport of CO2 in a Dissolved State dition to reacting with water, CO2 reacts directly with A small portion of the CO2 is transported in the dissolved amine radicals of the hemoglobin molecule to form the state to the lungs. Recall that the Pco2 of venous blood compound carbaminohemoglobin (CO2Hgb). This com- is 45 mm Hg and that of arterial blood is 40 mm Hg. bination of CO2 and hemoglobin is a reversible reaction 528  Chapter 41 Transport of Oxygen and Carbon Dioxide in Blood and Tissue Fluids 55 80 CO2 in blood (volumes %) CO2 in blood (volumes %) 70 A Normal operating range 60 PO2 = 40 mm Hg UNIT VII 50 40 50 30 PO2 = 100 mm Hg 20 B 10 0 0 10 20 30 40 50 60 70 80 90 100 110 120 45 35 40 45 50 Gas pressure of carbon dioxide (mm Hg) PCO2 (mm Hg) Figure 41-14 Carbon dioxide dissociation curve. Figure 41-15 Portions of the carbon dioxide dissociation curve when the PO2 is 100 or 40 mm Hg. The arrow represents the Haldane effect that occurs with a loose bond, so the CO2 is easily re- on the transport of carbon dioxide. leased into the alveoli, where the Pco2 is lower than in the pulmonary capillaries. A small amount of CO2 also reacts in the same way The Haldane effect results from the simple fact that the with the plasma proteins in tissue capillaries. This reac- combination of O2 with hemoglobin in the lungs causes tion is much less significant for the transport of CO2 the hemoglobin to become a stronger acid. This displaces because the quantity of these proteins in the blood is only CO2 from the blood and into the alveoli in two ways. First, one-fourth as great as the quantity of hemoglobin. the more highly acidic hemoglobin has less tendency to The quantity of CO2 that can be carried from the combine with CO2 to form carbaminohemoglobin, thus peripheral tissues to the lungs by carbamino combination displacing much of the CO2 that is present in the carb- with hemoglobin and plasma proteins is about 30% of the amino form from the blood. Second, the increased acidity total quantity transported—that is, normally about 1.5 ml of the hemoglobin also causes it to release an excess of H+, of CO2 in each 100 ml of blood. However, because this and these ions bind with HCO3− to form carbonic acid, reaction is much slower than the reaction of CO2 with which then dissociates into water and CO2, and the CO2 water inside the red blood cells, it is doubtful that under is released from the blood into the alveoli and, finally, into normal conditions this carbamino mechanism transports the air. more than 20% of the total CO2. Figure 41-15 demonstrates quantitatively the signifi- cance of the Haldane effect on the transport of CO2 from CARBON DIOXIDE DISSOCIATION CURVE the tissues to the lungs. This figure shows small portions of The curve shown in Figure 41-14, the CO2 dissociation two CO2 dissociation curves: (1) when the Po2 is 100 mm curve, depicts the dependence of total blood CO2 in all its Hg, which is the case in the blood capillaries of the lungs; forms on Pco2. Note that the normal blood Pco2 is within a and (2) when the Po2 is 40 mm Hg, which is the case in narrow range of 40 mm Hg in arterial blood and 45 mm Hg the tissue capillaries. Point A shows that the normal Pco2 in venous blood. Note also that the normal concentration of of 45 mm Hg in the tissues causes 52 volume percent of CO2 in the blood in all its different forms is about 50 volume CO2 to combine with the blood. On entering the lungs, percent, but only 4 volume percent of this is exchanged dur- the Pco2 falls to 40 mm Hg, and the Po2 rises to 100 mm ing normal transport of CO2 from the tissues to the lungs. Hg. If the CO2 dissociation curve did not shift because of That is, the concentration rises to about 52 volume percent the Haldane effect, the CO2 content of the blood would fall as the blood passes through the tissues and falls to about 48 only to 50 volume percent, which would be a loss of only volume percent as it passes through the lungs. 