HL Gas transport 10_30 PDF

Pulmonary Gas Exchange: Now let’s continue to the heart of the matter – gas exchange between the blood and the alveoli. Specifically, we need to understand the movement of oxygen from the alveoli into the blood, and the movement of carbon dioxide from the blood into the alveoli. Gas Partial Pressu...

Pulmonary Gas Exchange: Now let’s continue to the heart of the matter – gas exchange between the blood and the alveoli. Specifically, we need to understand the movement of oxygen from the alveoli into the blood, and the movement of carbon dioxide from the blood into the alveoli. Gas Partial Pressures: When we think about gas molecules moving from one place to another, we need to apply the same ideas as we have for ions moving across a membrane. Gas moves from areas of high pressure to low pressure – down its electrochemical gradient. In this case though, gases are uncharged, so the only force acting on them is their concentration gradient. 1 Atmosphere Mt. Everest When comparing the concentration of a = 760 mm Hg 29,000 feet gas in one compartment to that in another, = 253 mm Hg we use the partial pressure for that gas. What is a partial pressure? Well, we live  on the surface of the Earth and we are surrounded by air. The air extends up to the limits of the atmosphere and each molecule in the air has a certain mass and is pulled toward the Earth’s surface by gravity. Therefore, as we walk around we have a column of air weighing Sea Level  down upon us – atmospheric pressure.  Atmospheric pressure is 760 mm Hg (meaning that the weight of the atmosphere is enough to support a column of mercury 760 mm high). Air is primarily comprised of nitrogen and oxygen – where nitrogen is 79% of air and oxygen makes up most of the remaining 21%. The other gases and water vapor are negligible. Now the neat part: If nitrogen is 79% of the atmosphere, and total atmospheric pressure is 760 mm Hg, then the partial pressure of nitrogen in the atmosphere is: (0.79)(760) = 600 mm Hg Similarly, the partial pressure of oxygen in the atmosphere is: (0.21)(760) = 160 mm Hg There are 4 partial pressures we will be considering: PO2, PCO2, PH2O and PN2 We just saw that PN2 = 600 mm Hg and PO2 = 160 mm Hg, while PCO2 and PH2O were roughly zero in the atmosphere. When we inhale, the first thing that happens is humidification of the inhaled air. Humidification means that we are adding water vapor to the atmospheric air, yet total atmospheric pressure remains constant at 760 mm Hg. The water vapor (at normal body temperature) has a partial pressure of 47 mm Hg. So, 47 of the 760 mm Hg total air pressure heading toward our lungs is now water vapor. This decreases the partial pressures of oxygen and nitrogen in that air sample: Inhaled Air PO2 = (760 - 47)(0.21) = 150 mm Hg Inhaled Air PN2 = (760 - 47)(0.79) = 563 mm Hg The air which we are inhaling with one breath is called the Tidal Volume, and we saw that only a portion of the Tidal Volume (about 350 ml of the 500 ml) actually reaches the alveoli and mixes with the air left in the alveoli at the end of the previous breath. Therefore, we are constantly mixing some fresh air with some “old” air each time we inhale. This means that the partial pressures in the alveoli will be different from those of the Tidal Volume (just as the partial pressures of the Tidal Volume are different from atmospheric air due to humidification). The list below shows the partial pressures for nitrogen, oxygen carbon dioxide and water in 4 different locations (in mm Hg): Nitrogen Oxygen Carbon Dioxide Water Atmospheric Air 600 160 0.3 3.7 Humidified Air 560 150 0.3 47 Alveolar Air 570 105 40 47 Exhaled Air 565 120 27 47 Notice how alveolar air partial pressures differ from those of atmospheric and humidified air. This is because only a portion of alveolar air is replaced by atmospheric air with each breath, and also because there is a constant loss of oxygen and gain of carbon dioxide due to gas exchange with the blood. For instance, we previously saw that the