Pocket Companion to Guyton Circulatory System PDF

UNIT IV The Circulation 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance, 91 15 Vascular Distensibility and Functions of the Arterial and Venous Systems, 97 16 The Mi...

UNIT IV The Circulation 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance, 91 15 Vascular Distensibility and Functions of the Arterial and Venous Systems, 97 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow, 103 17 Local and Humoral Control of Tissue Blood Flow, 113 18 Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure, 123 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension: The Integrated System for Arterial Pressure Regulation, 131 20 Cardiac Output, Venous Return, and Their Regulation, 142 21 Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease, 148 22 Cardiac Failure, 154 23 Heart Valves and Heart Sounds; Valvular and Congenital Heart Defects, 160 24 Circulatory Shock and Its Treatment, 165  CHAPTER 14 Overview of the Circulation; Biophysics of Pressure, Flow, and Resistance The function of the circulation is to serve the needs of the tissues by transporting nutrients to them, transport- ing away waste products, carrying hormones from one part of the body to another, and in general maintaining homeostatic conditions in the tissue fluids for optimal survival and function of the cells. PHYSICAL CHARACTERISTICS OF THE CIRCULATION (p. 169) The circulation is divided into the pulmonary circula- tion, which supplies the lungs, and the systemic circu- lation, which supplies tissues in the remainder of the body. The functional parts of the circulation are: The arteries, which transport blood under high pres- sure to the tissues and have strong vascular walls and rapid blood flow. The arterioles, which are the last small branches of the arterial system and act as control conduits through which blood is released into the capillaries. These vessels have strong muscular walls that can be constricted or dilated, giving them the capability of markedly altering blood flow to the capillaries in re- sponse to changing tissue needs. The capillaries, which exchange fluids, nutrients, and other substances between the blood and the in- terstitial fluid. They have thin walls and are highly permeable to small molecules. The venules, which collect blood from the capillaries and gradually coalesce into progressively larger veins. The veins, which function as conduits to transport blood from the tissues back to the heart; veins also serve as reservoirs for blood. They have thin walls, low pressure, and rapid blood flow. The Circulation Is a Complete Circuit. Contraction of the left heart propels blood into the systemic circulation through the aorta, which empties into smaller arteries, arterioles, and eventually capillaries. Because the blood vessels are distensible, each contraction of the heart distends the vessels; during relaxation of the heart, the vessels recoil, thereby continuing flow to the tissues, even between heartbeats. Blood leaving the tissues enters the venules and then flows into increasingly larger veins, which carry the blood to the right heart. 91 92 UNIT IV The Circulation The right heart then pumps the blood through the pulmonary artery, small arteries, arterioles, and capil- laries, where oxygen and carbon dioxide are exchanged between the blood and the tissues. From the pulmo- nary capillaries, blood flows into venules and large veins and empties into the left atrium and left ventricle before it is again pumped into the systemic circulation. A Change in Flow in Any Part of the Circulation Transiently Alters Flow in Other Parts. An example is strong constriction of the arteries in the systemic circulation, which can transiently reduce the total cardiac output, in which case blood flow to the lungs decreases equally as much as flow through the systemic circulation. In addition, sudden constriction of a blood vessel must always be accompanied by opposite dilation of another part of the circulation because blood volume cannot change rapidly and blood is not compressible. For instance, strong constriction of the veins in the sys- temic circulation displaces blood into the heart, dilating the heart and causing it to pump with increased force; this is one of the mechanisms by which cardiac output is regulated. With prolonged constriction or dilation of a portion of the circulation, changes in total blood volume can occur through exchange with the interstitial fluid or because of changes in fluid excretion by the kidneys. Most of the Blood Volume Is Distributed in the Veins of the Systemic Circulation. About 84 percent of the total blood volume is in the systemic circulation, with 64 percent in the veins, 13 percent in the arteries, and 7 percent in the systemic arterioles and capillaries. The heart contains about 7 percent of the blood volume, and the pulmonary vessels contain about 9 percent. Velocity of Blood Flow Is Inversely Proportional to the Vascular Cross-Sectional Area. Because approximately the same volume of blood flows through each segment of the circulation, vessels with a large cross-sectional area, such as the capillaries, have slower blood flow velocity. The approximate total cross-sectional areas of the systemic vessels for the average human being are as follows: Vessel Cross-Sectional Area (cm2) Aorta 2.5 Small arteries 20 Arterioles 40 Capillaries 2500 Venules 250 Small veins 80 Venae cavae 8  Overview of the Circulation; Biophysics of Pressure, Flow, 93 and Resistance Thus, under resting conditions, the velocity of blood flow in capillaries is only about 1/1000 the velocity of flow in the aorta. Pressures Vary in the Different Parts of the Circulation. Because the pumping action of the heart is pulsatile, the aortic arterial pressure rises to its highest point, the systolic pressure, during systole and falls to its lowest point, the diastolic pressure, at the end of diastole. In a healthy adult, systolic pressure is approximately 120 mm Hg, and diastolic pressure is 80 mm Hg. This blood pressure is usually written as 120/80 mm Hg. The difference between systolic and diastolic pressure is called the pulse pressure (120 − 80 = 40 mm Hg). As blood flows through the systemic circulation, its pressure falls progressively to approximately 0 mm Hg by the time it reaches the termination of the venae cavae in the right atrium of the heart. Pressure in the systemic capillaries varies from as high as 35 mm Hg near the arteriolar ends to as low as 10 mm Hg near the venous ends, but the average func- tional capillary pressure is about 17 mm Hg. In some capillaries, such as the glomerular capillaries of the kid- neys, the pressure is much higher, normally averaging around 60 mm Hg. Pressures in the Pulmonary Circulation Are Much Lower Than Those in the Systemic Circulation. Pressure in the pulmonary arteries is also pulsatile, but systolic arterial pressure is about 25 mm Hg and diastolic pressure is about 8 mm Hg, with a mean pulmonary artery pressure of only 16 mm Hg. Pulmonary capillary pressure averages only 8 mm Hg, yet the total blood flow through the lungs is the same as that in the systemic circulation because of the lower vascular resistance of the pulmonary blood vessels. BASIC PRINCIPLES OF CIRCULATORY FUNCTION (p. 170) The details of circulatory function are complex and are described later. However, three basic principles underlie the major functions of the circulatory system: The blood flow to each tissue of the body is controlled according to the tissue’s needs. Tissues need more blood flow when they are active than when they are at rest—occasionally as much as 20 times more blood flow. The microvessels of each tissue continu- ously monitor the tissue needs and control the blood flow at the level required for the tissue activity. Ner- vous and hormonal mechanisms provide additional control of tissue blood flow. 94 UNIT IV The Circulation The cardiac output is the sum of all the local tis- sue blood flows. After blood flows through a tissue, it immediately returns by way of the veins to the heart. The heart responds automatically to the in- flow of blood by pumping almost all of it immedi- ately back into the arteries. In this sense, the heart responds to the demands of the tissues, although it often needs help in the form of nervous stimu- lation to make it pump the required amounts of blood flow. The arterial pressure is usually controlled indepen- dently of local blood flow or cardiac output control. The circulatory system is provided with an extensive system for controlling arterial pressure. If arterial pressure falls below normal, a barrage of nervous reflexes elicits a series of circulatory changes that elevate the pressure back toward normal, includ- ing increased force of heart pumping, contraction of large venous reservoirs to provide more blood to the heart, and constriction of most of the arterioles throughout the body. Over more prolonged peri- ods, the kidneys play additional roles by secreting pressure-controlling hormones and by regulating blood volume. INTERRELATIONSHIPS OF PRESSURE, FLOW, AND RESISTANCE (p. 171) Blood Flow Through a Vessel Is Determined by the Pressure Gradient and Vascular Resistance. The flow of blood through a vessel can be calculated by the formula , where F is blood flow, is the pressure difference between the two ends of the vessel, and R is the vascular resistance. Note that it is the difference in pressure between the two ends of the vessel that provides the driving force for flow, not the absolute pressure in the vessel. For example, if the pressure at both ends of the vessel were 100 mm Hg, there would be no flow despite the presence of high pressure. Because of the extreme importance of the relation- ship among pressure, flow, and resistance, the reader should become familiar with the other two algebraic forms of this relationship:. Blood pressure is usually expressed in millimeters of mercury (mm Hg), and blood flow is expressed in milliliters per minute (ml/min); vascular resistance is expressed as mm Hg/ml per minute. In the pul- monary circulation, the pressure gradient is much lower than that in the systemic circulation, whereas  Overview of the Circulation; Biophysics of Pressure, Flow, 95 and Resistance the blood flow is the same as that in the systemic circulation. Therefore, the total pulmonary vascular resistance is much lower than the systemic vascular resistance. Vessel Diameter Has a Marked Effect on Resistance to Blood Flow—Poiseuille’s Law. According to the theory of Poiseuille, vascular resistance is directly proportional to the viscosity of the blood and the length of the blood vessel and inversely proportional to the radius of the vessel raised to the fourth power: Constant ¥ Viscosity ¥ Length Resistance Radius4 Decreased Radius of a Blood Vessel Markedly Increases Vascular Resistance. Because vascular resistance is inversely related to the fourth power of the radius, even small changes in radius can cause very large changes in resistance. For example, if the radius of a blood vessel increases from one to two (two times normal), resistance decreases to 1/16 of normal (½4) and flow increases to 16 times normal if the pressure gradient remains unchanged. Small vessels in the circulation have the greatest amount of resistance, whereas large vessels have little resistance to blood flow. For a parallel arrangement of blood vessels, as occurs in the systemic circulation in which different organs are each supplied by an artery that branches into multiple vessels, the total resistance can be expressed as 1 1 1 1... Rtotal R1 R2 Rn where R1, R2, and Rn are the resistances of each of the various vascular beds in the circulation. The total resis- tance is less than the resistance of any of the individual vascular beds. For a series arrangement of blood vessels, as occurs within a tissue in which blood flows through arteries, arterioles, capillaries, and veins, the total resistance is the sum of the individual resistances, as... where R1, R2, and Rn are the resistances of the various blood vessels in series within the tissues. Conductance is a measure of the ease of which blood can flow through a vessel and is the reciprocal of resistance. 