VPSL 121 Module III Lecture 5,6 PDF

VPSL 121 Module III Lesson 5- Capillaries and Fluid Exchange Lesson 6- Local Control of Blood Flow KEY POINTS 1. Capillaries, the smallest blood vessels, are the sites for the exchange of water and solutes between the bloodstream and the interstitial fluid. 2. Lipid-soluble sub...

VPSL 121 Module III Lesson 5- Capillaries and Fluid Exchange Lesson 6- Local Control of Blood Flow KEY POINTS 1. Capillaries, the smallest blood vessels, are the sites for the exchange of water and solutes between the bloodstream and the interstitial fluid. 2. Lipid-soluble substances diffuse readily through capillary walls, whereas lipid- insoluble substances must pass through capillary pores. 3. Fick’s law of diffusion is a simple mathematical accounting of the physical factors that affect the rate of diffusion. 4. Water moves across capillary walls both by diffusion (osmosis) and by bulk flow. 5. The Starling equation quantifies the interaction of oncotic and hydrostatic forces acting on water. 6. Several common physiological changes alter the normal balance of Starling forces and increase the filtration of water out of capillaries. 7. Edema is a clinically noticeable excess of interstitial fluid. Capillaries, the Smallest Blood Vessels, Are the Sites for the Exchange of Water and Solutes Between the Bloodstream and the Interstitial Fluid the capillaries are called the microcirculation- small size also called the exchange vessels- role in the exchange of water and solutes between the bloodstream and the interstitial fluid takes place across the walls of the capillaries feature of the walls of the aorta and large arteries: 1. presence of a large amount of elastic material along with smooth muscle So called the elastic vessels- need to distend with each pulsatile ejection of blood from the heart Elasticity denotes distensibility and an ability to return to the original shape after the distending force or pressure is removed 2. strong and quite stiff (low compliance) Compliance is a measure of how much force or pressure is required to achieve distention arteries are elastic, but a high pressure (systolic pressure) is required to distend them Capillaries, the Smallest Blood Vessels, Are the Sites for the Exchange of Water and Solutes Between the Bloodstream and the Interstitial Fluid Features of blood vessels: 1. Small arteries, like arterioles, have thick walls with less elastic tissue and a predominance of smooth muscle- so called the muscular vessels Smooth m. contraction and relaxation- vessels constrict or dilate; varies their resistance to blood flow the total peripheral resistance and direct blood flow toward or away from particular organs or particular regions within an organ is due to the smooth m. Capillaries, the Smallest Blood Vessels, Are the Sites for the Exchange of Water and Solutes Between the Bloodstream and the Interstitial Fluid Capillaries, the Smallest Blood Vessels, Are the Sites for the Exchange of Water and Solutes Between the Bloodstream and the Interstitial Fluid 2. Capillaries- smallest vessels, about 8 μm in diameter and about 0.5 mm long red blood cells (7.5 μm in diameter) need to squeeze through in single file single layer of endothelial cells small diameter of the capillaries and the thinness of their walls-- facilitate exchange of water and solutes between the blood within capillaries and the interstitial fluid Capillaries, the Smallest Blood Vessels, Are the Sites for the Exchange of Water and Solutes Between the Bloodstream and the Interstitial Fluid 3. Venules and veins are larger than capillaries, and they have thicker walls. elastic tissue and smooth muscle in their walls walls of veins are not as thick or as muscular as the walls of arteries or arterioles primary role of veins: serve as reservoir vessels very compliant, and normally in a state of partial collapse accommodate substantial changes in blood volume without much change in venous pressure Capillaries, the Smallest Blood Vessels, Are the Sites for the Exchange of Water and Solutes Between the Bloodstream and the Interstitial Fluid Capillaries as site of exchange: form a network not all the capillaries carry blood at all times– since the arterioles alternate between constriction and dilation, so blood flow is periodically reduced or even stopped in some capillaries in some tissues (e.g., intestinal circulation), precapillary sphincters or tiny cuffs of smooth muscle encircle capillaries at the points where they branch off from arterioles and can reduce or stop the flow of blood in individual capillaries during contraction Increase metabolic rate of a tissue--- increase blood flow- the arterioles and precapillary sphincters constrict periodically---increases the fraction of capillaries in which blood is flowing at any one time At maximal metabolic rate (e.g., maximal exercise in a skeletal muscle)--- blood flows to the capillaries all the time blood flow to all the capillaries---increases the total blood flow through a tissue and minimizes the distance between each cell of the tissue and the nearest capillary carrying blood by bulk flow Lipid-Soluble Substances Diffuse Readily Through Capillary Walls, Whereas Lipid- Insoluble Substances Must Pass Through Capillary Pores Factors that affect the rate of diffusional exchange between capillary blood and the surrounding interstitial fluid: 1. properties of the substances being exchanged Small, lipid-soluble substances (e.g., dissolved oxygen and carbon dioxide, fatty acids, ethanol, and some hormones)- readily dissolve and diffuse in the cell membranes of the endothelial cells lipid-insoluble substances (e.g., ions, glucose, and amino acids) do not dissolve in cell membranes and so cannot diffuse through the endothelial cells 2. features of the capillary wall substances must pass through the pores, or clefts, that exist between the endothelial cells create tiny, water-filled channels between the capillary blood and the interstitial fluid. The diffusional movement of lipid insoluble substances across capillary walls is much slower than the movement of lipid-soluble substances, because these substances are restricted to passage through the capillary pores, which constitute only about 1% of the Lipid-Soluble Substances Diffuse Readily Through Capillary Walls, Whereas Lipid- Insoluble Substances Must Pass Through Capillary Pores continuous capillaries- the endothelial cells form a continuous tube, except for the tiny, water-filled pores between the endothelial cells. the diameter of the pores is about 4 nm, which is large enough to permit the passage of water and of all the small solutes in plasma and interstitial fluid plasma protein molecules and blood cells are a little too large to pass through The main route for the delivery of plasma proteins into the interstitial fluid is through the three-step process of transcytosis. 