Guyton and Hall Textbook of Medical Physiology, 12th Ed

CHAPTER 17

Local and Humoral Control of Tissue Blood Flow

image Local Control of Blood Flow in Response to Tissue Needs

One of the most fundamental principles of circulatory function is the ability of each tissue to control its own local blood flow in proportion to its metabolic needs.

What are some of the specific needs of the tissues for blood flow? The answer to this is manyfold, including the following:

1. Delivery of oxygen to the tissues.

2. Delivery of other nutrients, such as glucose, amino acids, and fatty acids.

3. Removal of carbon dioxide from the tissues.

4. Removal of hydrogen ions from the tissues.

5. Maintenance of proper concentrations of other ions in the tissues.

6. Transport of various hormones and other substances to the different tissues.

Certain organs have special requirements. For instance, blood flow to the skin determines heat loss from the body and in this way helps to control body temperature. Also, delivery of adequate quantities of blood plasma to the kidneys allows the kidneys to excrete the waste products of the body and to regulate body fluid volumes and electrolytes.

We shall see that these factors exert extreme degrees of local blood flow control and that different tissues place different levels of importance on these factors in controlling blood flow.

Variations in Blood Flow in Different Tissues and Organs

Note in Table 17-1 the very large blood flows in some organs—for example, several hundred ml/min per 100 g of thyroid or adrenal gland tissue and a total blood flow of 1350 ml/min in the liver, which is 95 ml/min/100 g of liver tissue.

Table 17-1 Blood Flow to Different Organs and Tissues Under Basal Conditions

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Also note the extremely large blood flow through the kidneys—1100 ml/min. This extreme amount of flow is required for the kidneys to perform their function of cleansing the blood of waste products.

Conversely, most surprising is the low blood flow to all the inactive muscles of the body, only a total of 750 ml/min, even though the muscles constitute between 30 and 40 percent of the total body mass. In the resting state, the metabolic activity of the muscles is very low, and so also is the blood flow, only 4 ml/min/100 g. Yet, during heavy exercise, muscle metabolic activity can increase more than 60-fold and the blood flow as much as 20-fold, increasing to as high as 16,000 ml/min in the body’s total muscle vascular bed (or 80 ml/min/100 g of muscle).

Importance of Blood Flow Control by the Local Tissues

One might ask the simple question: Why not simply allow a very large blood flow all the time through every tissue of the body, always enough to supply the tissue’s needs whether the activity of the tissue is little or great? The answer is equally simple: To do this would require many times more blood flow than the heart can pump.

Experiments have shown that the blood flow to each tissue usually is regulated at the minimal level that will supply the tissue’s requirements—no more, no less. For instance, in tissues for which the most important requirement is delivery of oxygen, the blood flow is always controlled at a level only slightly more than required to maintain full tissue oxygenation but no more than this. By controlling local blood flow in such an exact way, the tissues almost never suffer from oxygen nutritional deficiency and the workload on the heart is kept at a minimum.

Mechanisms of Blood Flow Control

Local blood flow control can be divided into two phases: (1) acute control and (2) long-term control.

Acute control is achieved by rapid changes in local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters, occurring within seconds to minutes to provide very rapid maintenance of appropriate local tissue blood flow.

Long-term control, however, means slow, controlled changes in flow over a period of days, weeks, or even months. In general, these long-term changes provide even better control of the flow in proportion to the needs of the tissues. These changes come about as a result of an increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues.

Acute Control of Local Blood Flow

Effect of Tissue Metabolism on Local Blood Flow

Figure 17-1 shows the approximate acute effect on blood flow of increasing the rate of metabolism in a local tissue, such as in a skeletal muscle. Note that an increase in metabolism up to eight times normal increases the blood flow acutely about fourfold.

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Figure 17-1 Effect of increasing rate of metabolism on tissue blood flow.

Acute Local Blood Flow Regulation When Oxygen Availability Changes

One of the most necessary of the metabolic nutrients is oxygen. Whenever the availability of oxygen to the tissues decreases, such as (1) at high altitude at the top of a high mountain, (2) in pneumonia, (3) in carbon monoxide poisoning (which poisons the ability of hemoglobin to transport oxygen), or (4) in cyanide poisoning (which poisons the ability of the tissues 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 percent of normal, the blood flow through an isolated leg increases about threefold; 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.

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Figure 17-2 Effect of decreasing arterial oxygen saturation on blood flow through an isolated dog leg.

Total cyanide poisoning of oxygen usage by a local tissue area can cause local blood flow to increase as much as sevenfold, thus demonstrating the extreme effect of oxygen deficiency to increase blood flow.