96 UNIT IV The Circulation Increased Hematocrit and Increased Viscosity Raise Vascular Resistance and Decrease Blood Flow. The greater the viscosity, the less is the flow of blood in a vessel if all other factors remain constant. The normal viscosity of blood is about three times as great as the viscosity of water. The main factor that makes blood so viscous is that it has large numbers of suspended red blood cells, each of which exerts frictional drag against adjacent cells and against the wall of the blood vessel. The percentage of blood composed of cells, called the hematocrit, is normally about 40, which indicates that about 40 percent of the blood is cells and the remainder is plasma. The greater the percentage of cells in the blood—that is, the greater the hematocrit—the greater the viscosity of blood and therefore the greater the resistance to blood flow. “Autoregulation” Attenuates the Effect of Arterial Pressure on Tissue Blood Flow. The effect of arterial pressure on blood flow in many tissues is usually far less than one would expect, based on our previous discussion. The reason for this effect is that an increase in arterial pressure usually initiates compensatory increases in vascular resistance within a few seconds through activation of the local control mechanisms, which are discussed in Chapter 17. Conversely, with reductions in arterial pressure, vascular resistance is promptly reduced in most tissues and blood flow is maintained at a relatively constant level. The ability of each tissue to adjust its vascular resistance and to maintain normal blood flow during changes in arterial pressure between approximately 70 and 175 mm Hg is called blood flow autoregulation. Changes in tissue blood flow rarely last for more than a few hours even when increases in arterial pres- sure or increased levels of vasoconstrictors or vasodila- tors are sustained. The reason for the relative constancy of blood flow is that each tissue’s local autoregulatory mechanisms eventually override most of the effects of vasoconstrictors to provide a blood flow that is appro- priate for the needs of the tissue.  CHAPTER 15 Vascular Distensibility and Functions of the Arterial and Venous Systems VASCULAR DISTENSIBILITY (p. 179) The distensibility of arteries allows them to accommo- date the pulsatile output of the heart and average out pressure pulsations, which provides smooth, continu- ous flow of blood through the small blood vessels of the tissues. Veins are even more distensible than arteries, allowing them to store large quantities of blood that can be called into use when needed. On average, veins are about eight times as distensible as arteries in the sys- temic circulation. In the pulmonary circulation, the distensibility of veins is similar to that of veins in the systemic circulation. The lung’s arteries, however, are more distensible than those of the systemic circulation. Vascular distensibility is normally expressed as fol- lows: Vascular distensibilty Increase in volume Increase in pressure ¥ Original volume Vascular compliance (capacitance) is the total quan- tity of blood that can be stored in a given part of the circulation for each millimeter of mercury of pressure. It is calculated as follows: Increase in volume Vascular compliance Increase in pressure The greater the compliance of the vessel, the more easily it can be distended by pressure. Compliance is related to distensibility as follows: The compliance of a vein in the systemic circulation is about 24 times as great as its corresponding artery because it is about eight times as distensible and has a volume that is three times as great (8 × 3 = 24). Sympathetic Stimulation Decreases Vascular Capa- citance. Sympathetic stimulation increases smooth muscle tone in veins and arteries, causing a shift of blood to the heart, which is an important method used by the body to increase heart pumping. For example, during hemorrhage, enhanced sympathetic tone of the vessels, especially of the veins, reduces vessel size so the circulation can continue to operate almost normally 97 98 UNIT IV The Circulation even when as much as 25 percent of the total blood volume has been lost. Vessels Exposed to Increased Volume Initially Exhibit a Large Increase in Pressure, but Delayed Stretch of the Vessel Wall Allows the Pressure to Return Toward Normal. The effect of delayed stretch is often referred to as delayed compliance or stress relaxation. Delayed compliance is a valuable mechanism by which the circulation can accommodate extra amounts of blood when necessary, such as after a transfusion that was too large. Delayed compliance in the reverse direction permits the circulation to readjust itself over a period of minutes or hours to a diminished blood volume after serious hemorrhage. ARTERIAL PRESSURE PULSATIONS (p. 180) With each heartbeat, a new surge of blood fills the arter- ies. Were it not for the distensibility of the arterial sys- tem, blood flow through the tissues would occur only during cardiac systole, with no blood flowing during diastole. The combination of distensibility of the arter- ies and their resistance to flow reduces the pressure pul- sations to almost none by the time the blood reaches the capillaries, allowing continuous rather than pulsatile flow through the tissues. In the young adult, the pressure at the height of each pulse, the systolic pressure, is normally about 120 mm Hg; pressure at its lowest point, the diastolic pressure, is about 80 mm Hg. The difference between these two pressures, about 40 mm Hg, is called the pulse pressure. The two most important factors that can increase pulse pressure are (1) increased stroke volume (i.e., the amount of blood pumped into the aorta with each heart- beat) and (2) decreased arterial compliance. Decreased arterial compliance can result when the arteries “harden” with aging (arteriosclerosis). Abnormal Pressure Pulse Contours. Several other pathophysiologic conditions of the circulation can cause abnormal contours of the pressure pulse wave in addition to changing the pulse pressure (Figure 15–1): With aortic valve stenosis, the aortic pulse pressure is greatly decreased because of diminished blood flow through the stenotic aortic valve. With patent ductus arteriosus, some of the blood pumped into the aorta flows immediately through the open ductus arteriosus into the pulmonary artery, allowing the diastolic pressure to fall very low before the next heartbeat, thereby increasing pulse pressure.  Vascular Distensibility and Functions of the Arterial 99 and Venous Systems 160 120 80 Pressure (mm Hg) Normal Arteriosclerosis Aortic stenosis 160 120 80 Normal 40 Patent ductus Aortic arteriosus regurgitation 0 Figure 15–1 Aortic pressure pulse contours in arteriosclerosis, aortic stenosis, patent ductus arteriosus, and aortic regurgitation. With aortic regurgitation, the aortic valve is absent or functions poorly. After each heartbeat, the blood that flows into the aorta flows immediately back into the left ventricle during diastole, causing the aortic pressure to fall to a very low level between heart- beats, thereby increasing the pulse pressure. The Pressure Pulses Are Damped in the Smaller Vessels. Pressure pulsations in the aorta are progressively diminished (damped) by (1) resistance to blood movement in the vessels and (2) compliance of the vessels. The resistance damps the pulsations because a small amount of blood must flow forward to distend the next segment of the vessel; the greater the resistance, the more difficult it is for this forward flow to occur. The compliance damps the pulsation because the more compliant a vessel, the more blood is required to cause a rise in pressure. The degree of damping of arterial pulsations is directly proportional to the product of the resistance and compliance. Blood Pressure Can Be Measured Indirectly by the Auscultatory Method. With the auscultatory method, a stethoscope is placed over a vessel, such as the antecubital artery, and a blood pressure cuff is inflated around the upper arm proximal to the vessel. As long as the cuff inflation is not sufficient to collapse the vessel, no sounds are heard with the stethoscope despite the fact that blood in the artery is pulsing. When the cuff pressure is sufficient to close the artery during part of the arterial pressure cycle, a sound is heard with each pulsation; these sounds are called Korotkoff sounds. 100 UNIT IV The Circulation When determining blood pressure by the ausculta- tory method, pressure in the cuff is first inflated well above the arterial systolic pressure. As long as the pressure is higher than the systolic pressure, the bra- chial artery remains collapsed and no blood jets into the lower artery during the cardiac cycle; therefore, no Korotkoff sounds are heard in the lower artery. As soon as the pressure in the cuff falls below the systolic pres- sure, blood slips through the artery underneath the cuff during the peak systolic pressure, and one begins to hear tapping sounds in the antecubital artery in synchrony with the heartbeat. As soon as these sounds are heard, the pressure level indicated by the manometer con- nected to the cuff is about equal to the systolic pressure. As pressure in the cuff is further lowered, the Korot- koff sounds change in quality, having a rhythmical, harsher sound. Finally, when the pressure in the cuff falls to the level of the diastolic pressure (i.e., the artery no longer closes during diastole), the sounds suddenly change to a muffled quality and then usually disappear entirely after another 5- to 10-millimeter drop in cuff pressure. When the Korotkoff sounds change to the muffled quality, the manometer pressure is about equal to the diastolic pressure, although this slightly overes- timates the diastolic pressure. Many clinicians believe that the pressure at which the Korotkoff sounds com- pletely disappear should be used as the diastolic pres- sure except in situations in which the disappearance of sounds cannot reliably be determined, because sounds are audible even after complete deflation of the cuff. For example, in patients who have arteriovenous fistulas for hemodialysis or aortic insufficiency, Korotkoff sounds may be heard after complete deflation of the cuff. The mean arterial pressure can be estimated from the systolic and diastolic pressures measured by the auscultatory method as follows: Mean arterial pressure Diastolic pressure + Systolic pressure For the average young adult, the mean arterial pres- sure is about (⅔ × 80 mm Hg) + (⅓ × 120 mm Hg), or 93.3 mm Hg. VEINS AND THEIR FUNCTIONS (p. 184) As discussed previously, the veins are capable of con- stricting and enlarging and thereby storing either small or large quantities of blood, making this blood avail- able when it is needed by the circulatory system. Veins  Vascular Distensibility and Functions of the Arterial 101 and Venous Systems can also propel blood forward by means of a “venous