1. pinocytosis (a form of endocytosis)- involves the invagination of the capillary endothelial cell membrane to form an intracellular vesicle that contains plasma, including plasma proteins 2. some of these vesicles cross the capillary endothelial cell from the side facing the bloodstream to the side facing the interstitial fluid. In the third step, these vesicles fuse with the membrane of the endothelial cell on the interstitial fluid side; the vesicles discharge their contents into the interstitial space. 3. exocytosis. delivery of plasma constituents into the interstitial fluid by transcytosis is extremely slow, compared with the diffusion of lipid soluble substances through endothelial cells, or the passage of small, lipid-insoluble substances through capillary pores Lipid-Soluble Substances Diffuse Readily Through Capillary Walls, Whereas Lipid- Insoluble Substances Must Pass Through Capillary Pores The size of the capillary pores, or clefts: varies from tissue to tissue extremes are found in the brain and the liver: 1. brain capillaries-- the junctions between adjacent endothelial cells are tight--- only water and small ions (e.g., Na+ and Cl−) can pass through them; glucose or amino acid molecules cannot pass through these tiny pores. but brain neurons require glucose to carry out their normal metabolism---moved across the brain capillary endothelial cells by specialized protein carrier molecules embedded in the cell membranes of the endothelial cells. facilitated diffusion comes from the glucose concentration difference between the blood and the brain interstitial fluid. tight junctions are called the blood-brain barrier--create a barrier between the bloodstream and the brain tissue to protect brain neurons from exposure to toxic substances that may be in the blood Lipid-Soluble Substances Diffuse Readily Through Capillary Walls, Whereas Lipid- Insoluble Substances Must Pass Through Capillary Pores 2. liver has large clefts between capillary endothelial cells are so large---called discontinuous capillaries (or sinusoids). plasma proteins such as albumin and globulin can readily pass through these large clefts, which typically exceed 100 nm in width Importance: A. permit the newly synthesized protein molecules to enter the bloodstream– since plasma proteins are produced by liver cells (hepatocytes) B. role of the liver in detoxification--- some toxins bound to plasma proteins in the bloodstream, and removed from the blood by the liver and chemically changed into less toxic substances. Discontinuous (sinusoidal) capillaries are also found in the spleen and bone marrow.  Lipid-Soluble Substances Diffuse Readily Through Capillary Walls, Whereas Lipid- Insoluble Substances Must Pass Through Capillary Pores Fenestrated capillaries (“capillaries with windows”) Another variation on capillary pores. holes or perforations through (not between) endothelial cells. 50 to 80 nm in diameter- larger than the intercellular clefts of typical continuous capillaries but smaller than the clefts of discontinuous capillaries. w/ very fine diaphragms span- do not prevent the passage of either lipid-soluble or lipid- insoluble substances. formed when endocytotic and exocytotic vesicles line up and merge, thus creating a temporary water-filled channel through an endothelial cell. found in places where large amounts of fluid and solutes must pass into or out of capillaries (e.g., gastrointestinal tract, endocrine glands, Fick’s Law of Diffusion Is a Simple Mathematical Accounting of the Physical Factors That Affect the Rate of Diffusion Recap: the factors that affect the rate of diffusional exchange between capillary blood and interstitial fluid--- include the distance involved, the size of the capillary pores (or fenestrae, when present), and the properties of the diffusing substance (i.e., lipid-soluble vs. lipid insoluble). German physiologist Adolph Fick incorporated all these factors into an equation: Fick’s law of diffusion. The rate of diffusion of any substance (S) depends: 1. concentration difference- the difference between the concentration of the substance in capillary fluid and its concentration in interstitial fluid. Diffusion is driven by this concentration difference Proceeds from the area of higher concentration toward the area of lower concentration 2. area available for diffusion- the term A in the equation. lipid soluble substances= this area is equivalent to the total surface area of the capillaries lipid-insoluble substances= this area is much smaller, being equal to the area of the pores (or clefts) between capillary endothelial cells (plus the area of fenestrae, when present). Fick’s Law of Diffusion Is a Simple Mathematical Accounting of the Physical Factors That Affect the Rate of Diffusion 3. distance over which diffusion must occur- Δx in the equation Δx = the distance from a tissue cell to the nearest capillary that is carrying blood by bulk flow The greater the distance from the tissue cells to the capillaries, the slower is the rate of diffusional exchange of substances between that cell and the capillary blood 4. diffusion coefficient= D in the equation D increases with temperature- diffusion depends on the random (Brownian) motion of particles in solution, and the velocity of Brownian motion increases with temperature D also depends on the molecular weight of the diffusing substance and on its solubility. Example: D for carbon dioxide is about 20 times greater than D for oxygen carbon dioxide diffuses much more rapidly than does oxygen for a given concentration difference, area, and diffusion distance. In disease states, the area available for diffusion decreases, and the diffusion distance increases the delivery of oxygen to the metabolizing cells of a tissue becomes critically Fick’s Law of Diffusion Is a Simple Mathematical Accounting of the Physical Factors That Affect the Rate of Diffusion factors that affect the rate of diffusion are physiologically adjustable: Example: in skeletal muscle at rest, the arterioles cycle between open and closed, and even when open, their diameter is small low and “part-time” blood flow through capillaries-- adequate to deliver oxygen and nutrients to the resting skeletal muscle cells and to remove the small amounts of carbon dioxide and other waste products being produced by those cells during exercise, the metabolic rate of the skeletal muscle cells increases several-fold, also for the need for blood flow. skeletal muscle arterioles dilate--more of them remain open on a “full-time” basis as the level of exercise increases---so blood flow through the capillaries increases and becomes more continuous Fick’s Law of Diffusion Is a Simple Mathematical Accounting of the Physical Factors That Affect the Rate of Diffusion How these changes act to speed the delivery of oxygen and metabolic substrates to the exercising muscle cells and to facilitate the removal of carbon dioxide and other metabolic waste products: 1. when more capillaries carry blood, the area available for diffusion (A in Fick’s diffusion equation) is increased. 