There are two basic theories for the regulation of local blood flow when either the rate of tissue metabolism changes or the availability of oxygen changes. They are (1) the vasodilator theory and (2) the oxygen lack theory.

Vasodilator Theory for Acute Local Blood Flow Regulation—Possible Special Role of Adenosine

According to this theory, the greater the rate of metabolism or the less the availability of oxygen or some other nutrients to a tissue, the greater the rate of formation of vasodilator substances in the tissue cells.The vasodilator substances then are believed to diffuse through the tissues to the precapillary sphincters, metarterioles, and arterioles to cause dilation. Some of the different vasodilator substances that have been suggested are adenosine, carbon dioxide, adenosine phosphate compounds, histamine, potassium ions, and hydrogen ions.

Vasodilator substances may be released from the tissue in response to oxygen deficiency. For instance, experiments have shown that decreased availability of oxygen can cause both adenosine and lactic acid (containing hydrogen ions) to be released into the spaces between the tissue cells; these substances then cause intense acute vasodilation and therefore are responsible, or partially responsible, for the local blood flow regulation. Vasodilator substances, such as carbon dioxide, lactic acid, and potassium ions, tend to increase in the tissues when blood flow is reduced and cell metabolism continues at the same rate, or when cell metabolism is suddenly increased. As the concentration of vasodilator metabolites increases, this causes vasodilation of the arterioles, increasing the tissue blood flow and returning the tissue concentration of the metabolites toward normal.

Many physiologists believe that adenosine is an important 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 little, and this causes enough local vasodilation in the heart to return coronary blood flow back to normal. Also, whenever the heart becomes more active than normal and the heart’s metabolism increases an extra amount, this, too, causes increased utilization of oxygen, followed by (1) decreased oxygen concentration in the heart muscle cells with (2) consequent degradation of adenosine triphosphate (ATP), which (3) increases the release of adenosine. It is believed 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 demands of the active heart.

Although research evidence is less clear, many physiologists also have suggested that the same adenosine mechanism is an important controller of blood flow in skeletal muscle and many other tissues, as well as in the heart. It has been difficult, however, to prove that sufficient quantities of any single vasodilator substance, including adenosine, are indeed formed in the tissues to cause all the measured increase in blood flow. It is likely that a combination of several different vasodilators released by the tissues contributes to blood flow regulation.

Oxygen Lack Theory for Local Blood Flow Control

Although the vasodilator theory is widely accepted, several critical facts have made other physiologists favor still another theory, which can be called either the oxygen lack theory or, more accurately, the nutrient lack theory (because other nutrients besides oxygen are involved). Oxygen (and other nutrients as well) is required as one of the metabolic nutrients to cause vascular muscle contraction. Therefore, in the absence of adequate oxygen, it is reasonable to believe that the blood vessels simply would relax and therefore naturally dilate. Also, increased utilization of oxygen in the tissues as a result of increased metabolism theoretically could decrease the availability of oxygen to the smooth muscle fibers in the local blood vessels, and this, too, would cause local vasodilation.

A mechanism by which the oxygen lack theory could operate is shown in Figure 17-3. This figure shows a tissue unit, consisting of a metarteriole with a single sidearm capillary and its surrounding tissue. At the origin of the capillary is a precapillary sphincter, and around the metarteriole are several other smooth muscle fibers. Observing such a tissue under a microscope—for example, in a bat’s wing—one sees that the precapillary sphincters are normally either completely open or completely closed. The number of precapillary sphincters that are open at any given time is roughly proportional to the requirements of the tissue for nutrition. The precapillary sphincters and metarterioles open and close cyclically several times per minute, with the duration of the open phases being proportional to the metabolic needs of the tissues for oxygen. The cyclical opening and closing is called vasomotion.

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Figure 17-3 Diagram of a tissue unit area for explanation of acute local feedback control of blood flow, showing a metarteriole passing through the tissue and a sidearm capillary with its precapillary sphincterfor controlling capillary blood flow.

Let us explain how oxygen concentration in the local tissue could regulate blood flow through the area. Because smooth muscle requires oxygen to remain contracted, one might assume that the strength of contraction of the sphincters would increase with an increase in oxygen concentration. Consequently, when the oxygen concentration in the tissue rises above a certain level, the precapillary and metarteriole sphincters presumably would close until the tissue cells consume the excess oxygen. But when the excess oxygen is gone and the oxygen concentration falls low enough, the sphincters would open once more to begin the cycle again.

Thus, on the basis of available data, either a vasodilator substance theory or an oxygen lack theory could explain acute local blood flow regulation in response to the metabolic needs of the tissues. Probably the truth lies in a combination of the two mechanisms.

