Local and Humoral Control of Tissue Blood Flow PDF

CHAPTER 17 Local and Humoral Control of Tissue UNIT IV Blood Flow...

CHAPTER 17 Local and Humoral Control of Tissue UNIT IV Blood Flow metabolic activity of the muscles is low, as is the blood LOCAL CONTROL OF BLOOD FLOW IN flow—only 4 ml/min/100 g. Yet, during heavy exercise, RESPONSE TO TISSUE NEEDS muscle metabolic activity can increase more than 60-fold A fundamental principle of circulatory function is that and the blood flow as much as 20-fold, increasing to as most tissues have the ability to control their own local high as 16,000 ml/min in the body’s total muscle vascular blood flow in proportion to their specific metabolic bed (or 80 ml/min/100 g of muscle).␣ needs. Some of the specific needs of the tissues for blood flow include the following: Importance of Blood Flow Control by the Local 1. Delivery of oxygen to the tissues Tissues. The following question might be asked: Why not 2. Delivery of other nutrients such as glucose, amino continuously provide a very large blood flow through eve- acids, and fatty acids ry tissue of the body that would always be enough to sup- 3. Removal of carbon dioxide from the tissues ply the tissue’s needs, regardless of whether the activity of 4. Removal of hydrogen ions from the tissues the tissue is small or large? The answer is equally simple; 5. Maintenance of proper concentrations of ions in such a mechanism would require many times more blood the tissues flow than the heart can pump. 6. Transport of various hormones and other substanc- Experiments have shown that the blood flow to each es to the different tissue. tissue usually is regulated at the minimal level that will Certain organs have special requirements. For example, supply the tissue’s requirements—no more, no less. For blood flow to the skin determines heat loss from the body example, in tissues for which the most important require- and, in this way, helps control body temperature. Also, deliv- ment is delivery of oxygen, the blood flow is always con- ery of adequate quantities of blood plasma to the kidneys trolled at a level only slightly more than that required to allows the kidneys to filter and excrete the waste products of maintain full tissue oxygenation but no more than this. the body and to regulate body fluid volumes and electrolytes. By controlling local blood flow in such an exact way, We shall see that these factors exert extreme degrees the tissues almost never experience oxygen nutritional of local blood flow control and that different tissues place deficiency, and the workload on the heart is kept at a different levels of importance on these factors in control- minimum.␣ ling blood flow. MECHANISMS OF BLOOD FLOW Variations in Blood Flow in Different Tissues and CONTROL Organs. Note the very large blood flows listed in Table 17-1 for some organs—for example, several hundred mil- Local blood flow control can be divided into two phases, liliters per minute per 100 grams of thyroid or adrenal acute control and long-term control. Acute control is gland tissue and a total blood flow of 1350 ml/min in the achieved by rapid changes in local vasodilation or vaso- liver, which is 95 ml/min/100 g of liver tissue. constriction of the arterioles, metarterioles, and precap- Also note the extremely large blood flow through the illary sphincters that occur within seconds to minutes kidneys—1100 ml/min. This extreme amount of flow to provide rapid maintenance of appropriate local tissue is required for the kidneys to perform their function of blood flow. Long-term control means slow, controlled cleansing the blood of waste products and regulating changes in flow over a period of days, weeks, or even composition of the body fluids precisely. months. In general, these long-term changes provide even Conversely, most surprising is the low blood flow to all better control of the flow in proportion to the needs of the inactive muscles of the body—only a total of 750 ml/ the tissues. These changes come about as a result of an min—even though the muscles constitute between 30% increase or decrease in the physical sizes and numbers of and 40% of the total body mass. In the resting state, the blood vessels supplying the tissues. 205 UNIT IV The Circulation Table 17-1 Blood Flow to Different Organs and Tissues 3 Under Basal Conditions Blood flow (× normal) Percentage ml/min/100 of Cardiac g of Tissue Output ml/min Weight 2 Brain 14 700 50 Heart 4 200 70 Bronchi 2 100 25 1 Kidneys 22 1100 360 Liver 27 1350 95 Portal (21) (1050) 0 Arterial (6) (300) 100 75 50 25 Muscle (inactive 15 750 4 Arterial oxygen saturation (percent) state) Figure 17-2. Effect of decreasing arterial oxygen saturation on blood Bone 5 250 3 flow through an isolated dog leg. Skin (cool 6 300 3 weather) the tissues decreases, such as during the following: (1) at Thyroid gland 1 50 160 a high altitude at the top of a high mountain; (2) in pneu- monia; (3) in carbon monoxide poisoning (which poisons Adrenal glands 0.5 25 300 the ability of hemoglobin to transport oxygen); or (4) in Other tissues 3.5 175 1.3 cyanide poisoning (which poisons the ability of the tis- Total 100.0 5000 sues to use oxygen), the blood flow through the tissues increases markedly. Figure 17-2 shows that as the arterial oxygen saturation decreases to about 25% of normal, the blood flow through an isolated leg increases about three- 4 fold; that is, the blood flow increases almost enough, but not quite enough, to make up for the decreased amount of oxygen in the blood, thus almost maintaining a relatively constant supply of oxygen to the tissues. Blood flow (× normal) 3 Total cyanide poisoning of oxygen usage by a local tis- sue area can cause local blood flow to increase as much as 2 sevenfold, thus demonstrating the extreme effect of oxy- gen deficiency to increase blood flow. The mechanisms whereby changes in tissue metabolism or oxygen avail- 1 ability alter tissue blood flow are not fully understood, but Normal level two main theories have been proposed, the vasodilator theory and the oxygen demand theory.