Transport in mammals

A closed double circulation and the four main vessels

Mammals are endothermic and very active, so every cell needs a fast, steady supply of oxygen and glucose and a fast way of removing carbon dioxide and urea. Diffusion alone cannot do the job once a body is more than a millimetre or two thick, because the distances are too great and the concentration gradients would be used up long before substances reached the middle of the body. Mammals therefore have a mass transport system: a closed circulatory system in which blood is always inside the heart or inside blood vessels and never free in a body cavity, so it can be kept at pressure and pumped quickly to every tissue.

The circulation is double, which means that blood passes through the heart twice for each complete circuit of the body. In the pulmonary circulation the right ventricle pumps deoxygenated blood to the lungs, where it is oxygenated, and it returns to the left atrium. In the systemic circulation the left ventricle pumps that oxygenated blood around the rest of the body, and it returns to the right atrium. There is some mixing of the two sides only where the circuits meet at the heart, and the valves keep the flow one way.

A double circulation does two useful things. First, blood is fully loaded with oxygen before it is pumped to the body, so the tissues receive blood at the highest possible oxygen concentration; a single circulation, as in a fish, loses pressure and oxygen as the blood passes through the gills before it reaches the tissues. Second, the two circuits can run at different pressures: the systemic circulation is at a high pressure because it is long and offers great resistance, while the pulmonary circulation stays at a much lower pressure. That matters, because the walls of the lungs are extremely thin, and a high pressure would force tissue fluid out of the capillaries into the alveoli.

Learn the four vessels named in the syllabus as a set, because examiners ask for the pair that seems backwards. The pulmonary artery carries deoxygenated blood from the right ventricle to the lungs; the pulmonary vein carries oxygenated blood from the lungs to the left atrium; the aorta carries oxygenated blood from the left ventricle to the whole body; and the vena cava carries deoxygenated blood from the body back to the right atrium.

Vessel structure related to function

All vessels except capillaries have the same three layers, but in very different proportions. Inside is a lining of endothelium, a single layer of smooth flattened cells that reduces friction with the flowing blood. Around it is a middle layer containing elastic fibres and smooth muscle, and outside that is a tough outer coat of collagen fibres that stops the vessel over-stretching. Which of elastic fibres and muscle dominates is what decides the job the vessel can do.

Elastic arteries such as the aorta, the pulmonary artery and the carotid arteries are close to the heart and are conducting vessels: they carry blood away at the full pressure of systole. They have a thick layer of elastin and a wide lumen. As the left ventricle forces blood into the aorta, the wall stretches and stores energy; when the ventricle relaxes the wall recoils and pushes blood onwards. That recoil smooths out the pressure pulse into a more continuous flow and keeps the diastolic pressure up, which is why blood keeps moving through the capillary beds even between heartbeats. Muscular arteries further from the heart have more smooth muscle and less elastin. Their muscle lets them constrict or dilate to change their diameter, which alters the share of blood flowing to each organ: during exercise the arteries to the skeletal muscles dilate and those to the gut constrict. Arterioles are the very narrow vessels that branch from arteries and lead into the capillary beds. Their walls are almost entirely smooth muscle with a little elastic tissue, and their diameter is adjustable. Because there are so many arterioles, their total diameter is the main factor determining the peripheral resistance to blood flow, so narrowing them raises blood pressure and widening them lowers it. Constricting the arterioles feeding one capillary bed diverts blood elsewhere, which is how the body sends blood to where it is needed and shuts down beds in tissues that are not active.

Veins and venules carry blood back to the heart at low pressure, and their structure reflects that. Venules are the small vessels that collect blood from capillaries and join to form veins. Veins have a thin wall with little muscle and elastin, a wide lumen that keeps resistance low, and a large internal volume, so most of the body's blood is in the veins at any moment. Veins are also flattened and irregular in section, because with so little tissue they collapse when pressure falls. Blood is moved along by the pressure from behind, by the squeezing of surrounding skeletal muscle during movement, and by the changes in pressure in the chest during breathing. Pocket valves along the vein stop the blood running backwards between these pushes.

Capillaries are where exchange actually happens, and every feature of them serves that end. The wall is a single layer of flattened endothelial cells, often with pores or fenestrations, so the diffusion distance is only about one cell thick. The lumen is extremely narrow, so red blood cells must deform to pass through, which slows the blood down. The capillary bed as a whole has an enormous total cross-sectional area and a huge surface area, and capillaries penetrate almost every tissue so that no cell is far from one. Slow flow, a short diffusion distance and a large surface area together give the maximum time and the best conditions for the exchange of oxygen, carbon dioxide, glucose and waste.