Possible Role of Other Nutrients Besides Oxygen in Control of Local Blood Flow

Under special conditions, it has been shown that lack of glucose in the perfusing blood can cause local tissue vasodilation. Also, it is possible that this same effect occurs when other nutrients, such as amino acids or fatty acids, are deficient, although this has not been studied adequately. In addition, vasodilation occurs in the vitamin deficiency disease beriberi, in which the patient has deficiencies of the vitamin B substances thiamine, niacin, and riboflavin. In this disease, the peripheral vascular blood flow almost everywhere in the body often increases twofold to threefold. Because all these vitamins are necessary for oxygen-induced phosphorylation, which is required to produce ATP in the tissue cells, one can well understand how deficiency of these vitamins might lead to diminished smooth muscle contractile ability and therefore also local vasodilation.

Special Examples of Acute “Metabolic” Control of Local Blood Flow

The mechanisms that we have described thus far for local blood flow control are called “metabolic mechanisms” because all of them function in response to the metabolic needs of the tissues. Two additional special examples of metabolic control of local blood flow are reactive hyperemia and active hyperemia.

Reactive Hyperemia

When the blood supply to a tissue is blocked for a few seconds to as long as an hour or more and then is unblocked, blood flow through the tissue usually increases immediately to four to seven times normal; this increased flow will continue for a few seconds if the block has lasted only a few seconds but sometimes continues for as long as many hours if the blood flow has been stopped for an hour or more. This phenomenon is called reactive hyperemia.

Reactive hyperemia is another manifestation of the local “metabolic” blood flow regulation mechanism; that is, lack of flow sets into motion all of those factors that cause vasodilation. After short periods of vascular occlusion, the extra blood flow during the reactive hyperemia phase lasts long enough to repay almost exactly the tissue oxygen deficit that has accrued during the period of occlusion. This mechanism emphasizes the close connection between local blood flow regulation and delivery of oxygen and other nutrients to the tissues.

Active Hyperemia

When any tissue becomes highly active, such as an exercising muscle, a gastrointestinal gland during a hypersecretory period, or even the brain during rapid mental activity, the rate of blood flow through the tissue increases. Here again, by simply applying the basic principles of local blood flow control, one can easily understand this active hyperemia. The increase in local metabolism causes the cells to devour tissue fluid nutrients rapidly and also to release large quantities of vasodilator substances. The result is to dilate the local blood vessels and, therefore, to increase local blood flow. In this way, the active tissue receives the additional nutrients required to sustain its new level of function. As pointed out earlier, active hyperemia in skeletal muscle can increase local muscle blood flow as much as 20-fold during intense exercise.

“Autoregulation” of Blood Flow When the Arterial Pressure Changes from Normal—“Metabolic” and “Myogenic” Mechanisms

In any tissue of the body, a rapid increase in arterial pressure causes an immediate rise in blood flow. But, within less than a minute, the blood flow in most tissues returns almost to the normal level, even though the arterial pressure is kept elevated. This return of flow toward normal is called “autoregulation” of blood flow. After autoregulation has occurred, the local blood flow in most body tissues will be related to arterial pressure approximately in accord with the solid “acute” curve in Figure 17-4. Note that between arterial pressures of about 70 mm Hg and 175 mm Hg the blood flow increases only 20 to 30 percent even though the arterial pressure increases 150 percent.

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Figure 17-4 Effect of different levels of arterial pressure on blood flow through a muscle. The solid red curve shows the effect if the arterial pressure is raised over a period of a few minutes. The dashed green curve shows the effect if the arterial pressure is raised slowly over a period of many weeks.

For almost a century, two views have been proposed to explain this acute autoregulation mechanism. They have been called (1) the metabolic theory and (2) the myogenic theory.

The metabolic theory can be understood easily by applying the basic principles of local blood flow regulation discussed in previous sections. Thus, when the arterial pressure becomes too great, the excess flow provides too much oxygen and too many other nutrients to the tissues and “washes out” the vasodilators released by the tissues. These nutrients (especially oxygen) and decreased tissue levels of vasodilators then cause the blood vessels to constrict and the flow to return nearly to normal despite the increased pressure.

The myogenic theory, however, suggests that still another mechanism not related to tissue metabolism explains the phenomenon of autoregulation. This theory is based on the observation that sudden stretch of small blood vessels causes the smooth muscle of the vessel wall to contract. Therefore, it has been proposed that when high arterial pressure stretches the vessel, this in turn causes reactive vascular constriction that reduces blood flow nearly back to normal. Conversely, at low pressures, the degree of stretch of the vessel is less, so that the smooth muscle relaxes, reducing vascular resistance and helping to return flow toward normal.