␣ 0 0 1 2 3 4 5 6 7 8 Rate of metabolism (× normal) Vasodilator Theory for Acute Local Blood Flow Regulation—Possible Special Role of Adenosine. Figure 17-1. Effect of increasing rate of metabolism on tissue blood According to the vasodilator theory, the greater the rate of flow. metabolism or the less the availability of oxygen or some other nutrients to a tissue, the greater the rate of forma- ACUTE CONTROL OF LOCAL BLOOD FLOW tion of vasodilator substances in the tissue cells. The vaso- dilator substances are then believed to diffuse through the Increases in Tissue Metabolism Increase tissues to the precapillary sphincters, metarterioles, and Tissue Blood Flow arterioles to cause dilation. Some of the different vasodi- Figure 17-1 shows the approximate acute effect on blood lator substances that have been suggested are adenosine, flow of increasing the rate of metabolism in a local tis- carbon dioxide, adenosine phosphate compounds, hista- sue, such as in a skeletal muscle. Note that an increase in mine, potassium ions, and hydrogen ions. metabolism up to eight times normal increases the blood Vasodilator substances may be released from the tis- flow acutely about fourfold. sue in response to oxygen deficiency. For example, experi- ments have shown that decreased oxygen availability can Reduced Oxygen Availability Increases Tissue Blood cause adenosine and lactic acid (containing hydrogen ions) Flow. One of the most necessary of the metabolic nu- to be released into the spaces between the tissue cells; trients is oxygen. Whenever the availability of oxygen to these substances then cause intense acute vasodilation 206  Chapter 17 Local and Humoral Control of Tissue Blood Flow and therefore are responsible, or partially responsible, for Metarteriole Precapillary sphincter the local blood flow regulation. Other vasodilator sub- stances, such as carbon dioxide, lactic acid, and potas- sium ions, also tend to increase in the tissues when blood flow is reduced and cell metabolism continues at the same UNIT IV rate, or when cell metabolism is suddenly increased. An increase in the concentration of vasodilator metabolites Tissue cells causes vasodilation of the arterioles, thus increasing the Sidearm capillary tissue blood flow and returning the tissue concentration of the metabolites toward normal. Many physiologists believe that adenosine is an impor- tant local vasodilator for controlling local blood flow. For example, minute quantities of adenosine are released from heart muscle cells when coronary blood flow becomes too Relaxation of O2 delivery arterioles and little, and this release of adenosine causes enough local or Tissue O2 precapillary Tissue metabolism vasodilation in the heart to return coronary blood flow to sphincters normal. Also, whenever the heart becomes more active than normal, the heart’s metabolism increases, causing Tissue increased utilization of oxygen, followed by (1) decreased blood flow oxygen concentration in the heart muscle cells with (2) Figure 17-3. Diagram of a tissue unit area for an explanation of consequent degradation of adenosine triphosphate (ATP), acute local feedback control of blood flow, showing a metarteriole which (3) increases the release of adenosine. It is believed passing through the tissue and a sidearm capillary with its precapillary sphincter for controlling capillary blood flow. that much of this adenosine leaks out of the heart muscle cells to cause coronary vasodilation, providing increased coronary blood flow to supply the increased nutrient the metarteriole are several other smooth muscle fibers. demands of the active heart. When observing such a tissue under a microscope, the Although research evidence is less clear, many physi- precapillary sphincters are normally completely open or ologists also have suggested that the same adenosine completely closed. The number of precapillary sphincters mechanism is an important controller of blood flow in that are open at any given time is roughly proportional to skeletal muscle and many other tissues, as well as in the the requirements of the tissue for nutrition. The precap- heart. However, it has been difficult to prove that suf- illary sphincters and metarterioles open and close cycli- ficient quantities of any single vasodilator substance, cally several times per minute, with the duration of the including adenosine, are formed in the tissues to cause open phases being proportional to the metabolic needs of all the measured increase in blood flow. It is likely that a the tissues for oxygen. The cyclical opening and closing is combination of several different vasodilators released by called vasomotion. the tissues contributes to blood flow regulation.␣ Because smooth muscle requires oxygen to remain contracted, one might assume that the strength of con- Oxygen Demand Theory for Local Blood Flow Control. traction of the sphincters would increase with an increase Although the vasodilator theory is widely accepted, sever- in oxygen concentration. Consequently, when the oxygen al critical facts have made other physiologists favor anoth- concentration in the tissue rises above a certain level, er theory, which can be called the oxygen demand theory the precapillary and metarteriole sphincters presumably or, more accurately, the nutrient demand theory (because would close until the tissue cells consume the excess oxy- other nutrients besides oxygen are involved). Oxygen is gen. However, when the excess oxygen is gone and the one of the metabolic nutrients required to cause vascu- oxygen concentration falls low enough, the sphincters lar muscle contraction, with other nutrients required as open once more to begin the cycle again. well. Therefore, in the absence of adequate oxygen, it is Thus, on the basis of available data, either the vaso- reasonable to believe that the blood vessels would relax dilator substance theory or oxygen demand theory could and therefore dilate. Also, increased utilization of oxygen explain acute local blood flow regulation in response to in the tissues as a result of increased metabolism theo- the metabolic needs of the tissues. It is probably a combi- retically could decrease the availability of oxygen to the nation of the two mechanisms.␣ smooth muscle fibers in the local blood vessels, causing local vasodilation. Possible Role of Other Nutrients Besides Oxygen in A mechanism whereby oxygen availability could oper- Control of Local Blood Flow. Under special conditions, ate is shown in Figure 17-3. This figure shows a tissue it has been shown that the lack of glucose in the perfusing vascular unit, consisting of a metarteriole with a single blood can cause local tissue vasodilation. It also is pos- sidearm capillary and its surrounding tissue. At the ori- sible that this same effect occurs when other nutrients, gin of the capillary is a precapillary sphincter and around such as amino acids or fatty acids, are deficient, although 207 UNIT IV The Circulation 6 2.5 Acute 5 Reactive Blood flow (× normal) 4 hyperemia 2.0 Muscle blood flow 3 (× normal) 1.5 2 Artery 1 occlusion 1.0 Long term 0 0 1 2 3 4 5 0.5 0 7 0 50 100 150 200 250 Active 6 hyperemia Mean arterial pressure (mm Hg) 5 Figure 17-5. Effect of different levels of arterial pressure on blood Muscle 4 flow through a muscle. The solid red curve shows the effect if the blood flow arterial pressure is raised over a period of a few minutes. The dashed 3 Muscle (× normal) green curve shows the effect if the arterial pressure is raised slowly stimulation 2 over many weeks. 