NROSCI-BIOSC-MSNBIO 1070-2070 Respiration 3 November 5, 2018

Effects of Pulmonary Disease on Pulmonary Blood Flow Abbreviations: eNOS: endothelial nitric oxide synthase PGl2S: prostacyclin synthase (prostacyclin prevents clotting and causes vasodilation) VEGF: vascular endothelial growth factor SMC: smooth muscle cell PAP: pulmonary artery pressure

Effects of Pulmonary Disease on Pulmonary Blood Flow Sustained high pulmonary artery pressure results in a condition called pulmonary hypertension. The right ventricular myocardium thickens due to the sustained intense contractions needed to overcome the afterload imposed by the pulmonary circulation. Over time, the problem may become so severe that there is a mismatch in output from the left and right heart (congestive heart failure). Blood accumulates in the veins, particularly in the legs, resulting in edema.

Effects of Pulmonary Disease on Pulmonary Blood Flow Iloprost: Synthetic prostacyclin

Transport of O2 in the Blood and Exchange with Tissues Blood in the pulmonary veins has a slightly lower PO2 than blood in the lung capillaries. This is because some capillaries in the lung perfuse tissues which are not gas-exchanging surfaces. Simple diffusion explains the exchange of gases between the body tissues and the blood in the systemic capillaries. Typically, PO2 in the blood falls to about 40 mm Hg after passing through systemic capillaries. Tissue PO2 is both influenced by the rate of oxygen transport and the rate at which oxygen is used by the tissues. Carbon dioxide, a major waste product of cells, is picked-up by the blood in the systemic capillaries and transported to the lungs for elimination. Carbon dioxide can diffuse about 20X as fast as oxygen, and thus there is almost the same PCO2 in the systemic veins as in the cells.

Ductus Arteriosus and Foramen Ovale In the developing fetus, two shunts divert blood away from the lungs. The foramen ovale is a shunt between the left atrium and right atrium. In addition, ductus arteriosus is a blood vessel connecting the pulmonary artery to the proximal descending aorta. Between the two, coupled with the extremely high resistance of the pulmonary circulation, practically no blood enters the lungs.

Ductus Arteriosus and Foramen Ovale Since practically no blood is moving from the lungs to the left atrium, left atrial pressure is extremely low in the fetus. Thus, the pressure gradient favors the movement of blood from the right to the left atrium.

Ductus Arteriosus and Foramen Ovale Pressures in the pulmonary artery and aorta are nearly equal in the fetus, or pressure is slightly higher in the pulmonary artery. This is due to relatively weak contractions of the developing left ventricle, as well as the fact that preload to the left ventricle is relatively low. Thus, blood moves from from the pulmonary artery to the descending aorta through ductus arteriosus.

Ductus Arteriosus and Foramen Ovale The trajectory of blood flow from the inferior vena cava favors movement through foramen ovale into the left atrium. The trajectory of blood flow from the superior vena cava favors movement through the tricuspid valve into the right ventricle, and then through ductus arteriosus to the descending aorta and placenta.

Ductus Arteriosus and Foramen Ovale At birth, the shunts must close immediately to permit the normal circulation to commence. Once the fetus is born and begins to breathe, pulmonary circulatory resistance drops precipitously. Blood thus begins to flow through the pulmonary circulation instead of ductus arteriosus, as resistance in the ductus arteriosus is higher.

Ductus Arteriosus and Foramen Ovale High pO2 after birth acts as a paracrine to cause constriction of smooth muscle in ductus arteriosus The patency of ductus arteriosus is also dependent on prostaglandins that are produced in part by the placenta. The prostaglandins inhibit the contraction of smooth muscle within the wall of ductus arteriosus. The prostaglandin levels drop at birth, causing the ductus to collapse as smooth muscle within contracts.

Ductus Arteriosus and Foramen Ovale As blood from the lungs returns to the left atrium, pressure in the left atrium exceeds that in the right atrium. This causes a flap of tissue to press against the foramen ovale, blocking the flow of blood between the atria. Within a few weeks, a full closure of the opening occurs.

Transport of O2 by Blood Normally, about 97% of the oxygen carried in the blood is bound to hemoglobin in the red blood cells. The other 3% is dissolved in the plasma. Thus, hemoglobin greatly increases the oxygen-carrying capacity of blood. The amount of oxygen that binds to hemoglobin depends on two factors: the PO2 of the plasma and the number of free hemoglobin oxygen binding sites. Dissolved oxygen in the plasma diffuses into the red blood cells, where it is rapidly bound by hemoglobin. This rapid removal of oxygen from the plasma helps to ensure that diffusion from the alveoli to the plasma occurs very efficiently. O2 Alveolus Plasma RBC O2

Hemoglobin Each hemoglobin molecule can bind 4 oxygen molecules, to form oxyhemoglobin. The oxygen-hemoglobin dissociation curve shows the relationship between PO2 and binding of oxygen to hemoglobin. If PO2 > 60 mm Hg, then hemoglobin will still be almost totally saturated with oxygen. In other words, even moderate pulmonary problems that compromise alveolar ventilation won’t have a serious effect on the amount of oxygen in the blood.

Hemoglobin When blood reaches the systemic capillaries, and PO2 of the plasma drops, then oxygen will tend to dissociate from the hemoglobin. Note, however, even at typical tissue levels of PO2, hemoglobin still carries about 75% of the oxygen that it is capable of moving. This “reserve” helps to assure that more oxygen can be released if a tissue shows a tremendous amount of metabolic activity. For example, PO2 in the plasma of capillaries of exercising muscle is frequently near 20 mm Hg.