The myogenic response is inherent to vascular smooth muscle and can occur in the absence of neural or hormonal influences. It is most pronounced in arterioles but can also be observed in arteries, venules, veins, and even lymphatic vessels. Myogenic contraction is initiated by stretch-induced vascular depolarization, which then rapidly increases calcium ion entry from the extracellular fluid into the cells, causing them to contract. Changes in vascular pressure may also open or close other ion channels that influence vascular contraction. The precise mechanisms by which changes in pressure cause opening or closing of vascular ion channels are still uncertain but likely involve mechanical effects of pressure on extracellular proteins that are tethered to cytoskeleton elements of the vascular wall or to the ion channels themselves.

The myogenic mechanism appears to be important in preventing excessive stretch of blood vessel when blood pressure is increased. However, the role of the myogenic mechanism in blood flow regulation is unclear because this pressure-sensing mechanism cannot directly detect changes in blood flow in the tissue. Indeed, metabolic factors appear to override the myogenic mechanism in circumstances where the metabolic demands of the tissues are significantly increased, such as during vigorous muscle exercise, which can cause dramatic increases in skeletal muscle blood flow.

Special Mechanisms for Acute Blood Flow Control in Specific Tissues

Although the general mechanisms for local blood flow control discussed thus far are present in almost all tissues of the body, distinctly different mechanisms operate in a few special areas. All mechanisms are discussed throughout this text in relation to specific organs, but two notable ones are as follows:

1. In the kidneys, blood flow control is vested to a great extent in a mechanism called tubuloglomerular feedback, in which the composition of the fluid in the early distal tubule is detected by an epithelial structure of the distal tubule itself called the macula densa. This is located where the distal tubule lies adjacent to the afferent and efferent arterioles at the nephron juxtaglomerular apparatus. When too much fluid filters from the blood through the glomerulus into the tubular system, feedback signals from the macula densa cause constriction of the afferent arterioles, in this way reducing both renal blood flow and glomerular filtration rate back to or near to normal. The details of this mechanism are discussed in Chapter 26.

2. In the brain, in addition to control of blood flow by tissue oxygen concentration, the concentrations of carbon dioxide and hydrogen ions play prominent roles. An increase of either or both of these dilates the cerebral vessels and allows rapid washout of the excess carbon dioxide or hydrogen ions from the brain tissues. This is important because the level of excitability of the brain itself is highly dependent on exact control of both carbon dioxide concentration and hydrogen ion concentration. This special mechanism for cerebral blood flow control is presented in Chapter 61.

3. In the skin, blood flow control is closely linked to regulation of body temperature. Cutaneous and subcutaneous flow regulates heat loss from the body by metering the flow of heat from the core to the surface of the body, where heat is lost to the environment. Skin blood flow is controlled largely by the central nervous system through the sympathetic nerves, as discussed in Chapter 73. Although skin blood flow is only about 3 ml/min/100 g of tissue in cool weather, large changes from that value can occur as needed. When humans are exposed to body heating, 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. Even with severe vasoconstriction, skin blood flow is usually great enough to meet the basic metabolic demands of the skin.

Control of Tissue Blood Flow by Endothelial-Derived Relaxing or Constricting Factors

The endothelial cells lining the blood vessels synthesize several substances that, when released, can affect the degree of relaxation or contraction of the arterial wall. For many of these endothelial-derived relaxing or constrictor factors, the physiological roles are just beginning to be understood and clinical applications have, in most cases, not yet been developed.

Nitric Oxide—A Vasodilator Released from Healthy Endothelial Cells

The most important of the endothelial-derived relaxing factors is nitric oxide (NO), a lipophilic gas that is released from endothelial cells in response to a variety of chemical and physical stimuli. Nitric oxide synthase (NOS) enzymesin endothelial cells synthesize NO from arginine and oxygen and by reduction of inorganic nitrate. After diffusing out of the endothelial cell, NO has a half-life in the blood of only about 6 seconds and acts mainly in the local tissues where it is released. NO activates soluble guanylate cyclases in vascular smooth muscle cells (Figure 17-5), resulting in conversion of cyclic guanosine triphosphate (cGTP) to cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG), which has several actions that cause the blood vessels to relax.

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Figure 17-5 Nitric oxide synthase (eNOS) enzyme in endothelial cells synthesizes nitric oxide (NO) from arginine and oxygen. NO activates soluble guanylate cyclases in vascular smooth muscle cells, resulting in conversion of cyclic guanosine triphosphate (cGTP) to cyclic guanosine monophosphate (cGMP) which ultimately causes the blood vessels to relax.