1 0 Reactive hyperemia is another manifestation of the 0 1 2 3 4 5 local metabolic blood flow regulation mechanism—that Time (minutes) is, lack of flow sets into motion all the factors that cause Figure 17-4. Reactive hyperemia in a tissue after temporary occlu- vasodilation. After short periods of vascular occlusion, sion of the artery supplying blood flow and active hyperemia follow- the extra blood flow during the reactive hyperemia phase ing increased tissue metabolic activity. lasts long enough to repay almost exactly the tissue oxy- gen deficit that has accrued during the period of occlu- this is still uncertain. In addition, vasodilation occurs in sion. This mechanism emphasizes the close connection the vitamin deficiency disease beriberi, in which the pa- between local blood flow regulation and delivery of oxy- tient has deficiencies of the vitamin B substances thia- gen and other nutrients to the tissues.␣ mine, niacin, and riboflavin. In this disease, the peripheral vascular blood flow almost everywhere in the body often Active Hyperemia Occurs When Tissue Metabolic increases twofold to threefold. Because all these vitamins Rate Increases. When a tissue becomes highly active, are necessary for oxygen-induced phosphorylation, which such as an exercising muscle, a gastrointestinal gland is required to produce ATP in the tissue cells, one can un- during a hypersecretory period, or even the brain during derstand how deficiency of these vitamins might lead to increased mental activity, the rate of blood flow through diminished smooth muscle contractile ability and there- the tissue increases (see Figure 17-4). The increase in lo- fore local vasodilation as well.␣ cal metabolism causes the cells to devour tissue fluid nu- trients rapidly and release large quantities of vasodilator Special Examples of Acute Metabolic substances. The result is dilation of local blood vessels and Control of Local Blood Flow increased local blood flow. In this way, the active tissue The mechanisms we have described thus far for local receives the additional nutrients required to sustain its blood flow control are called metabolic mechanisms new level of function. As noted earlier, active hyperemia because they all function in response to the metabolic in skeletal muscle can increase local muscle blood flow as needs of the tissues. Two additional special examples of much as 20-fold during intense exercise.␣ metabolic control of local blood flow are reactive hyper- emia and active hyperemia (Figure 17-4). Autoregulation of Blood Flow During Changes in Arterial Pressure—Metabolic Reactive Hyperemia Occurs After Tissue Blood Sup- and Myogenic Mechanisms ply Is Blocked for a Short Time. When the blood sup- In any tissue of the body, a rapid increase in arterial pres- ply to a tissue is blocked for a few seconds to as long as 1 sure causes an immediate rise in blood flow. However, hour or more and then is unblocked, blood flow through within less than 1 minute, the blood flow in most tissues the tissue usually increases immediately to four to sev- returns almost to the normal level, even though the arte- en times normal. This increased flow will continue for rial pressure is kept elevated. This return of flow toward a few seconds if the block has lasted only a few seconds normal is called autoregulation. After autoregulation but sometimes continues for as long as many hours if the has occurred, the local blood flow in most tissues will be blood flow has been stopped for an hour or more. This related to arterial pressure approximately in accord with phenomenon is called reactive hyperemia. the solid acute curve in Figure 17-5. Note that between 208  Chapter 17 Local and Humoral Control of Tissue Blood Flow arterial pressures of about 70 and 175 mm Hg, the blood flow increases only 20% to 30%, even though the arte- Special Mechanisms for Acute Blood Flow rial pressure increases 150%. In some tissues, such as the Control in Specific Tissues brain and heart, this autoregulation is even more precise. Although the general mechanisms for local blood flow For almost a century, two views have been proposed control discussed thus far are present in almost all tissues UNIT IV to explain this acute autoregulation mechanism. They of the body, distinctly different mechanisms operate in a have been called the metabolic theory and the myogenic few special areas. All mechanisms are discussed through- theory. out this text in relation to specific organs, but two notable The metabolic theory can be understood easily by mechanisms are as follows: applying the basic principles of local blood flow regula- 1. In the kidneys, blood flow control is significantly tion discussed in previous sections. Thus, when the arte- vested in a mechanism called tubuloglomerular rial pressure becomes too great, the excess flow provides feedback, in which the composition of the fluid in too much oxygen and too many other nutrients to the the early distal tubule is detected by an epithelial tissues and washes out the vasodilators released by the structure of the distal tubule, called the macula den- tissues. These nutrients (especially oxygen) and decreased sa. This structure is located where the distal tubule tissue levels of vasodilators then cause the blood vessels lies adjacent to the afferent and efferent arterioles at to constrict and return flow to nearly normal, despite the the nephron juxtaglomerular apparatus. When too increased pressure. much fluid filters from the blood through the glo- The myogenic theory, however, suggests that another merulus into the tubular system, feedback signals mechanism not related to tissue metabolism explains the from the macula densa cause constriction of the af- phenomenon of autoregulation. This theory is based on ferent arterioles, thereby reducing renal blood flow the observation that a sudden stretch of small blood ves- and glomerular filtration rate back to nearly nor- sels causes the smooth muscle of the vessel wall to con- mal. The details of this mechanism are discussed in tract. Therefore, it has been proposed that when high Chapter 27. arterial pressure stretches the vessel, reactive vascular 2. In the brain, in addition to control of blood flow constriction results, which reduces blood flow nearly back by tissue oxygen concentration, the concentra- to normal. Conversely, at low pressures, the degree of tions of carbon dioxide and hydrogen ions play stretch of the vessel is less, so the smooth muscle relaxes, prominent roles. An increase of either or both of reducing vascular resistance and helping to return flow these substances dilates the cerebral vessels and toward normal. allows rapid washout of the excess carbon diox- The myogenic response is inherent to vascular ide or hydrogen ions from the brain tissues. This smooth muscle and can occur in the absence of neu- mechanism is important because the level of ex- ral or hormonal influences. It is most pronounced in citability of the brain is highly dependent on exact arterioles but can also be observed in arteries, venules, control of both carbon dioxide concentration and veins, and