2. because more capillaries carry blood, the distance between each exercising skeletal muscle cell and the nearest open capillary (Δx in the diffusion equation) is decreased. 3. the driving force for diffusion of oxygen (the oxygen concentration difference between the capillary blood and the interstitial fluid) is increased. The concentration difference is increased because: (1) the greater blood flow brings more freshly oxygenated blood into the capillaries, (2) the rapid utilization of oxygen by the exercising skeletal muscle cells decreases the concentration of oxygen within these cells and therefore within the surrounding interstitial fluid. Fick’s Law of Diffusion Is a Simple Mathematical Accounting of the Physical Factors That Affect the Rate of Diffusion factors that increase the rate of oxygen diffusion during exercise also increase the rate of delivery of glucose and other nutrients. These factors act also to increase the rate at which carbon dioxide and other metabolic products are removed from the tissue cells and into the bloodstream. For carbon dioxide and other metabolic products, the concentration is highest in the cells and lowest in the capillary plasma, so diffusional movement is from the cells toward the bloodstream. Fick’s law: the four factors that affect the rate of diffusion of a particular substance S from the capillary plasma to the interstitial fluid next to a tissue cell: 1. [S]c − [S]i, the concentration difference between the capillary plasma and interstitial fluid; 2. A, area available for diffusion; 3. Δx, distance involved; and 4. D, diffusion coefficient for the substance. Water Moves Across Capillary Walls Both by Diffusion (Osmosis) and by Bulk Flow 2 considerations for the exchange of water between the capillary plasma and the interstitial fluid: 1. the forces that govern water movement are complicated than the simple diffusive forces that affect solute movement. 2. a particular imbalance in these forces causes an excessive amount of water to accumulate in the interstitial space, which leads to the important clinical sign, edema. Recap: solutes such as oxygen, carbon dioxide, glucose, electrolytes, and fatty acids move between the capillary plasma and the interstitial fluid by diffusion. Water also moves by diffusion; the diffusional movement of water is called osmosis. The physical prerequisites for osmosis: (1) the presence of a semipermeable membrane (a membrane that is permeable to water but not to specific solutes) (2) a difference in the total concentration of the impermeable solutes on the two sides of the membrane. Water Moves Across Capillary Walls Both by Diffusion (Osmosis) and by Bulk Flow A. Water moves across capillary walls by diffusion: capillary wall---semipermeable membrane Water readily pass through capillary pores the pores in continuous capillaries are too small to permit the passage of plasma proteins the concentration of plasma proteins is higher in the capillary plasma than in the interstitial fluid Protein concentration= 7 grams per deciliter (g/dL) within the capillary plasma but 0.2 g/dL in the interstitial fluid dissimilar protein concentrations create an osmotic imbalance– causes water molecules tend to move by osmosis from the interstitial fluid into the capillary blood plasma. (Remember that water moves by osmosis toward the side of the semi-permeable membrane with the higher concentration of impermeable solute.) osmotic pressure - tendency for water to move by diffusion The normal osmotic pressure created by the proteins in the plasma is 25 mm Hg plasma oncotic pressure or colloid osmotic pressure- the osmotic pressure created by the plasma proteins ; colloid is used because the plasma proteins are not in a true solution but Water Moves Across Capillary Walls Both by Diffusion (Osmosis) and by Bulk Flow The plasma proteins in the interstitial fluid also exert an osmotic effect. the concentration of plasma proteins in interstitial fluid is low, so the oncotic pressure created in the interstitial fluid by these proteins is about 1 mm Hg The imbalance of oncotic pressures (higher in the capillary fluid than in the interstitial fluid) creates a net driving force for the diffusion (osmotic movement) of water from the interstitial fluid into the capillaries Reabsorption- movement of water into a capillary filtration- movement of water in the opposite direction, from the capillary plasma into the interstitial fluid oncotic pressure difference favors reabsorption. calculated by subtracting the oncotic pressure of interstitial fluid from the oncotic pressure of capillary blood (e.g., 25 mm Hg − 1 mm Hg = 24 mm Hg). Water Moves Across Capillary Walls Both by Diffusion (Osmosis) and by Bulk Flow 2. water moves across capillary walls by bulk flow Hydrostatic pressure differences cause water to move by bulk flow; occurs through the capillary pores capillary blood pressure –the hydrostatic pressure within the capillaries; higher at the arteriolar end of capillaries than at the venous end average capillary hydrostatic pressure= 18 mm Hg interstitial fluid hydrostatic pressure = about −7 mm Hg negative sign simply means that interstitial fluid pressure is less, (although only slightly less) than atmospheric pressure creates a hydrostatic pressure difference of 25 mm Hg across the wall of a typical capillary hydrostatic pressure difference tends to force water out of the capillaries and into the interstitial spaces; hydrostatic pressure difference favors filtration. Water Moves Across Capillary Walls Both by Diffusion (Osmosis) and by Bulk Flow the hydrostatic pressure difference (which favors filtration) almost balances the oncotic pressure difference (which favors reabsorption) the hydrostatic pressure difference may slightly exceed the oncotic pressure difference, causing net filtration of water out of the capillaries- water would accumulate in the interstitial spaces--- cause swelling--- lymph vessels wld collect excess interstitial fluid and return it to the bloodstream through the subclavian veins Capillary hydrostatic pressure and interstitial fluid