pump,” which helps regulate cardiac output. Relationship to Right Atrial Pressure (Central Venous Pressure) and Peripheral Venous Pressure. Because blood from systemic veins flows into the right atrium, anything that affects the right atrial pressure usually affects venous pressure everywhere in the body. Right atrial pressure is regulated by a balance between the ability of the heart to pump blood out of the right atrium and a tendency of blood to flow from the peripheral vessels back to the right atrium. The normal right atrial pressure is about 0 mm Hg, but it can rise to as high as 20 to 30 mm Hg under abnormal conditions, such as with serious heart failure or after a massive transfusion. Increased Venous Resistance Can Increase the Peripheral Venous Pressure. When large veins are distended, they offer little resistance to blood flow. Many of the large veins entering the thorax are compressed by the surrounding tissues, however, so they are at least partially collapsed or collapsed to an ovoid state. For these reasons, large veins usually offer significant resistance to blood flow, and the pressure in the peripheral veins is usually 4 to 7 mm Hg higher than the right atrial pressure. Partial obstruction of a large vein markedly increases the peripheral venous pressure distal to the obstruction. Increased Right Atrial Pressure Increases Peripheral Venous Pressure. When the right atrial pressure rises above its normal level of 0 mm Hg, blood begins to back up in large veins and open them up. Pressures in the peripheral veins do not rise until the collapsed points between the peripheral veins and the large central veins have opened, which usually occurs at a right atrial pressure of about 4 to 6 mm Hg. When the right atrial pressure rises further, as occurs during severe heart failure, it causes a corresponding rise in peripheral venous pressure. Gravitational Pressure Affects Venous Pressure. The pressure at the surface of a body of water exposed to air is equal to the atmospheric pressure, but the pressure rises 1 mm Hg for each 13.6 mm Hg distance below the surface. This pressure results from the weight of the water and therefore is called gravitational hydrostatic pressure. Gravitational hydrostatic pressure also occurs in the vascular system because of the weight of the blood in the vessels. In an adult who is standing absolutely still, pressure in the veins of the feet is approximately +90 mm Hg because of the hydrostatic weight of the blood in the veins between the heart and the feet. 102 UNIT IV The Circulation The Venous Valves and “Venous Pump” Influence Venous Pressure. Were it not for the valves of the veins, the gravitational pressure effect would cause venous pressure in the feet to always be about +90 mm Hg in a standing adult. Each time one tightens the muscles and moves the legs, however, this compresses the veins either in the muscles or adjacent to them and squeezes the blood out of the veins. The valves in the veins are arranged so the direc- tion of blood flow can only be toward the heart. Conse- quently, each time a person moves the legs or tenses the muscles, a certain amount of blood is propelled toward the heart, and the pressure in the veins is lowered. This pumping system is known as the “venous pump” or “muscle pump,” and it keeps the venous pressure in the feet of a walking adult near 25 mm Hg. If a person stands perfectly still, however, the venous pump does not work, and venous pressure quickly rises to the full hydrostatic value of 90 mm Hg. If the valves of the venous system become incompetent or are destroyed, the effectiveness of the venous pump is also decreased. When valve incompetence develops, greater pressure in the veins of the legs may further increase the size of the veins and finally destroy the function of the valves entirely. When the function of the valves is destroyed entirely, varicose veins develop, and the venous and capillary pressures increase to high levels, causing leakage of fluid from the capillaries and edema in the legs when standing. The Veins Function as Blood Reservoirs. More than 60 percent of the blood in the circulatory system is usually contained in the veins. For this reason and because the veins are so compliant, the venous system can serve as a blood reservoir for the circulation. For example, when blood is lost from the body, activation of the sympathetic nervous system causes the veins to constrict, which takes up much of the “slack” of the circulatory system caused by the lost blood. Certain portions of the circulatory system are so compliant that they are especially important as blood reservoirs. These areas include (1) the spleen, which can sometimes decrease in size to release as much as 100 milliliters of blood into the reservoir of the circulation; (2) the liver, the sinuses of which can release several hundred milliliters of blood into the remainder of the circulation; (3) the large abdominal veins, which can contribute as much as 300 milliliters; and (4) the venous plexus underneath the skin, which can contribute sev- eral hundred milliliters.  CHAPTER 16 The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow A primary function of the microcirculation—to trans- port nutrients to the tissues and remove waste prod- ucts—occurs in the capillaries. The capillaries have only a single layer of highly permeable endothelial cells, per- mitting rapid interchange of nutrients and cellular waste products between the tissues and circulating blood. About 10 billion capillaries, which have a total surface area of 500 to 700 square meters (about one eighth the size of a football field), provide this function for the body. STRUCTURE OF THE MICROCIRCULATION AND CAPILLARY SYSTEM (p. 189) Blood Enters the Capillaries Through an Arteriole and Leaves Through a Venule. Blood from the arteriole passes into a series of metarterioles, which have structures midway between those of arterioles and capillaries (Figure 16–1). Arterioles are highly muscular and play a major role in controlling blood flow to the tissues. The metarterioles do not have a continuous smooth muscle coat, but smooth muscle fibers encircle the vessel at intermittent points called precapillary sphincters. Contraction of the muscle in these sphincters can open and close the entrance to the capillary. This arrangement of the microcirculation is not found in all parts of the body, but similar arrangements serve the same purposes. Both the metarterioles and arterioles are in close contact with the tissues they serve, and local conditions, such as changes in the concentration of nutri- ents or waste products of metabolism, can have direct effects on these vessels in controlling the local blood flow. The Thin Capillary Wall Consists of a Single Layer of Endothelial Cells. Capillaries are also very porous, with several million slits, or pores, between the cells that make up their walls to each square centimeter of capillary surface. Because of the high permeability of the capillaries for most solutes and the high surface area, as blood flows through the capillaries, large amounts of dissolved substances diffuse in both directions through these pores. In this way almost all dissolved substances in the plasma, except the plasma proteins, continually mix with the interstitial fluid. 103 104 UNIT IV The Circulation Arteriole Venule Precapillary sphincters Capillaries Smooth muscle cells Metarteriole Arteriovenous bypass Figure 16–1 Components of the microcirculation. Blood Flows Intermittently Through Capillaries, a Phenomenon Called “Vasomotion.” In many tissues, blood flow through capillaries is not continuous but instead turns on and off every few seconds. The cause of this intermittence is contraction of the metarterioles and precapillary sphincters, which are influenced mainly by oxygen and waste products of tissue metabolism. When oxygen concentrations of the tissue are reduced (e.g., because of increased oxygen utilization), the periods of blood flow occur more often and last longer, thereby allowing the blood to carry increased quantities of oxygen and other nutrients to the tissues. EXCHANGE OF WATER, NUTRIENTS, AND OTHER SUBSTANCES BETWEEN BLOOD AND INTERSTITIAL FLUID (p. 191) Diffusion Is the Most Important Means for Transferring Substances Between Plasma and Interstitial Fluid. As blood  The Microcirculation and Lymphatic System: Capillary Fluid 105 Exchange, Interstitial Fluid, and Lymph Flow traverses the capillary, tremendous numbers of water molecules and dissolved substances diffuse back and forth through the capillary wall, providing continual mixture of the interstitial fluid and plasma. Lipid-soluble substances such as oxygen and carbon dioxide can diffuse directly through the cell membranes without having to go through the pores. Water-soluble substances, such as glucose and electrolytes, diffuse only through intercellular pores in the capillary membrane. The rate of diffusion for most solutes is so great that cells as far as 50 micrometers away from the capillaries can receive adequate quantities of nutrients. The following primary factors affect the rate of diffu- sion across the capillary walls: 1. The pore size in the capillary. In most capillaries, the pore size is 6 to 7 nanometers. The pores of some capillary membranes, such as the liver capillary sinu- soids, are much larger and are therefore much more highly permeable to substances dissolved in plasma. 2. The molecular size of the diffusing substance. Water and most electrolytes, such as sodium and chlo- ride, have a molecular size that is smaller than the pore size, allowing rapid diffusion across the capil- lary wall. Plasma proteins, however, have a molecu- lar size that is slightly greater than the width of the pores, restricting their diffusion. 3. The concentration difference of the substance between the two sides of the membrane. The greater the differ- ence between the concentrations of a substance on the two sides of the capillary membrane, the greater is the rate of diffusion in one direction through the membrane. The concentration of oxygen in blood is normally higher than in interstitial fluid, allowing large quantities of oxygen to move from the blood toward the tissues. Conversely, concentrations of the waste products of metabolism are greater in tissues than in blood, allowing them to move into the blood and to be carried away from the tissues. INTERSTITIUM AND INTERSTITIAL FLUID (p. 192) About one sixth of the body consists of spaces between cells, which collectively are called the interstitium. The fluid in these spaces is the interstitial fluid. The intersti- tium has two major types of solid structures: (1) collagen fiber bundles and (2) proteoglycan filaments. The colla- gen provides most of the tensional strength of the tissues, whereas the proteoglycan filaments, composed mainly of hyaluronic acid, are very thin and form a filler of fine reticular filaments, often described as a “brush pile.” 106 UNIT IV The Circulation “Gel” in the Interstitium Consists of Proteoglycan Filaments and Entrapped Fluid. Fluid in the interstitium is derived by filtration and diffusion from the capillaries and has almost the same constituency as plasma except with lower concentrations of protein. The interstitial fluid is mainly entrapped in the minute spaces among the proteoglycan filaments and has the characteristics of a gel. Because of the large number of proteoglycan fila- ments, fluid and solutes do not flow easily through the tissue gel. Instead, solutes mainly diffuse through the gel. This diffusion occurs about 95 to 99 percent as rap- idly as it does through free fluid. The Amount of “Free” Fluid in the Interstitium in Most Tissues Is Less Than 1 Percent of the Total Fluid in the Tissues. Although almost all the fluid in the interstitium is entrapped in the tissue gel, small amounts of “free” fluid are also present. When the tissues develop edema, these small pockets of free fluid can expand tremendously. CAPILLARY FLUID FILTRATION IS DETERMINED BY HYDROSTATIC AND COLLOID OSMOTIC PRESSURES AND THE CAPILLARY FILTRATION COEFFICIENT (p. 193) Although the exchange of nutrients, oxygen, and meta- bolic waste products across the capillaries occurs almost entirely by diffusion, the distribution of fluid across the capillaries is determined by another process—the bulk flow or ultrafiltration of protein-free plasma. As dis- cussed previously, capillary walls are highly permeable to water and most plasma solutes, except plasma pro- teins; therefore, hydrostatic pressure differences across the capillary wall push protein-free plasma (ultrafil- trate) through the capillary wall into the interstitium. In contrast, osmotic pressure caused by the plasma proteins (called colloid osmotic pressure) tends to cause fluid movement by osmosis from the interstitial spaces into the blood. Interstitial fluid hydrostatic and colloid osmotic pressures also influence fluid filtration across the capillary wall. The rate at which ultrafiltration occurs across the capillary depends on the difference in hydrostatic and colloid osmotic pressures of the capillary and intersti- tial fluid. These forces are often called Starling forces in honor of Ernest Starling, the physiologist who described their functional significance more than a century ago.  