even lymphatic vessels. Myogenic contraction hydrogen ion concentration. This special mecha- is initiated by stretch-induced vascular depolarization, nism for cerebral blood flow control is presented which then rapidly increases calcium ion entry from the in Chapter 62. extracellular fluid into the cells, causing them to con- 3. In the skin, blood flow control is closely linked to tract. Changes in vascular pressure may also open or body temperature regulation. Cutaneous and sub- close other ion channels that influence vascular contrac- cutaneous flow regulates heat loss from the body tion. The precise mechanisms whereby changes in pres- by metering the flow of heat from the core to the sure cause opening or closing of vascular ion channels surface of the body, where heat is lost to the en- are still uncertain but likely involve mechanical effects vironment. Skin blood flow is controlled largely of pressure on extracellular proteins that are tethered to by the central nervous system through the sym- cytoskeleton elements of the vascular wall or to the ion pathetic nerves, as discussed in Chapter 74. Al- channels themselves. though skin blood flow is only about 3 ml/min/100 The myogenic mechanism appears to be important g of tissue in cool weather, large changes from in preventing excessive stretching of blood vessels when that value can occur as needed. When humans are blood pressure is increased. However, the role of the exposed to body heating, skin blood flow may in- myogenic mechanism in blood flow regulation is unclear crease greatly, to as high as 7 to 8 L/min for the because this pressure-sensing mechanism cannot detect entire body. When body temperature is reduced, changes in blood flow in the tissue directly. Metabolic skin blood flow decreases, falling to barely above factors appear to override the myogenic mechanism in zero at very low temperatures. Even with severe circumstances in which the metabolic demands of the tis- vasoconstriction, skin blood flow is usually great sues are significantly increased, such as during vigorous enough to meet the basic metabolic demands of muscle exercise, which causes dramatic increases in skel- the skin.␣ etal muscle blood flow.␣ 209 UNIT IV The Circulation larger vessels as a result of increased flow and shear Blood stress in these vessels. The released NO increases the Receptor-dependent Shear stress activation diameters of the larger upstream blood vessels whenever microvascular blood flow increases downstream. With- eNOS out such a response, the effectiveness of local blood flow O2 + L-Arginine NO + L-Citrulline control would be decreased because a significant part of the resistance to blood flow is in the upstream small Endothelial cells arteries. Soluble guanylate cyclase NO synthesis and release from endothelial cells are also stimulated by some vasoconstrictors, such as angio- cGTP cGMP tensin II, which bind to specific receptors on endothelial Relaxation cells. The increased NO release protects against excessive Vascular smooth muscle vasoconstriction. Figure 17-6. Nitric oxide synthase (eNOS) enzyme in endothelial cells When endothelial cells are damaged by chronic hyper- synthesizes nitric oxide (NO) from arginine and oxygen. NO activates tension or atherosclerosis, impaired NO synthesis may soluble guanylate cyclases in vascular smooth muscle cells, resulting contribute to excessive vasoconstriction and worsening in conversion of cyclic guanosine triphosphate (cGTP) to cyclic guano- sine monophosphate (cGMP), which ultimately causes the blood ves- of the hypertension and endothelial damage. If untreated, sels to relax. this may eventually cause vascular injury and damage to vulnerable tissues such as the heart, kidneys, and brain. Even before NO was discovered, clinicians used nitro- Control of Tissue Blood Flow: glycerin, amyl nitrate, and other nitrate derivatives to treat Endothelium-Derived Relaxing or patients who had angina pectoris—that is, severe chest Constricting Factors pain caused by ischemia of the heart muscle. These drugs, The endothelial cells lining the blood vessels synthesize when broken down chemically, release NO and cause several substances that when released, can affect the dilation of blood vessels throughout the body, including degree of relaxation or contraction of the vascular wall. the coronary blood vessels. For many of these endothelium-derived relaxing or con- Other important applications of NO physiology and strictor factors, the physiological roles are just beginning pharmacology are the development and clinical use of to be understood. drugs (e.g., sildenafil) that inhibit cGMP-specific phospho- diesterase-5 (PDE-5), an enzyme that degrades cGMP. By Nitric Oxide Is a Vasodilator Released from Healthy preventing the degradation of cGMP, the PDE-5 inhibitors Endothelial Cells. The most important of the endothelium- effectively prolong the actions of NO to cause vasodilation. derived relaxing factors is nitric oxide (NO), a lipophilic The primary clinical use of the PDE-5 inhibitors is to treat gas that is released from endothelial cells in response to erectile dysfunction. Penile erection is caused by parasym- a variety of chemical and physical stimuli. Endothelial- pathetic nerve impulses through the pelvic nerves to the derived nitric oxide synthase (eNOS) enzymes synthesize penis, where the neurotransmitters acetylcholine and NO NO from arginine and oxygen and by reduction of inor- are released. By preventing the degradation of NO, the ganic nitrate. After diffusing out of the endothelial cell, PDE-5 inhibitors enhance the dilation of the blood vessels NO has a half-life in the blood of only about 6 seconds and in the penis and aid in erection, as discussed in Chapter 81.␣ acts mainly in the local tissues, where it is released. NO activates soluble guanylate cyclases in vascular smooth Endothelin Is a Powerful Vasoconstrictor Released muscle cells (Figure 17-6), resulting in the conversion of From Damaged Endothelium. Endothelial cells also re- cyclic guanosine triphosphate (cGTP) to cyclic guano- lease vasoconstrictor substances. The most important of sine monophosphate (cGMP) and activation of cGMP- these is endothelin, a large, 27–amino acid peptide that dependent protein kinase (PKG), which has several actions requires only minute amounts (nanograms) to cause that cause the blood vessels to relax. powerful vasoconstriction. This substance is present The flow of blood through the arteries and arterioles in the endothelial cells of all or most blood vessels but causes shear stress on the endothelial cells because of vis- greatly increases when the vessels are injured. The usual cous drag of the blood against the vascular walls. This stimulus for release is damage to the endothelium, such as stress contorts the endothelial cells in the direction of that caused by crushing the tissues or injecting a trauma- flow and causes significant increase in NO release. The tizing chemical into the blood vessel. After severe blood NO then relaxes the blood vessels, fortunately, because vessel damage, local release of endothelin and subsequent the local metabolic mechanisms for controlling tis- vasoconstriction helps prevent extensive bleeding from sue blood flow mainly dilate the very small arteries and arteries as large as 5 millimeters in diameter that might arterioles in each tissue. Yet, when blood flow through a have been torn open by crushing injury. microvascular portion of the circulation increases, this Increased endothelin release is also believed to con- action secondarily stimulates the release of NO from tribute to vasoconstriction when the endothelium is 210  Chapter 17 Local and Humoral Control of Tissue Blood Flow damaged by hypertension. Drugs that block endothelin receptors have been used to treat pulmonary hyperten- sion but generally have not been used for lowering blood pressure in patients with systemic arterial hypertension.