hydrostatic pressure are measured relative to atmospheric pressure since “negative”– implies that interstitial pressure is slightly below atmospheric pressure interstitial spaces of the body had a hydrostatic pressure higher than atmospheric pressure, all parts of the body would bulge outward The sub-atmospheric interstitial fluid pressure accounts for the fact that the skin normally stays snug against the underlying tissue and that some body surfaces normally have a concave shape (e.g., axillary space, orbits of the eyes) The Starling Equation Quantifies the Interaction of Oncotic and Hydrostatic Forces Acting on Water The following equation expresses mathematically the interaction between osmotic pressures and hydrostatic pressures in determination of the net force (net pressure) acting on water: Where : Pc (capillary hydrostatic pressure) = 18 mm Hg Pi (interstitial fluid hydrostatic pressure) = −7 mm Hg πc (capillary plasma oncotic pressure) = 25 mm Hg πi (interstitial fluid oncotic pressure) = 1 mm Hg Solution: The Starling Equation Quantifies the Interaction of Oncotic and Hydrostatic Forces Acting on Water A positive net pressure favors filtration (a negative net pressure would indicate that reabsorption is favored). The small magnitude of the net pressure (1 mm Hg) indicates that the hydrostatic and osmotic forces that affect water are almost in balance (i.e., there is only a slight tendency for filtration). oncotic and hydrostatic pressures that act on water are often called Starling forces. the tendency for the net oncotic effect to be closely balanced by the net hydrostatic effect is often referred to as the balance of Starling forces. basis: the actual rate of water movement across capillary walls is affected both by the magnitude of the imbalance between hydrostatic and oncotic forces and by the permeability of the capillary wall to water. the following equation indicates that the movement of water is equal to the permeability of the capillary wall (given as the filtration coefficient Kf) multiplied by the net difference between the hydrostatic and oncotic pressures: The Starling Equation Quantifies the Interaction of Oncotic and Hydrostatic Forces Acting on Water Starling equation shows that the tendency for the filtration of water out of capillaries can be enhanced by: (1) increasing the hydrostatic pressure difference between capillary blood and interstitial fluid, (2) decreasing the osmotic tendency for water to be reabsorbed, or (3) increasing the permeability of the capillary to water (i.e., increasing the filtration coefficient). Several Common Physiological Changes Alter the Normal Balance of Starling Forces and Increase the Filtration of Water Out of Capillaries increase in capillary hydrostatic pressure (Pc) favors a greater filtration of water cases that increase capillary hydrostatic pressure: 1. increase in arterial pressure causes more pressure to be transmitted down through the arterioles and into the capillaries. 2. a decrease in arteriolar resistance (e.g., a dilation of the arterioles) allows a greater portion of the arterial pressure to be transmitted into the capillaries. 3. increased by a “backing up” (or “damming up”) of venous blood. an increase in central venous pressure causes blood to accumulate in the systemic capillaries and raises capillary pressure. 4. obstruction to venous outflow (e.g., too tight a dressing on a limb) also causes blood to back up in the capillaries of the limb, which increases capillary hydrostatic pressure Several Common Physiological Changes Alter the Normal Balance of Starling Forces and Increase the Filtration of Water Out of Capillaries The primary determinant of interstitial fluid hydrostatic pressure is the volume of fluid present in the interstitial space accumulation of interstitial fluid increases interstitial hydrostatic pressure. Remember: interstitial fluid hydrostatic pressure is usually slightly subatmospheric (e.g., −7 mm Hg) If it rises above atmospheric pressure, the accumulation of interstitial fluid becomes clinically noticeable as a swelling, or edema The net oncotic pressure depends on the concentrations of proteins in the capillary plasma and in the interstitial fluid. normal protein concentration in plasma= 7 g/dL plasma oncotic pressure= 25 mm Hg alteration in the concentration of proteins in the capillary plasma alters the plasma oncotic pressure changes in the interstitial protein concentration alter interstitial fluid oncotic pressure. Several Common Physiological Changes Alter the Normal Balance of Starling Forces and Increase the Filtration of Water Out of Capillaries protein molecules do not readily pass through the capillary pores or clefts the main route for the delivery is by transcytosis. increase in the rate of vesicle formation and discharge increases the delivery of plasma proteins into the interstitial space and therefore increases interstitial fluid oncotic pressure. abnormal circumstances (e.g., tissue inflammation) can cause the capillary pores to open wide enough that plasma proteins can pass through. Plasma proteins are removed from the interstitial space through lymph flow. lymphatic capillaries are structured much like blood capillaries. clefts between the endothelial cells of lymphatic capillaries are large enough to readily accommodate the passage of plasma protein molecules. The lymphatic fluid, containing these plasma proteins, flows to the thorax, where the fluid reenters the bloodstream at the subclavian veins important in the lungs Several Common Physiological Changes Alter the Normal Balance of Starling Forces and Increase the Filtration of Water Out of Capillaries Lung capillaries are more permeable to plasma proteins than are most capillaries the oncotic pressure of interstitial fluid in the lungs is normally rather high (nominally 18 mm Hg). Capillary hydrostatic pressure in the lungs= about 12 mm Hg. (lower than the capillary hydrostatic pressure in systemic capillaries because pulmonary arterial pressure is so much lower than systemic arterial pressure.) Interstitial hydrostatic pressure in the lungs= about −4 mm Hg (the same as intrapleural pressure) Summation of these Starling forces for lung capillaries: A net pressure of +9 mm Hg means there is a substantial driving force for filtration of fluid out of the capillaries and into the lung interstitial spaces. The lung interstitial spaces would fill rapidly with water, and pulmonary edema would develop, were it not for the well-developed system of lymph vessels in the Edema Is a Clinically Noticeable Excess of Interstitial Fluid Edema- common clinical problem results of excessive filtration of fluid out of capillaries or