The Microcirculation and Lymphatic System: Capillary Fluid 107 Exchange, Interstitial Fluid, and Lymph Flow Four Forces Determine Fluid Filtration Through the Capillary Membrane. The following four primary forces determine fluid movement across the capillaries: The capillary hydrostatic pressure (Pc), which forces fluid outward through the capillary membrane The interstitial fluid hydrostatic pressure (Pif ), which forces fluid inward through the capillary membrane when the Pif is positive but outward into the intersti- tium when the Pif is negative The plasma colloid osmotic pressure (Πp), which tends to cause osmosis of the fluid inward through the capillary membrane The interstitial fluid colloid osmotic pressure (Πif ), which tends to cause osmosis of fluid outward through the capillary membrane The net rate of filtration out of the capillary is deter- mined by the balance of these forces and by the capil- lary filtration coefficient (Kf), as follows: “Functional” Capillary Hydrostatic Pressure. When blood is flowing through many capillaries, the pressure averages 30 to 40 mm Hg on the arterial ends and 10 to 15 mm Hg on the venous ends, or about 25 mm Hg in the middle. When the capillaries are closed, the pressure in the capillaries beyond the closure is about equal to the pressure at the venous ends of the capillaries (10 mm Hg). When averaged over a period of time, including the periods of opening and closure of the capillaries, the functional mean capillary pressure is closer to the pressure in the venous ends of the capillaries than to the pressure in the arteriole ends. Although functional capillary pressure averages about 17 mm Hg in many tissues, such as skeletal muscle, in some tissues, such as the kidneys, capillary hydrostatic pressure may be as high as 60 to 65 mm Hg (see Chapter 26). Negative Interstitial Fluid Hydrostatic Pressure (Subatmospheric) in Loose Subcutaneous Tissue. Measurements of interstitial fluid hydrostatic pressure have yielded an average value of about −3 mm Hg in loose subcutaneous tissue. One of the basic reasons for this negative pressure is the lymphatic pumping system (discussed later). When fluid enters the lymphatic capillaries, any movement of the tissue propels the fluid forward through the lymphatic system and eventually back into the circulation. In this way, free fluid that accumulates in the tissue is pumped away as a consequence of tissue movement. This pumping action of lymphatic capillaries appears to account for 108 UNIT IV The Circulation the slight intermittent negative pressure that occurs in the tissues at rest. In Tissues Surrounded By Tight Encasements (Fibrous Sheaths), Such as the Brain, Kidneys, and Skeletal Muscle, Interstitial Fluid Hydrostatic Pressures Are Positive. For instance, the brain interstitial fluid hydrostatic pressure averages about +4 to +16 mm Hg. In the kidneys, interstitial fluid hydrostatic pressure averages about +6 mm Hg. Plasma Colloid Osmotic Pressure Averages About 28 mm Hg. The proteins are the only dissolved substances in the plasma that do not readily pass through the capillary membrane. These substances exert an osmotic pressure referred to as the colloid osmotic pressure. The normal concentration of plasma protein averages about 7.3 g/dl. About 19 mm Hg of the colloid osmotic pressure is due to the dissolved protein, but an additional 9 mm Hg is due to the positively charged cations, mainly sodium ions, that bind to the negatively charged plasma proteins. This effect is called the Donnan equilibrium effect, which causes the colloid osmotic pressure in the plasma to be about 50 percent greater than that produced by the proteins alone. The plasma proteins are mainly a mixture of albu- min, globulin, and fibrinogen. About 80 percent of the total colloid osmotic pressure of the plasma results from the albumin fraction, 20 percent from the globulin, and only a tiny amount from the fibrinogen. Interstitial Fluid Colloid Osmotic Pressure Averages About 8 mm Hg. Although the size of the usual capillary pore is smaller than the molecular size of the plasma protein, this is not true of all pores; therefore, small amounts of plasma protein leak through the pores into the interstitial spaces. The average protein concentration of the interstitial fluid is around 40 percent of that in the plasma, or about 3 g/dl, giving a colloid osmotic pressure of about 8 mm Hg. In some tissues, such as the liver, the interstitial fluid colloid osmotic pressure is much greater because the capillaries are much more permeable to plasma proteins. Summary of Fluid Volume Exchange Through the Capillary Membrane. The average capillary pressure at the arteriolar ends of the capillaries is 15 to 25 mm Hg greater than at the venular ends. Because of this difference, fluid filters out of the capillaries at the arteriolar ends, and fluid is reabsorbed back into the capillaries at their venular ends. A small amount of fluid flows through the tissues from the arteriolar ends of the capillaries to the venular ends.  The Microcirculation and Lymphatic System: Capillary Fluid 109 Exchange, Interstitial Fluid, and Lymph Flow Table 16–1 Equilibrium of Forces Across Capillaries Forces mm Hg Mean forces tending to move fluid outward Mean capillary hydrostatic pressure 17.3 Negative interstitial free fluid pressure 3.0 Interstitial fluid colloid osmotic pressure 8.0 Total outward force 28.3 Mean force tending to move fluid inward Plasma colloid osmotic pressure 28.0 Total inward force 28.0 Summation of mean forces Outward 28.3 Inward −28.0 Net outward force 0.3 A state of near-equilibrium, however, normally exists between the amount of fluid filtering outward at the arteriolar ends of the capillaries and the amount of fluid returned to the circulation by absorption at the venular ends of the capillaries. A slight disequilibrium occurs, and a small amount of fluid is filtered in excess of the amount reabsorbed. This fluid is eventually returned to the circu- lation by way of the lymphatic system. Table 16–1 shows the average forces that exist across the entire capillaries and illustrates the principles of this equilibrium. The pres- sures in the arterial and venous capillaries in Table 16–1 are averaged to calculate the mean functional capillary pressure, which is about 17.3 mm Hg. The small imbalance of forces, 0.3 mm Hg, causes slightly more filtration than reabsorption of fluid into the interstitial spaces. The Rate of Filtration in the Capillaries Is Also Determined By the Capillary Filtration Coefficient (Kf). The filtration coefficient in an average tissue is about 0.01 ml/min of fluid per mm Hg per 100 grams of tissue. For the entire body, the capillary filtration coefficient is about 6.67 ml/ min of fluid per mm Hg. Thus, the net rate of capillary filtration for the entire body is expressed as follows: Because of the extreme differences in the perme- abilities and surface areas of the capillary systems in different tissues, the capillary filtration coefficient may 110 UNIT IV The Circulation vary more than 100-fold among tissues. For example, the capillary filtration coefficient in the kidneys is about 4.2 ml/min/mm Hg per 100 grams of kidney weight, a value almost 400 times as great as the Kf of many other tissues, which obviously causes a much greater rate of filtration in the glomerular capillaries of the kidney. An Abnormal Imbalance of Pressures in the Capillary Can Cause Edema. If the mean capillary hydrostatic pressure rises above the normal 17 mm Hg, the net pressure causing filtration of fluid into the tissue spaces also rises. A rise in mean capillary pressure of 20 mm Hg causes an increase in the net filtration pressure from 0.3 mm Hg to 20.3 mm Hg, which results in 68 times as much net filtration of fluid into the interstitial spaces as normally occurs. Prevention of accumulation of excess fluid in the spaces would require 68 times the normal flow of fluid into the lymphatic system, an amount that is too great for the lymphatics to carry away. As a result, large increases in capillary pressure can cause accumulation of fluid in the interstitial spaces, a condition referred to as edema. Similarly, a decrease in plasma colloid osmotic pres- sure increases the net filtration force and therefore the net filtration rate of fluid into the tissues. THE LYMPHATIC SYSTEM (p. 198) The lymphatic system carries fluid from tissue spaces into the blood. Importantly, the lymphatics also carry away proteins and large particulate matter from the tis- sue spaces, neither of which can be removed through absorption directly into the blood capillary. Almost all tissues of the body have lymphatic chan- nels. Most of the lymph from the lower part of the body flows up the thoracic duct and empties into the venous system at the juncture of the left interior jugular vein and subclavian vein. Lymph from the left side of the head, left arm, and parts of the chest region also enters the thoracic duct before it empties into the veins. Lymph from the right side of the neck and head, right arm, and parts of the thorax enter the right lymph duct, which then empties into the venous system at the juncture of the right subclavian vein and internal jugular vein. Lymph Is Derived From Interstitial Fluid. As lymph first flows from the tissue, it has almost the same composition as the interstitial fluid. In many tissues, the protein concentration averages about 2 g/dl, but in other tissues such as the liver, the protein concentration may be as high as 6 g/dl.  