␣ UNIT IV LONG-TERM BLOOD FLOW REGULATION Thus far, most of the mechanisms for local blood flow regulation that we have discussed act within a few sec- onds to a few minutes after the local tissue conditions have changed. Yet, even after full activation of these acute mechanisms, the blood flow usually is adjusted only about three quarters of the way to the exact additional requirements of the tissues. For example, when the arte- rial pressure suddenly increases from 100 to 150 mm A 50 µm Hg, the blood flow increases almost instantaneously, by about 100%. Then, within 30 seconds to 2 minutes, the flow decreases back to about 10% to 15% above the origi- nal control value. This example illustrates the rapidity of the acute mechanisms for local blood flow regulation, but also demonstrates that the regulation is still incomplete because a 10% to 15% excess blood flow remains in some tissues. However, over a period of hours, days, and weeks, a long-term type of local blood flow regulation develops in addition to the acute control. This long-term regula- tion gives far more complete control of blood flow. In the aforementioned example, if the arterial pressure remains at 150 mm Hg indefinitely, the blood flow through the tissues gradually approaches almost exactly the normal flow level within a few weeks. Figure 17-5 shows (dashed B green curve) the extreme effectiveness of this long-term local blood flow regulation. Note that once the long-term Figure 17-7. A large increase in the number of capillaries (white dots) in a rat anterior tibialis muscle that was stimulated electrically to regulation has had time to occur, long-term changes in contract for short periods each day for 30 days (B), compared with arterial pressure between 50 and 200 mm Hg have little the unstimulated muscle (A). The 30 days of intermittent electrical effect on the rate of local blood flow. stimulation converted the predominantly fast-twitch, glycolytic ante- Long-term regulation of blood flow is especially impor- rior tibialis muscle to a predominantly slow-twitch, oxidative muscle tant when the metabolic demands of a tissue change. Thus, with increased numbers of capillaries and decreased fiber diameter, as shown. (Courtesy Dr. Thomas Adair.) if a tissue becomes chronically overactive and requires increased quantities of oxygen and other nutrients, the arterioles and capillary vessels usually increase both in Thus, actual physical reconstruction of the tissue vas- number and size within a few weeks to match the needs culature occurs to meet the needs of the tissues. This of the tissue, unless the circulatory system has become reconstruction occurs rapidly (within days) in young ani- pathological or too old to respond. mals. It also occurs rapidly in new growth tissue, such as in cancerous tissue, but occurs much more slowly in old, Blood Flow Regulation by Changes in well-established tissues. Therefore, the time required for Tissue Vascularity long-term regulation to take place may be only a few days A key mechanism for long-term local blood flow regula- in the neonate or as long as months in older adults. Fur- tion is to change the amount of vascularity of the tissues. thermore, the final degree of response is much better in For example, if the metabolism in a tissue is increased younger than in older tissues; thus, in the neonate, the for a prolonged period, vascularity increases, a pro- vascularity will adjust to match almost exactly the needs cess generally called angiogenesis; if the metabolism is of the tissue for blood flow, whereas in older tissues, vas- decreased, vascularity decreases. Figure 17-7 shows the cularity frequently lags far behind the needs of the tissues. large increase in the number of capillaries in a rat anterior tibialis muscle that was stimulated electrically to contract Role of Oxygen in Long-Term Regulation. Oxygen is for short periods each day for 30 days, compared with the important not only for acute control of local blood flow unstimulated muscle in the other leg of the animal. but also for long-term control. One example of this is 211 UNIT IV The Circulation increased vascularity in tissues of animals that live at vessel growth in cancerous tumors and therefore prevent- high altitudes, where the atmospheric oxygen is low. In ing the large increases in blood flow needed to sustain the premature babies who are put into oxygen tents for ther- nutrient supply of rapidly growing tumors.␣ apeutic purposes, the excess oxygen causes almost im- mediate cessation of new vascular growth in the retina of Vascularity Determined by Maximum Blood Flow the premature baby’s eyes and even causes degeneration Need, Not by Average Need. An especially valuable of some of the small vessels that already have formed. characteristic of long-term vascular control is that vas- When the infant is taken out of the oxygen tent, explo- cularity is determined mainly by the maximum level of sive overgrowth of new vessels then occurs to make up blood flow required by the tissue rather than by aver- for the sudden decrease in available oxygen. Often, so age need. For example, during heavy exercise, the need much overgrowth occurs that the retinal vessels grow for whole-body blood flow often increases to six to eight out from the retina into the eye’s vitreous humor, even- times the resting blood flow. This great excess of flow tually causing blindness, a condition called retrolental may not be required for more than a few minutes each fibroplasia.