from depressed lymphatic function Causes: 1. increased venous pressure Ex: the application of a too-tight dressing on the extremity of an animal– constriction of the veins--- impedes the outflow of venous blood from the limb-- blood backs up in the limb veins---increases venous pressure-- blood then backs up in the capillaries and increases capillary hydrostatic pressure-- excessive filtration of capillary fluid into the interstitial space---accumulation of fluids---edema 2. severe pulmonic stenosis 3. severe heartworm disease excessive volume of blood accumulation in the right atrium and systemic veins-- - increase in venous pressure--- blood to back up in the systemic capillaries--- increase capillary hydrostatic pressure---edema Increase in venous pressure leads to increase in interstitial fluid volume (edema). The dashed lines (negative feedback) indicate the counteracting effects of the three safety factors against edema. First, an increase in interstitial fluid hydrostatic pressure reduces the rate of filtration back toward normal. Second, an increase in lymph flow reduces interstitial fluid volume back toward normal. Third, a decrease in interstitial fluid protein concentration reduces the rate of filtration back toward normal. Edema Is a Clinically Noticeable Excess of Interstitial Fluid three factors (safety factors) limit the degree of the resulting edema: 1. the increased interstitial fluid pressure acts directly to oppose or limit filtration. Interstitial fluid pressure does not need to rise above capillary hydrostatic pressure to limit edema. Any increase in interstitial fluid pressure (e.g., from a normal value of −7 to +2 mm Hg) helps to change the net balance of the Starling forces in the direction of reducing excessive filtration. 2. increased interstitial fluid pressure promotes lymph flow. 3. indirect consequence of increased lymph flow. Edema Is a Clinically Noticeable Excess of Interstitial Fluid Mechanism: interstitial fluid contains a small amount of plasma protein--- exerts a small but significant oncotic pressure-- favors filtration--- during increased capillary hydrostatic pressure, the increased capillary filtration delivers fluid into the interstitial space that is relatively free of proteins--- the elevated lymph flow carries away interstitial fluid and proteins the combination of increased filtration and increased lymph flow leads to a reduction in the interstitial protein concentration– result to decrease in interstitial fluid oncotic pressure--- reduce the excess filtration back toward normal. Summary: an increase in venous pressure leads to an increase in capillary hydrostatic pressure--- increases filtration---edema develops---three safety factors to reduce filtration back toward normal and to limit the degree of edema. Edema Is a Clinically Noticeable Excess of Interstitial Fluid systemic edema- results from an increase in systemic venous pressure noticeable in the dependent regions of the body (lower extremities in human patients or the abdominal organs in humans or animals) Ascites- excessive fluid in the peritoneum Marked systemic edema and ascites: associated with right ventricular heart failure pulmonary edema- associated w/ failure of the left ventricle Ineffective pumping by the left ventricle--- increased blood volume and increased pressure in the left atrium and pulmonary veins, pulmonary capillaries-- increases capillary filtration in the lung tissue-- interstitial fluid oozes into the alveoli and bronchial airways—coughing of frothy fluid. Excess edema fluid may also ooze into the intrapleural space- pleural effusion. Edema Is a Clinically Noticeable Excess of Interstitial Fluid Effect of hypoproteinemia to edema: decreased plasma protein concentration (hypoproteinemia) causes of hypoproteinemia: 1. decrease in the rate of plasma protein production by the liver. Seen in malnutrition-- clinical syndrome= kwashiorkor Emaciation and the abdomen is grossly distended by edema and ascites 2. an increase in the rate of loss of plasma protein Example: A. in nephrotic syndrome, the kidney glomerular capillaries become permeable to plasma proteins--- leave the bloodstream and enter the urinary tubules (nephrons) of the kidney--- loss of proteins in the urine--- reduces the plasma protein concentration Decrease in plasma protein concentration leads to edema, but the degree of edema is limited by the same three safety factors Edema Is a Clinically Noticeable Excess of Interstitial Fluid b. Severe burns The capillaries of burned skin become very permeable to both fluid and proteins---plasma can leave the body through these damaged capillaries. plasma proteins in the fluid weeping from a burn site– seen as the yellow color of that fluid hypoproteinemia leads to a decrease in plasma colloid osmotic pressure. alters the balance of the Starling forces in a direction that favors excessive filtration of fluid from the capillaries Interstitial fluid accumulates and edema is noticed. three safety factors that limit edema in the case of increased venous pressure: (1) an increased interstitial fluid pressure, (2) an increased lymph flow, and (3) a decreased interstitial protein concentration. Edema Is a Clinically Noticeable Excess of Interstitial Fluid edema and lymphatic obstruction: called lymphedema Causes: 1. inflammation of the nodal tissue or cancerous tumors growing within the nodes affect passage of lymph 2. parasitic diseases, microfilariae lodge in the lymph nodes and obstruct lymph flow. elephantiasis- Filarial parasites cause the pronounced edema 3. secondary consequence of surgical procedures that damage lymph nodes. edema of the arm that follows radical mastectomy Edema Is a Clinically Noticeable Excess of Interstitial Fluid Mechanism of lymphedema: Lymphatic obstruction decreases lymph flow--- Interstitial fluid] accumulates in the tissues---raises interstitial fluid pressure--- acts as a safety factor by reducing capillary filtration but the second and third safety factors are absent in the case of lymphedema since dependent on an increase in lymph flow-- when lymph flow is impaired, plasma proteins accumulate in the interstitial fluid instead of being carried away by the lymph edema during physical injury or an allergic reaction to antigen challenges: Physical trauma results in a localized bump or swelling. Also seen when the skin reacts to an irritating agent or antigen challenge (e.g., response to an insect bite). An allergic swelling can also occur in bronchial tissue during an asthmatic reaction. Lymphatic obstruction leads to edema. Histamine mediates the changes that lead to edema in Lymphedema is clinically troublesome response to a physical injury or an antigen challenge. because only one of the normal three The normal three safety factors against edema are intact. safety factors is operative to limit the Treatment with an antihistamine (a drug that blocks degree of edema histamine receptors on arterioles and capillaries) also helps to reduce edema. Edema Is a Clinically Noticeable Excess of Interstitial Fluid an injury or antigen challenge---release of histamine from mast cells in the affected tissue. two effects of histamine that cause edema: 1. increases the permeability of capillaries to proteins Accumulate of proteins in the interstitial space of the damaged tissue-- increase the interstitial fluid oncotic pressure--- promotes filtration of fluid. 