The Microcirculation and Lymphatic System: Capillary Fluid 111 Exchange, Interstitial Fluid, and Lymph Flow In addition to carrying fluid and protein from the interstitial spaces to the circulation, the lymphatic sys- tem is one of the major routes for absorption of nutrients from the gastrointestinal tract, as discussed in Chapter 66. After a fatty meal, for instance, thoracic duct lymph sometimes contains as much as 1 to 2 percent fat. Lymph Flow Rate Is Determined By Interstitial Fluid Hydrostatic Pressure and the Lymphatic Pump. The total rate of lymph flow is approximately 120 ml/h, or 2 to 3 L/day. This rate of formation can change dramatically, however, in certain pathological conditions associated with excessive fluid filtration from the capillaries into the interstitium. Increased interstitial fluid hydrostatic pressure in- creases the lymph flow rate. At normal interstitial fluid hydrostatic pressures in the subatmospheric range, lymph flow is very low in loose tissues such as skin. As the pressure rises to values slightly higher than 0 mm Hg, the lymph flow increases by more than 20-fold. When interstitial pressure reaches +1 to +2 mm Hg, lymph flow fails to rise further be- cause rising tissue pressure not only increases the entry of fluid into the lymphatic capillaries, but also compresses the larger lymphatics, thereby impeding lymph flow. The lymphatic pump increases lymph flow. Valves ex- ist in all lymph channels. In addition, each segment of the lymphatic vessel functions as a separate auto- matic pump; that is, filling of a segment causes it to contract, and the fluid is pumped through the valve into the next lymphatic segment. This action fills the lymphatic segment, and within a few seconds it too contracts, with the process continuing along the lymph vessel until the fluid is finally emptied. This pumping action propels the lymph forward toward the circulation. In addition to pumping caused by intrinsic contraction of the vessels, external factors also compress lymph vessels. For example, contraction of muscles surrounding lymph vessels or movement of body parts may increase lymphatic pumping. Under some conditions, such as during exercise, the lymphatic pump may increase lymph flow by as much as 10- to 30-fold. The Lymphatic System Provides an “Overflow Mechanism” That Returns to the Circulation Excess Proteins and Fluid Volume That Enter the Tissue Spaces. When the lymphatic system fails, such as when blockade of a major lymphatic vessel occurs, proteins and fluid accumulate in the interstitium and cause edema. The 112 UNIT IV The Circulation accumulation of protein in the interstitium is especially important in causing edema because the lymphatic system provides the only mechanism for proteins that leak out of the capillaries to re-enter the circulation in significant quantities. When protein accumulates in the interstitial spaces owing to lymphatic failure, the colloid osmotic pressure of the interstitial fluid increases, allowing more fluid filtration into the interstitium. Thus, complete blockade of the lymphatic vessels results in severe edema. Bacteria and Debris From the Tissues Are Removed By the Lymphatic System at Lymph Nodes. Because of the very high permeability of the lymphatic capillaries, bacteria and other small particulate matter in the tissues can pass into the lymph. The lymph passes through a series of nodes on its way out to the blood. It is in these nodes that bacteria and other debris are filtered out, phagocytized by macrophages in the nodes, and finally digested and converted to amino acids, glucose, fatty acids, and other low-molecular-weight substances before being released into the blood.  CHAPTER 17 Local and Humoral Control of Tissue Blood Flow Local Tissues Autoregulate Blood Flow in Response to Their Individual Needs. Most tissues “autoregulate” their own blood flow. This is beneficial to the tissue because it allows the delivery of oxygen and nutrients and removal of waste products to parallel the rate of tissue activity. Autoregulation permits blood flow from one tissue to be regulated independently of flow to another tissue. In certain organs, blood flow serves purposes other than supplying nutrients and removing waste products. For instance, blood flow to the skin influences heat loss from the body and in this way helps control body tem- perature. Delivery of adequate quantities of blood to the kidneys allows them to excrete the waste products of the body rapidly. The ability of the tissues to regulate their own blood flow permits them to maintain adequate nutrition and perform necessary functions to main- tain homeostasis. In general, the greater the rate of metabolism in an organ, the greater its blood flow. For example, Table 17–1 shows that there is high blood flow in glandular organs such as the thyroid and adrenal glands, which have a high metabolic rate. In contrast, blood flow in resting skeletal muscles is low because metabolic activity of the muscle is also low in the resting state. However, during heavy exer- cise, skeletal muscle metabolic activity can increase by more than 60-fold and the blood flow can increase by as much as 20-fold. MECHANISMS OF BLOOD FLOW CONTROL (p. 203) Local tissue blood flow control can be divided into two phases: (1) acute control and (2) long-term con- trol. Acute control occurs within seconds to minutes via constriction or dilation of arterioles, metarterioles, and precapillary sphincters. Long-term control occurs over a period of days, weeks, or even months and, in general, provides even better control of flow in pro- portion to the needs of the tissues. Long-term control occurs mainly as a result of increases or decreases in the physical size and number of blood vessels supply- ing the tissues. 113 114 UNIT IV The Circulation Table 17–1 Blood Flow to Various Organs and Tissues Under Basal Conditions Cardiac Output ml/min/100 g of Organ (%) Flow (ml/min) Tissue Brain 14 700 50 Heart 4 200 70 Bronchi 2 100 25 Kidneys 22 1100 360 Liver 27 1350 95 Portal (21) (1050) Arterial (6) (300) Muscle (inactive 15 750 4 state) Bone 5 250 3 Skin (cool 6 300 3 weather) Thyroid gland 1 50 160 Adrenal glands 0.5 25 300 Other tissues 3.5 175 1.3 Total 100.0 Acute Control of Local Blood Flow (p. 204) Increased Tissue Metabolic Rate Usually Increases Tissue Blood Flow. In many tissues, such as skeletal muscle, increases in metabolism up to eight times normal acutely increase blood flow about fourfold. Initially, the rise in flow is less than that of the metabolism, but once the metabolism increases sufficiently to remove most of the nutrients from the blood, a further rise in metabolism can occur only with a concomitant increase in blood flow to supply the required nutrients. Decreased Oxygen Availability Increases Tissue Blood Flow. One of the required nutrients for tissue metabolism is oxygen. Whenever the availability of oxygen in the tissues decreases, such as at high altitude, in the presence of pneumonia, or with carbon monoxide poisoning (which inhibits the ability of hemoglobin to transport oxygen), tissue blood flow increases markedly. For instance, cyanide poisoning, which reduces the  Local and Humoral Control of Tissue Blood Flow 115 ability of tissues to utilize oxygen, can increase tissue blood flow by as much as sevenfold. Increased Demand for Oxygen and Nutrients Increases Tissue Blood Flow. In the absence of an adequate supply of oxygen and nutrients (e.g., as a result of increased tissue metabolism), the arterioles, metarterioles, and precapillary sphincters relax, thereby decreasing vascular resistance and allowing more flow to the tissues. The relaxation of precapillary sphincters allows flow to occur more often in capillaries that are closed because of periodic contraction of precapillary sphincters (vasomotion). Accumulation of Vasodilator Metabolites Increases Tissue Blood Flow. The greater the rate of metabolism in the tissue, the greater the rate of production of tissue metabolites, such as adenosine, adenosine phosphate compounds, carbon dioxide, lactic acid, potassium ions, and hydrogen ions. Each of these substances has been suggested to act as a vasodilator that contributes to increased blood flow associated with stimulation of tissue metabolism. Lack of Other Nutrients May Cause Vasodilation. Deficiency of glucose, amino acids, or fatty acids may contribute to local vasodilation, although this has not been proven. Vasodilation occurs in patients with beriberi, who usually have a deficiency of the vitamin B substances thiamine, niacin, and riboflavin. Because these vitamins are all involved in the oxidative phosphorylation mechanism for generating adenosine triphosphate, a deficiency of these vitamins may lead to diminished ability of the smooth muscle to contract, thereby causing local vasodilation. Special Examples of Acute “Metabolic” Control of Local Blood Flow (p. 206) “Reactive Hyperemia” Occurs After the Blood Supply to a Tissue Is Blocked for a Short Time. If blood flow is blocked for a few seconds to several hours and then unblocked, flow to the tissue usually increases to four to seven times normal. The increased flow continues for a few seconds or much longer if the flow has been stopped for 1 hour or longer. This phenomenon is called reactive hyperemia and appears to be a manifestation of local “metabolic” blood flow regulation mechanisms. After vascular occlusion, tissue vasodilator metabolites accumulate in the tissues and oxygen deficiency develops. The extra blood flow during reactive hyperemia lasts long enough 116 UNIT IV The Circulation to almost exactly repay the tissue oxygen deficiency and wash out accumulated vasodilator metabolites. “Active Hyperemia” Occurs When the Tissue Metabolic Rate Increases. When a tissue becomes highly active, such as muscle during exercise or even the brain during increased mental activity, blood flow to the tissue increases. Again, this appears to be related to increases in local tissue metabolism that cause accumulation of vasodilator substances and possibly a slight oxygen deficit. The dilation of local blood vessels helps the tissue receive the additional nutrients required to sustain its new level of function. Tissue Blood Flow Is “Autoregulated” During Changes in Arterial Pressure. In any tissue of the body, acute increases in arterial pressure cause an immediate increase in blood flow. Within less than 1 minute, however, the blood flow in many tissues returns toward the normal level even though the arterial pressure remains elevated. This is called autoregulation of blood flow. The metabolic theory of autoregulation suggests that when arterial pressure rises and blood flow becomes too great, the excess provides surplus oxygen and nutrients to the tissues, causing the blood vessels to constrict and the flow to return toward normal de- spite the increased arterial pressure. The myogenic theory of autoregulation suggests that sudden stretch of small blood vessels causes the smooth muscles in the vessel walls to contract automatically. This intrinsic property of smooth muscles allows them to resist excessive stretching. Conversely, at low pressures the degree of stretch of the vessel is less and the smooth muscle relaxes, decreasing vascular resistance and allowing flow to be maintained relatively constant despite the lower blood pressure. The relative importance of these two mechanisms for autoregulation of blood flow is still debated by physi- ologists. It seems likely that both mechanisms contrib- ute to maintaining a relatively stable blood flow during variations in arterial pressure. Additional Mechanisms for Blood Flow Control in Specific Tissues. The general mechanisms for local blood flow control discussed thus far are present in most tissues of the body; however, special mechanisms also exist that control blood flow in certain areas. These mechanisms are discussed in relation to specific organs, but the following three mechanisms are notable: In the