␣ day. Nevertheless, even this short time of need can cause enough angiogenic factors to be formed by the muscles Importance of Vascular Growth Factors in Formation to increase their vascularity as required. Were it not for of New Blood Vessels. A dozen or more factors that this capability, every time a person attempted heavy exer- increase growth of new blood vessels have been found, cise, the muscles would fail to receive the required nutri- almost all of which are small peptides. The four factors ents, especially the required oxygen, and thus the muscles that have been best characterized are vascular endothelial would fail to contract. growth factor (VEGF), fibroblast growth factor, platelet- However, after extra vascularity does develop, the extra derived growth factor (PDGF), and angiogenin, each of blood vessels normally remain mainly vasoconstricted, which has been isolated from tissues that have inadequate opening to allow extra flow only when appropriate local blood supply. Deficiency of tissue oxygen induces expres- stimuli such as a lack of oxygen, nerve vasodilatory stim- sion of hypoxia inducible factors (HIFs), transcription uli, or other stimuli call forth the required extra flow.␣ factors that in turn upregulate gene expression and the formation of vascular growth factors (also called angio- Blood Flow Regulation by Development genic factors). of Collateral Circulation Angiogenesis begins with new vessels sprouting from In most tissues of the body, when an artery or a vein is other small vessels. The first step is dissolution of the base- blocked, a new vascular channel usually develops around ment membrane of the endothelial cells at the point of the blockage and allows at least partial resupply of blood sprouting. This step is followed by rapid reproduction of to the affected tissue. The first stage in this process is dila- new endothelial cells, which stream outward through the tion of small vascular loops that already connect the ves- vessel wall in extended cords directed toward the source sel above the blockage to the vessel below. This dilation of the angiogenic factor. The cells in each cord continue occurs within the first minute or two, indicating that the to divide and rapidly fold over into a tube. Next, the tube dilation is likely mediated by metabolic factors. After this connects with another tube budding from another donor initial opening of collateral vessels, the blood flow often is vessel (another arteriole or venule) and forms a capillary still less than 25% of that required to supply all the tissue loop through which blood begins to flow. If the flow is needs. However, further opening occurs within the ensu- great enough, smooth muscle cells eventually invade the ing hours, so that within 1 day as much as half the tissue wall, so some of the new vessels eventually grow to be new needs may be met and, within a few days, the blood flow arterioles or venules or perhaps even larger vessels. Thus, is usually sufficient to meet the tissue needs. angiogenesis explains how metabolic factors in local tis- The collateral vessels continue to grow for many sues can cause growth of new vessels. months thereafter, usually forming multiple small col- Certain other substances, such as some steroid hor- lateral channels rather than one single large vessel. mones, have the opposite effect on small blood vessels, Under resting conditions, the blood flow may return to occasionally even causing dissolution of vascular cells and nearly normal, but the new channels seldom become disappearance of vessels. Therefore, blood vessels can also large enough to supply the blood flow needed during be made to disappear when they are not needed. Peptides strenuous tissue activity. Thus, development of collateral produced in the tissues can also block the growth of new vessels follows the usual principles of acute and long- blood vessels. For example, angiostatin, a fragment of term local blood flow control; the acute control is rapid the protein plasminogen, is a naturally occurring inhibi- metabolic dilation, followed chronically by growth and tor of angiogenesis. Endostatin is another antiangiogenic enlargement of new vessels over a period of weeks and peptide derived from the breakdown of collagen type months. XVII. Although the precise physiological functions of An important example of the development of collat- these antiangiogenic substances are still unknown, there eral blood vessels occurs after thrombosis of one of the is great interest in their potential use in arresting blood coronary arteries. By the age of 60 years, many people 212  Chapter 17 Local and Humoral Control of Tissue Blood Flow have experienced closure or at least partial occlusion of at least one of the smaller branch coronary vessels, but they Inward eutrophic are not aware of it because collateral blood vessels have remodeling developed rapidly enough to prevent myocardial dam- age. When collateral blood vessels are unable to develop UNIT IV quickly enough to maintain blood flow because of the rapidity or severity of the coronary insufficiency, serious Hypertrophic heart attacks can occur.␣ remodeling Vascular Remodeling in Response to Chronic Changes in Blood Flow or Blood Pressure Vascular growth and remodeling are critical compo- nents of tissue development and growth and occur as an Outward remodeling adaptive response to long- term changes in blood pres- sure or blood flow. For example, after several months of chronic exercise training, vascularity of the trained muscles increases to accommodate their higher blood flow requirements. In addition to changes in capillary density, there may also be changes in the structure of Outward large blood vessels in response to long- term changes hypertrophic in blood pressure and blood flow. When blood pres- remodeling sure is chronically elevated above normal, for example, the large and small arteries and arterioles remodel to accommodate the increased mechanical wall stress of Figure 17-8. Vascular remodeling in response to a chronic increase the higher blood pressure. In most tissues, the small in blood pressure or blood flow. In small arteries and arterioles that arteries and arterioles rapidly respond (within sec- constrict in response to increased blood pressure, inward eutrophic onds) to increased arterial pressure with vasoconstric- remodeling typically occurs because the lumen diameter is smaller tion, which helps autoregulate tissue blood flow, as and the vascular wall is thicker, but the total cross-sectional area of discussed previously. The vasoconstriction decreases the vessel wall is hardly changed. In large blood vessels that do not constrict in response to increased blood pressure, there may be hy- lumen diameter, which in turn tends to normalize the pertrophic remodeling, with increases in thickness and total cross- vascular wall tension (T), which, according to Laplace’s sectional area of the vascular wall. If blood vessels are exposed to equation, is the product of the radius (r) of the blood chronic increases in blood flow, there is typically outward remodeling, vessel and its pressure (P): T = r × P with increases in lumen diameter, little change in wall thickness, and In small blood vessels that constrict in response to increased total cross-sectional area of the vascular