typical functional residual capacity of the lungs is around 2.3 liters (the volume of air remaining in the lungs after we exhale normally). Then when we inhale, only 350 of the 500 ml of the Tidal Volume actually gets into the alveoli to mix with that residual gas. This means that with each breath we take we replace only about 15% of the gas in the lungs (350/2300 = 15%). Tidal Volume (150 ml) Dead Space (150 ml of previously Dead Space alveolar air) (150 ml of fresh air) Residual capacity Only 350 ml of (2,300 ml) the tidal volume actually reaches the alveoli At first this may seem like an inefficient way to try and maintain or maximize oxygen transport to the blood, but it has a distinct benefit: The relatively slow replacement (or turnover) of alveolar gas means that the alveolar gas concentrations remain fairly stable throughout time. This in turn will help assure that the resulting blood gases leaving the lungs will remain constant, independent of whether we had just inhaled or exhaled. This makes the respiratory monitoring and control mechanisms (to be discussed later) much more stable. 85% of gas is 104 mm Hg, 100% of gas is 104 mm Hg 15% is 149 mm Hg PO2 = PO2 = 104 mm Hg 110 mm Hg Just before inhaling Just after inhaling Something else to take note of here: Normal alveolar ventilation at rest is 4.2 liters/min ([350 ml per tidal volume][12 breathes per minute]). At rest, 250 ml of oxygen will be removed from the alveoli to the blood each minute, and 200 ml of carbon dioxide will leave the blood and enter the alveoli during that same minute. During moderate exercise the alveolar ventilation will rise to around 17 liters/min, oxygen loss rises to 1000 ml/min and carbon dioxide gained from the blood rises to 800 ml/min. Yet, alveolar partial pressure of oxygen remains at 104 mm Hg and CO 2 at 40 mm Hg. In other words, the increase in ventilation rate matches the increased demand for oxygen and CO 2 replacement, maintaining the gas partial pressures in the alveoli at a stable value over a wide range of ventilation. 4,200 ml gas 17,000 ml gas exchange/min exchange/min At Rest: During Moderate Exercise: 200 ml 250 ml 800 ml 1,000 ml CO2/min O2/min CO2/min O2/min Gas Transport in Blood: Gas Composition in Blood Entering Pulmonary Capillaries: Let’s start by looking at the situation for gases in venous blood traveling back to the right atrium. That blood has just passed through systemic capillaries, offloading oxygen to the tissues and taking up carbon dioxide from metabolizing cells. The carbon dioxide that entered the blood is transported back to the heart in three forms: 1.About 7% of the carbon dioxide remains in the plasma, in the form of carbon dioxide in free solution. This produces a venous partial pressure for CO2 of 45 mm Hg (in contrast to the systemic arterial P CO2 of 40 mm Hg). CO2 CO2 CO2 CO2 (7%) PCO2 = 45 mm Hg CO2 (100%) 93% CO2 in another form 2.The remaining 93% of the carbon dioxide enters erythrocytes, where one of two things happen: A. 23% of the carbon dioxide becomes bound to hemoglobin, producing the compound called carbaminohemoglobin (CO2HHb). NOTE: Some carbon dioxide can also bind to plasma proteins, thereby taking it out of solution, but the amount of binding to plasma proteins is fairly trivial. CO2 CO2 CO2 CO2 (7%) PCO2 = 45 mm Hg CO2 (100%) 93% CO2 CO2 (23%) HHb 23% RBC O2 CO2HHb B. The remaining 70% of carbon dioxide which is found in venous blood is converted in red blood cells to carbonic acid, using the enzyme carbonic anhydrase (CO 2 + H2O → H2CO3). Carbonic acid is a weak acid and the majority of the molecules dissociate to form H + and HCO3-. The bicarbonate is then transported out of the red blood cell and back into the plasma by a chloride-bicarbonate antiport protein. Therefore, in venous blood we see elevated levels of bicarbonate and lowered levels of chloride in plasma – a phenomenon referred to as the chloride shift. CO2 CO2 CO2 CO2 (7%) PCO2 = 45 mm Hg CO2 (100%) 93% CO2 CO2 (70%) H2O 70% Carbonic RBC Anhydrase Cl- H2CO3 HCO3- H+  