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Transcapillary Solute Diffusion
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Capillaries act as efficient exchange sites where most substances cross the capillary walls simply by
passively diffusing from regions of high concentration to regions of low concentration. As in any diffusion situation, there are four factors that determine the diffusion rate of a substance between the blood and the interstitial fluid: (1) the concentration difference, (2) the surface area for exchange, (3) the diffusion distance, and (4) the permeability of the capillary wall to the diffusing substance.
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Capillary beds allow huge amounts of materials to enter and leave blood because they maximize the area across which exchange can occur while minimizing the distance over which the diffusing substances must travel. Capillaries are extremely fine vessels with a lumen (inside) diameter of approximately 5 μm, a wall thickness of approximately 1 μm, and an average length of perhaps 0.5 mm. (For comparison, a human hair is roughly 100 μm in diameter.) Capillaries are distributed in incredible numbers in organs and communicate intimately with all regions of the interstitial space. It is estimated that there are approximately 1010 capillaries in the systemic organs with a collective surface area of approximately 100 m2. That is roughly the area of one player’s side of a single tennis court. Recall from Chapter 1 that no cell is more than approximately 10 μm (less than 1/10th the thickness of paper) from a capillary. Diffusion is a tremendously powerful mechanism for material exchange when operating over such a short distance and through such a large area. We are far from being able to duplicate—in an artificial lung or kidney, for example—the favorable geometry for diffusional exchange that exists in our own tissues.
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As illustrated in Figure 6–1, the capillary wall itself consists of only a single thickness of endothelial cells joined to form a tube. The ease with which a particular solute crosses the capillary wall is expressed in a parameter called its capillary permeability. Permeability takes into account all the factors (diffusion coefficient, diffusion distance, and surface area)—except concentration difference—that affect the rate at which a solute crosses the capillary wall.
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Careful experimental studies on how rapidly different substances cross capillary walls indicate that two fundamentally distinct pathways exist for transcapillary exchange. Lipid-soluble substances, such as the gases oxygen and carbon dioxide, cross the capillary wall easily. Because the lipid endothelial cell plasma membranes are not a significant diffusion barrier for lipid-soluble substances, transcapillary movement of these substances can occur through the entire capillary surface area.
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The capillary permeability to small polar particles such as sodium and potassium ions is approximately 10,000-fold less than that for oxygen. Nevertheless, the capillary permeability to small ions is several orders of magnitude higher than the permeability that would be expected if the ions were forced to move through the lipid plasma membranes. It is therefore postulated that capillaries are somehow perforated at intervals with water-filled channels or pores.2 Calculations from diffusion data indicate that the collective cross-sectional area of the pores relative to the total capillary surface area varies greatly between capillaries in different organs. Brain capillaries appear to be very tight (have few pores), whereas capillaries in the kidney and fluid-producing glands are much more leaky. On an average, however, pores constitute only a very small fraction of total capillary surface area—perhaps 0.01%. This area is, nevertheless, sufficient to allow very rapid equilibration of small water-soluble substances between the plasma and interstitial fluids of most organs. Thus, the concentrations of inorganic ions measured in a plasma sample can be taken to indicate their concentrations throughout the entire extracellular space.
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An effective maximum diameter of approximately 40 Å has been assigned to individual pores because substances with molecular diameters larger than this essentially do not cross capillary walls.3 Thus, albumin and other proteins in the plasma are normally confined to the plasma space.
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In addition to forming capillaries, a layer of endothelial cells lines the entire cardiovascular system—including the heart chambers and valves. Because of their ubiquitous and intimate contact with blood, endothelial cells have evolved to serve many functions other than acting as a barrier to transcapillary solute and water exchange. For example, endothelial cell membranes contain specific enzymes that convert some circulating hormones from inactive to active forms. Endothelial cells are also intimately involved in producing substances that lead to blood clot formation and the stemming of bleeding in the event of tissue injury. Moreover, and as discussed in the next chapter, the endothelial cells lining muscular vessels such as arterioles can produce vasoactive substances that act on the smooth muscle cells that surround them to influence arteriolar diameter.