wall. If the blood vessel is exposed to long-term increases in blood pressure and blood increased blood pressure, the vascular smooth muscle flow, there is usually outward hypertrophic remodeling, with increas- cells and endothelial cells gradually—over a period of es in lumen diameter, wall thickness, and total cross-sectional area several days or weeks—rearrange themselves around of the vascular wall. Chronic reductions in blood pressure and blood the smaller lumen diameter, a process called inward flow have the opposite effects, as previously described. eutrophic remodeling, with no change in the total cross-sectional area of the vascular wall (Figure 17-8). pressures than arteries and have much thinner walls, but In larger arteries that do not constrict in response to when a vein is sewn onto the aorta and connected to a the increased pressure, the vessel wall is exposed to coronary artery, it is exposed to increases in intralumi- increased wall tension that stimulates a hypertrophic nal pressure and wall tension. The increased wall tension remodeling response and an increase in the cross- initiates hypertrophy of vascular smooth muscle cells and sectional area of the vascular wall. The hypertrophic increased extracellular matrix formation, which thicken response increases the size of vascular smooth muscle and strengthen the wall of the vein; as a result, several cells and stimulates formation of additional extracel- months after implantation into the arterial system, the lular matrix proteins, such as collagen and fibronec- vein will typically have a wall thickness similar to that of tin, that reinforce the strength of the vascular wall to an artery. withstand the higher blood pressures. However, this Vascular remodeling also occurs when a blood vessel is hypertrophic response also makes the large blood ves- exposed chronically to increased or decreased blood flow. sels stiffer, which is a hallmark of chronic hypertension. The creation of a fistula connecting a large artery and large Another example of vascular remodeling is the change vein, thereby completely bypassing high-resistance small that occurs when a large vein (often the saphenous vein) vessels and capillaries, provides an especially interesting is implanted in a patient for a coronary artery bypass graft example of remodeling in the affected artery and vein. procedure. Veins are normally exposed to much lower In patients with renal failure who undergo dialysis, an 213 UNIT IV The Circulation arteriovenous (A-V) fistula directly from the radial artery secrete norepinephrine and epinephrine into the blood. to the antecubital vein of the forearm is created to per- These hormones then circulate to all areas of the body and mit vascular access for dialysis. The blood flow rate in the cause almost the same effects on the circulation as direct radial artery may increase as much as 10 to 50 times the sympathetic stimulation, thus providing a dual system normal flow rate, depending on the patency of the fistula. of control: (1) direct nerve stimulation; and (2) indirect As a result of the high flow rate and high shear stress on effects of norepinephrine and/or epinephrine in the cir- the vessel wall, the luminal diameter of the radial artery culating blood.␣ increases progressively (outward remodeling), whereas the thickness of the vessel wall may remain unchanged, Angiotensin II. Angiotensin II is another powerful vaso- resulting in an increase in cross-sectional area of the vas- constrictor substance. As little as one millionth of a gram cular wall. In contrast, wall thickness, lumen diameter, can increase the arterial pressure of a person by 50 mm and cross-sectional area of the vascular wall on the venous Hg or more. side of the fistula increase in response to increases in pres- The effect of angiotensin II is to constrict the small sure and blood flow (outward hypertrophic remodeling). arterioles powerfully. If this constriction occurs in an iso- This pattern of remodeling is consistent with the idea that lated tissue area, the blood flow to that area can be severely long-term increases in vascular wall tension cause hyper- depressed. However, the real importance of angiotensin II trophy and increased wall thickness in large blood vessels, is that it normally acts on many arterioles of the body at whereas increased blood flow rate and shear stress cause the same time to increase the total peripheral resistance outward remodeling and increased luminal diameter to and decrease sodium and water excretion by the kidneys, accommodate the increased blood flow. thereby increasing the arterial pressure. Thus, this hor- Chronic reductions in blood pressure and blood flow mone plays an integral role in the regulation of arterial have effects opposite to those previously described. When pressure, as is discussed in detail in Chapter 19.␣ blood flow is greatly reduced, the diameter of the vascular lumen is also reduced and, when blood pressure is reduced, Vasopressin. Vasopressin, also called antidiuretic hor- the thickness of the vascular wall usually decreases. Thus, mone, is even more powerful than angiotensin II as a vaso- vascular remodeling is an important adaptive response of constrictor, thus making it one of the body’s most potent the blood vessels to tissue growth and development, as vascular constrictor substances. It is formed in nerve cells well as to physiological and pathological changes in blood in the hypothalamus of the brain (see Chapters 29 and 76) pressure and blood flow to the tissues.␣ but is then transported downward by nerve axons to the posterior pituitary gland, where it is finally secreted into the blood. HUMORAL CONTROL OF THE It is clear that vasopressin could have enormous effects CIRCULATION on circulatory function. Yet, because only minute amounts Humoral control of the circulation means control by sub- of vasopressin are secreted in most physiological condi- stances secreted or absorbed into the body fluids, such tions, most physiologists have thought that vasopressin as hormones and locally produced factors. Some of these plays little role in vascular control. However, experiments substances are formed by special glands and transported have shown that the concentration of circulating blood in the blood throughout the entire body. Others are vasopressin after severe hemorrhage can increase enough formed in local tissue areas and cause only local circula- to attenuate reductions in arterial pressure markedly. In tory effects. Among the most important of the humoral some cases, this action can, by itself, bring the arterial factors that affect circulatory function are those described pressure almost back up to normal. in the following sections. Vasopressin has the major function of greatly increas- ing water reabsorption from the renal tubules back into the blood (discussed in Chapter 29) and therefore helps VASOCONSTRICTORS control body fluid volume. That is why this hormone is Norepinephrine and Epinephrine. Norepinephrine is an also called antidiuretic hormone.