The distribution pattern described above makes it clear that the majority of carbon dioxide transported in the blood to the lungs is in the form of bicarbonate (HCO3-). If the carbonic anhydrase of red blood cells is inhibited (such as by acetazolamide) we see that venous PCO2 levels rise dramatically – up to 80 mm Hg instead of 45 mm Hg. Oxygen is also present in venous blood. The partial pressure of oxygen in free solution is 40 mm Hg (in contrast to the 95 mm Hg partial pressure for oxygen in systemic arterial blood). However, the majority of the oxygen present in venous blood is in a form bound to hemoglobin in red blood cells. When ambient oxygen partial pressure is 40 mm Hg, hemoglobin is still about 75% saturated with oxygen – meaning that only a fraction of the oxygen available from hemoglobin has been lost in the systemic capillary. Venous Blood: CO2 7% in solution O2 Oxygen in solution (PCO2 = 45 mm Hg) (PO2 = 40 mm Hg) 23% bound to Hb Oxygen bound to Hb (Hb is 75% saturated) 70% as HCO3- Gas Exchange in Pulmonary Capillaries: At the arterial end of a pulmonary capillary plasma PO2 is 40 mm Hg and alveolar PO2 is 104 mm Hg. Therefore, there is an initial P of 64 mm Hg forcing oxygen into plasma. Oxygen diffuses into the plasma, and within 1/3rd the length of the capillary there is equilibration of plasma and alveolar P O2 (both are 104 mm Hg). Note the large “safety” factor here: It doesn’t take the entire length of the capillary to equilibrate, just 1/3rd the length. Similarly, carbon dioxide equilibrates about as rapidly, with plasma PCO2 equilibrating with alveolar PCO2 (40 mm Hg) during the first third of the capillary transit. Notice that the P for CO2 is only 5 mm Hg (45 mm Hg in blood and 40 mm Hg in alveoli) compared to the initial 64 mm Hg gradient driving oxygen diffusion across the alveolar capillary. At rest, about 5 ml oxygen per 100 ml of blood needs to enter the capillary while 4 ml of carbon dioxide needs to exit into the alveoli. Therefore, similar amounts of carbon dioxide and oxygen need to diffuse across the alveolar capillary at the same rate, but carbon dioxide has a much lower driving force. It is possible for this to occur because of the 20-fold greater diffusion coefficient for carbon dioxide (e.g. Carbon dioxide needs its greater diffusion coefficient because it has a much smaller diffusion gradient across the alveolus). O2 PO2 5 ml/100 ml O2 PO2 O2 diffusion coefficient CO2 CO2 diffusion coefficient PCO2 4 ml/100 ml CO2 PCO2 This safety margin becomes more important during exercise: During strenuous exercise there is a 20-fold increase in oxygen demand by the body. One way that demand is met is by a large increase in cardiac output. As the amount of blood per minute increases, it means that each milliliter of blood spends less time in transiting the alveolar capillary. If it took 100% of total transit time at rest to allow oxygen equilibration, then during exercise we would expect to see blood being less than 100% saturated with oxygen. The safety margin means that we still have ample time to equilibrate with alveolar oxygen, even during periods of increased cardiac output.  Cardiac Output NOTE: The safety margin is not the only thing allowing us to maintain oxygen saturation. Two other changes which help assure saturation  Transit time during exercise are: 1) the three-fold increase in oxygen diffusing capacity (due to opening of previously closed capillaries), and 2) improved ventilation-perfusion matching (increased flow to well-ventilated alveoli). During Exercise Gas Transport in Arterial Blood: So, the blood reaching the venous end of the alveolar capillary has a PO2 of 104 mm Hg and PCO2 of 40 mm Hg, even during periods of moderate to heavy exercise (increased oxygen demand). Yet when we measure oxygen pressure in systemic arteries (or even in the pulmonary vein) we see P O2 is only 95 mm Hg. What happened to the missing oxygen? The PO2 drops because about 2% of total pulmonary blood flow has bypassed alveolar capillaries and has