Vet Cardiology and Respiratory Function - Lecture 5 PDF

RESPIRATORY PHYSIOLOGY: LECTURE 5 Oxyhaemoglobin dissociation curve As the pO2 increases, the % of Hb saturated with O2 increases until all O2-binding sites are occupied (100% saturation) I would like to review the oxyhemog...

RESPIRATORY PHYSIOLOGY: LECTURE 5 Oxyhaemoglobin dissociation curve As the pO2 increases, the % of Hb saturated with O2 increases until all O2-binding sites are occupied (100% saturation) I would like to review the oxyhemoglobin dissociation curve again, as it is crucial for understanding and interpreting oxygen transport. This curve visually represents the relationship between the partial pressure of oxygen and hemoglobin saturation. The curve itself is sigmoidal, or S-shaped, due to a process called positive cooperativity. This means that when hemoglobin binds to one oxygen molecule, the remaining binding sites on the hemoglobin undergo a conformational change, increasing their affinity for oxygen. At the start of the curve, you will notice that the initial portion is quite linear. This represents the fact that, as one oxygen molecule binds to hemoglobin, it alters the affinity of the other binding sites. As a result, even small changes in the partial pressure of oxygen can lead to significant increases in hemoglobin saturation, allowing for rapid binding of oxygen. This process not only facilitates oxygen binding but also oxygen release. Hemoglobin functions as a transport carrier, picking up oxygen in the lungs and delivering it to active cellular sites where metabolism is occurring. Once at the cellular level, the partial pressure of oxygen is lower, prompting oxygen to dissociate from hemoglobin and enter the cells. As oxygen is released, the affinity for remaining oxygen molecules decreases, allowing more oxygen to be quickly unloaded, even with minor reductions in the partial pressure of oxygen. Several factors can influence the affinity of hemoglobin for oxygen, which will be discussed in subsequent slides. As the partial pressure of oxygen continues to increase, the curve begins to flatten. This plateau indicates that hemoglobin is nearly fully saturated with oxygen, and further increases in partial pressure will not significantly increase hemoglobin saturation. This flattening acts as a protective mechanism, ensuring that oxygen delivery to tissues remains adequate, even in cases of arterial hypoxemia (reduced oxygen in the blood). Under normal conditions, the partial pressure of oxygen in arterial blood mirrors that of alveolar oxygen, approximately 100 mmHg. Around 60 mmHg, the curve flattens, indicating that despite a decrease in oxygen partial pressure— representing hypoxemia — hemoglobin saturation remains high. This protective mechanism ensures that oxygen content in the blood is maintained, even in cases of significant hypoxemia. Now, let’s review the steps involved in oxygen transport, from the alveoli to the tissues. Oxygen can be transported in two forms: dissolved in the blood or bound to hemoglobin. Because oxygen is poorly soluble in blood, only about 2% is transported in its dissolved form, which is represented by the partial pressure of oxygen. However, this dissolved form is crucial as it drives the movement of oxygen through the blood. A higher partial pressure in the alveoli compared to venous blood creates a gradient, allowing oxygen to move from the alveoli into the blood. Once oxygen enters the bloodstream, it raises the partial pressure of oxygen in the blood, allowing diffusion into red blood cells, where it binds to hemoglobin. Inside the red blood cell, the partial pressure of oxygen is higher than the oxygen bound to hemoglobin. As carbon dioxide (CO2) and hydrogen ions attached to hemoglobin detach from hemoglobin, oxygen binding sites become available. After the initial oxygen molecule binds, the remaining sites undergo a conformational change, allowing for rapid binding of additional oxygen molecules. This process lowers the partial pressure of oxygen in the red blood cell, maintaining a gradient that encourages more oxygen to enter the cell from the plasma, which, in turn, lowers the partial pressure in the blood, allowing oxygen to flow from the alveoli into the blood. Once the blood, now rich in oxygen, reaches metabolically active tissues, the lower partial pressure of oxygen in these cells drives the movement of oxygen from the blood into the cells. This lowers the partial pressure of oxygen in the blood, encouraging oxygen to leave hemoglobin, enter the plasma, and then diffuse into the cells. This forward momentum is maintained by the difference in partial pressures. Understanding these processes is essential for making informed clinical decisions. Oxygen content in the blood depends not only on the partial pressure of oxygen but also on hemoglobin concentration and its saturation. These factors must be considered when choosing treatment options. For instance, the total oxygen content equation takes into account both the partial pressure of oxygen and hemoglobin concentration, though I do not expect you to memorize or calculate it. 