When blood flows through the arteries and arterioles, this causes shear stress on the endothelial cells because of viscous drag of the blood against the vascular walls. This stress contorts the endothelial cells in the direction of flow and causes significant increase in the release of NO. The NO then relaxes the blood vessels. This is fortunate because the local metabolic mechanisms for controlling tissue blood flow dilate mainly the very small arteries and arterioles in each tissue. Yet, when blood flow through a microvascular portion of the circulation increases, this secondarily stimulates the release of NO from larger vessels due to increased flow and shear stress in these vessels. The released NO increases the diameters of the larger upstream blood vessels whenever microvascular blood flow increases downstream. Without such a response, the effectiveness of local blood flow control would be decreased because a significant part of the resistance to blood flow is in the upstream small arteries.

NO synthesis and release from endothelial cells are also stimulated by some vasoconstrictors, such as angiotensin II, which bind to specific receptors on endothelial cells. The increased NO release protects against excessive vasoconstriction.

When endothelial cells are damaged by chronic hypertension or atherosclerosis, impaired NO synthesis may contribute to excessive vasoconstriction and worsening of the hypertension and endothelial damage, which, if untreated, may eventually cause vascular injury and damage to vulnerable tissues such as the heart, kidneys, and brain.

Even before NO was discovered, clinicians used nitroglycerin, amyl nitrates, and other nitrate derivatives to treat patients suffering from angina pectoris, severe chest pain caused by ischemia of the heart muscle. These drugs, when broken down chemically, release NO and evoke dilation of blood vessels throughout the body, including the coronary blood vessels.

Other important applications of NO physiology and pharmacology are the development and clinical use of drugs (e.g., sildenafil) that inhibit cGMP specific phosphodiesterase-5 (PDE-5), an enzyme that degrades cGMP. By preventing the degradation of cGMP the PDE-5 inhibitors effectively prolong the actions of NO to cause vasodilation. The primary clinical use of the PDE-5 inhibitors is to treat erectile dysfunction. Penile erection is caused by parasympathetic nerve impulses through the pelvic nerves to the penis, where the neurotransmitters acetylcholine and NO are released. By preventing the degradation of NO, the PDE-5 inhibitors enhance the dilation of the blood vessels in the penis and aid in erection, as discussed in Chapter 80.

Endothelin—A Powerful Vasoconstrictor Released from Damaged Endothelium

Endothelial cells also release vasoconstrictor substances. The most important of these is endothelin, a large 21 amino acid peptide that requires only nanogram quantities to cause powerful vasoconstriction. This substance is present in the endothelial cells of all or most blood vessels but greatly increases when the vessels are injured. The usual stimulus for release is damage to 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 helps to prevent extensive bleeding from arteries as large as 5 millimeters in diameter that might have been torn open by crushing injury.

Increased endothelin release is also believed to contribute to vasoconstriction when the endothelium is damaged by hypertension. Drugs that block endothelin receptors have been used to treat pulmonary hypertension but have not generally been used for lowering blood pressure in patients with systemic arterial hypertension.

Long-Term Blood Flow Regulation

Thus far, most of the mechanisms for local blood flow regulation that we have discussed act within a few seconds 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 instance, when the arterial pressure suddenly increases from 100 to 150 mm Hg, the blood flow increases almost instantaneously about 100 percent. Then, within 30 seconds to 2 minutes, the flow decreases back to about 10 to 15 percent above the original control value. This illustrates the rapidity of the acute mechanisms for local blood flow regulation, but at the same time, it demonstrates that the regulation is still incomplete because there remains a 10 to 15 percent excess blood flow.

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 regulation gives far more complete control of blood flow. For instance, in the aforementioned example, if the arterial pressure remains at 150 mm Hg indefinitely, within a few weeks the blood flow through the tissues gradually approaches almost exactly the normal flow level. Figure 17-4 shows by the dashed green curve the extreme effectiveness of this long-term local blood flow regulation. Note that once the long-term regulation has had time to occur, long-term changes in arterial pressure between 50 and 250 mm Hg have little effect on the rate of local blood flow.

Long-term regulation of blood flow is especially important when the metabolic demands of a tissue change. Thus, if a tissue becomes chronically overactive and therefore requires increased quantities of oxygen and other nutrients, the arterioles and capillary vessels usually increase both in number and size within a few weeks to match the needs of the tissue—unless the circulatory system has become pathological or too old to respond.

Mechanism of Long-Term Regulation—Change in “Tissue Vascularity”

The mechanism of long-term local blood flow regulation is principally to change the amount of vascularity of the tissues. For instance, if the metabolism in a tissue is increased for a prolonged period, vascularity increases, a process generally called angiogenesis; if the metabolism is decreased, vascularity decreases. Figure 17-6 shows the large increase in the number of capillaries in a rat anterior tibialis muscle that was stimulated electrically to contract for short periods of time each day for 30 days, compared with the unstimulated muscle in the other leg of the animal.