kidneys, blood flow is regulated, in part, via a mechanism called tubuloglomerular feedback, in  Local and Humoral Control of Tissue Blood Flow 117 which the composition of fluid in the early distal tu- bule is detected by the macula densa. The macula densa is located where the tubule abuts the afferent and efferent arterioles at the juxtaglomerular appa- ratus. When too much fluid filters from the blood through the glomerulus into the tubular system, feedback signals from the macula densa cause con- striction of the afferent arterioles, thereby reducing renal blood flow and returning the glomerular filtra- tion rate toward normal (see Chapter 26 for further discussion). In the brain, the concentrations of carbon dioxide and hydrogen play prominent roles in local blood flow control. An increase in either carbon dioxide or hydrogen dilates the cerebral blood vessels, which al- lows rapid washout of the excess carbon dioxide and hydrogen ions. In the skin, blood flow control is closely linked to body temperature and is controlled largely by the central nervous system through the sympathetic nerves, as discussed in Chapter 74. When humans are exposed to heating of the body, skin blood flow may increase manyfold, to as high as 7 to 8 L/min for the entire body. When body temperature is reduced, skin blood flow decreases, falling to barely above zero at very low temperatures. Endothelial Cells Control Blood Flow By Releasing the Vasodilator Nitric Oxide. The local mechanisms for controlling tissue blood flow act mainly on the very small microvessels of the tissues because local feedback by vasodilator substances or oxygen deficiency can reach only these vessels, not the larger arteries upstream. When blood flow through the microvascular portion of the circulation increases, however, the endothelial cells lining the larger vessels release a vasodilator substance called endothelium-derived relaxing factor, which appears to be mainly nitric oxide. This release of nitric oxide is caused, in part, by increased shear stress on the endothelial walls, which occurs as blood flows more rapidly through the larger vessels. The release of nitric oxide then relaxes the larger vessels, causing them to dilate. Without the dilation of larger vessels, the effectiveness of local blood flow would be compromised because a significant part of the resistance in blood flow is in the upstream arterioles and small arteries. Endothelial Cells Also Release Vasoconstrictor Substances. The most important of these substances is endothelin, a peptide that is released when blood vessels are injured. The usual stimulus for release is damage to 118 UNIT IV The Circulation the endothelium, such as that caused by crushing the tissues or injecting a traumatizing chemical into the blood vessel. After severe blood vessel damage, release of local endothelin and subsequent vasoconstriction help prevent extensive bleeding from arteries. Long-Term Blood Flow Regulation (p. 209) Most of the mechanisms discussed thus far act within a few seconds to a few minutes after local tissue con- ditions have changed. Even with full function of these acute mechanisms, blood flow usually is adjusted only about three fourths of the way back to the exact require- ments of the tissues. Over a period of hours, days, and weeks, long-term local blood flow regulation develops that helps adjust the blood flow so it matches precisely the metabolic needs of the tissues. Changes in Tissue Vascularity Contribute to Long-Term Regulation of Blood Flow. If metabolism of a tissue is increased for prolonged periods, the physical size of the vessels in the tissue increases; under some conditions, the number of blood vessels also increases. One of the major factors that stimulates this increased vascularity is low oxygen concentration in the tissues. Animals that live at high altitudes, for instance, have increased vascularity. Likewise, fetal chicks hatched at low oxygen levels have up to twice as much vascularity as normal fetal chicks. This growth of new vessels is called angiogenesis. Angiogenesis occurs mainly in response to the pres- ence of angiogenic factors released from (1) ischemic tissues, (2) tissues that are growing rapidly, and (3) tis- sues that have excessively high metabolic rates. Many Angiogenic Factors Are Small Peptides. Four of the best characterized angiogenic factors are vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and angiogenin, each of which has been isolated from tumors or other tissues that are rapidly growing or have an inadequate blood supply. Angiogenesis begins with new vessels sprouting from small venules or, occasionally, capillaries. The basement membrane of the endothelial cells is dis- solved, followed by the rapid production of new endo- thelial cells that stream out of the vessel in extended cords directed toward the source of the angiogenic factor. The cells continue to divide and eventually fold over into a tube. The tube then connects with another tube budding from another donor vessel and forms a  Local and Humoral Control of Tissue Blood Flow 119 capillary loop through which blood begins to flow. If the flow is sufficient, smooth muscle cells eventually invade the wall so that some of these vessels grow to be small arterioles and/or perhaps even larger vessels. Collateral Blood Vessels Develop When an Artery or a Vein Is Blocked. New vascular channels usually develop around a blocked artery or vein and allow the affected tissue to be at least partially resupplied with blood. An important example is the development of collateral blood vessels after thrombosis of one of the coronary arteries. Many people older than 60 years have blockage of at least one of the smaller coronary vessels, yet most people do not know that it has happened because collateral blood vessels have gradually developed as the vessels have begun to close, thereby providing blood flow to the tissue sufficient to prevent myocardial damage. It is in instances in which thrombosis occurs too rapidly for the development of collateral blood vessels that serious heart attacks occur. Vascular Remodeling in Response to Chronic Changes in Blood Flow or Blood Pressure The structure of large blood vessels also adapts to long-term changes in blood pressure and blood flow. In chronic hypertension, for example, the large and small arteries and arterioles remodel to accommodate the increased stress of higher blood pressure. In small blood vessels that constrict in response to increased blood pressure, the vascular smooth muscle cells and endothelial cells gradually (over a period of several days or weeks) rearrange themselves around the smaller lumen diameter; this process is called inward eutrophic remodeling and results in no change in the total cross- sectional area of the vascular wall (Figure 17–1). In larger arteries that do not constrict in response to the increased pressure, the vessel wall is exposed to increased wall tension that stimulates a hypertro- phic remodeling response and an increase in the cross- sectional area of the vascular wall. The hypertrophic response increases the size of vascular smooth muscle cells and stimulates the formation of additional extracel- lular matrix that reinforces the strength of the vascular wall to withstand the higher pressures. Vascular remodeling also occurs when a blood ves- sel is exposed chronically to increased or decreased blood flow. After creation of a fistula connecting a large artery and a large vein, the blood flow rate increases in the artery (due to a reduction in downstream vascular 120 UNIT IV The Circulation Inward eutrophic remodeling Hypertrophic remodeling Outward remodeling Outward hypertrophic remodeling Figure 17–1 Vascular remodeling in response to a chronic increase in blood pressure or blood flow. resistance) and eventually leads to increased diameter of the artery (outward remodeling), while the thickness of the vessel may remain unchanged. However, wall thick- ness, lumen diameter, and cross-sectional area of the vascular wall on the venous side of the fistula increase in response to increases in pressure and blood flow (out- ward hypertrophic remodeling). These patterns of remodeling suggest that long- term increases in vascular wall tension cause hyper- trophy and increased wall thickness in large blood vessels, while increased blood flow rate causes outward remodeling and increased luminal diameter in order to accommodate the increased blood flow. Chronic reduc- tions in blood pressure and blood flow have the oppo- site effects. Thus, vascular remodeling is an important adaptive response of the blood vessels to tissue growth and development, as well as to physiological and patho- logical changes in blood pressure and tissue blood flow.  Local and Humoral Control of Tissue Blood Flow 121 HUMORAL CONTROL OF THE CIRCULATION (p. 212) Several hormones are secreted into the circulation and transported in the blood throughout the entire body. Some of these hormones have important effects on cir- culatory function. Norepinephrine and epinephrine, released by the ad- renal medulla, act as vasoconstrictors in many tis- sues by stimulating α-adrenergic receptors; however, epinephrine is much less potent as a vasoconstrictor and may even cause mild vasodilation through stim- ulation of β-adrenergic receptors in some tissues, such as skeletal muscle. Angiotensin II is a powerful vasoconstrictor that is usually formed in response to volume depletion or decreased blood pressure. Vasopressin, also called antidiuretic hormone, is one of the most powerful vasoconstrictors in the body. It is formed in the hypothalamus and transported to the posterior pituitary, where it is released in re- sponse to decreased blood volume, as occurs with hemorrhage, or increased plasma osmolarity, as oc- curs with dehydration. Prostaglandins are formed in almost every tissue in the body. These substances have important intracel- lular effects, but some of them are released in the cir- culation, especially prostacyclin and prostaglandins of the E series, which are vasodilators. Some pros- taglandins, such as thromboxane A2 and prostaglan- dins of the F series, are vasoconstrictors. Bradykinin, which is formed in the blood and in tis- sue fluids, is a powerful vasodilator that also increas- es capillary permeability. For this reason, increased levels of bradykinin may cause marked edema and increased blood flow in some tissues. Histamine, a powerful vasodilator, is released into the tissues when they become damaged or inflamed. Most of the histamine is released from mast cells in damaged tissues or from basophils in the blood. Histamine, like bradykinin, increases capillary permeability and causes tissue edema, as well as greater blood flow. Ions and Other Chemical Factors Can Also Alter Local Blood Flow. Many ions and chemical factors can either dilate or constrict local blood vessels. Their specific effects are as follows: Increased calcium ion concentration causes vaso- constriction. Increased potassium ion concentration causes vaso- dilation. 122 UNIT IV The Circulation Increased magnesium ion concentration causes vasodilation. Increased sodium ion concentration causes vasodi- lation. Increased osmolarity of the blood, caused by in- creased quantities of glucose or other nonvasoactive substances, causes vasodilation. Increased hydrogen ion concentration (decreased pH) causes vasodilation. Increased carbon dioxide concentration causes va- sodilation in most tissues and marked vasodilation in the brain.  