instead been shunted to oxygenate pulmonary tissue which is not next to alveoli – just like systemic blood flow is used to provide oxygen to peripheral tissues. The blood that has been shunted has a P O2 of 40 mm Hg, and it is the mixing of this 2% of “deoxygenated” pulmonary blood with the 98% of pulmonary blood with a PO2 of 104 mm Hg which yields a systemic arterial PO2 of 95 mm Hg. Deoxygenated blood from O2 bronchial vessels Lung cells To systemic Deoxygenated circulation blood enters lungs PO2 = PO2 = O2 104 mm Hg 95 mm Hg Alveoli (PO2 = 104 mm Hg) The partial pressure of oxygen (and carbon dioxide) is unchanged from the time the blood enters the pulmonary vein until it reaches the arterial end of systemic capillaries (the gas content of the blood remains constant except in capillary beds). The interstitial fluid P O2 is about 40 mm Hg, because oxygen is constantly being consumed by the mitochondria of metabolizing cells (Therefore, interstitial oxygen diffuses to the lower P O2 found intracellularly – around 5 mm Hg). From there it diffuses into the mitochondrial matrix, where PO2 is approximately zero because oxygen is promptly consumed in the final step of electron transport. So, capillary PO2 rapidly equilibrates with interstitial PO2, replacing the oxygen that is being consumed by cells. This means that the plasma P O2 of blood entering the systemic veins is 40 mm Hg, and remains at that value until reaching the arterial end of the pulmonary capillaries. Arterial end PO2 = 104 mm Hg PO2 = 40 PO2 = 5 PO2 = mm Hg mm Hg 0 mm Hg Venous end PO2 = 40 mm Hg The movement of carbon dioxide from cells into the blood obeys the same principles as does oxygen moving from the blood into the cell, just with a lower pressure gradient: The highest partial pressure of carbon dioxide in the body is in the mitochondrial matrix (where the majority of CO2 is produced during metabolism). Overall, intracellular PCO2 is about 46 mm Hg and interstitial PCO2 is 45 mm Hg. This is a small concentration gradient (1 mm Hg), but remember that carbon dioxide’s diffusion coefficient is 20-times greater than that for oxygen. Therefore, carbon dioxide produced in cells readily diffuses into the interstitium. From the interstitium to the plasma we have a 5 mm Hg gradient for diffusion, and carbon dioxide rapidly enters the blood. This results in systemic venous P CO2 being 45 mm Hg, the value we see for blood entering the alveolar capillary. Arterial end PCO2 = 40 mm Hg PCO2 = 45 PCO2 = 46 PCO2 = mm Hg mm Hg 46 mm Hg Venous end PCO2 = 45 mm Hg  Up until now we have been talking about the movement and transport of oxygen and carbon dioxide in terms of their partial pressures. Let’s shift now to considering the total AMOUNT of oxygen required by the peripheral tissues (and therefore the amount that must be transported in the blood). At rest, the tissues of the body require about 250 ml of oxygen per minute (5 ml extracted per deciliter [0.1 liter] of blood). 0.29 ml of oxygen is dissolved in every deciliter of blood when PO2 = 95 mm Hg, and that falls to 0.12 ml at PO2 = 40 mm Hg. Therefore, if ONLY dissolved oxygen was transported in blood we could deliver (0.29 – 0.12)(Cardiac Output = 5 L/min) = 8.5 ml/min oxygen. Clearly, that will not meet the resting body requirement of 250 ml/min. Even at maximal cardiac output during exercise (about 13 liters/min) oxygen in free solution can deliver only 22.1 ml/min. Fortunately, we have hemoglobin to loosely bind and transport oxygen – taking it out of free solution. NOTE: Oxygen bound to hemoglobin does not contribute to partial pressure. Partial pressure is only exerted by gas molecules in free solution. Normally, roughly 97% of all oxygen delivered to the tissues is transported bound to hemoglobin: [250 ml/min total delivery – 8.5 ml/min in solution]/250 ml/min total delivery = 96.6% and only 3% of total oxygen transport to tissues occurs in the form of free solution of oxygen. Now, normal blood contains about 15 grams of hemoglobin per deciliter of blood and