WINDSOR UNIVERSITY SCHOOL OF MEDICINE Microcirculation. Dr.Vishal Surender.MD.

Learning objectives Define the microcirculation Define the anatomy and functions of endothelium Describe the structure of three different types of capillaries Explain how fluid, in contrast to solutes, cross the capillary membrane Describe the four Starling forces, and explain for each, whether they favor absorption or filtration Explain how these forces differ between the arterial end and the venous end of the capillary From a given set of data, calculate the net forces, stating whether filtration or reabsorption is likely to occur State Starling’s law in capillary filtration Explain how leaked plasma proteins and fluid find their way back into the circulation Briefly explain how interstitial fluid oncotic pressure and volume are kept constant Define edema Explain how changes in Starling factors promote edema Define lymphedema

Introduction The vital exchange of the respiratory gases and nutrients takes place across the capillary endothelial wall. Here, because of the parallel arrangement of the capillary network, blood flow is slow (~0.5 – 2.0 s) thus ensuring adequate time for exchange. However, as blood flows through the capillaries, fluid flows back and forth between the blood and the interstitial space. In this chapter we will consider the forces that govern this fluid movement and look at what happens when these forces are out of balance. Anatomy of the Microcirculation Capillaries, together with the terminal arterioles and postcapillary venules make up the microcirculation. One terminal arteriole supplies blood to a cluster of capillaries. Each capillary is 500 – 1000 μm long and 6 μm wide. The venous ends of capillaries unite to form postcapillary venules. We have ~ 10 billion capillaries in our bodies, with a total surface area of 500 – 700 m2 (1/8th the surface area of a soccer pitch). Capillary density varies between tissues and reflects tissue function. The lung (where gas exchange takes place) has a density of 3500 cm2/gm of tissue, the brain and heart ~500, and skeletal muscle ~ 100. Fig. 1. Branching in a typical microcirculation, that of the smooth muscle and submucosa of the intestine. r, radius

Capillary Circulation: Revision of the anatomical structure of the capillaries Different types of capillary endothelium 3 types of capillary endothelium exist and they differ according to permeability. Each type is suited to the particular needs of the tissue. 1. Continuous: Continuous ring of endothelial cells with a continuous basement membrane. Found in most tissues. 2. Fenestrated: Endothelium is perforated by small windows (fenestrae). Very permeable to water and small solutes. Found in tissues that specialize in fluid exchange: kidneys, exocrine glands, choroid plexus, ciliary body of eye. 3. Discontinuous: Large junctions and discontinuities in the basement membrane. Highly permeable even to plasma proteins. Found in organs where RBC and WBC need to migrate between blood and tissue e.g. bone marrow, spleen; and proteins need to move across the membranes e.g. liver. Fig. 2. Three types of capillaries

Blood-Brain Barrier -The capillary of the brain form the blood-brain barrier since the junctions between the endothelial cells are very tight such that only very small molecules (H2 O) pass through. O2 , CO2 and anesthetic gases can diffuse across easily - Essential solutes like glucose cross by facilitated diffusion The barrier is very impermeable to catecholamines and plasma proteins, and protects the brain from them - The barrier works the other way around to prevent the washout of neurotransmitters from the brain -The barrier breaks down in some neurological disorders and in infections such as meningitis.

B. Passage of substances across the capillary wall 1. Lipid‑soluble substances ‑can cross the membranes of capillary endothelial cells by simple diffusion. ‑include O2 and CO2. 2. Small water‑soluble substances ‑can cross via the water‑filled clefts between the endothelial cells. ‑include water, glucose, and amino acids. ‑Generally, protein molecules are too large to pass freely through the clefts. 3. Large water-soluble substances ‑can cross by pinocytosis.

Filtration is the process by which fluid is forced through a membrane (capillary wall) because of a difference in pressure on the two sides, i.e. there is net flow of fluid out of the capillary Absorption is said to occur when there is net flow of fluid into the capillary The rate of filtration at any point along a capillary depends upon a balance of forces called the Starling Forces: Capillary hydrostatic pressure (Pc) Interstitial fluid hydrostatic pressure (Pif) Plasma colloid osmotic (oncotic) pressure (p ) Interstitial fluid colloid osmotic (oncotic) pressure (if )

Fig. 4. (a) above: The four factors (Starling forces) determining fluid movement across capillaries. (b) down: Quantitation of forces causing filtration at the arterial end of the capillary and absorption at the venous end. Arrows in (b) denote magnitude of forces [no arrow is shown for interstitial-fluid hydrostatic pressure (Pif in (b) because it is ~ zero]

Capillary Hydrostatic Pressure (Pc ) - Favors filtration (downward force) The mean Pc is ~ 18-25 mm Hg. At the arteriolar end of capillary it is higher than at the venous end, i.e. it declines along the capillary – Pc is more affected by changes in venous pressure than by changes in arterial pressure - Pc favors filtration (see the above figure) Interstitial Fluid Pressure (Pif ) – Favors absorption (upward force) - Difficult to measure, but accepted value is ~ -3 mm Hg (it is negative because of the action of lymphatic system) - It is a force that opposes filtration

