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Microcirculation Roland Pittman, Ph.D. OBJECTIVES: 1. Associate the structure and function of the microcirculation. 2. State the determinants of diffusion of small solutes across the capillary wall. 3. Compare and contrast the permeability of the capillary wall to water-soluble and lipid-soluble solutes. 4. State the four pressures that determine capillary exchange of water, according to Starling’s hypothesis of fluid exchange. 5. Quantify the exchange of fluid between the intravascular and interstitial spaces according to Starling’s hypothesis. 6. Identify the characteristics of the lymphatic system, including the determinants of lymph flow. SUGGESTED READING ASSIGNMENT R. M. Berne, B. M. Koeppen, M. N. Levy, and B. A. Stanton, Physiology, 5th Ed., St. Louis: Mosby, pp. 368-379, 2004. L. S. Costanzo, Physiology, 3rd Ed. Philadelphia: W.B. Saunders, pp. 163-166, 2006. I. STRUCTURE AND FUNCTION OF THE MICROCIRCULATION A. Structure: Types of microvessels Figure 1. Composite schematic drawing of the microcirculation. The circular structures on the arteriole and venule represent smooth muscle fibers; branching solid lines represent sympathetic nerve fibers. The arrows indicate the direction of blood flow. B. Function The primary function of the circulatory system is to exchange substances between blood and tissue. The exchange processes take place in the microcirculation. The classes of vessels playing a role there are the arterioles (resistance vessels which regulate flow), capillaries (the primary exchange vessels) and venules (exchange and collecting vessels). The amount of flow through the capillaries appears to be regulated to maintain adequate tissue oxygenation. This regulation appears to be accomplished in part by the elaboration of tissue metabolites which affect the flow of blood through precapillary vessels. II. TRANSCAPILLARY EXCHANGE OF SOLUTES A. Diffusion This passive mechanism of transport is a rapid and efficient mode of exchange over the small distances (tens of :m) between the blood supply (capillaries) and tissue cells. Figure 2. Fick's first law describes the net rate of transfer of a substance from a location of higher concentration to one of lower concentration: ΔN/Δt = DA (Δc/Δx) = PA Δc ΔN/Δt = number of moles of substance exchanged per unit time D = diffusion coefficient for substance through the capillary wall A = surface area available for diffusion (α number of perfused capillaries) Δc = concentration difference across capillary wall = c(blood) - c(ISF) Δx = thickness of the capillary wall (~ 1 :m) P = permeability of the capillary wall defined as D/Δx B. Permeability characteristics of the capillary wall 1. The wall is composed of a single layer of endothelial cells about l :m thick. 2. For lipid soluble substances (e.g., oxygen), the entire wall surface is available for diffusion. 3. For water soluble substances (e.g., glucose), there are small aqueous pathways equivalent to cylindrical pores 80 to 90 Å in diameter through which they may pass. Total pore area is about 1/1000 (i.e., 0.1%) of the surface area of a capillary. 4. The permeability of the wall to a particular substance depends upon the relative size of the substance and the pore ("restricted" diffusion). Figure 3. C. The amount of a substance which is exchanged can be increased by the opening of more capillaries - this increases the surface area available for exchange. Normally only a fraction (about 1/3 to 1/2) of the capillaries in a given tissue are being perfused at any given moment. During times of increased demand for nutrients (e.g., heart and muscle tissue during exercise) more can be opened. Whether a given capillary is open or closed depends on the contractile state of a region of smooth muscle (probably a terminal arteriole) located near the entrance to a capillary. III. TRANSCAPILLARY EXCHANGE OF WATER A. The processes whereby water passes back and forth across the capillary wall are called filtration and absorption. The flow of water depends upon the relative magnitude of hydraulic and osmotic pressures across the capillary wall. B. Fluid compartments of "average" adult (70 kg person) 1. Extracellular space (19 L) a. b. 2. 3. Plasma space (3 L) Interstitial space (16 L) Intracellular space (23 L) Compartmental exchanges Figure 4. B. Why doesn't all the water leak out of the capillaries? 1. The effective "diameter" of a water molecule is about 2 Å, whereas the effective "diameter" of the transendothelial pathways is about 80 Å. 2. The mean hydraulic pressure inside a capillary is about 25 mmHg higher than that outside the capillary. Figure 5. In this diagram Ra and Rv represent the precapillary and postcapillary resistances to blood flow, respectively. Since Rv/Ra is about 1/5, a given change in Pv has much more impact on Pc than the same change in Pa. 3. Since the facts noted above in items 1 and 2 suggest that water should leave the vascular system, why in reality is there no large net flow of water from the vascular space to the interstitial space? 4. Proteins in plasma (primarily albumin and globulins) are too large to cross the capillary wall which for them behaves like a semipermeable membrane (i.e., the reflection coefficient, σ, is near 1) separating blood from interstitial fluid. Thus, there is a net osmotic pressure established between plasma and interstitial fluid and this tends to prevent the leakage of water from the vascular compartment. 5. Note that the osmotic pressure of either plasma or interstitial fluid can be written as the sum of three terms: Π(total) = Π(electrolytes) + Π(nonelectrolytes) + Π(proteins) Although small electrolytes and nonelectrolytes are osmotically active particles, they can readily pass across the capillary wall (σ ≈ 0) and their concentrations are approximately equal on both sides of the capillary. Thus, no net osmotic pressure difference is created by these substances and only the plasma proteins are responsible for the observed net osmotic pressure. This quantity is generally referred to as the colloid osmotic pressure or oncotic pressure. 