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑂𝑂2 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 = (1.34 ∙ [𝐻𝐻𝐻𝐻] ∙ %𝐻𝐻𝐻𝐻) + 0.003 ∙ 𝑝𝑝𝑝𝑝2 Now, let us look at a few scenarios that can alter the oxyhemoglobin dissociation curve. 1. The first scenario involves normal hemoglobin concentration, around 15 grams per deciliter, with a typical dissociation curve. 2. The second scenario shows polycythemia, where hemoglobin levels are higher than normal (around 20 grams per deciliter). In this case, the oxygen-carrying capacity is increased, and the curve shifts upward due to higher oxygen content. 3. The third scenario is anemia, where hemoglobin levels are lower than normal (around 10 grams per deciliter). Here, despite full hemoglobin saturation, the curve is compressed, reflecting reduced oxygen content. Consider three clinical cases labeled A, B, and C: 1. Case A represents a severe anemia scenario where there is no hemoglobin available to carry oxygen. Despite normal gas exchange, the total oxygen content in the blood is severely decreased. In such a case, treatment would involve increasing the oxygen-carrying capacity via a blood transfusion, not supplemental oxygen. 2. In Case B, a normal scenario, the partial pressure of oxygen in the alveoli and blood is around 100 mmHg, with adequate hemoglobin available to bind oxygen, resulting in normal oxygen transport. 3. Case C involves a situation where there is a lower-than-normal partial pressure of oxygen in the alveoli (around 28 mmHg), which leads to reduced oxygen partial pressure in the blood. This could result from: hypoventilation, V/Q mismatch, or diffusion limitations. Despite adequate hemoglobin levels, the lower partial pressure prevents sufficient oxygen from binding to hemoglobin, resulting in decreased oxygen content. In this scenario, supplementing with oxygen to increase the partial pressure in the blood would be the appropriate treatment. In all cases, understanding the underlying causes of oxygen deficiency—whether it's due to low partial pressure or insufficient hemoglobin—is critical to determining the right clinical intervention. There are several factors that influence the affinity of hemoglobin for oxygen binding. As previously mentioned, oxygen itself affects hemoglobin's affinity for additional oxygen molecules. Once oxygen binds to hemoglobin, it increases hemoglobin's affinity for more oxygen. Similarly, when oxygen is released from hemoglobin, the affinity for the remaining oxygen molecules decreases. Other factors that affect hemoglobin’s affinity for oxygen are outlined in the accompanying table. One of the primary factors is pH. Changes in pH can significantly alter hemoglobin’s affinity for oxygen. This shift occurs due to conformational changes in the hemoglobin molecule’s binding sites, which can increase or decrease the attraction for oxygen. In an acidic environment, hemoglobin’s affinity for oxygen decreases. Additionally, an increased partial pressure of carbon dioxide (CO2) also reduces oxygen affinity. This is because CO2 acts as an acid, contributing to the acidic environment. Other factors, such as elevated temperature and increased concentrations of 2,3-DPG, also decrease hemoglobin’s affinity for oxygen. 2,3-diphosphoglycerate. To elaborate on 2,3-DPG, it is a byproduct of anaerobic metabolism and binds to hemoglobin, thereby reducing its affinity for oxygen. To better understand these factors, consider the scenario of a contracting skeletal muscle. During muscle contraction, oxygen is needed to produce energy. As the muscle metabolizes oxygen, it generates waste products such as heat, CO2, and hydrogen ions, contributing to an anaerobic environment. This increased 2,3-DPG production decreases hemoglobin's affinity for oxygen, facilitating the release of oxygen to the muscle cells, allowing energy production to continue. Conversely, at the level of the lungs, the opposite effect is desired. In the lungs, CO2 is expelled, which reduces the acidity of the environment, decreases temperature, and lowers 2,3-DPG concentrations. These conditions favor hemoglobin’s increased affinity for oxygen, which is essential for oxygen uptake at the lungs. Graphically, these changes in hemoglobin’s oxygen affinity can be observed by shifts in the oxyhemoglobin dissociation curve. A rightward shift in the curve indicates decreased affinity for oxygen, often seen in acidic environments with increased CO2, heat, and 2,3-DPG—such as in contracting muscle. A leftward shift represents increased affinity for oxygen, which is typical at the lungs, where conditions favor oxygen binding. The normal curve is represented in orange, a contracting muscle in light purple, and the lungs in light blue. 