2. relaxes arteriolar smooth muscle arterioles dilate—result to decrease in arteriolar resistance--- allows more of the arterial blood pressure to impinge on the capillaries--- leads to an increase in the capillary hydrostatic pressure--- which promotes filtration. three safety factors that protect against edema are intact and act to limit the degree of edema. Local Control of Blood Flow KEY POINTS 1. Vascular resistance is affected by intrinsic and extrinsic control mechanisms. 2. Metabolic control of blood flow is a local mechanism that matches the blood flow of a tissue to its metabolic rate. 3. Autoregulation is a relative constancy of blood flow in an organ despite changes in perfusion pressure. 4. Many chemical signals act locally (as paracrines) to exert important control on vascular resistance. 5. Regardless of the status of arterioles, mechanical compression can reduce blood flow to a tissue. Vascular Resistance Is Affected by Intrinsic and Extrinsic Control Mechanisms Recap: the blood flow through any organ or tissue is determined by the perfusion pressure (arterial pressure minus venous pressure) and by the resistance of the blood vessels of the organ (and by no other factors), as follows differences in blood flow to the various organs result from their different vascular resistances w/c determined by the diameter of its arterioles. arteriolar vasodilation and vasoconstriction are the mechanisms that increase or decrease the blood flow in one organ relative to another organ factors that affect arteriolar resistance: 1. Extrinsic control involves mechanisms that act from outside an organ or tissue, through nerves or hormones, to alter arteriolar resistance. 2. Intrinsic control is exerted by local mechanisms within an organ or tissue. Vascular Resistance Is Affected by Intrinsic and Extrinsic Control Mechanisms Example of intrinsic cx: 1. histamine released from mast cells of a tissue in response to injury or during an allergic reaction. acts locally on the arteriolar smooth muscle to relax it--Dilation of the arterioles decreases arteriolar resistance and therefore increases blood flow to the tissue paracrine: a substance released from one type of cell that acts on another cell type in the vicinity. Ex: histamine 2. arteriolar dilation and increased blood flow during exercise in skeletal muscle. metabolic control of blood flow: tissues tend to increase their blood flow whenever their metabolic rate increases. Vascular Resistance Is Affected by Intrinsic and Extrinsic Control Mechanisms intrinsic mechanisms predominate over extrinsic mechanisms in the control of arterioles in the brain, heart (i.e., coronary circulation), and working skeletal muscle. extrinsic mechanisms predominate over intrinsic mechanisms in the control of blood flow to the kidneys, splanchnic organs, and resting skeletal muscle. Skin- both intrinsic and extrinsic control mechanisms have strong influences. local (intrinsic) control dominates extrinsic control in the critical organs: those that must have sufficient blood flow to meet their metabolic needs on a second- by-second basis for an animal to survive. Extrinsic control dominates intrinsic control in organs that can withstand temporary reductions in blood flow (and metabolism) to make extra blood available for the critical organs. Metabolic Control of Blood Flow Is a Local Mechanism That Matches the Blood Flow of a Tissue to Its Metabolic Rate Metabolic control of blood flow is the most important local control mechanism metabolic control accounts for the huge increase in blood flow through a skeletal muscle as it goes from rest to maximal exercise. it matches the blood flow in a tissue to the metabolic rate of the tissue increase in tissue blood flow in response to increased metabolic rate is called active hyperemia (hyper means “elevated,” emia refers to blood, and active implies an increased metabolic rate). Metabolic control of blood flow works by means of chemical changes within the tissue. An increase in metabolic rate of a tissue– increase consumption of oxygen, and production of metabolic products, including carbon dioxide, adenosine, and lactic acid. potassium ions (K+) escape from rapidly metabolizing cells, and these ions accumulate in the interstitial fluid. w/ increase metabolism of a tissue increases: decrease interstitial concentration of  Chemical Signals Important in Local Control of Systemic Arterioles* Effect on the arterioles: The arterioles dilate, vascular resistance decreases, and more blood flows through the tissue. Metabolic Control of Blood Flow Is a Local Mechanism That Matches the Blood Flow of a Tissue to Its Metabolic Rate Low levels of oxygen and high concentrations of metabolic products and K+ also cause relaxation of the precapillary sphincters--- opens more of the capillaries in the tissue to blood flow--decreases the diffusion distance between fresh, oxygenated blood and the metabolizing cells of the tissue and increases the total capillary surface area for diffusional exchange. net result of the increased blood flow, the decreased diffusion distance, and the increased total capillary surface area: rapid delivery of oxygen and other metabolic substrates to the tissue cells and a more rapid removal of metabolic waste products from the tissue.  