Oxygen Transport – Protein Functions

by Kevin Ahern, PhD

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    00:01 So the mechanisms that we described so far for ventilation and oxygen uptake by the blood are really very simple. Ventilation just requires a little bit of expansion of the lung. Oxygen uptake is diffusion. Very straight forward simple mechanisms. Oxygen transport via blood is a little bit more complex. There are two main forms by which oxygen that reaches the blood can be transferred using that blood to the tissues to oxygenate the body. One is the dissolved oxygen, that is measured by doing the arterial PAO2 level. That actually only represents a very small amount of the total oxygen in the blood, 1% or 2%. It represents the oxygen dissolved in the liquid phase of the blood. The majority of the oxygen transport in the blood is by the red cells. And that is because the red cell is packed full of haemoglobin and each haemoglobin molecules can carry four oxygen molecules. There are about 250 million haemoglobin molecules per red cells and red cells are by far the most dominant cell present in the blood so that provides a massive oxygen carrying capacity.

    01:09 So the oxygen picked up by the blood in the lungs is transferred to the haemoglobin and then using the red cells being transported by the blood through the left side of the circulation and then through the systemic arterial circulation will reach the tissues and deliver oxygen to where it is needed in the muscles, the brain, the kidneys etc., which are working and require the oxygen for aerobic metabolism.

    01:36 The saturation of haemoglobin, how much oxygen is carrying is measured by using the pulse oximeter probe which you just place on somebody’s finger or their toe, or their ear and would give a feel for whether the haemoglobin has its maximum oxygen saturation or the oxygen saturation is low. So the total amount of oxygen delivery to the peripheral tissues depending on a few factors.

    02:02 1. Is the oxygen content of the blood. That is dependent as we have already mentioned on haemoglobin largely and to a certain extent on PA2 how much oxygen is dissolved in liquid phase of the blood. 2. But in addition it depends on cardiac output.

    02:17 How much blood is being delivered to the tissue. So that is why cardiac function is very important for the patients with breathlessness. As it is a significant component of how oxygen gets to peripheral tissues.

    02:31 If you look at the curve in the lung tissue we get left shift of the curve so there is higher affinity of haemoglobin for oxygen and that occurs because of the relatively low carbon dioxide concentration, the relatively low temperature present there, and the relatively non acidotic conditions found within the lung. In the tissue the opposite occurs. Metabolizing tissue will cause acidosis because it produces hydrogen ions, there will be CO2 present because of the metabolism as well. There will be temperature being produced by the active cells and in addition there is a compound called 2 free diphosphoglyceric, 2 free DPG which has high concentrations within skeletal tissue but low concentrations in the lung and that helps cause the shift to the right for release of oxygen in metabolizing tissue.

    03:29 So this is how the affinity of haemoglobin for oxygen can be manipulated so that actually it is able to take up oxygen in the lungs but deliver it to tissues which are metabolizing.

    03:42 Carbon dioxide is also transported by the blood. But there are three different forms here rather than just two for oxygen. Like oxygen, you can dissolve carbon dioxide into the blood but that actually makes a significant contribution towards the carbon dioxide delivery from metabolizing tissues back to the lung about 8%. It also can be attached like oxygen to haemoglobin but that is relatively a weak process for carbon dioxide compared to oxygen and only about 11% of carbon dioxide is being transferred from tissues back to the lungs is in the form of carbaminohaemoglobin attached to deoxygenated haemoglobin. The majority of carbon dioxide transported from the tissues back to the lungs as it is dissolved bicarbonate.

    04:28 So how does carbon dioxide become bicarbonate. Well this is the reaction that is catalysed by an enzyme called carbonic anhydrase mainly carrying in red blood cells. Carbon dioxide plus water is converted by carbonic anhydrase into carbonic acid and that quickly dissociates to form bicarbonate and hydrogen ions. And this is why carbon dioxide increases the concentration of hydrogen ions and therefore can cause acidosis.

    04:54 There are a couple of effects of this. The hydrogen ion binding to haemoglobin lowers affinity for oxygen, that is called the Bohr effect. And as mentioned before that was one of the main mechanisms, that makes oxygen dissociation curve shift to the right and releases oxygen for the tissue to use. Oxygen binding to haemoglobin reduces the affinity of carbon dioxide and that is called the Haldane effect and so you end up with the reverse occurring in the lungs, where the oxygen binding to the haemoglobin actually releases carbon dioxide and allows better excretion of carbon dioxide. So carbon dioxide and acid base are very closely related. PH of the body is actually very tightly regulated. The normal pH varies from 7.36 and 7.45. You can just about tolerate pH of 6.8 and 6, but essentially I haven’t seen many people who have survived with pH that low of respiratory acidosis. A metabolic or respiratory alkalosis can push your pH as high as 7.7. And that reflects hydrogen ion concentration over 84 range over 116 to 129 mL/L.

