Physiology of microcirculation
The most purposeful function of the circulation occurs in the microcirculation: this is transport of nutrients to the tissues and removal of cell excreta. The small arterioles control blood flow to each tissue area, and local conditions in the tissues in turn control the diameters of the arterioles. Thus, each tissue, in most instances, controls its own blood flow in relation to its individual needs.
The walls of the capillaries are extremely thin, constructed of single-layer, highly permeable endothelial cells. Therefore, water, cell nutrients, and cell excreta can all interchange quickly and easily between the tissues and the circulating blood. The peripheral circulation of the whole body has about 10 billion capillaries with a total surface area estimated to be 500 to
Structure of the Microcirculation and Capillary System
The microcirculation of each organ is organized specifically to serve that organ’s needs. In general, each nutrient artery entering an organ branches six to eight times before the arteries become small enough to be called arterioles, which generally have internal diameters of only 10 to 15 micrometers.Then the arterioles themselves branch two to five times, reaching diameters of 5 to 9 micrometers at their ends where they supply blood to the capillaries.
The arterioles are highly muscular, and their diameters can change manyfold. The metarterioles (the terminal arterioles) do not have a continuous muscular coat, but smooth muscle fibers encircle the vessel at intermittent points.
At the point where each true capillary originates from a metarteriole, a smooth muscle fiber usually encircles the capillary. This is called the precapillary sphincter.
This sphincter can open and close the entrance to the capillary. The venules are larger than the arterioles and have a much weaker muscular coat. Yet it must be remembered that the pressure in the venules is much less than that in the arterioles, so that the venules still can contract considerably despite the weak muscle.
This typical arrangement of the capillary bed is not found in all parts of the body; however, some similar arrangement serves the same purposes.Most important, the metarterioles and the precapillary sphincters are in close contact with the tissues they serve. Therefore, the local conditions of the tissues—the concentrations of nutrients, end products of metabolism, hydrogen ions, and so forth—can cause direct effects on the vessels in controlling local blood flow in each small tissue area.
Structure of the Capillary Wall. The wall is composed of a unicellular layer of endothelial cells and is surrounded by a very thin basement membrane on the outside of the capillary.The total thickness of the capillary wall is only about 0.5 micrometer. The internal diameter of the capillary is 4 to 9 micrometers, barely large enough for red blood cells and other blood cells to squeeze through.
“Pores” in the Capillary Membrane. One of these is an intercellular cleft, which is the thin-slit, curving channel that lies at the bottom of the figure between adjacent endothelial cells. Each cleft is interrupted periodically by short ridges of protein attachments that hold the endothelial cells together, but between these ridges fluid can percolate freely through the cleft. The cleft normally has a uniform spacing with a width of about 6 to 7 nanometers (60 to 70 angstroms), slightly smaller than the diameter of an albumin protein molecule.
Because the intercellular clefts are located only at the edges of the endothelial cells, they usually represent no more than 1/1000 of the total surface area of the capillary wall. Nevertheless, the rate of thermal motion of water molecules as well as most watersoluble ions and small solutes is so rapid that all of these diffuse with ease between the interior and exterior of the capillaries through these “slit-pores,” the intercellular clefts.
Also present in the endothelial cells are many minute plasmalemmal vesicles. These form at one surface of the cell by imbibing small packets of plasma or extracellular fluid. They can then move slowly through the endothelial cell. It also has been postulated that some of these vesicles coalesce to form vesicular channels all the way through the endothelial cell.
However, careful measurements in laboratory animals probably have proved that these vesicular forms of transport are quantitatively of little importance.
Special Types of “Pores” Occur in the Capillaries of Certain Organs. The “pores” in the capillaries of some organs have special characteristics to meet the peculiar needs of the organs. Some of these characteristics are as follows:
3. The pores of the gastrointestinal capillary membranes are midway between those of the muscles and those of the liver.
CAPILLARY CIRCULATION
At any one time, only 5% of the circulating blood is in the capillaries, but this 5% is in a sense the most important part of the blood volume because it is across the systemic capillary walls that O2 and nutrients enter the interstitial fluid and CO2 and waste products enter the bloodstream. The exchange across the capillary walls is essential to the survival of the tissues.