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Figure 17-6 Large increase in the number of capillaries (white dots) in a rat anterior tibialis muscle that was stimulated electrically to contract for short periods of time each day for 30 days (B), compared with the unstimulated muscle (A).The 30 days of intermittent electrical stimulation converted the predominantly fast twitch, glycolytic anterior tibialis muscle to a predominantly slow twitch, oxidative muscle with increased numbers of capillaries and decreased fiber diameter as shown.

(Photo courtesy Dr. Thomas Adair.)

Thus, there is actual physical reconstruction of the tissue vasculature to meet the needs of the tissues. This reconstruction occurs rapidly (within days) in young animals. It also occurs rapidly in new growth tissue, such as in scar tissue and cancerous tissue; however, it occurs much slower in old, well-established tissues. Therefore, the time required for long-term regulation to take place may be only a few days in the neonate or as long as months in the elderly person. Furthermore, the final degree of response is much better in younger tissues than in older, so that in the neonate, the vascularity will adjust to match almost exactly the needs of the tissue for blood flow, whereas in older tissues, vascularity frequently lags far behind the needs of the tissues.

Role of Oxygen in Long-Term Regulation

Oxygen is important not only for acute control of local blood flow but also for long-term control. One example of this is increased vascularity in tissues of animals that live at high altitudes, where the atmospheric oxygen is low. A second example is that fetal chicks hatched in low oxygen have up to twice as much tissue blood vessel conductivity as is normally true. This same effect is also dramatically demonstrated in premature human babies put into oxygen tents for therapeutic purposes. The excess oxygen causes almost immediate cessation of new vascular growth in the retina of the premature baby’s eyes and even causes degeneration of some of the small vessels that already have formed. Then when the infant is taken out of the oxygen tent, there is explosive overgrowth of new vessels to make up for the sudden decrease in available oxygen; indeed, there is often so much overgrowth that the retinal vessels grow out from the retina into the eye’s vitreous humor and eventually cause blindness. (This condition is called retrolental fibroplasia.)

Importance of Vascular Endothelial Growth Factor in Formation of New Blood Vessels

A dozen or more factors that increase growth of new blood vessels have been found, almost all of which are small peptides. Three of those that have been best characterized are vascular endothelial growth factor (VEGF), fibroblast growth factor, and angiogenin, each of which has been isolated from tissues that have inadequate blood supply. Presumably, it is deficiency of tissue oxygen or other nutrients, or both, that leads to formation of the vascular growth factors (also called “angiogenic factors”).

Essentially all the angiogenic factors promote new vessel growth in the same way. They cause new vessels to sprout from other small vessels. The first step is dissolution of the basement membrane of the endothelial cells at the point of sprouting. This is followed by rapid reproduction of new endothelial cells that stream outward through the vessel wall in extended cords directed toward the source of the angiogenic factor. The cells in each cord continue to divide and rapidly fold over into a tube. Next, the tube connects with another tube budding from another donor vessel (another arteriole or venule) and forms a capillary loop through which blood begins to flow. If the flow is great enough, smooth muscle cells eventually invade the wall, so some of the new vessels eventually grow to be new arterioles or venules or perhaps even larger vessels. Thus, angiogenesis explains the manner in which metabolic factors in local tissues can cause growth of new vessels.

Certain other substances, such as some steroid hormones, have exactly the opposite effect on small blood vessels, occasionally even causing dissolution of vascular cells and disappearance of vessels. Therefore, blood vessels can also be made to disappear when not needed. Peptides produced in the tissues can also block the growth of new blood vessels. For example, angiostatin, a fragment of the protein plasminogen, is a naturally occurring inhibitor of angiogenesis. Endostatin is another antiangiogenic peptide that is derived from the breakdown of collagen type XVII. Although the precise physiological functions of these antiangiogenic substances are still unknown, there is great interest in their potential use in arresting blood vessel growth in cancerous tumors and therefore preventing the large increases in blood flow needed to sustain the nutrient supply of rapidly growing tumors.

Vascularity Is Determined by Maximum Blood Flow Need, Not by Average Need

An especially valuable characteristic of long-term vascular control is that vascularity is determined mainly by the maximum level of blood flow need rather than by average need. For instance, during heavy exercise the need for whole body blood flow often increases to six to eight times the resting blood flow. This great excess of flow may not be required for more than a few minutes each day. Nevertheless, even this short need can cause enough VEGF to be formed by the muscles to increase their vascularity as required. Were it not for this capability, every time that a person attempted heavy exercise, the muscles would fail to receive the required nutrients, especially the required oxygen, so that the muscles simply would fail to contract.