Metabolic control of blood flow involves negative feedback. The accumulation of metabolic products and the lack of oxygen initiate vasodilation, which increases blood flow. The increased blood flow removes the accumulating metabolic products and delivers additional oxygen. A new balance is reached when the increased blood flow closely matches the increased metabolic needs of the tissue. Metabolic control of blood flow is a local (intrinsic) mechanism that acts within a tissue to match the blood flow to the tissue with the metabolic activity of the tissue. As a tissue becomes more active metabolically, the metabolic control mechanism increases blood flow and thereby regulates the concentration of oxygen and metabolic products in the tissue. Metabolic Control of Blood Flow Is a Local Mechanism That Matches the Blood Flow of a Tissue to Its Metabolic Rate Reactive hyperemia- a temporary increase above normal in the flow of blood to a tissue after a period when blood flow was restricted. increased flow (hyperemia) is a response (reaction) to a period of inadequate blood flow. Ex: Mechanical compression of blood vessels cause inadequate blood flow--- release of that mechanical compression elicits reactive hyperemia. Mechanisms: the same as w/ active hyperemia mechanical compression restricts blood flow, metabolism continues in the compressed tissue--- metabolic products accumulate, and the local concentration of oxygen decreases- --metabolic effects cause dilation of the arterioles and a decrease in arteriolar resistance. When the mechanical obstruction to flow is removed, blood flow increases above normal until the “oxygen debt” is repaid and the excess metabolic products have been removed from the compressed tissue. Autoregulation Is a Relative Constancy of Blood Flow in an Organ Despite Changes in Perfusion Pressure Metabolic control mechanisms and blood flow autoregulation: Autoregulation is evident in denervated organs and organs in which local control of blood flow is predominant over neural and humoral control (e.g., in coronary circulation, brain, and working skeletal muscle). experiment that demonstrates autoregulation in the brain: Initially, the perfusion pressure (arterial pressure minus venous pressure) in this animal is 100 mm Hg, and the blood flow to the brain is 100 milliliters per minute (mL/ min) (point A). When perfusion pressure is increased suddenly to 140 mm Hg, brain blood flow rises initially to 140 mL/min but returns toward its initial level over the next 20 to 30 seconds. Eventually, blood flow reaches a stable level of about 110 mL/min (point B). Conversely, if the perfusion pressure is decreased suddenly from 100 to 60 mm Hg, blood flow in the brain decreases initially to 60 mL/min but returns toward its initial level over the next 20 to 30 seconds Eventually, blood flow reaches a stable level of about 90 mL/min (point C). Autoregulation Is a Relative Constancy of Blood Flow in an Organ Despite Changes in Perfusion Pressure The range of perfusion pressures over which flow remains relatively constant is called the autoregulatory range. Autoregulation fails at very high and very low perfusion pressures. Extremely high pressures- result in marked increases in blood flow extremely low pressures- result in marked decreases in blood flow. how metabolic control mechanisms account for the phenomenon of autoregulation: If the metabolic rate of an organ does not change but perfusion pressure is increased above normal, the increased pressure forces additional blood flow through the organ. The additional blood flow accelerates the removal of metabolic products from the interstitial fluid and increases the rate of oxygen delivery to the interstitial fluid. Therefore the concentration of vasodilating metabolic products in the interstitial fluid decreases, and the concentration of oxygen in the interstitial fluid Autoregulation Is a Relative Constancy of Blood Flow in an Organ Despite Changes in Perfusion Pressure These changes cause the arterioles of the tissue to constrict, which increases the resistance to blood flow above normal. The consequence is that blood flow decreases back toward its initial level, despite the continuation of the elevated perfusion pressure. Summary: 1. metabolic control mechanisms cause active hyperemia (the increase in blood flow in an organ in response to an increased metabolic rate, in the absence of any blood pressure change). 2. metabolic mechanisms can also cause reactive hyperemia (the increase in blood flow above normal in an organ after a period of flow restriction). 3. metabolic mechanisms lead to autoregulation (the relative constancy of blood flow in an organ when there has been no change in metabolic rate but blood pressure has either increased or decreased). The same metabolic mechanism that is responsible for active hyperemia and reactive hyperemia can also account for autoregulation, in which blood flow to an organ stays relatively constant despite changes in perfusion pressure. Many Chemical Signals Act Locally (as Paracrines) to Exert Important Control on Vascular Resistance Remember: metabolic control of blood flow is mediated by chemical changes that occur when tissue metabolism increases. Examples: 1. Endothelin-1 (ET1)- released from endothelial cells in response to a variety of mechanical or chemical stimuli, like in traumatized endothelium. causes vascular smooth muscle to contract, which results in vasoconstriction and a decrease in blood flow. 2. Nitric oxide (NO)- released from endothelial cells; opposite effect. relaxes vascular smooth muscle--- vasodilatio. Stimulated by an increase in blood flow velocity past the endothelium. acts locally to dilate vessels---accommodate an increased blood flow without high flow velocities. erectile tissues of the external genital organs (penis and clitoris), parasympathetic nerve endings release NO and acetylcholine-- acetylcholine stimulates endothelial cells to release additional NO. The NO from the nerve endings and from the endothelial cells, dilates local blood vessels--- engorgement of the tissues with blood--- erection Many Chemical Signals Act Locally (as Paracrines) to Exert Important Control on Vascular Resistance 3. Thromboxane A2 (TXA2) and prostacyclin (PGI2)- antagonistic effect in the control of vascular smooth muscle and of platelet aggregation. relative balance between TXA2 and PGI2 is more important to ensure adequate blood flow to tissues and prevents platelet aggregation. In some pathological states: imbalances develop between TXA2 and PGI2. the result of imbalance: either excessive vasoconstriction and blood coagulation or excessive vasodilation and bleeding 4. Histamine- released from mast cells 5. Bradykinin- causes vasodilation. a small polypeptide that is split away by the proteolytic enzyme kallikrein from globulin proteins present in plasma or tissue fluid also formed in sweat glands---activated by acetylcholine released from sympathetic nerve endings. Result: vasodilation of skin blood vessels, plus evaporation of sweat, promotes heat loss from the skin. Both histamine and bradykinin can exert their vasodilating effects by stimulating the formation of NO Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue Mechanical compression can reduce blood flow in a tissue by literally squeezing down on all its blood vessels. trigger a readily visible reactive hyperemia prolonged period of subnormal blood flow (ischemia) leads to irreversible tissue damage (infarction) and cell death (necrosis) Ex: Pressure sores Three specific instances of mechanical compression: 1. effect of mechanical compression on blood flow through the coronary vessels blood flow through the coronary circulation would be highest during ventricular systole (when the aortic pressure is highest) and that flow would be lowest during diastole (when the aortic pressure is lowest). Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue If tracings of left coronary blood flow indicate that blood flow through the left ventricular wall is actually depressed during systole and much higher during diastole---flow even reverses (blood flows backward, toward the aorta) momentarily near the beginning of systole. If left coronary blood flow is much lower during systole, even though the perfusion pressure is higher, the resistance of the coronary vessels must be substantially higher during systole than during diastole. Left coronary resistance is high during systole because the contracting left ventricular muscle squeezes down on the coronary blood vessels. The coronary vessels are not constricted in this way during diastole because the ventricular muscle is relaxed. Therefore, coronary vascular resistance decreases dramatically (and blood flow increases) during diastole. Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue mechanical compression has relatively little influence on blood flow through the right ventricular wall. Right coronary flow is not restricted by mechanical compression during systole because the right ventricle contracts with much less force than the left ventricle. In a resting animal with a low heart rate, there is adequate time during diastole for the coronary vessels to supply the amount of blood needed by the ventricular tissue. During exercise, heart rate and cardiac contractility both increase, which greatly increases the metabolic rate of the ventricular muscle cells. To support the increased metabolic rate, the ventricular tissue needs much more blood flow than at rest. However, the duration of diastole is reduced during exercise, so there is less time available for delivery of this increased flow. Nevertheless, normal, healthy coronary vessels have a sufficiently low resistance (during diastole) to supply the needed blood flow, even during maximal exercise. Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue The situation is different, however, in animals with coronary artery disease. In animals whose coronary vessels are narrowed because of atherosclerosis, blood flow cannot increase enough to supply the needs of the vigorously working ventricular muscles. This is why ventricular ischemia develops during exercise in patients with coronary artery disease. Ischemic areas of the ventricle fail to contract normally. Ischemia can also cause arrhythmias or even ventricular fibrillation (sudden death). Coronary artery disease is more common in humans than in veterinary species, so this scenario is more likely to occur in the veterinarian than in the veterinarian’s patients. Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue 2. Mechanical compression caused by muscle contraction can also restrict blood flow through skeletal muscles. blood vessels within skeletal muscles become compressed during strenuous, sustained contractions of the muscle-- reduces blood flow through the muscle, which can create ischemia. Ischemic muscles cannot contract with normal vigor and activates sensory nerve endings in the muscle, which causes pain. Activation of receptors also triggers a reflex increase in arterial pressure. Advantage of this high arterial p: force blood flow through the skeletal muscle blood vessels, despite the compressive effects of the muscle contraction. But is risky for patients with coronary artery disease--- the high arterial pressure imposes a tremendous increase in workload on the heart. Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue 3. Mechanical compression has important effects on the pulmonary circulation. Pulmonary vessels are more compliant-- more distensible, but more susceptible to narrowing under the influence of mechanical compression. pulmonary arterial pressure is much lower than systemic arterial pressure, there is less intravascular pressure in a pulmonary vessel to oppose any external force acting to compress the vessel. an abnormal elevation in airway pressure can compress pulmonary blood vessels. happen during surgery if a patient has a tracheal tube inserted into its airway and if the tracheal tube is attached to a source of elevated pressure. the pressures generated in the tracheal tube are transmitted through the airways and into the alveoli. An increase in airway pressure exerts a compressing force on the pulmonary blood vessels. Regardless of the Status of Arterioles, Mechanical Compression Can Reduce Blood Flow to a Tissue Alveolar pressures exceeding 10 to 15 mm Hg compress pulmonary blood vessels to raise the resistance to blood flow through the lungs--- blood ejected by the right ventricle dams up in the pulmonary arteries--- causes pulmonary arterial pressure to increase---elevated pulmonary arterial pressure helps force blood through the compressed vessels but the increased pulmonary artery pressure imposes an increased workload on the right ventricle. pulmonary blood flow falls substantially below normal. Because the left heart can only pump as much blood as it receives via the pulmonary circulation, left ventricular output also decreases. This is the risk of high airway pressures whenever a patient is intubated and attached to a mechanical respiratory device Pulmonary blood vessels are susceptible to mechanical compression, which can be created by abnormally high pressure within the airways. A, Under normal conditions pulmonary arterial pressure is about 13 mm Hg and the venous pressure is about 5 mm Hg. The pressure within the pulmonary capillary depicted here would be intermediate between these two values. The pressure just outside the capillary (in the alveolar air space) is even lower; alveolar pressures typically vary between −1 mm Hg (during inspiration) and +1 mm Hg (during expiration). Because the pressure inside pulmonary vessels is greater than the pressure outside, the vessels are not compressed. B, If alveolar pressure increases to 15 mm Hg or higher, the pulmonary vessels become compressed. The resulting increase in pulmonary vascular resistance causes pulmonary blood flow to decrease, pulmonary arterial pressure to increase, and pulmonary venous pressure to decrease