Methods of Study
It is difficult to obtain accurate measurements of capillary pressures and flows. The capillaries in the mesentery of experimental animals and the fingernail beds of humans are readily visible under the dissecting microscope, and observations on flow patterns under various conditions have been made in these and in some other tissues. Capillary pressure has been estimated by determining the amount of external pressure necessary to occlude the capillaries or the amount of pressure necessary to make saline start to flow through a micropipette inserted so that its tip faces the arteriolar end of the capillary.
Flow of Blood in the Capillaries—Vasomotion
Blood usually does not flow continuously through the capillaries. Instead, it flows intermittently, turning on and off every few seconds or minutes. The cause of this intermittency is the phenomenon called vasomotion, which means intermittent contraction of the metarterioles and precapillary sphincters (and sometimes even the very small arterioles as well).
Regulation of Vasomotion. The most important factor found thus far to affect the degree of opening and closing of the metarterioles and precapillary sphincters is the concentration of oxygen in the tissues. When the rate of oxygen usage by the tissue is great so that tissue oxygen concentration decreases below normal, the intermittent periods of capillary blood flow occur more often, and the duration of each period of flow lasts longer, thereby allowing the capillary blood to carry increased quantities of oxygen (as well as other nutrients) to the tissues.
Average Function of the Capillary System
Despite the fact that blood flow through each capillary is intermittent, so many capillaries are present in the tissues that their overall function becomes averaged. That is, there is an average rate of blood flow through each tissue capillary bed, an average capillary pressure within the capillaries, and an average rate of transfer of substances between the blood of the capillaries and the surrounding interstitial fluid. In the remainder of this chapter, we will be concerned with these averages, although one must remember that the average functions are, in reality, the functions of literally billions of individual capillaries, each operating intermittently in response to local conditions in the tissues.
Exchange of Water, Nutrients, and Other Substances Between the Blood and Interstitial Fluid
Diffusion Through the Capillary Membrane. By far the most important means by which substances are transferred between the plasma and the interstitial fluid is diffusion. As the blood flows along the lumen of the capillary, tremendous numbers of water molecules and dissolved particles diffuse back and forth through the capillary wall, providing continual mixing between the interstitial fluid and the plasma. Diffusion results from thermal motion of the water molecules and dissolved substances in the fluid, the different molecules and ions moving first in one direction and then another, bouncing randomly in every direction.
Lipid-Soluble Substances Can Diffuse Directly Through the Cell Membranes of the Capillary Endothelium. If a substance is lipid soluble, it can diffuse directly through the cell membranes of the capillary without having to go through the pores. Such substances include oxygen and carbon dioxide. Because these substances can permeate all areas of the capillary membrane, their rates of transport through the capillary membrane are many times faster than the rates for lipid-insoluble substances, such as sodium ions and glucose that can go only through the pores.
Water-Soluble, Non-Lipid-Soluble Substances Diffuse Only Through Intercellular “Pores” in the Capillary Membrane. Many substances needed by the tissues are soluble in water but cannot pass through the lipid membranes of the endothelial cells; such substances include water molecules themselves, sodium ions, chloride ions, and glucose. Despite the fact that not more than 1/1000 of the surface area of the capillaries is represented by the intercellular clefts between the endothelial cells, the velocity of thermal molecular motion in the clefts is so great that even this small area is sufficient to allow tremendous diffusion of water and water-soluble substances through these cleft-pores. To give one an idea of the rapidity with which these substances diffuse, the rate at which water molecules diffuse through the capillary membrane is about 80 times as great as the rate at which plasma itself flows linearly along the capillary.
That is, the water of the plasma is exchanged with the water of the interstitial fluid 80 times before the plasma can flow the entire distance through the capillary.