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Transcapillary Fluid Movement
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In addition to providing a diffusion pathway for small charged molecules, the water-filled channels that traverse capillary walls permit fluid flow through the capillary wall.
4 Net shifts of fluid between the blood and the interstitial compartments are important for a host of physiological functions, including the maintenance of circulating blood volume, intestinal fluid absorption, tissue edema formation, and saliva, sweat, and urine production. Net fluid movement out of capillaries is referred to as
filtration, and fluid movement into capillaries is called
reabsorption.
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Fluid flows through transcapillary channels in response to pressure differences between the interstitial and intracapillary fluids according to the basic flow equation. However, both hydrostatic and osmotic pressures influence transcapillary fluid movement. The fact that intravascular hydrostatic pressure provides the driving force for causing blood flow along vessels has been discussed previously. For example, the hydrostatic pressure inside capillaries, Pc, is approximately 25 mm Hg and is the driving force that causes blood to return to the right side of the heart from the capillaries of systemic organs. In addition, however, the 25-mm Hg hydrostatic intracapillary pressure tends to cause fluid to flow through the transcapillary pores into the interstitium where the hydrostatic pressure (Pi) is near or below 0 mm Hg. Thus, there is normally a large hydrostatic pressure difference favoring fluid filtration across the capillary wall. Our entire plasma volume would soon be in the interstitium if there were not some counteracting force tending to draw fluid into the capillaries. The balancing force is an osmotic pressure that arises from the fact that plasma has a higher protein concentration than does interstitial fluid.
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Recall that water always tends to move from regions of low to regions of high total solute concentration in establishing osmotic equilibrium. Also, recall that osmotic forces are quantitatively expressed in terms of osmotic pressure. The osmotic pressure of a given solution is defined as the hydrostatic pressure necessary to prevent osmotic water movement into the test solution when it is exposed to pure water across a membrane permeable only to water. The total osmotic pressure of a solution is proportional to the total concentration of individual solute particles in the solution.5 Plasma, for example, has a total osmotic pressure of approximately 5000 mm Hg—nearly all of which is attributable to dissolved mineral salts such as NaCl and KCl. As discussed, the capillary permeability to small ions is very high. Their concentrations in plasma and interstitial fluid are very nearly equal and, consequently, they do not affect transcapillary fluid movement.
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There is however a small but important difference in the osmotic pressures of plasma and interstitial fluid that is due to the presence of
albumin and other large proteins in the plasma, which are normally absent from the interstitial fluid. A special term,
oncotic pressure (or
colloid osmotic pressure), is used to denote the portion of a solution’s total osmotic pressure that is due to particles that do not move freely across capillaries. Because of the plasma proteins, the oncotic pressure of plasma (π
c) is approximately 25 mm Hg. Because of the absence of proteins, the oncotic pressure of the interstitial fluid (π
i) is near 0 mm Hg. Thus, there is normally a large osmotic force for fluid reabsorption into capillaries that counteracts the tendency for intracapillary hydrostatic pressure to drive fluid out of capillaries. The forces that influence transcapillary fluid movement are summarized on the left side of
Figure 6–2.
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The relationship among the factors that influence transcapillary fluid movement, known as the Starling hypothesis,7 can be expressed by the equation:
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Fluid balance within a tissue (the absence of net transcapillary water movement) occurs when the bracketed term in this equation is zero. This equilibrium may be upset by alterations in any of the four pressure terms. The pressure imbalances that cause capillary filtration and reabsorption are indicated on the right side of Figure 6–2.
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In most tissues, rapid net filtration of fluid is abnormal and causes tissue swelling as a result of excess fluid in the interstitial space (edema). For example, a substance called histamine is often released in damaged tissue. One of the actions of histamine is to increase capillary permeability to the extent that proteins leak into the interstitium. Net filtration and edema accompany histamine release, in part, because the oncotic pressure difference (πc − πi) is reduced below normal.