𝐏𝐏𝐎𝐎𝟐𝟐 (𝐦𝐦𝐦𝐦𝐦𝐦𝐦𝐦) 𝐏𝐏𝐎𝐎𝟐𝟐 (𝐦𝐦𝐦𝐦𝐦𝐦𝐦𝐦) 𝐏𝐏𝐎𝐎𝟐𝟐 (𝐦𝐦𝐦𝐦𝐦𝐦𝐦𝐦) When pH decreases (more acidic), the curve shifts to the right, signaling a lower affinity for oxygen, while a higher pH (less acidic) shifts the curve to the left, indicating increased affinity. Similarly, higher temperatures and elevated 2,3-DPG levels shift the curve to the right, while lower values of these factors shift the curve to the left. Carbon dioxide transport Next, I will discuss how carbon dioxide (CO2) is transported in the blood. Unlike oxygen, CO2 is transported in three different forms. 1. First, it is dissolved in plasma, with about 5% of the total CO2 in the blood being transported in this dissolved form, represented by the partial pressure of CO2. 2. Second, CO2 binds reversibly to hemoglobin, similar to oxygen, but only about 25% of CO2 in the blood is transported this way. 3. Third, the majority—around 70%—of CO2 is transported in the form of bicarbonate (HCO− 3 ). CO2 forms a diacid after dissolution in water: Dissolution (function of pO2) 𝐶𝐶𝐶𝐶2𝑔𝑔𝑔𝑔𝑠𝑠 ⇄ 𝑪𝑪𝑪𝑪𝟐𝟐𝒂𝒂𝒂𝒂 ↕ pKa = 6.3 Diacid form (carbonic acid) 𝐶𝐶𝐶𝐶2𝑎𝑎𝑎𝑎 + 𝐻𝐻2 𝑂𝑂 ⇄ 𝑯𝑯𝟐𝟐 𝑪𝑪𝑪𝑪𝟑𝟑 ↕ pHblood = 7.4 Amphoteric form (bicarbonate ion; buffer) 𝐻𝐻2 𝐶𝐶𝐶𝐶3 ⇄ 𝑯𝑯+ + 𝑯𝑯𝑯𝑯𝑯𝑯−𝟑𝟑 ↕ pKa = 10.3 Diprotic base (carbonate ion) 𝐻𝐻𝐻𝐻𝐻𝐻3− ⇄ 𝑯𝑯+ + 𝑪𝑪𝑪𝑪𝟐𝟐− 𝟑𝟑 A useful schematic illustrates the steps involved in CO2 transport. Starting at a working muscle, where metabolic activity produces CO2 as a waste product, the partial pressure of CO2 is higher inside the muscle cells compared to the blood. CO2 diffuses from the muscle cells into the blood, increasing the partial pressure of CO2 in the blood, where a portion remains dissolved. The remaining CO2 diffuses into red blood cells, where it either binds to hemoglobin or undergoes a reversible reaction catalyzed by the enzyme carbonic anhydrase. This reaction converts CO2 and water into bicarbonate and hydrogen ions. Most of the bicarbonate leaves the red blood cell through a chloride exchange mechanism, while the hydrogen ions produced bind to hemoglobin, acting as a buffer to prevent changes in blood acidity. Bohr effect The Bohr effect, an essential concept, describes the influence of hydrogen ions (H+) and CO2 on hemoglobin’s oxygen- binding affinity. The Bohr effect describes the change in hemoglobin affinity for O2 due to changes in H+ and CO2 (primarily H+) 1. Changes in pH alters hemoglobin affinity for O2 due to conformational change in the binding site (acidic/alkaline pH decreases/increases affinity) 2. When hemoglobin binds O2, a conformational change occurs increasing the affinity for O2 and decreasing affinity for CO2 and H+ 3. This results in rapid binding of additional O2 and release of CO2 and H+ 4. When O2 is released, it decreases the affinity for O2 with a rapid release of additional O2 5. This results in an increased affinity for H+ and CO2 To summarize oxygen and CO2 transport: Oxygen moves from the alveoli (where partial pressure is highest) into the plasma and red blood cells, binding to hemoglobin for transport to active tissues. The partial pressure gradients facilitate oxygen’s movement from the blood into tissues, where oxygen is utilized for metabolism. Simultaneously, CO2 produced by cells moves into the blood, where it is transported primarily as bicarbonate, as well as dissolved CO2 and CO2 bound to hemoglobin. The CO2 is ultimately carried to the lungs, where it is expelled through expiration, maintaining the partial pressure gradient necessary for continued gas exchange. In conclusion, understanding the factors that affect hemoglobin’s affinity for oxygen, the Bohr effect, and the mechanisms of oxygen and CO2 transport is essential for comprehending how the body ensures adequate tissue oxygenation and waste removal during metabolism. Many of the H+ ions formed by the dissociation of carbonic acid bind to hemoglobin and do not contribute to the acidic content of blood. At the level of the lungs, the partial pressure gradient of O2 favours its movement from the alveoli into the capillary.  At the level of active cells, the utilisation of O2 sets up a gradient such that O2 moves from the blood into the active cells. At the level of active cells, the production of CO2 during metabolic activity sets up the gradient to move it from the cells into the blood. The low pACO2 sets up the gradient so that CO2 moves from the blood into the alveoli