6. Starling's hypothesis (1896) combines all this information and states that in the steady state there is a delicate balance between hydraulic and osmotic pressures which leads to little or no net flow of water. Algebraically this is expressed by the following equation: F = K {(Pc - PISF) - (Πpl -ΠISF)} = K {ΔP-ΔΠ} F = rate of fluid flow across the capillary wall K = capillary filtration coefficient, or hydraulic conductance (α permeability to water x perfused capillary surface area) Pc = capillary hydraulic pressure (32 mmHg to 15 mm Hg). PISF = hydraulic pressure in ISF (0 mmHg) Πpl = osmotic pressure due to plasma proteins (28 mmHg) ΠISF = osmotic pressure due to proteins in ISF (5 mmHg) If F > 0, water is filtered from blood into ISF. If F < 0, water is absorbed into blood from ISF. Figure 6. Schematic representation of the factors responsible for filtration and absorption across the capillary wall and the formation of the lymph. IV. THE LYMPHATIC SYSTEM A. In 24 hours more fluid is filtered than is reabsorbed; 20 L/day are filtered and 16 L/day are reabsorbed by the capillaries. The overflow is carried back to the vascular system (via the superior vena cava) by the lymphatic circulation. B. Characteristics of the lymphatic system 1. 2. 3. C. There are a large number of small vessels whose ends are closed. Flap valves (similar to those in veins) provide for unidirectional flow back to the cardiovascular system. The smallest (terminal) vessels are very permeable, even to proteins which occasionally leak from systemic capillaries. Lymph flow is determined by: 1. 2. Interstitial fluid pressure (↑ PISF → ↑ Qlymph) The lymphatic "pump" (moves fluid from the extremities to the central circulation) a. b. c. One-way flap valves (produce unidirectional flow) Skeletal muscle contraction (periodically squeezes fluid in lymphatics) Tissue compression (squeezes fluid in lymphatics) d. Periodic (~ 5/min) lymphatic smooth muscle contraction in response to stretch D. Control of ISF protein concentration is one of the most important functions of the lymphatic system. E. Edema formation: If more net fluid is filtered than can be handled by the lymphatics, the volume of interstitial fluid increases. This fluid accumulation is called edema. This circumstance is important clinically since solute exchange (e.g., oxygen) decreases due to the increased diffusion distances produced when the accumulated fluid pushes the capillaries, tethered to the interstitial matrix, away from each other. STUDY QUESTIONS 1. Which of the following will produce increased capillary hydraulic pressure? 1. 2. 3. 4. Increased venous pressure. Decreased venous resistance. Increased arterial pressure. Increased arterial resistance. ANSWER: B (1 & 3) You need to remember the four factors that determine capillary hydraulic pressure: arterial and venous pressures and resistances. You can determine the effect of each one either by the equation from class or by thinking intuitively about what would happen as a consequence of each change. 2. Which of the following statements is/are true about capillary exchange of solutes? 1. Passage of water-soluble substances is generally restricted to small channels between adjacent endothelial cells. 2. The aqueous channels that allow the passage of substances like glucose comprise a surface area of about 10% of the capillary wall. 3. Lipid soluble substances can generally pass through the entire capillary wall. 4. Proteins generally pass across the capillary wall by active transport. ANSWER: B (1 & 3) You need to remember that small water-soluble molecules are restricted to pass through aqueous channels between adjacent endothelial cells that make up about 0.1 % of the surface area of the capillary wall. Lipid soluble substances have access to the entire capillary wall and proteins are generally restricted to the intravascular space. 3. Which of the following will produce increased lymph flow? A. B. C. D. E. Decreased venous pressure. Decreased venous resistance. Decreased plasma protein concentration. Increased arterial resistance. Decreased interstitial fluid pressure. ANSWER: C Decreased venous pressure and decreased venous resistance will both result in lower capillary hydraulic pressure, and hence less filtration and lower lymph flow. Decreased plasma protein concentration will produce lower osmotic pressure in the plasma and will produce more filtration and hence increased lymph flow. Increased arterial resistance will lower capillary hydraulic pressure and lead to less filtration and lymph flow. Decreased interstitial fluid pressure (the driving force for fluid entry into the lymphatics) will lead to decreased lymph flow. 4. Consider a typical capillary in which the following values are observed: hydraulic pressure at the beginning of a capillary hydraulic pressure at the end of a capillary interstitial hydraulic pressure interstitial colloid osmotic pressure = 30 mm Hg = 15 mm Hg = 3 mm Hg = 1 mm Hg. For what value of plasma colloid osmotic pressure will there be absorption of fluid all along the capillary? A. B. C. D. E. 20 mm Hg. 22 mm Hg. 24 mm Hg. 26 mm Hg. 28 mm Hg. ANSWER: E In order to have fluid absorption all along the capillary, the net pressure at all points along the capillary must be < 0. The pertinent combination of pressures is [(PC – PISF) – (ΠPL - ΠISF)]. (PC – PISF) represents the net filtration pressure due to the hydraulic pressures inside and outside the capillary, respectively. (ΠPL - ΠISF) represents the net absorption pressure due to the protein osmotic (oncotic) pressures inside and outside the capillary, respectively. To ensure that there will be absorption all along the capillary, it is necessary to make sure that the net pressure at the entrance to the capillary (arterial end) is < 0. Plugging in the numbers, we require that (30 – 3) – (ΠPL – 1) = 27 + 1 - ΠPL < 0. So, if ΠPL > 28, there will be absorption all along the capillary.