Plasma Colloid Osmotic Pressure (p ) – Favors absorption (upward force) - This is the effective osmotic pressure of capillary blood due to presence of plasma proteins (oncotic pressure). The proteins are the only significant plasma constituents that exert an osmotic pressure - Normal oncotic pressure is ~ 28 mm Hg and it depnds on the protein concentration which is ~ 7 gm/dL - Oncotic pressure opposes filtration Interstitial Fluid Osmotic Pressure (if ) – Favors filtration (downward force) - Small amounts of plasma proteins leak across capillary wall into the interstitial spaces to exert an osmotic pressure - The average if is only ~ 40% of that in plasma, i.e. ~ 8 mm Hg - This force favors filtration

Movement of fluids at the arterial end of capillary: Fig. 5. In this example the total outward force is 41 mm Hg [30 + 8 – (-3)], and the total inward force is 28 mm Hg (28). Net outward force at arterial end = 41 – 28 = 13 mm Hg

Movement of fluids at the venous end of capillary: Venous end of a capillary Fig. 6. Total outward force is 21 mm Hg [10 + 8 – (-3)] and total inward force is 28 mm Hg (28). Net inward force at the venous end is 7 (28 – 21) mm Hg

Fig. 7. Summary of Starling’s forces

From the above examples it is evident that the reabsorption pressure causes about 90% of the fluid that has filtered out of the arterial ends of the capillaries to be reabsorbed at the venous end. The remaining 10% is drained by the lymphatic system

Starling’s hypothesis Starling stated that “under normal conditions the amount of fluid filtering outward from the arterial ends of the capillaries equals almost exactly the fluid returned to the circulation by absorption” Fluid movement = k [Pc + i ) – (Pi + c )] Fluid movement reflects the net filtration pressure K is capillary filtration coefficient which takes into account, and is proportionate to, the permeability of the capillary wall and the area available for filtration. I is usually negligible, so the osmotic pressure gradient (c - i) usually equals the oncotic pressure

Lymph and Lymphatic system Fig. 8. The lymphatic system (green) in relation to the cardiovascular system (blue and red). The lymphatic system is a one-way system from interstitial fluid to the cardiovascular system

Lymph and Lymphatic system The lymphatic system functions as an “overflow mechanism” to return to the circulation excess proteins and excess fluid volume from tissue spaces. This keeps interstitial fluid pressure from rising and promotes the turnover of tissue fluid. The normal 24-hour lymph flow is 2-4 L. The amount of protein returned in this fashion in one day is equal to 25-50% of the total circulating plasma proteins The lymphatic capillaries lie in the interstitial spaces, close to the vascular capillaries

They have one way valves which allow interstitial fluid and proteins to enter, but not to leave. The lymphatic capillaries merge into larger vessels and into the largest lymphatic vessel, the thoracic duct, which empties lymph into the vein (at the junction between the internal jugular and the subclavian vein) Lymph flow is due to movements of skeletal muscle, the negative intrathoracic pressure during inspiration, the suction effect of high-velocity flow of blood in the veins in which the lymphatics terminate, and rhythmic contractions of the walls of the large lymph ducts (principal factor propelling the lymph) The lymphatic valves prevent backflow and skeletal contractions and rhythmic contractions of lymphatic vessels push the lymph toward the heart

Fig. 9. Components of the lymphatic system

Fig. 10. Lymph vessel

Other functions of the Lymphatic System - The lymphatic walls are permeable to macromolecules, and the proteins are returned to the bloodstream via the lymphatics. As mentioned, the amount of proteins returned in this fashion in one day is equal to 25-50% of the total circulating plasma protein - The transport of absorbed long-chain fatty acids and cholesterol from the intestine via the lymphatics is discussed in GIT physiology - The lyphatics play a role in controlling the volume of the interstitial fluid and interstitial fluid pressure and vice versa

Interstitial Fluid Volume The amount of fluid in the interstitial spaces depends upon: - the capillary pressure - the interstitial fluid pressure - the oncotic pressure - the capillary filtration coefficient - the number of active capillaries - the lymph flow - the total ECF volume - the ratio of precapillary to postcapillary venular resistance (precapillary constriction  filtration pressure, whereas postcapillary constriction  it Changes of any of the above variables lead to changes in the volume of interstitial fluid

Edema is the accumulation of interstitial fluid in abnormally large amount Causes of interstitial fluid volume and edema Increased filtration pressure - Arteriolar dilation - Venular constriction - Increased venous pressure (heart failure, incompetent valves, venous obstruction, increased total ECF volume, effect of gravity, etc) Decreased osmotic pressure gradient across capillary - Decreased plasma protein level - Accumulation of osmotically active substances in interstitial space Increased capillary permeability

4. Increased capillary permeability - Substance P - Histamine and related substances - Kinins, etc. 5. Inadequate lymph flow (lymphedema), is combined with protein content - Radical mastectomy (in 10-30% of patients) - In filariasis: parasitic worms migrate into lymphatics and obstruct them (elphantiasis, edema of legs or scrotum)

Fig. 12. Filariasis causes the formation of edema and swelling of the afflicted areas. R. Rhoades & R. Pflanzer, Human Physiology