CHAPTER 18 Nervous Regulation of the Circulation and Rapid Control of Arterial Pressure Except for certain tissues, such as skin, blood flow regu- lation is mainly a function of local control mechanisms. Nervous control mainly affects more global functions, such as redistributing blood flow to various parts of the body, increasing the pumping activity of the heart, and providing rapid control of arterial pressure. This con- trol of the circulation by the nervous system is exerted almost entirely through the autonomic nervous system. AUTONOMIC NERVOUS SYSTEM (p. 215) The two components of the autonomic nervous sys- tem are the sympathetic nervous system, which is most important for controlling the circulation, and the para- sympathetic nervous system, which contributes to the regulation of heart function. Sympathetic Stimulation Causes Vasoconstriction and Increases Heart Rate and Cardiac Contractility. Sympathetic vasomotor fibers exit the spinal cord through all of the thoracic and the first one or two lumbar spinal nerves. They pass into the sympathetic chain and then go via two routes to the circulation: (1) through specific sympathetic nerves that mainly innervate the vasculature of the internal viscera and heart and (2) through spinal nerves that mainly innervate the vasculature of the peripheral areas. Almost all of the blood vessels, except the capillaries, are innervated by sympathetic nerve fibers. Sympathetic stimulation of the small arteries and arterioles increases the vascular resistance and decreases the rate of blood flow through the tissues. Innervation of large vessels, especially the veins, makes it possible for sympathetic stimulation to decrease the volume of the vessels. Sympathetic fibers also go to the heart and stimu- late its activity, increasing both the rate and strength of pumping. Parasympathetic Stimulation Decreases Heart Rate and Cardiac Contractility. Although the parasympathetic system plays an important role in controlling many other autonomic functions of the body, its main role in controlling the circulation is to decrease the heart rate markedly and slightly decrease heart muscle contractility. 123 124 UNIT IV The Circulation Control of the Sympathetic Vasoconstrictor System by the Central Nervous System (p. 216) The sympathetic nerves carry large numbers of vasocon- strictor nerve fibers and only a few vasodilator fibers. The vasoconstrictor fibers are distributed to almost all segments of the circulation. Their distribution is greater in some tissues, such as skin, gut, and spleen. Vasomotor Centers of the Brain Control the Sympathetic Vasoconstrictor System. Located bilaterally in the reticular substance of the medulla and the lower third of the pons is an area called the vasomotor center, which transmits parasympathetic impulses through the vagus nerves to the heart and sympathetic impulses through the cord and peripheral sympathetic nerves to almost all blood vessels of the body (Figure 18–1). Although the organization of the vasomotor centers is not completely understood, certain areas appear to be especially important. A vasoconstrictor area is located bilaterally in the anterolateral portions of the upper medulla. The neurons originating in this area secrete norepineph- rine, and their fibers are distributed throughout the cord, where they excite vasoconstrictor neurons of the sympathetic nervous system. A vasodilator area is located bilaterally in the antero- lateral portions of the lower half of the medulla. The fibers from these neurons inhibit vasoconstrictor ac- tivity of the C-1 area, causing vasodilation. A sensory area is located bilaterally in the nucleus tractus solitarius (NTS) in the posterolateral por- tions of the medulla and lower pons. The neurons of this area receive sensory nerve signals mainly through the vagus and glossopharyngeal nerves, and the output signals from this sensory area help control the activities of vasoconstrictor and vasodi- lator areas, providing “reflex” control of many cir- culatory functions. An example is the baroreceptor reflex for controlling arterial pressure (discussed later). Continuous Sympathetic Vasoconstrictor Tone Causes Partial Constriction of Most Blood Vessels. Normally, the vasoconstrictor area of the vasomotor center transmits signals continuously to the sympathetic vasoconstrictor nerve fibers over the entire body, causing slow firing of these fibers at a rate of about one impulse per second. This sympathetic vasoconstrictor tone maintains a partial state of contraction of the blood vessels. When this tone is blocked (e.g., by spinal anesthesia), the blood  Nervous Regulation of the Circulation and Rapid Control 125 of Arterial Pressure Vasoconstrictor Cardioinhibitor Vasodilator Vasomotor center Blood vessels Vagus Sympathetic chain Heart Blood vessels Figure 18–1 Anatomy of sympathetic nervous control of the circula- tion. Also shown by the dashed red line a vagus nerve that carries para- sympathetic signals to the heart. 126 UNIT IV The Circulation vessels throughout the body dilate, and arterial pressure may fall to as low as 50 mm Hg. The Vasomotor System Is Influenced by Higher Nervous Centers. Large numbers of areas throughout the reticular substance of the pons, mesencephalon, and diencephalon can either excite or inhibit the vasomotor center. The hypothalamus plays a special role in control- ling the vasoconstrictor system and can exert powerful excitatory or inhibitory effects on the vasomotor center. Many parts of the cerebral cortex can also excite or inhibit the vasomotor center; for example, stimulation of the motor cortex excites the vasomotor center. Many areas of the brain can have profound effects on cardio- vascular function. Norepinephrine Is the Sympathetic Vasoconstriction Neurotransmitter. Norepinephrine, which is secreted at the endings of the vasoconstrictor nerves, acts directly on α-adrenergic receptors of vascular smooth muscle to cause vasoconstriction. The Adrenal Medulla Releases Norepinephrine and Epinephrine During Sympathetic Stimulation. Sympathetic impulses are usually transmitted to the adrenal medullae at the same time they are transmitted to the blood vessels, stimulating release of epinephrine and norepinephrine into the circulating blood. These two hormones are carried in the bloodstream to all parts of the body, where they act directly on the blood vessels to cause vasoconstriction through stimulation of α-adrenergic receptors. Epinephrine, however, also has potent β- adrenergic effects, which cause vasodilation in certain tissues, such as skeletal muscle. ROLE OF THE NERVOUS SYSTEM IN RAPID CONTROL OF ARTERIAL PRESSURE (p. 218) One of the most important functions of the sympathetic nervous system is to provide rapid control of arterial pressure by causing vasoconstriction and stimulation of the heart. At the same time that sympathetic activity is increased, there is often reciprocal inhibition of para- sympathetic vagal signals to the heart that also contrib- ute to a higher heart rate. As a consequence, three major changes take place to increase arterial pressure through stimulation of the autonomic nervous system: Most arterioles throughout the body are constricted, causing increased total peripheral vascular resis- tance and raising the blood pressure. The veins and larger vessels of the circulation are constricted, displacing blood from the peripheral vessels  Nervous Regulation of the Circulation and Rapid Control 127 of Arterial Pressure toward the heart and causing the heart to pump with greater force, which also helps raise the arterial pressure. The heart is directly stimulated by the autonomic nervous system, further enhancing cardiac pumping. Much of this is caused by an increased heart rate, sometimes to as much as three times normal. In ad- dition, sympathetic stimulation directly increases the contractile force of the heart muscle, thus in- creasing its ability to pump larger volumes of blood. An important characteristic of nervous control is that it is rapid, beginning within seconds. Conversely, sudden inhibition of nervous stimulation can decrease arterial pressure within seconds. The Autonomic Nervous System Contributes to Increased Arterial Pressure During Muscle Exercise. During heavy exercise, the muscles require greatly increased blood flow. Part of this increase results from local vasodilation, but additional increase in flow results from simultaneous elevation of arterial pressure during exercise. During heavy exercise, arterial pressure may rise as much as 30 percent to 40 percent. The rise in arterial pressure during exercise is believed to result mainly from the following effect: At the same time the motor areas of the nervous system become activated to cause exercise, most of the reticular activating system in the brain is also activated, which greatly increases stimulation of the vasoconstrictor and cardioaccelerator areas of the vasomotor center. These effects increase the arterial pressure instantly to keep pace with increased muscle activity. Vasodilation of the muscle, however, is maintained despite increased sym- pathetic activity because of the overriding effect of local control mechanisms in the muscle. The Autonomic Nervous System Increases Arterial Pressure During the “Alarm Reaction.” During extreme fright, the arterial pressure often rises to as high as 200 mm Hg within a few seconds. This alarm reaction provides the necessary increase in arterial pressure that can immediately supply blood to any of the muscles of the body that might need to respond instantly to flee from the perceived danger. Reflex Mechanisms Help Maintain Normal Arterial Pressure (p. 219) Aside from special circumstances such as stress and exercise, the autonomic nervous system operates to maintain the arterial pressure at or near its normal level through negative feedback reflex mechanisms. 128 UNIT IV The Circulation The Arterial Baroreceptor Reflex Control System. The arterial baroreceptor reflex is initiated by stretch receptors, called baroreceptors, that are located in the walls of large systemic arteries, particularly in the walls of the carotid sinus and the aortic arch. Signals from the carotid sinus receptors are transmitted through Herring’s nerve to the glossopharyngeal nerve and then to the nucleus tractus solitarius in the medullary area of the brain stem. Signals from the aortic arch are transmitted through the vagus nerves to the same area of the medulla. The baroreceptors control arterial pressure as follows: Increased pressure in blood vessels containing baro- receptors causes increased impulse firing. Baroreceptor signals enter the nucleus tractus soli- tarius, inhibit the vasoconstrictor center of the medulla, and excite the vagal center. The net effects are inhibition of sympathetic ac- tivity and stimulation of parasympathetic activity, which cause (1) vasodilation of veins and arterioles and (2) decreased heart rate and strength of heart contraction. Vasodilation of veins and arterioles and decreased heart rate and strength of heart contraction cause the arterial pressure to decrease because of a decline in peripheral vascular resistance and cardiac output. The Baroreceptors Maintain Arterial Pressure at a Relatively Constant Level During Changes in Body Posture and Other Daily Activities. When a person stands up after lying down, the arterial pressure in the head and upper parts of the body tends to fall. The reduction in pressure decreases the signals sent from the baroreceptors to the vasomotor centers, eliciting a strong sympathetic discharge that minimizes the reduction in arterial pressure. In the absence of functional