Effects of pH on Hemoglobin (Bohr Effect) Increasing H+ in the blood (lowering pH) shifts the oxygen- hemoglobin dissociation curve to the right, so hemoglobin sheds oxygen more easily to the tissues.

Effects of Temperature on Hemoglobin Increasing temperature shifts the oxygen- hemoglobin dissociation curve to the right, so hemoglobin sheds oxygen more easily to the tissues

Fetal Hemoglobin Fetal hemoglobin has a higher affinity for oxygen than maternal hemoglobin, a necessary adaptation for getting O2 across the placenta.

Effects of 2,3 DPG on Hemoglobin Oxygen-hemoglobin binding is also affected by 2,3- phosphoglycerate (2,3-DPG), a compound made from the intermediate of the glycolysis pathway. Through mechanisms that are not well understood, chronic hypoxia (as during anemia or high altitude exposure) leads to an increase in 2,3-DPG production by red blood cells. This compound shifts the oxygen-hemoglobin dissociation curve to the right, thereby causing more oxygen to be released at a particular PO2 level.

Carbon Monoxide Poisoning Carbon monoxide combines with hemoglobin in a similar manner as does oxygen, but does so about 250x more effectively. As a result, only a small amount of CO in the atmosphere will displace the oxygen from hemoglobin, and the amount of oxygen carried by the blood will be greatly reduced.

Carbon Monoxide Poisoning In terms of the Hb-O2 dissociation curve, the maximum height will be reduced by the presence of CO, as the toxic gas is occupying binding sites on the hemoglobin. Furthermore, CO affects the manner in which the unoccupied sites bind to oxygen, causing a small left-shift in the curve. This impairs unloading of oxygen from hemoglobin in the tissues.

Carbon Monoxide Poisoning Patients with CO poisoning are placed in a hyperbaric chamber (an extremely high PO2 environment) so that oxygen can compete with CO and drive CO out of the blood.

Carbon Monoxide Poisoning Nitric oxide (which is used as a chemical signaling agent in the body) also very effectively binds to hemoglobin. In fact, its binding is about 200,000 times as effective as that of oxygen. Fortunately, nitric oxide is not typically found in the environment (it is a by product of burning of fuel by automobile engines but is removed by catalytic converters). It is interesting that we use such a lethal substance as a paracrine factor.

CO2 Transport Although carbon dioxide dissolves better in plasma than does oxygen, only about 7% of carbon dioxide is found in the plasma of venous blood. The other 93% is found in red blood cells, either bound to hemoglobin or in the form of bicarbonate. The conversion of carbon dioxide to bicarbonate is useful, as it : 1) increases the capacity of the blood to carry this molecule and 2) tends to stabilize blood pH (bicarbonate is a buffer).

CO2 Transport The conversion of carbon dioxide to bicarbonate is catalyzed by the enzyme carbonic anhydrase. The end result is H+ and HCO3-. Typically, the hydrogen ion binds to hemoglobin (a buffer), and the bicarbonate is transported out of the red blood cell in exchange for chloride ion. This process is called the chloride shift. When blood reaches the capillaries in the lungs, the process goes in reverse.

CO2 Transport Note that the ability of hemoglobin to bind H+ is essential, or the blood would become very acidic.

Summary of Gas Transport

Blood Flow and Gas Exchange The release of oxygen and vasodilator substances from erythrocytes are coupled: an increase in O2 release is associated with more vasodilator release. As such, tissues utilizing considerable oxygen will receive increased blood flow, as nearby arterioles will dilate.

Blood Flow and Gas Exchange NO is continuosly produced by endothelial cells. Some of the NO reacts with O2 to form the nitrite anion (NO2-), which can be taken up by the erythrocytes. The deoxygenated hemoglobin can function as a nitrite reductase that regenerates NO from nitrite. NO O2 NO2

Blood Flow and Gas Exchange As such, NO production by erythrocytes is coupled to how much oxygen they have released to surrounding tissues. ATP is produced in the erythrocyte by glycolysis and is released in response to off-loading of O2. How O2 dissociation from hemoglobin activates this process is still not known. The release of ATP triggers the release of NO from endothelial cells.

Blood Flow and Gas Exchange Through these mechanisms, the off-loading of O2 from erythrocytes leads to local vasodilation, and thus delivery of more erythrocytes to the area utilizing O2. During exercise, this mechanism enhances oxygen delivery to working muscle.

Measurement of Oxygen Delivery to Tissues: the Fick Principle The Fick Principle is based on the idea that delivery of oxygen (or any substance) to a tissue is the difference between the concentration of that substance in arterial and venous blood.

Measurement of Oxygen Delivery to Tissues: the Fick Principle Let: CaO2 = arterial O2 content (O2/ml blood) CvO2 = venous O2 content (O2/ml blood) F = blood flow (ml/min) Then: Rate of O2 delivery = F * CaO2 (O2/min) Rate of O2 removal = F * CvO2 (O2/min) QO2 (oxygen delivery) = F * CaO2 — F * CvO2 OR QO2 (oxygen delivery) = F * (CaO2 — CvO2) Applying algebra: F = QO2/(CaO2 — CvO2)

Measurement of Oxygen Delivery to Tissues: the Fick Principle The Fick Principle is applied in clinical medicine to determine pulmonary blood flow (hence cardiac output) . One can calculate CaO2 and CvO2 from samples of arterial and venous blood, and QO2 can also be calculated. However, QO2 is normally assumed to be: 125 ml O2 per minute per square meter of body surface area.