However, after extra vascularity does develop, the extra blood vessels normally remain mainly vasoconstricted, opening to allow extra flow only when appropriate local stimuli such as oxygen lack, nerve vasodilatory stimuli, or other stimuli call forth the required extra flow.

Development of Collateral Circulation— a Phenomenon of Long-Term Local Blood Flow Regulation

When an artery or a vein is blocked in virtually any tissue of the body, a new vascular channel usually develops around the blockage and allows at least partial resupply of blood to the affected tissue. The first stage in this process is dilation of small vascular loops that already connect the vessel above the blockage to the vessel below. This dilation occurs within the first minute or two, indicating that the dilation is likely mediated by metabolic factors that relax the muscle fibers of the small vessels involved. After this initial opening of collateral vessels, the blood flow often is still less than one quarter that is needed to supply all the tissue needs. However, further opening occurs within the ensuing hours, so within 1 day as much as half the tissue needs may be met, and within a few days the blood flow is usually sufficient to meet the tissue needs.

The collateral vessels continue to grow for many months thereafter, almost always forming multiple small collateral channels rather than one single large vessel. Under resting conditions, the blood flow usually returns very near to normal, but the new channels seldom become large enough to supply the blood flow needed during strenuous tissue activity. Thus, the development of collateral vessels follows the usual principles of both acute and long-term local blood flow control, the acute control being rapid metabolic dilation, followed chronically by growth and enlargement of new vessels over a period of weeks and months.

The most important example of the development of collateral blood vessels occurs after thrombosis of one of the coronary arteries. Almost all people by the age of 60 years have had at least one of the smaller branch coronary vessels closed, or at least partially occluded. Yet most people do not know that this has happened because collaterals have developed rapidly enough to prevent myocardial damage. It is in those other instances in which coronary insufficiency occurs too rapidly or too severely for collaterals to develop that serious heart attacks occur.

Humoral Control of the Circulation

Humoral control of the circulation means control by substances secreted or absorbed into the body fluids—such as hormones and locally produced factors. Some of these substances are formed by special glands and transported in the blood throughout the entire body. Others are formed in local tissue areas and cause only local circulatory effects. Among the most important of the humoral factors that affect circulatory function are the following.

Vasoconstrictor Agents

Norepinephrine and Epinephrine

Norepinephrine is an especially powerful vasoconstrictor hormone; epinephrine is less so and in some tissues even causes mild vasodilation. (A special example of vasodilation caused by epinephrine occurs to dilate the coronary arteries during increased heart activity.)

When the sympathetic nervous system is stimulated in most or all parts of the body during stress or exercise, the sympathetic nerve endings in the individual tissues release norepinephrine, which excites the heart and contracts the veins and arterioles. In addition, the sympathetic nerves to the adrenal medullae cause these glands to secrete both norepinephrine and epinephrine into the blood. These hormones then circulate to all areas of the body and cause almost the same effects on the circulation as direct sympathetic stimulation, thus providing a dual system of control: (1) direct nerve stimulation and (2) indirect effects of norepinephrine and/or epinephrine in the circulating blood.

Angiotensin II

Angiotensin II is another powerful vasoconstrictor substance. As little as one millionth of a gram can increase the arterial pressure of a human being 50 mm Hg or more.

The effect of angiotensin II is to constrict powerfully the small arterioles. If this occurs in an isolated tissue area, the blood flow to that area can be severely depressed. However, the real importance of angiotensin II is that it normally acts on many of the arterioles of the body at the same time to increase the total peripheral resistance, thereby increasing the arterial pressure. Thus, this hormone plays an integral role in the regulation of arterial pressure, as is discussed in detail in Chapter 19.

Vasopressin

Vasopressin, also called antidiuretic hormone, is even more powerful than angiotensin II as a vasoconstrictor, thus making it one of the body’s most potent vascular constrictor substances. It is formed in nerve cells in the hypothalamus of the brain (see Chapters 28 and 75) but is then transported downward by nerve axons to the posterior pituitary gland, where it is finally secreted into the blood.

It is clear that vasopressin could have enormous effects on circulatory function. Yet normally, only minute amounts of vasopressin are secreted, so most physiologists have thought that vasopressin plays little role in vascular control. However, experiments have shown that the concentration of circulating blood vasopressin after severe hemorrhage can increase enough to raise the arterial pressure as much as 60 mm Hg. In many instances, this can, by itself, bring the arterial pressure almost back up to normal.