    06:08 So how is pH regulated? Well it is by getting rid of acid. And the way we get rid of acid is by almost 100% through the lungs, 99%. And that is a rapid method of controlling pH. The kidneys can also get rid of acid but they are much slower responder and that takes hours and days to actually respond to an increase in hydrogen ions. So largely it is a lung controlled situation. You can also buffer acid. So if there is an excess of hydrogen ion present, buffers are substances that will pick up those hydrogen ions and make the acidosis less of a problem, reduce the pH effects. And the key buffers that do that is bicarbonate, because if you have bicarbonate and you add hydrogen ion to it, then that will convert it to carbon dioxide and water and you can breathe out the carbon dioxide and water of course is a safe substance. Again that is a process that is catalyzed by carbonic anhydrase.

    07:08 It is one of those enzymes that can catalyse the process in either direction.

    07:13 Another key buffer is haemoglobin. Deoxygenated haemoglobin as a negative charge and that allows it to attract some of the positive charged hydrogen ions and buffer some of the effects of excess acid. But largely, speaking bicarbonate is the most important buffer.

    07:28 There are other components of the blood which can act as a buffer as well. So this is the slide that describes an overview of acid-based balance. And the lungs are very central to control the pH because of this business about carbon dioxide. Because pH is largely dictated by the concentration of carbon dioxide and bicarbonate. So on the left we have tissue production or ingested hydrogen ions that causes a degree of acidosis. That acidosis means that bicarbonate is converted into carbon dioxide and water and that carbon dioxide is breathed out by the lungs, getting rid of that excess acid. So if you have a problem with respiration, hyperventilation that will lead to respiratory acidosis because you are not able to get rid of the carbon dioxide and that you are not able to get rid of the acid that is being produced by the body’s metabolism. Importantly, if you have an acidosis due to poor respiration, if you increase the amount of bicarbonate around, that acts as a buffer and it helps control some of the problems that you might get with the excess hydrogen ions. So there is compensation occurs in people with long term under ventilation of the lung over hours and days you get an increase in bicarbonate to compensate for respiratory acidosis.

    08:48 Conversely, if you breathe very fast for no particularly good reason, hyperventilation, and then in fact you will blow off a little carbon dioxide and that will drive up the pH and cause respiratory ankylosis. Other causes of acid-base imbalance, the most important one is excess acid production most classically that happens in diabetic ketoacidosis and in renal failure where there is a lot of extra acid being produced and you require the lungs to ventilate faster to try and get rid of some of the extra acid. There is an equation called the Henderson-Hasselbalch acid base equation which dictates pH. This is the equation when pH is 6.1+ log [HCO3]/log[90.0.0301 x PCO2] what this really means is that the pH is dependent on the bicarbonate and the carbon dioxide concentrations. The carbon dioxide concentration is set by the lungs, the bicarbonate is largely set by the kidneys. So when you get respiratory acidosis and compensation with increased bicarbonate that is because the kidneys are retaining more bicarbonate. If you do a blood gas on somebody with an acid base imbalance due to the lungs the respiratory acidosis under ventilation you get a low pH acid, a high PCO2, because of this issue, the problem here is that you are not able to get rid of the CO2 that is driving the acidosis, and incompensation over time over day or two you will get a positive base excess which represents the amount of buffer available within this system, a positive base excess, means there is a lot more buffer than normal and a high bicarbonate, as we discussed just now. In respiratory alkaloses reverse occurs you get a low, if you breathe too fast you get a high pH a low PCO2 and a thereby carbonate gets blown off by the hyperventilation which is why you are getting an alkaloses in the first place.

    10:52 So now we will move on to describe the pulmonary circulation. Now what is important here is how much blood is being delivered to each alveoli. And what we mean by that is that, if we have an alveolus that is not being ventilated for whatever reason then you deliver the blood to the alveolus, it won’t be oxygenated because there is no oxygen in the alveolar units. And that is called the V/Q mismatching. And the opposite can happen. You can have blood not being delivered to an alveolus and that alveolus is being ventilated that means that alveolus ventilation actually has no functional consequences. There is no blood being delivered so no oxygen can be taken out by the blood. This occurs at different part of lungs to a different extent. So for example, in the normal lung the relative underperfusion of the lung apices. There is less blood being delivered compared to how much ventilation is occurring whereas at the bottom of the lungs it is the other way around, more blood is being delivered compared to the amount of ventilation that is being delivered. So these are normal physiological situation where there is a little bit of V/Q mismatching occurring.