␣ especially powerful vasoconstrictor hormone; epinephrine is less powerful as a vasoconstrictor and, in some tissues, VASODILATORS even causes mild vasodilation. (A special example of vaso- dilation caused by epinephrine is that which occurs to di- Bradykinin. Several substances called kinins cause pow- late the coronary arteries during increased heart activity.) erful vasodilation when formed in the blood and tissue When the sympathetic nervous system is stimulated in fluids of some organs. The kinins are small polypep- most parts of the body during stress or exercise, the sym- tides that are split away by proteolytic enzymes from pathetic nerve endings in the individual tissues release α2-globulins in the plasma or tissue fluids. A proteolytic norepinephrine, which excites the heart and constricts enzyme of particular importance for this purpose is kal- the veins and arterioles. In addition, the sympathetic likrein, which is present in the blood and tissue fluids in nerves to the adrenal medullae cause these glands to an inactive form. This inactive kallikrein is activated by 214  Chapter 17 Local and Humoral Control of Tissue Blood Flow maceration of the blood, tissue inflammation, or other 4. An increase in hydrogen ion concentration (de- similar chemical or physical effects on the blood or tis- crease in pH) causes dilation of the arterioles. Con- sues. As kallikrein becomes activated, it acts immediately versely, a slight decrease in hydrogen ion concentra- on α2-globulin to release a kinin called kallidin, which is tion causes arteriolar constriction. then converted by tissue enzymes into bradykinin. Once 5. Anions that have significant effects on blood vessels UNIT IV formed, bradykinin persists for only a few minutes be- are acetate and citrate, both of which cause mild de- cause it is inactivated by the enzyme carboxypeptidase grees of vasodilation. or by converting enzyme, the same enzyme that also plays 6. An increase in carbon dioxide concentration causes an essential role in activating angiotensin, as discussed in moderate vasodilation in most tissues but marked Chapter 19. The activated kallikrein enzyme is destroyed vasodilation in the brain. Also, carbon dioxide in by a kallikrein inhibitor that is also present in body fluids. the blood, acting on the brain vasomotor center, has Bradykinin causes both powerful arteriolar dilation an extremely powerful indirect effect, transmitted and increased capillary permeability. For example, injec- through the sympathetic nervous vasoconstrictor tion of 1 microgram of bradykinin into the brachial artery system, that causes widespread vasoconstriction of a person increases blood flow through the arm as much throughout the body. as sixfold, and even smaller amounts injected locally into tissues can cause marked local edema resulting from an Most Vasodilators or Vasoconstrictors Have Little increase in capillary pore size. Effect on Long-Term Blood Flow Unless They Alter Kinins appear to play special roles in regulating blood the Metabolic Rate of the Tissues. In most experimen- flow and capillary leakage of fluids in inflamed tissues. It tal studies, tissue blood flow and cardiac output (the sum is also believed that bradykinin plays a normal role to help of flow to all the body’s tissues) are not substantially al- regulate blood flow in the skin, as well as in the salivary tered, except for 1 or 2 days, when large amounts of pow- and gastrointestinal glands.␣ erful vasoconstrictors such as angiotensin II or vasodila- tors such as bradykinin are chronically infused. Why is Histamine. Histamine is released in almost every tissue blood flow not significantly altered in most tissues, even of the body if the tissue becomes damaged or inflamed in the presence of very large amounts of these vasoactive or is the subject of an allergic reaction. Most of the his- agents? tamine is derived from mast cells in the damaged tissues To answer this question, we must return to one of the and from basophils in the blood. fundamental principles of circulatory function that was Histamine has a powerful vasodilator effect on the previously discussed—the ability of each tissue to auto- arterioles and, like bradykinin, has the ability to increase regulate its own blood flow according to the metabolic capillary porosity greatly, allowing leakage of fluid and needs and other functions of the tissue. Administration plasma protein into the tissues. In many pathological of a powerful vasoconstrictor, such as angiotensin II, conditions, the intense arteriolar dilation and increased may cause transient decreases in tissue blood flow and capillary porosity produced by histamine cause large cardiac output but usually has little long-term effect if quantities of fluid to leak out of the circulation into the tis- it does not alter metabolic rate of the tissues. Likewise, sues, inducing edema. The local vasodilatory and edema- most vasodilators cause only short-term changes in tis- producing effects of histamine are especially prominent sue blood flow and cardiac output if they do not alter during allergic reactions and are discussed in Chapter 35.␣ tissue metabolism. Therefore, blood flow is generally regulated according to the specific needs of the tissues, as long as the arterial pressure is adequate to perfuse the VASCULAR CONTROL BY IONS AND tissues. OTHER CHEMICAL FACTORS Many different ions and other chemical factors can dilate or constrict local blood vessels. The following list details Bibliography some of their specific effects: Adair TH: Growth regulation of the vascular system: an emerging role 1. An increase in intracellular calcium ion concentra- for adenosine. Am J Physiol Regul Integr Comp Physiol 289:R283, tion causes vasoconstriction because of the general 2005. Apte RS, Chen DS, Ferrara N: VEGF in Signaling and Disease: Beyond effect of calcium to stimulate smooth muscle con- Discovery and Development. Cell 176:1248, 2019. traction, as discussed in Chapter 8. Bolduc V, Thorin-Trescases N, Thorin E: Endothelium-dependent con- 2. An increase in potassium ion concentration, within trol of cerebrovascular functions through age: exercise for healthy the physiological range, causes vasodilation. This cerebrovascular aging. Am J Physiol Heart Circ Physiol 305:H620, effect results from the ability of potassium ions to 2013. Briet M, Schiffrin EL: Treatment of arterial remodeling in essential inhibit smooth muscle contraction. hypertension. Curr Hypertens Rep 15:3, 2013. 3. An increase in magnesium ion concentration causes Casey DP, Joyner MJ: Compensatory vasodilatation during hypoxic powerful vasodilation because magnesium ions in- exercise: mechanisms responsible for matching oxygen supply to hibit smooth muscle contraction. demand. J Physiol 590:6321, 2012. 215