each gram of hemoglobin can bind 1.34 ml of oxygen. Therefore, each deciliter of blood can hold 20 ml of oxygen bound to hemoglobin. If cardiac output at rest is 5 L/min (50 deciliters/min), then the total potential oxygen output to the circulation each minute is: (20)(50) = 1000 ml oxygen/min – more than sufficient to meet the 250 ml/min used by the tissues at rest. Now that’s an upper limit, because hemoglobin isn’t saturated with oxygen when the P O2 is 95 mm Hg (as it is in blood leaving the lungs). At P O2 = 95 mm Hg hemoglobin is 97% saturated, meaning that the normal resting oxygen available from the circulation is: (1000)(0.97) = 970 ml oxygen/min (or, 19.4 ml/deciliter of blood). Hemoglobin binding to oxygen is an allosteric relationship – the hemoglobin dissociation curve is often used to illustrate allosteric binding relationships. While the hemoglobin is 97% saturated at PO2 = 95 mm Hg (as occurs in the lungs), when it is placed in an environment where ambient PO2 = 40 mm Hg (such as is the case in the systemic capillaries) there is significant unbinding of oxygen from hemoglobin. Not all of the oxygen becomes unbound. In fact, we see that hemoglobin is 75% saturated with oxygen when oxygen partial pressure falls to 40 mm Hg. Therefore, only a fraction of the oxygen being transported in the bound state is off-loaded at tissue capillaries: (0.97-0.75)(970 ml/min) = 213 ml/min oxygen delivered to the tissues (or, 19.4 – 14.4 ml oxygen/deciliter of blood flow = 5 ml oxygen/deciliter – the amount of oxygen being consumed per minute by the tissues). Looking at it slightly differently, at rest there is 4 times the amount of oxygen being transported each minute than the total oxygen consumption by the tissues (The tissues use only 25% of the total oxygen supply present). Small local increases in oxygen consumption can easily be supplied by greater oxygen extraction, while during exercise we can further increase oxygen delivery by the 6-7 fold increase in cardiac output. The allosteric nature of hemoglobin binding to oxygen acts to naturally regulate the level of oxygen that is present in the interstitium within a few mm Hg of the normal 40 mm Hg, through a range from 60-500 mm Hg PO2 for inhaled air. In addition, the hemoglobin dissociation curve can be shifted to the left or right by different regulatory compounds and situations. A shift to the right means that it is more difficult to get oxygen to bind to hemoglobin, meaning that the hemoglobin will off-load more oxygen in the tissues. A shift to the left makes it easier to saturate hemoglobin, but the hemoglobin will release less oxygen to the tissues. Factors that shift the dissociation curve to the right: 1) Increased blood acidity: A drop in blood pH from 7.4 to 7.2 shifts the dissociation curve to the right by about 15%. This could occur if oxygen supply was not meeting oxygen demand by the tissue, increasing lactate production locally. The right shift will cause more oxygen to dissociate from hemoglobin, thereby supplying more oxygen to the metabolizing tissue. 2) Increased blood PCO2: An increase in carbon dioxide (hypercapnia) causes a right shift in the hemoglobin dissociation curve (basically for the same reasons as listed for acidification). When a tissue becomes metabolically more active it produces more carbon dioxide, and its need for oxygen will also increase. 3) Increased blood 2,3-diphosphoglycerate (2,3-DPG – a compound which now called 2,3 bisphosphoglycerate): 2,3-DPG is synthesized in greater amounts when we are in hypoxic conditions for periods of several hours or more (such as when you visit a high altitude). 