Blood, tissue fluid and why water matters

Plasma is the liquid part of blood and makes up a little over half of its volume; it is about 90% water, and water is also the main component of tissue fluid. Two properties of water make transport in mammals possible. Its solvent action means that ions such as sodium, chloride and hydrogencarbonate, sugars, amino acids, urea, hormones and the plasma proteins all travel dissolved in plasma, so a small volume of fluid carries a great many substances and delivers them to cells; carbon dioxide is carried in the same way, dissolved and as hydrogencarbonate ions. Its high specific heat capacity means that a large transfer of heat energy changes the temperature of water only a little, so blood buffers the temperature of the body as it moves between organs producing very different amounts of heat, such as the liver and the skin. That helps because mammalian enzymes work within a narrow optimum temperature range.

Red blood cells are biconcave discs about 7 µm across, with no nucleus and no mitochondria, and their cytoplasm is packed with haemoglobin. The biconcave shape gives a large surface area to volume ratio for gas exchange, and the flexible, nucleus-free cell can squeeze through capillaries narrower than itself. In a stained blood film they look like pale pink discs with a pale centre and no nucleus. Monocytes are the largest white cells, with a kidney-shaped nucleus and plenty of cytoplasm, and they leave the blood to become macrophages; neutrophils have a lobed nucleus and granular cytoplasm and are the most numerous phagocytes, arriving first at an infection; lymphocytes have a large round nucleus that almost fills the cell with very little cytoplasm, and they carry out the specific immune response, making antibodies and destroying infected cells. Every white cell has a nucleus, and that is the quickest way to tell one from a red blood cell on a slide.

Tissue fluid is the fluid that bathes the cells of a tissue: it is the immediate environment of every cell. It brings oxygen, glucose, amino acids, ions, hormones and water to the cells and carries carbon dioxide, urea and other waste products away, and it is the medium through which all these substances diffuse, since cells are never more than a short distance from a capillary. It also holds the cells in place and allows white cells to move through a tissue to reach an infection.

Tissue fluid is formed by pressure filtration at the arterial end of a capillary, not by osmosis. Blood arriving from an arteriole is still under pressure from the heart, so at the arterial end the hydrostatic pressure of the blood is greater than the osmotic pull of the plasma proteins, and water, glucose, amino acids, ions and oxygen are forced out through the capillary wall and its pores. Blood cells and the large plasma proteins cannot fit through, so they stay in the capillary; that is why tissue fluid contains no red blood cells and very little protein. At the venous end the hydrostatic pressure has fallen a long way, and the plasma proteins left behind give the blood a lower water potential than the tissue fluid, so water re-enters the capillary by osmosis. Not quite all of it is returned: the remainder is collected by lymph capillaries, carried through the lymphatic system and returned to the blood in the subclavian vein, which is why a blocked lymph vessel causes the tissue to swell with oedema.

The heart: chambers, valves and the thickness of the walls

Externally, the mammalian heart is a muscular pump divided into a left and a right side by a thick wall called the septum, and each side has an upper atrium and a lower ventricle. It sits inside the pericardium, a fluid-filled sac that reduces friction as the heart beats. Running over the surface of the heart are the coronary arteries, which branch from the base of the aorta and carry oxygenated blood to the muscle of the heart itself, because heart muscle is far too thick to be supplied by diffusion from the blood inside the chambers. The vena cava opens into the right atrium and the pulmonary vein into the left atrium; the pulmonary artery leaves the right ventricle and the aorta leaves the left ventricle.

Internally, the right side of the heart carries deoxygenated blood from the body to the lungs, and the left side carries oxygenated blood from the lungs to the body. Blood can only flow one way because of the valves, which are flaps of tough tissue with no muscle in them. The atrioventricular (AV) valves sit between each atrium and its ventricle, the tricuspid valve on the right and the bicuspid (mitral) valve on the left. They are held in place by the chordae tendineae, strong strands attached to the papillary muscles on the ventricle wall, which stop the valve being turned inside out when the ventricle contracts hard. The semilunar valves sit in the aorta and in the pulmonary artery at the base of the heart, and they stop blood falling back into the relaxing ventricles between beats.

The difference in the thickness of the walls follows directly from the work each chamber does. The atria have thin walls because an atrium only has to push blood a short distance downwards into the ventricle lying immediately beneath it, at low pressure. The ventricles have much thicker walls because they have to pump blood out of the heart against the resistance of the arteries and the capillary networks. The left ventricle has the thickest wall of all because it pumps blood right around the systemic circulation, which is long and offers a great deal of resistance, so it must generate a much higher pressure. The right ventricle pumps blood only to the lungs, which are close by, lie in the same cavity and offer far less resistance, so it needs a weaker contraction and has a much thinner wall. Keeping the pulmonary pressure low matters for one more reason: the walls of the alveoli are extremely thin, and a high pressure would force tissue fluid out of the lung capillaries into the alveoli and make gas exchange harder.