Effect of Molecular Size on Passage Through the Pores. The width of the capillary intercellular cleftpores, 6 to 7 nanometers, is about 20 times the diameter of the water molecule, which is the smallest molecule that normally passes through the capillary pores. Conversely, the diameters of plasma protein molecules are slightly greater than the width of the pores. Other substances, such as sodium ions, chloride ions, glucose, and urea, have intermediate diameters. Therefore, the permeability of the capillary pores for different substances varies according to their molecular diameters. The permeability for glucose molecules is 0.6 times that for water molecules, whereas the permeability for albumin molecules is very, very slight, only 1/1000 that for water molecules. A word of caution must be issued at this point.
The capillaries in different tissues have extreme differences in their permeabilities. For instance, the membrane of the liver capillary sinusoids is so permeable that even plasma proteins pass freely through these walls, almost as easily as water and other substances.
Also, the permeability of the renal glomerular membrane for water and electrolytes is about 500 times the permeability of the muscle capillaries, but this is not true for the plasma proteins; for these, the capillary permeabilities are very slight, as in other tissues and organs.When we study these different organs later in this text, it should become clear why some tissues—the liver, for instance—require greater degrees of capillary permeability than others to transfer tremendous amounts of nutrients between the blood and liver parenchymal cells, and the kidneys to allow filtration of large quantities of fluid for formation of urine.
Effect of Concentration Difference on Net Rate of Diffusion
Through the Capillary Membrane. The “net” rate of diffusion of a substance through any membrane is proportional to the concentration difference of the substance between the two sides of the membrane. That is, the greater the difference between the concentrations of any given substance on the two sides of the capillary membrane, the greater the net movement of the substance in one direction through the membrane. For instance, the concentration of oxygen in capillary blood is normally greater than in the interstitial fluid. Therefore, large quantities of oxygeormally move from the blood toward the tissues. Conversely, the concentration of carbon dioxide is greater in the tissues than in the blood, which causes excess carbon dioxide to move into the blood and to be carried away from the tissues.
The rates of diffusion through the capillary membranes of most nutritionally important substances are so great that only slight concentration differences suffice to cause more than adequate transport between the plasma and interstitial fluid. For instance, the concentration of oxygen in the interstitial fluid immediately outside the capillary is no more than a few per cent less than its concentration in the plasma of the blood, yet this slight difference causes enough oxygen to move from the blood into the interstitial spaces to provide all the oxygen required for tissue metabolism, often as much as several liters of oxygen per minute during very active states of the body.
Capillary Pressure & Flow
Capillary pressures vary considerably, but typical values in human nail bed capillaries are
Equilibration With Interstitial Fluid
As noted above, the capillary wall is a thin membrane made up of endothelial cells. Substances pass through the junctions between endothelial cells and through fenestrations, when they are present. Some also pass through the cells by vesicular transport or, in the case of lipid-soluble substances, through the cytoplasm.
The factors other than vesicular transport that are responsible for transport across the capillary wall are diffusion and filtration. Diffusion is quantitatively much more important in terms of the exchange of nutrients and waste materials between blood and tissue. O2 and glucose are in higher concentration in the bloodstream than in the interstitial fluid and diffuse into the interstitial fluid, whereas CO2 diffuses in the opposite direction.
The rate of filtration at any point along a capillary depends upon a balance of forces sometimes called the Starling forces after the physiologist who first described their operation in detail. One of these forces is the hydrostatic pressure gradient (the hydrostatic pressure in the capillary minus the hydrostatic pressure of the interstitial fluid) at that point. The interstitial fluid pressure varies from one organ to another, and there is considerable evidence that it is subatmospheric—about
The capillary filtration coefficient takes into account, and is proportionate to, the permeability of the capillary wall and the area available for filtration. Fluid moves into the interstitial space at the arteriolar end of the capillary, where the filtration pressure across its wall exceeds the oncotic pressure, and into the capillary at the venular end, where the oncotic pressure exceeds the filtration pressure. In other capillaries, the balance of Starling forces is different and, for example, fluid moves out of almost the entire length of the capillaries in the renal glomeruli. On the other hand, fluid moves into the capillaries through almost their entire length in the intestines.