Vasopressin has a major function to increase greatly water reabsorption from the renal tubules back into the blood (discussed in Chapter 28), and therefore to help control body fluid volume. That is why this hormone is also called antidiuretic hormone.

Vasodilator Agents

Bradykinin

Several substances called kinins cause powerful vasodilation when formed in the blood and tissue fluids of some organs.

The kinins are small polypeptides that are split away by proteolytic enzymes from alpha2-globulins in the plasma or tissue fluids. A proteolytic enzyme of particular importance for this purpose is kallikrein,which is present in the blood and tissue fluids in an inactive form. This inactive kallikrein is activated by maceration of the blood, by tissue inflammation, or by other similar chemical or physical effects on the blood or tissues. As kallikrein becomes activated, it acts immediately on alpha2-globulin to release a kinin called kallidin that is then converted by tissue enzymes into bradykinin. Once formed, bradykinin persists for only a few minutes because it is inactivated by the enzyme carboxypeptidase or by converting enzyme, the same enzyme that also plays an essential role in activating angiotensin, as discussed in Chapter 19. The activated kallikrein enzyme is destroyed by a kallikrein inhibitor also present in the body fluids.

Bradykinin causes both powerful arteriolar dilation and increased capillary permeability. For instance, injection of 1 microgram of bradykinin into the brachial artery of a person increases blood flow through the arm as much as sixfold, and even smaller amounts injected locally into tissues can cause marked local edema resulting from increase in capillary pore size.

There is reason to believe that kinins play special roles in regulating blood flow and capillary leakage of fluids in inflamed tissues. It also is believed that bradykinin plays a normal role to help regulate blood flow in the skin, as well as in the salivary and gastrointestinal glands.

Histamine

Histamine is released in essentially every tissue of the body if the tissue becomes damaged or inflamed or is the subject of an allergic reaction. Most of the histamine is derived from mast cells in the damaged tissues and from basophils in the blood.

Histamine has a powerful vasodilator effect on the arterioles and, like bradykinin, has the ability to increase greatly capillary porosity, allowing leakage of both fluid and plasma protein into the tissues. In many pathological conditions, the intense arteriolar dilation and increased capillary porosity produced by histamine cause tremendous quantities of fluid to leak out of the circulation into the tissues, inducing edema. The local vasodilatory and edema-producing effects of histamine are especially prominent during allergic reactions and are discussed in Chapter 34.

Vascular Control by Ions and Other Chemical Factors

Many different ions and other chemical factors can either dilate or constrict local blood vessels. Most of them have little function in overall regulation of the circulation, but some specific effects are:

1. An increase in calcium ion concentration causes vasoconstriction. This results from the general effect of calcium to stimulate smooth muscle contraction, as discussed in Chapter 8.

2. An increase in potassium ion concentration, within the physiological range, causes vasodilation. This results from the ability of potassium ions to inhibit smooth muscle contraction.

3. An increase in magnesium ion concentration causes powerful vasodilation because magnesium ions inhibit smooth muscle contraction.

4. An increase in hydrogen ion concentration (decrease in pH) causes dilation of the arterioles. Conversely, slight decrease in hydrogen ion concentration causes arteriolar constriction.

5. Anions that have significant effects on blood vessels are acetate and citrate, both of which cause mild degrees of vasodilation.

6. An increase in carbon dioxide concentration causes moderate vasodilation in most tissues but marked vasodilation in the brain. Also, carbon dioxide in the blood, acting on the brain vasomotor center, has an extremely powerful indirect effect, transmitted through the sympathetic nervous vasoconstrictor system, to cause widespread vasoconstriction throughout the body.

Most Vasodilators or Vasoconstrictors Have Little Effect on Long-Term Blood Flow Unless They Alter Metabolic Rate of the Tissues

In most cases, tissue blood flow and cardiac output (the sum of flow to all of the body’s tissues) are not substantially altered, except for a day or two, in experimental studies when one chronically infuses large amounts of powerful vasoconstrictors such as angiotensin II or vasodilators such as bradykinin. Why is blood flow not significantly altered in most tissues even in the presence of very large amounts of these vasoactive agents?

To answer this question we must return to one of the fundamental principles of circulatory function that we previously discussed—the ability of each tissue to autoregulate its own blood flow according to the metabolic needs and other functions of the tissue. Administration of a powerful vasoconstrictor, such as angiotensin II, may cause transient decreases in tissue blood flow and cardiac output but usually has little long-term effect if it does not alter metabolic rate of the tissues. Likewise, most vasodilators cause only short-term changes in tissue blood flow and cardiac output if they do not alter 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 tissues.

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