Look at the heart as a set of pressure pumps in series rather than as one organ. Blood enters an atrium at low pressure, is pushed a short distance into the ventricle beneath it, and is then driven out of the heart by that ventricle at whatever pressure its circuit demands. The valves only open in the direction of the pressure gradient, so the whole sequence of filling and emptying follows automatically from the contraction of the muscle.

The cardiac cycle: systole, diastole and the pressure changes

The cardiac cycle is the sequence of events in one complete heartbeat. At a resting heart rate of about 75 beats per minute it lasts about 0.8 s, and it is divided into atrial systole, when the atria contract, ventricular systole, when the ventricles contract, and diastole, when the whole heart relaxes. The valves have no muscle, so they are completely passive: each one opens or closes only because the pressure on one side of it becomes greater than the pressure on the other. Blood always moves down the pressure gradient, from a region of higher pressure to a region of lower pressure.

During atrial systole the atria contract and the pressure inside them rises above the pressure in the ventricles, so the AV valves are pushed open and the blood still in the atria is squeezed down into the ventricles. The semilunar valves stay shut, because the pressure in the aorta and pulmonary artery is still higher than the pressure in the ventricles. Then ventricular systole begins: the ventricles contract, the pressure inside them rises sharply above the pressure in the atria, so the AV valves are forced shut, which makes the first heart sound. As the pressure in the ventricles rises further, above the pressure in the aorta and the pulmonary artery, the semilunar valves are pushed open and blood is forced out of the heart.

In diastole the ventricles relax and the pressure inside them falls. Blood already in the aorta and the pulmonary artery is at a higher pressure than the relaxing ventricles, so it falls back and closes the semilunar valves, which makes the second heart sound. As relaxation continues the pressure in the ventricles falls below the pressure in the atria, so the AV valves are pushed open again and blood flows passively from the vena cava, the pulmonary vein and the atria into the ventricles, so the atria are already filling the ventricles before the next atrial systole begins. Because the semilunar valves stay shut through diastole, and because the elastic walls of the arteries recoil, blood keeps flowing through the capillary beds even while the heart is relaxing.

Two volumes describe the beat. The stroke volume is the volume of blood forced out of one ventricle in a single contraction, about 70 cm3 at rest, and the cardiac output is the volume pumped out of one ventricle in one minute, so cardiac output = heart rate x stroke volume. At rest, 75 beats per minute x 70 cm3 gives about 5.25 dm3 per minute. During strenuous exercise both the heart rate and the stroke volume rise, because more blood returns to the heart and the muscle contracts more forcefully, so cardiac output can increase several times over.

The pacemaker: the sinoatrial node, the atrioventricular node and the Purkyne tissue

The heartbeat is myogenic, which means it starts inside the heart muscle itself and does not need a nerve impulse from the brain to set it going. The rhythm is set by the sinoatrial node (SAN), a small group of specialised muscle cells in the wall of the right atrium near the opening of the vena cava. The SAN depolarises spontaneously and at a regular rate, so it acts as the pacemaker of the heart; at rest it fires about 70 times a minute and every one of those firings starts one heartbeat.

The wave of excitation spreads from the SAN through the muscle of the atrial walls, and both atria contract together as atrial systole. The atria and the ventricles are separated by a layer of non-conducting tissue, so the excitation cannot pass straight down from the atrial muscle into the ventricular muscle. The only route through is the atrioventricular node (AVN), a second group of specialised cells in the wall of the septum at the base of the right atrium. The AVN conducts the impulse on to the ventricles, but only after a short delay of about 0.1 s.

That delay is essential, and it is the point examiners most often ask about. It gives the atria just enough time to finish contracting and to empty their blood into the ventricles, so the ventricles are properly filled before they contract. Without it the atria and the ventricles would contract at the same time and the ventricles would be half empty. From the AVN the impulse travels down the Purkyne tissue in the septum, which is also called the bundle of His, and then up through the walls of both ventricles from the apex at the bottom of the heart. Because the excitation arrives at the apex first and then spreads upwards, the ventricles contract from the bottom up, which squeezes the blood towards the base of the heart where the aorta and the pulmonary artery leave, so it is pushed out through the semilunar valves. The rate at which the SAN fires can be altered by the body, but nervous and hormonal control of the heart is not part of this topic.

Oxygen transport and the oxygen dissociation curve

Almost all the oxygen in blood is carried by haemoglobin inside red blood cells. Haemoglobin is a globular protein with four polypeptide chains, and each chain holds a haem group containing an iron ion (Fe2+). Each haem group can bind one molecule of oxygen, so one haemoglobin molecule carries four, forming oxyhaemoglobin. The reaction is reversible, and its direction depends on the partial pressure of oxygen: haemoglobin + oxygen <-> oxyhaemoglobin. A very small amount of oxygen also dissolves directly in the plasma, but that on its own would be nowhere near enough for a mammal's tissues, which is why haemoglobin, packed into cells with no nucleus to take up space, raises the oxygen-carrying capacity of blood so dramatically. Haemoglobin also keeps the oxygen from being carried as a simple solution, which means the blood is not too viscous to pump.