    12:03 Another very important point here is that the pulmonary arteries constrict in response to the oxygen concentration always. So if you have a low oxygen concentration, you get a pulmonary artery constriction occurring and that allows the amount of blood being delivered to be diverted away from parts of the lung which are not ventilating very well.

    12:23 So if you have got a bit of lung that is not delivering oxygen to the alveoli then there is no requirement for blood being delivered to that area and in fact the pulmonary arteries will constrict in response to the hypoxias occurring to that part of the lung. And that is fine because that allows the ventilation perfusion matching to occur as much as possible within the normal lung. The problem with that is that if you have a chronic lung disease where everywhere within the lung where within the lung is hypoxic essentially then you end up with pulmonary artery constriction occurring throughout the lung and that leads to pulmonary hypertension and cor pulmonale which is the end-stage problem that occurs in many patients of chronic lung disease. High blood pressure in the pulmonary artery circulation leading to right-sided cardiac failure and all down to the fact that you are getting the hypoxic vasoconstriction that is a normal physiological response in a normal lung but in pathological circumstance can have negative consequence.

    13:24 So the control of ventilation. Now ventilation is controlled mainly by the back of the brain by the medulla, the pons, and the brain stem. There is an inspiration send during the pons and that basically dries that ventilation process that we described earlier with diaphragmatic contraction, intercoastal muscle contraction leading to increased sizes of the lungs about at the rate of about 12 per minute. So that is your normal resting ventilation and that requires no thought and it occurs automatically. Expiration is normally a passive process when you are at rest, but if you are exercising, it becomes a more active process, with contractions of the intercostals being relevant and potentially abdominal muscles as well. And therefore there is an expiratory center which is on the medulla that works mainly during forced expiration when you are exercising or if you have chronic lung disease and have to respire at a greater rate than normal.

    14:22 How does the brain respond to what the environment, to work out, whether to breath faster or slow.

    14:27 And that is largely driven by chemoreceptors which sample the blood, peripherally in the aortic arch, the carotid arteries and the bifurcation of the carotid arteries and centrally in the medulla. What these respond to is evidence of respiratory acidosis. So the peripheral receptors will measure the carbon dioxide concentration and if that is increased, or the pH is decreased suggesting a degree of mild respiratory acidosis, then they will drive respiration up. They also will respond to oxygen but to a lesser extent that has required marked changes in the oxygen concentration of the blood to drive respiration up. The central receptors are largely driven by pH but that as we have discussed already is basically dependent on the concentration of carbon dioxide in the blood. So what happens here is that if for example you are working harder, you decide to run for a bus, that would drive a more carbon dioxide production by your skeletal muscles, that would decrease your pH and perhaps your pH might fall a little bit as well. This will be detected by the peripheral and central chemoreceptors and that would drive increased central respiratory drive. And then you will fire your phrenic nerve and intercostal nerves more. You will ventilate faster and that will overcome the mild degree of acidosis generated by your quick burst of activity. And then the opposite would occur if you are resting or you have been inactive with a decrease when ventilation occurring as the pH comes back up again and the CO2 goes down.

    About the Lecture

    The lecture Oxygen Transport – Protein Functions by Kevin Ahern, PhD is from the course Biochemistry: Basics.

    Included Quiz Questions

    1. Sigmoidal curve
    2. Hyperbolic curve
    3. Parabolic curve
    4. Elliptic curve
    5. J-shaped curve
    1. The myoglobin displays two different oxygen binding affinity patterns in the body; near the lungs it has the high affinity of oxygen; but in muscle cells, it shows the lowest affinity for oxygen.
    2. The hemoglobin displays the positive cooperativity phenomenon in the presence of high concentrations of oxygen
    3. The myoglobin oxygen binding follows the rectangular hyperbolic curve, whereas hemoglobin oxygen binding follows a sigmoidal curve pattern
    4. The hemoglobin participates in the transportation of oxygen from lungs to the tissues, whereas myoglobin stores the oxygen in the muscle cells
    5. The hemoglobin is composed of four subunits, whereas myoglobin is comprised of only one subunit

    Author of lecture Oxygen Transport – Protein Functions

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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