It is worth noting that small molecules often equilibrate with the tissues near the arteriolar end of each capillary. In this situation, total diffusion can be increased by increasing blood flow; ie, exchange is flow-limited. Conversely, transfer of substances that do not reach equilibrium with the tissues during their passage through the capillaries is said to be diffusion-limited.
It has been estimated that about
Active & Inactive Capillaries
In resting tissues, most of the capillaries are collapsed, and blood flows for the most part through the thoroughfare vessels from the arterioles to the venules. In active tissues, the metarterioles and the precapillary sphincters dilate. The intracapillary pressure rises, overcoming the critical closing pressure of the vessels, and blood flows through all the capillaries. Relaxation of the smooth muscle of the metarterioles and precapillary sphincters is due to the action of vasodilator metabolites formed in active tissue and possibly also to a decrease in the activity of the sympathetic vasoconstrictor nerves that innervate the smooth muscle.
After noxious stimulation, substance P released by the axon reflex increases capillary permeability. Bradykinin and histamine also increase capillary permeability. When capillaries are stimulated mechanically, they empty (white reaction), probably due to contraction of the precapillary sphincters.
The Interstitium and Interstitial Fluid
About one sixth of the total volume of the body consists of spaces between cells, which collectively are called the interstitium. The fluid in these spaces is the interstitial fluid.
The structure of the interstitium contains two major types of solid structures: (1) collagen fiber bundles and (2) proteoglycan filaments. The collagen fiber bundles extend long distances in the interstitium. They are extremely strong and therefore provide most of the tensional strength of the tissues.The proteoglycan filaments, however, are extremely thin coiled or twisted molecules composed of about 98 per cent hyaluronic acid and 2 per cent protein. These molecules are so thin that they caever be seen with a light microscope and are difficult to demonstrate even with the electron microscope.
Nevertheless, they form a mat of very fine reticular filaments aptly described as a “brush pile.” “Gel” in the Interstitium. The fluid in the interstitium is derived by filtration and diffusion from the capillaries. It contains almost the same constituents as plasma except for much lower concentrations of proteins because proteins do not pass outward through the pores of the capillaries with ease. The interstitial fluid is entrapped mainly in the minute spaces among the proteoglycan filaments. This combination of proteoglycan filaments and fluid entrapped within them has the characteristics of a gel and therefore is called tissue gel.
Because of the large number of proteoglycan filaments, it is difficult for fluid to flow easily through the tissue gel. Instead, it mainly diffuses through the gel; that is, it moves molecule by molecule from one place to another by kinetic, thermal motion rather than by large numbers of molecules moving together.
Diffusion through the gel occurs about 95 to 99 per cent as rapidly as it does through free fluid. For the short distances between the capillaries and the tissue cells, this diffusion allows rapid transport through the interstitium not only of water molecules but also of electrolytes, small molecular weight nutrients, cellular excreta, oxygen, carbon dioxide, and so forth.
“Free” Fluid in the Interstitium. Although almost all the fluid in the interstitium normally is entrapped within the tissue gel, occasionally small rivulets of “free” fluid and small free fluid vesicles are also present, which means fluid that is free of the proteoglycan molecules and therefore can flow freely. When a dye is injected into the circulating blood, it often can be seen to flow through the interstitium in the small rivulets, usually coursing along the surfaces of collagen fibers or surfaces of cells.
The amount of “free” fluid present iormal tissues is slight, usually much less than 1 per cent. Conversely, when the tissues develop edema, these small pockets and rivulets of free fluid expand tremendously until one half or more of the edema fluid becomes freely flowing fluid independent of the proteoglycan filaments.
Fluid Filtration Across Capillaries Is Determined by Hydrostatic and Colloid Osmotic Pressures, and Capillary Filtration Coefficient
The hydrostatic pressure in the capillaries tends to force fluid and its dissolved substances through the capillary pores into the interstitial spaces. Conversely, osmotic pressure caused by the plasma proteins (called colloid osmotic pressure) tends to cause fluid movement by osmosis from the interstitial spaces into the blood. This osmotic pressure exerted by the plasma proteins normally prevents significant loss of fluid volume from the blood into the interstitial
spaces.