The oxygen dissociation curve is a graph of the percentage saturation of haemoglobin with oxygen against the partial pressure of oxygen, measured in kPa. It is S-shaped, or sigmoid. At very low partial pressures very little oxygen binds, because the first oxygen molecule is the hardest one to attach. Once it is on, the haemoglobin molecule changes shape so that the second and third oxygen molecules bind more easily, which is called cooperative binding and is why the middle of the curve is steep. The fourth haem group becomes difficult to fill again, so at high partial pressures the curve flattens into a plateau, where the haemoglobin is almost fully saturated and can take up very little more.

In the lungs the partial pressure of oxygen is high, so haemoglobin is loaded with oxygen and becomes almost fully saturated. This is the plateau of the curve, and the plateau is a safety margin: because the curve is almost flat here, quite large changes in the partial pressure of oxygen in the alveoli barely alter how much oxygen the blood picks up. A person at high altitude, or with a lung disease such as emphysema, therefore still loads their blood with oxygen even though the partial pressure in their alveoli is well below normal.

In respiring tissues the partial pressure of oxygen is much lower, because the cells are using oxygen up, and here the curve is steep: a small fall in partial pressure releases a large amount of oxygen from oxyhaemoglobin. This is exactly what a mammal needs, because it means oxygen is unloaded where respiration is fastest. The steepness has a second benefit, because the tissue can carry on taking oxygen even if the blood flow through it falls for a moment: as the tissue uses up oxygen, its partial pressure drops a little further and the blood gives up still more.

Carbon dioxide transport, the chloride shift and the Bohr shift

Carbon dioxide is carried in three ways. A small fraction dissolves directly in the plasma, and a small fraction combines with the amino groups of haemoglobin to form carbaminohaemoglobin; this happens at a different part of the molecule from the haem groups, so it does not compete with oxygen. Most of the carbon dioxide, however, is carried in the plasma as hydrogencarbonate ions (HCO3-). The hydrogencarbonate is made inside the red blood cells and then released into the plasma, and that release is the reason the chloride shift has to happen.

Red blood cells contain the enzyme carbonic anhydrase, which catalyses the reaction of carbon dioxide with water: CO2 + H2O -> H2CO3, carbonic acid. Carbonic acid dissociates into H+ and HCO3- ions. The hydrogen ions would make the red blood cell dangerously acidic, so haemoglobin mops them up and becomes haemoglobinic acid (HHb): in other words haemoglobin acts as a buffer. This matters twice over, because it keeps the pH of the blood from falling too far, and because the hydrogen ions that haemoglobin has to deal with are the reason oxygen is released more readily in tissues that are producing carbon dioxide quickly.

The chloride shift is the movement of chloride ions (Cl-) from the plasma into the red blood cell as hydrogencarbonate ions leave it. Hydrogencarbonate is made inside the cell, so it diffuses out into the plasma down its concentration gradient, and because carbon dioxide keeps diffusing in, the enzyme reaction keeps going. The problem is charge: every hydrogencarbonate ion that leaves takes a negative charge with it, so the inside of the cell becomes progressively more positive, and that electrical gradient would very soon stop any more hydrogencarbonate leaving. The cell solves this by taking in chloride ions from the plasma through an anion exchange protein in the membrane, so that the charge inside the cell stays balanced. The importance of the chloride shift is that it allows a very large amount of carbon dioxide to be carried as hydrogencarbonate in the plasma without the build-up of charge stopping the process; it also explains why plasma chloride and plasma hydrogencarbonate change together, and why the reagent used to measure plasma carbon dioxide is really measuring hydrogencarbonate.

The Bohr shift is the change in the position of the oxygen dissociation curve caused by a change in the concentration of carbon dioxide. Where carbon dioxide is high, as in an actively respiring muscle, the curve shifts to the right, which means that at any given partial pressure of oxygen the haemoglobin has a lower affinity for oxygen and so releases more of it. The reason is the extra hydrogen ions: carbon dioxide forms carbonic acid, the acid releases H+ ions, and those hydrogen ions bind to haemoglobin as haemoglobinic acid and change its shape so that it holds oxygen less tightly. The advantage is obvious: the tissue that is respiring fastest produces the most carbon dioxide, so it is the tissue that receives the most oxygen from the blood, automatically and without any control system. In the lungs the opposite happens, because carbon dioxide diffuses out of the blood into the alveoli, so the partial pressure of carbon dioxide falls, the curve shifts back to the left, haemoglobin has a higher affinity for oxygen and the blood is loaded with oxygen more readily.