baroreceptors, marked reductions in arterial pressure can decrease cerebral blood flow to such a low level that consciousness is lost. Daily activities that tend to increase blood pressure, such as eating, excitement, defecation, and so forth, can cause extreme increases in blood pressure in the absence of normal baroreceptor reflexes. A primary purpose of the arterial baroreceptor system is to reduce the daily variation in arterial pressure to about one half to one third of the pressure that would occur if the baro- receptor system were not present. Are the Baroreceptors Important in Long-Term Regulation of Arterial Pressure? The arterial baroreceptors provide powerful moment-to-moment control of arterial pressure, but their importance in long-term blood pressure  Nervous Regulation of the Circulation and Rapid Control 129 of Arterial Pressure regulation is still uncertain because they tend to reset within 1 to 2 days to the blood pressure to which they are exposed. If, for example, the arterial pressure rises from the normal value of 100 mm Hg to a high value of 160 mm Hg, very high rates of baroreceptor impulses are at first transmitted. However, the rate of baroreceptor firing returns to nearly normal over a period of 1 to 2 days, even when the mean arterial pressure remains at 160 mm Hg. This “resetting” of the baroreceptors may attenu- ate their potency for correcting disturbances that tend to change arterial pressure for longer than a few days. Experimental studies, however, suggest that the baro- receptors do not completely reset and therefore may contribute to long-term blood pressure regulation, especially by influencing sympathetic nerve activity of the kidneys (see Chapters 19 and 30). Cardiopulmonary Reflexes Help Regulate Arterial Pres- sure. Located in the walls of both atria and pulmonary arteries are stretch receptors called cardiopulmonary receptors or low-pressure receptors that are similar to the baroreceptor stretch receptors of the systemic arteries. These low-pressure receptors play an important role in minimizing arterial pressure changes in response to blood volume changes. Although the low-pressure receptors do not directly detect systemic arterial pressure, they detect changes in pressure in the heart and pulmonary circulation caused by changes in volume, and they elicit reflexes that parallel the baroreceptor reflexes to make the total reflex system more potent for controlling arterial pressure. Increased stretch of the atria causes reflex decreases in sympathetic activity to the kidney, which causes vasodilation of the afferent arterioles and increases in the glomerular filtration rate, as well as decreases in tubular reabsorption of sodium. These changes cause the kidney to excrete more sodium and water, thereby ridding the body of excess volume. Control of Arterial Pressure by Carotid and Aortic Chemoreceptors, Which Are Sensitive to a Lack of Oxygen, an Excess of Carbon Dioxide Excess, or an Excess of Hydrogen Ions. Closely associated with the baroreceptor control system is a chemoreceptor reflex that operates in much the same way as the baroreceptor reflex, except that chemoreceptors, instead of stretch receptors, initiate the response. Chemoreceptors are located in two carotid bodies, one of which lies in the bifurcation of each common carotid artery, and in several aortic bodies adjacent to the 130 UNIT IV The Circulation aorta. Whenever the arterial pressure falls below a criti- cal level, the chemoreceptors become stimulated because of diminished blood flow to the bodies and the resulting diminished availability of oxygen and excess buildup of carbon dioxide and hydrogen ions that are not removed by the slow blood flow. Signals transmitted from the che- moreceptors into the vasomotor center excite the vaso- motor center, which in turn elevates the arterial pressure. The Central Nervous System Ischemic Response Raises Arterial Pressure in Response to Diminished Blood Flow in the Brain’s Vasomotor Center (p. 223) When blood flow to the vasomotor center in the lower brain stem becomes sufficiently decreased to cause cere- bral ischemia (i.e., nutritional deficiency), the neurons of the vasomotor center become strongly excited. When this occurs, the systemic arterial pressure often rises to a level as high as the heart can pump, which may be due to the effect of low blood flow, which causes buildup of carbon dioxide in the vasomotor centers. Increased carbon dioxide concentration is a potent agent for stim- ulating the sympathetic nervous control areas of the medulla of the brain. Other factors, such as buildup of lactic acid, may also contribute to marked stimulation of the vasomotor center and increased arterial pressure. This arterial pressure elevation in response to cerebral ischemia is known as the central nervous system ischemic response. This response is an emergency control sys- tem that acts rapidly and powerfully to prevent further decline in arterial pressure when blood flow to the brain becomes dangerously decreased; it is sometimes called the “last ditch” mechanism for blood pressure control. The Cushing Reaction Is a Central Nervous System Ischemic Response That Results From Increased Pressure in the Cranial Vault. When cerebrospinal fluid pressure rises to equal the arterial pressure, a central nervous system ischemic response is initiated that can raise the arterial pressure to as high as 250 mm Hg. This response helps protect the vital centers of the brain from loss of nutrition, which could occur if pressure in the cranial vault exceeds the normal arterial pressure and compresses blood vessels supplying the brain. If cerebral ischemia becomes so severe that a maxi- mal increase in arterial pressure still cannot relieve the ischemia, the neuronal cells begin to suffer metaboli- cally, and within 3 to 10 minutes they become inactive, which causes the arterial pressure to decrease.  CHAPTER 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension: The Integrated System for Arterial Pressure Regulation RENAL–BODY FLUID SYSTEM FOR ARTERIAL PRESSURE CONTROL (p. 227) Short-term control of arterial pressure by the sympa- thetic nervous system, which was discussed in Chapter 18, occurs mainly through changes in vascular resis- tance and capacitance and cardiac pumping ability. However, the body also has powerful mechanisms for long-term blood pressure regulation that are closely linked to control of body fluid volume by the kidneys, a mechanism known as the renal–body fluid feedback system. When arterial pressure rises too high, the kid- neys excrete increased quantities of sodium and water because of pressure natriuresis and pressure diuresis, respectively. As a result of the increased renal excretion, the extracellular fluid volume and blood volume both decrease until blood pressure returns to normal and the kidneys excrete normal amounts of sodium and water. Conversely, when the arterial pressure falls too low, renal sodium levels and water excretion are reduced; over a period of hours to days, if the person drinks enough water and eats enough salt to increase the blood volume, the arterial pressure returns to its previ- ous level. This mechanism for blood pressure control is slow to act, sometimes requiring several days, a week, or longer to reach equilibrium; therefore, it is not of major importance in the acute control of arterial pressure. However, it is by far the most potent of all long-term arterial pressure controllers. Renal Output of Salt and Water Is Balanced With the Intake of Salt and Water Under Steady-State Conditions. Figure 19–1 shows the effect of various arterial pressures on urine volume output by an isolated kidney, demonstrating marked increases in the output of volume (pressure diuresis) and sodium (pressure natriuresis) as arterial pressure rises. As long as the arterial pressure is above the normal equilibrium point, renal output exceeds intake of salt and water, resulting in a progressive decline in extracellular fluid volume. Conversely, if blood pressure falls below the equilibrium point, renal output of water and salt is 131 132 UNIT IV The Circulation Intake or output (× normal) Figure 19–1 Arterial pressure regulation can be analyzed by equating the renal output curve with the salt and water intake curve. The equi- librium point describes the level at which the arterial pressure is regu- lated. Curve A (red line) shows the normal renal output curve. Curve B (pink line) shows the renal output curve in hypertension. lower than intake, resulting in a progressive increase in extracellular fluid volume. The only point on the curve at which a balance between renal output and intake of salt and water can occur is at the normal arterial pressure (the equilibrium point). The Renal–Body Fluid Feedback Mechanism Demon- strates a Near “Infinite Feedback Gain” in Long-Term Blood Pressure Control. To illustrate why the renal–body fluid feedback mechanism demonstrates nearly “infinite gain” in controlling blood pressure, let us assume that the arterial pressure rises to 150 mm Hg. At this level, renal output of water and salt is about three times more than the intake. The body loses fluid, blood volume decreases, and arterial pressure decreases. Furthermore, this loss of fluid does not cease until the arterial pressure decreases to the equilibrium point (see Figure 19–1, curve A). Conversely, if blood pressure falls below the equilibrium point, the kidneys decrease salt and water excretion to a level below intake, causing accumulation of fluid and blood volume until arterial pressure returns to the equilibrium point. Because there is little or no remaining error in arterial pressure after full correction, this feedback system has nearly infinite gain. Two Primary Determinants of the Long-Term Arterial Pressure. As shown in Figure 19–1, one can see that two factors determine long-term arterial pressure: (1) the renal output curve for salt and water and (2) the level of salt and water intake. As long as these two factors  Role of the Kidneys in Long-Term Control of Arterial Pressure 133 and in Hypertension remain constant, the arterial pressure also remains exactly at the normal level of 100 mm Hg. For arterial pressure to deviate from the normal level for long periods, one of these two factors must be altered. In curve B of Figure 19–1, an abnormality of the kid- ney has caused the renal output curve to shift 50 mm Hg toward higher blood pressure. This shift results in a new equilibrium point, and arterial pressure follows to this new pressure level within a few days. Although greater salt and water intake can theoretically elevate arterial pressure (discussed later), the body has multiple neuro- humoral mechanisms that protect against large increases in arterial pressure when salt and water intake is elevated. This protection against large increases in arterial pres- sure is accomplished mainly by decreasing the formation of angiotensin II and aldosterone, which increases the ability of the kidneys to excrete salt and water and results in a steep renal output curve. Therefore, the chronic renal output curve is much steeper than the acute curve shown in Figure 19–1, and in most persons large increases in salt and water output can be accomplished with minimal increases in arterial pressure. Increased Total Peripheral Vascular Resistance Does Not Elevate the Long-Term Arterial Pressure if Fluid Intake or Renal Function Does Not Change. When total peripheral vascular resistance is acutely increased, arterial pressure increases almost immediately. However, if vascular resistance of the