2 volume percent of CO2. However, the increase in Po2 in the lungs lowers the CO2 dissociation curve from the top When Oxygen Binds With Hemoglobin, curve to the lower curve of the figure, so the CO2 con- CO2 Is Released (the Haldane Effect) to tent falls to 48 volume percent (point B). This represents Increase CO2 Transport an additional two volume percent loss of CO2. Thus, the Earlier in the chapter, we noted that an increase in CO2 in Haldane effect approximately doubles the amount of CO2 the blood causes O2 to be displaced from the hemoglobin released from the blood in the lungs and approximately (the Bohr effect), which is an important factor in increas- doubles the amount of CO2 picked up in the tissues. ing O2 transport. The reverse is also true—binding of O2 with hemoglobin tends to displace CO2 from the blood. Change in Blood Acidity During Co2 Transport This effect, called the Haldane effect, is quantitatively far The carbonic acid formed when CO2 enters the blood in more important in promoting CO2 transport than the peripheral tissues decreases blood pH. However, reaction Bohr effect in promoting O2 transport. of this acid with the acid–base buffers of the blood pre- 529 UNIT VII Respiration vents the H+ concentration from rising very much (and the O2 combines with hydrogen atoms from the fats to the pH from falling very much). Ordinarily, arterial blood form water instead of CO2. In other words, when fats are has a pH of about 7.41 and as the blood acquires CO2 metabolized, the respiratory quotient of the chemical reac- in the tissue capillaries the pH falls to a venous value of tions in the tissues is about 0.70 instead of 1.00. (The tis- about 7.37. In other words, a pH change of 0.04 unit takes sue respiratory quotient is discussed in Chapter 72.) For place. The reverse occurs when CO2 is released from the a person on a normal diet consuming average amounts of blood in the lungs, with the pH rising to the arterial value of 7.41 once again. During heavy exercise or other con- carbohydrates, fats, and proteins, the average value for R ditions of high metabolic activity, or when blood flow is considered to be 0.825. through the tissues is sluggish, the decrease in pH in the tissue blood (and in the tissues themselves) can be as much as 0.50, about 12 times normal, thus causing signifi- Bibliography cant tissue acidosis. Clanton TL, Hogan MC, Gladden LB: Regulation of cellular gas ex- change, oxygen sensing, and metabolic control. Compr Physiol 3:1135, 2013. RESPIRATORY EXCHANGE RATIO Geers C, Gros G: Carbon dioxide transport and carbonic anhydrase in blood and muscle. Physiol Rev 80:681, 2000. The discerning student will have noted that normal trans- Jensen FB: Red blood cell pH, the Bohr effect, and other oxygenation- port of O2 from the lungs to the tissues by each 100 ml linked phenomena in blood O2 and CO2 transport. Acta Physiol of blood is about 5 ml, whereas normal transport of CO2 Scand 182:215, 2004. from the tissues to the lungs is about 4 ml. Thus, under Jensen FB: The dual roles of red blood cells in tissue oxygen deliv- normal resting conditions, only about 82% as much CO2 ery: oxygen carriers and regulators of local blood flow. J Exp Biol 212:3387, 2009. is expired from the lungs as O2 is taken up by the lungs. Joyner MJ, Casey DP: Regulation of increased blood flow (hyperemia) The ratio of CO2 output to O2 uptake is called the respira- to muscles during exercise: a hierarchy of competing physiological tory exchange ratio (R). That is: needs. Physiol Rev 95:549, 2015. Maina JN, West JB: Thin and strong! The bioengineering dilemma 3BUFyPGyDBSCPOyEJPYJEFyPVUQVU in the structural and functional design of the blood-gas barrier. 3 3BUFyPGyPYZHFOyVQUBLF Physiol Rev 85:811, 2005. Mairbäurl H, Weber RE: Oxygen transport by hemoglobin. Compr Physiol 2:1463, 2012. The value for R changes under different metabolic con- Moore LG: Measuring high-altitude adaptation. J Appl Physiol ditions. When a person is using carbohydrates exclusively 123:1371, 2017. for body metabolism, R rises to 1.00. Conversely, when a Poole DC, Jones AM: Oxygen uptake kinetics. Compr Physiol 2:933, 2012. person is using fats exclusively for metabolic energy, the Richardson RS: Oxygen transport and utilization: an integration of the R level falls to as low as 0.7. The reason for this differ- muscle systems. Adv Physiol Educ 27:183, 2003. ence is that when O2 is metabolized with carbohydrates, Rossiter HB: Exercise: Kinetic considerations for gas exchange. 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