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Transcapillary fluid filtration is not always detrimental. Indeed, fluid-producing organs such as salivary glands and kidneys utilize high intracapillary hydrostatic pressure to produce continual net filtration. Moreover, in certain abnormal situations, such as severe loss of blood volume through hemorrhage, the net fluid reabsorption accompanying diminished intracapillary hydrostatic pressure helps restore the volume of circulating fluid.
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Despite the extremely low capillary permeability to proteins, these molecules as well as other large particles such as long-chain fatty acids and bacteria do slowly find their way into the interstitial space. If such particles are allowed to accumulate in the interstitial space, filtration forces will ultimately exceed reabsorption forces and edema would result. The lymphatic vessel network represents a flow pathway that normally operates to guard against such edema. It does so in two synergistic ways. First, it is a pathway for returning excess interstitial fluid to the plasma space. Second, it automatically removes colloid particles from the interstitium. The latter effect lowers interstitial colloid osmotic pressure and thus reduces the tendency for fluid filtration from blood plasma to the interstitium.
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The lymphatic system begins in the tissues with blind-ended lymphatic capillaries that are roughly equivalent in size to, but much less numerous than, regular capillaries. These capillaries are very porous and easily collect large particles accompanied by interstitial fluid. This fluid, called lymph, moves through the converging lymphatic vessels, is filtered through lymph nodes where bacteria and particulate matter are removed, and ultimately reenters the circulatory system near the point where the peripheral venous blood enters the right heart.
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Flow of lymph from the tissues toward the entry point into the circulatory system is promoted by two factors: (1) increases in tissue interstitial pressure (due to fluid accumulation or due to movement of surrounding tissue) and (2) contractions of the lymphatic vessels themselves. Valves located in these vessels also prevent backward flow.
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Roughly 2.5 L of lymphatic fluid enters the cardiovascular system each day. In the steady state, this indicates a total body net transcapillary fluid filtration rate of 2.5 L/day. When compared with the total amount of blood that circulates each day (approximately 7000 L), this may seem like an insignificant amount of net capillary fluid leakage. However, lymphatic blockage is a very serious problem and is accompanied by severe tissue swelling. Thus, the lymphatics play a critical role in keeping the interstitial protein concentration low and in removing excess capillary filtrate from the tissues.
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1 These factors are combined in an equation (Fick’s first law of diffusion) that describes the rate of diffusion (Ẋd) of a substance X across a barrier: Ẋd = DA(Δ[X]/ΔL) where D, A, Δ[X], and ΔL represent the diffusion coefficient, surface area, concentration difference, and diffusion distance, respectively.
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2 Pores, as such, are not readily apparent in electron micrographs of capillary endothelial cells. Most believe the pores are either clefts in the junctions between endothelial cells or perhaps specialized channels through the membrane.
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3 The precise mechanism responsible for this size selectivity remains controversial. It may stem from the actual physical dimensions of the “pores,” or it may represent the filtering properties of a fiber matrix that either covers or fills the pores.
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4 A family of specialized transmembrane proteins, aquaporins, is found in endothelial cells throughout the vasculature and may play important roles in regulating water permeability through this barrier in some vascular bed such as the brain, lungs, and kidney.
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5 The word “particles” in this sentence is very important to notice. For example, the “normal saline” solution used in medical practice is 150 mM NaCl. However, normal saline actually contains 300 milliosmoles/liter of dissolved particles because NaCl completely dissociates into Na+ and Cl− ions in water.
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6 The preceding is a simplified description of the effect of plasma proteins on transcapillary fluid movement. A more thorough analysis would include some additional factors (called Gibbs–Donnan effects) caused by the fact that proteins in solution carry multiple electrical charges. These nuances do not change the basic fact that plasma proteins create an osmotic force favoring fluid reabsorption across capillary walls.
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7 After the British physiologist Ernest Starling (1866–1927).