Also important is the lymphatic system, which returns to the circulation the small amounts of excess protein and fluid that leak from the blood into the interstitial spaces. In the remainder of this chapter, we discuss the mechanisms that control capillary filtration and lymph flow function together to regulate the respective volumes of the plasma and the interstitial fluid.
Four Primary Hydrostatic and Colloid Osmotic Forces Determine Fluid Movement Through the Capillary Membrane. The four primary forces determine whether fluid will move out of the blood into the interstitial fluid or in the opposite direction. These forces, called “Starling forces” in honor of the physiologist who first demonstrated their importance, are:
1. The capillary pressure (Pc), which tends to force fluid outward through the capillary membrane.
2. The interstitial fluid pressure (Pif), which tends to force fluid inward through the capillary membrane when Pif is positive but outward when Pif is negative.
3. The capillary plasma colloid osmotic pressure (Pp), which tends to cause osmosis of fluid inward through the capillary membrane.
4. The interstitial fluid colloid osmotic pressure (Pif), which tends to cause osmosis of fluid outward through the capillary membrane.
If the sum of these forces, the net filtration pressure, is positive, there will be a net fluid filtration across the capillaries. If the sum of the Starling forces is negative, there will be a net fluid absorption from the interstitial spaces into the capillaries. The net filtration pressure (NFP) is slightly positive under normal conditions, resulting in a net filtration of fluid across the capillaries into the interstitial space in most organs. The rate of fluid filtration in a tissue is also determined by the number and size of the pores in each capillary as well as the number of capillaries in which blood is flowing. These factors are usually expressed together as the capillary filtration coefficient (Kf). The Kf is therefore a measure of the capacity of the capillary membranes to filter water for a given NFP and is usually expressed as ml/min per mm Hg net filtration pressure.
Capillary Hydrostatic Pressure
Two experimental methods have been used to estimate the capillary hydrostatic pressure: (1) direct micropipette cannulation of the capillaries, which has given an average mean capillary pressure of about
Micropipette Method for Measuring Capillary Pressure. To measure pressure in a capillary by cannulation, a microscopic glass pipette is thrust directly into the capillary, and the pressure is measured by an appropriate micromanometer system. Using this method, capillary pressures have been measured in capillaries of exposed tissues of animals and in large capillary loops of the eponychium at the base of the fingernail in humans. These measurements have given pressures of 30 to
Isogravimetric Method for Indirectly Measuring “Functional” Capillary Pressure.
Blood is perfused through the blood vessels of the gut wall. When the arterial pressure is decreased, the resulting decrease in capillary pressure allows the osmotic pressure of the plasma proteins to cause absorption of fluid out of the gut wall and makes the weight of the gut decrease. This immediately causes displacement of the balance arm. To prevent this weight decrease, the venous pressure is increased an amount sufficient to overcome the effect of decreasing the arterial pressure. In other words, the capillary pressure is kept constant while simultaneously (1) decreasing the arterial pressure and (2) increasing the venous pressure.
In the graph in the lower part of the figure, the changes in arterial and venous pressures that exactly nullify all weight changes are shown. The arterial and venous lines meet each other at a value of
Thus, in a roundabout way, the “functional” capillary pressure is measured to be about
Why Is the Functional Capillary Pressure Lower than Capillary Pressure Measured by the Micropipette Method? It is clear that the aforementioned two methods do not give the same capillary pressure. However, the isogravimetric method determines the capillary pressure that exactly balances all the forces tending to move fluid into or out of the capillaries. Because such a balance of forces is the normal state, the average functional capillary pressure must be close to the pressure measured by the isogravimetric method. Therefore, one is justified in believing that the true functional capillary pressure averages about
It is easy to explain why the cannulation methods give higher pressure values. The most important reason is that these measurements usually are made in capillaries whose arterial ends are open and when blood is actively flowing into the capillary.However, it
should be recalled from the earlier discussion of capillary vasomotion that the metarterioles and precapillary sphincters normally are closed during a large part of the vasomotion cycle.When closed, the pressure in the capillaries beyond the closures should be almost equal to the pressure at the venous ends of the capillaries, about
There are two other reasons why the functional capillary pressure is less than the values measured by cannulation. First, there are far more capillaries nearer to the venules than to the arterioles. Second, the venous capillaries are several times as permeable as the arterial capillaries. Both of these effects further decrease the functional capillary pressure to a lower value.