4) Increased body temperature: As body temperature rises there is a right shift in the dissociation curve. This would help meet the oxygen demand for tissues that are producing and using ATP rapidly (exercising muscle, cells fighting infections, etc.). Factors 1 and 2 above (low pH and high PCO2) produce what is called the Bohr Effect – Blood passing through the lungs is in an environment where PCO2 is decreased and pH is increased relative to systemic capillaries. Therefore, the hemoglobin dissociation curve is shifted to the left in the lungs. This maximizes the amount of oxygen that binds to hemoglobin at the ambient PO2 in the lungs. Then, when this oxygenated blood reaches a systemic capillary it is in an environment where PCO2 is elevated and pH is relatively low (compared to that found in the alveolar capillaries). This causes a right shift in the dissociation curve, and more oxygen being off-loaded from the hemoglobin than if no shift had occurred. The Bohr Effect optimizes hemoglobin’s ability to load up with oxygen in the lungs and to then off-load oxygen in the tissues. Factors that shift the dissociation curve to the left: 1) Decreased blood acidity: Alkaline blood (pH = 7.6 or higher) causes hemoglobin to bind oxygen more tightly. 2) Decreased blood PCO2: Hypocapnia shifts the dissociation curve to the left. Hypocapnia can result from hyperventilation or low total metabolic rate. 3) Fetal hemoglobin: The form of hemoglobin found in fetal blood is different than that found in adult blood (adult hemoglobin). One major difference in their characteristics is that the dissociation curve for fetal hemoglobin is shifted to the left compared to adult hemoglobin. Why? The fetal hemoglobin must extract oxygen from the maternal circulation. This is made possible by the greater binding affinity of fetal hemoglobin for oxygen. In essence, the fetal blood plucks oxygen out of the maternal circulation. Sure, that fetal hemoglobin doesn’t give up its bound oxygen as readily, but it will still easily meet all of the metabolic oxygen demands of the developing fetus. Now on to carbon dioxide transport in the blood. We began this section by discussing how 70% of the carbon dioxide in blood is in the form of bicarbonate (HCO3-), 23% is bound to hemoglobin in red blood cells (Carbaminohemoglobin) and 7% is in free solution in plasma and intracellular fluid of blood cells. In terms of amounts of carbon dioxide present in blood, we must transport 4 ml carbon dioxide/100 ml of blood (the product of metabolism in the tissues which must be excreted from the body). NOTE: We do not get rid of all of the carbon dioxide that is present in the blood when the blood passes through the lungs. Rather, we get rid of 4 ml CO 2 per 100 ml of blood that passes through the lungs. The average total amount of carbon dioxide in the blood is 50 ml/100 ml of blood. In venous blood there is 52 ml CO2 per 100 ml blood, and in arterial blood there is 48 ml/100 ml of blood – so the 4 ml of carbon dioxide that we get rid of in the lungs is only a fraction (8%) of the total carbon dioxide present. This means that the carbon dioxide content of the blood stays quite stable, even when comparing arterial to venous content. Alveoli Pulmonary Pulmonary Artery 4 ml CO2/100 ml blood Vein End End Total CO2 = 52 ml/100 ml Total CO2 = 48 ml/100 ml PCO2 = 45 mm Hg PCO2 = 45 mm Hg NOTE: We saw earlier that the binding of protons and carbon dioxide decreased the affinity of hemoglobin for binding to oxygen (the Bohr Effect). It turns out that the binding of oxygen alters hemoglobin’s binding to carbon dioxide, and this is called the Haldane Effect. The Haldane Effect is simply that increased binding to oxygen decreases hemoglobin’s affinity for carbon dioxide. In practical physiological terms this means that in the alveolar capillaries (where PO2 is high and more oxygen will begin binding to hemoglobin) the hemoglobin will off-load carbon dioxide (which then diffuses into alveoli). Conversely, in the systemic capillaries, PO2 is relatively low and oxygen becomes unbound from hemoglobin. This causes the hemoglobin to increase binding to carbon dioxide. The bottom line: Although the Haldane Effect may not seem real critical, it actually doubles the amount of carbon dioxide that can be transported in the blood at any given time. CO2 (23%) HHb O2 CO2HHb O2 CO2 CO2HHb O2-Hb Bohr Effect - in tissues Haldane Effect - in lungs