Interstitial Fluid Hydrostatic Pressure
As is true for the measurement of capillary pressure, there are several methods for measuring interstitial fluid pressure, and each of these gives slightly different values but usually values that are a few millimeters of mercury less than atmospheric pressure, that is, values called negative interstitial fluid pressure. The methods most widely used have been (1) direct cannulation of the tissues with a micropipette, (2) measurement of the pressure from implanted perforated capsules, and (3) measurement of the pressure from a cotton wick inserted into the tissue.
Measurement of Interstitial Fluid Pressure Using the Micropipette. The same type of micropipette used for measuring capillary pressure can also be used in some tissues for measuring interstitial fluid pressure. The tip of the micropipette is about 1 micrometer in diameter, but even this is 20 or more times larger than the sizes of the spaces between the proteoglycan filaments of the interstitium. Therefore, the pressure that is measured is probably the pressure in a free fluid pocket.
The first pressures measured using the micropipette method ranged from -1 to +
Measurement of Interstitial Free Fluid Pressure in Implanted Perforated Hollow Capsules. Interstitial free fluid pressure measured by this method when using 2-centimeter diameter capsules iormal loose subcutaneous tissue averages about
Measurement of Interstitial Free Fluid Pressure by Means of a Cotton Wick. Still another method is to insert into a tissue a small Teflon tube with about eight cotton fibers protruding from its end. The cotton fibers form a “wick” that makes excellent contact with the tissue fluids and transmits interstitial fluid pressure into the Teflon tube: the pressure can then be measured from the tube by usual manometric means. Pressures measured by this technique in loose subcutaneous tissue also have beeegative, usually measuring -1 to -3mmHg.
Interstitial Fluid Pressures in Tightly Encased Tissues
Some tissues of the body are surrounded by tight encasements, such as the cranial vault around the brain, the strong fibrous capsule around the kidney, the fibrous sheaths around the muscles, and the sclera around the eye. In most of these, regardless of the method used for measurement, the interstitial fluid pressures are usually positive.However, these interstitial fluid pressures almost invariably are still less than the pressures exerted on the outsides of the tissues by their encasements. For instance, the cerebrospinal fluid pressure surrounding the brain of an animal lying on its side averages about +
Is the True Interstitial Fluid Pressure in Loose Subcutaneous Tissue Subatmospheric?
The concept that the interstitial fluid pressure is subatmospheric in many if not most tissues of the body began with clinical observations that could not be explained by the previously held concept that interstitial fluid pressure was always positive. Some of the pertinent observations are the following:
1. When a skin graft is placed on a concave surface of the body, such as in an eye socket after removal of the eye, before the skin becomes attached to the sublying socket, fluid tends to collect underneath the graft. Also, the skin attempts to shorten, with the result that it tends to pull it away from the concavity. Nevertheless, some negative force underneath the skin causes absorption of the fluid and usually literally pulls the skin back into the concavity.
2. Less than
4. The implanted capsule for measuring the interstitial fluid pressure can be used to record dynamic changes in this pressure. The changes are approximately those that one would calculate to occur (1) when the arterial pressure is increased or decreased, (2) when fluid is injected into the surrounding tissue space, or (3) when a highly concentrated colloid osmotic agent is injected into the blood to absorb fluid from the tissue spaces. It is not likely that these dynamic changes could be recorded this accurately unless the capsule pressure closely approximated the true interstitial pressure.
