Chapter 7_ Vascular Control | Cardiovascular Physiology: Mosby Physiology Monograph Series, 9e (Mosbys Physiology Monograph)

Print Close Window

Note: Large images and tables on this page may necessitate printing in landscape mode.

Copyright 2006 The McGraw-Hill Companies. All rights reserved.

Lange Cardiovascular Physiology > Chapter 7. Vascular Control >

Objectives

The student understands the general mechanisms involved in local vascular control:

Identifies the major ways in which smooth muscle differs anatomically and functionally from striated muscle.
Lists the steps leading to cross-bridge cycling in smooth muscle.
Lists the major ion channels involved in the regulation of membrane potential in smooth muscle.
Describes the processes of electromechanical and pharmacomechanical coupling in smooth muscle.
Defines basal tone.
Lists several substances potentially involved in local metabolic control.
States the local metabolic vasodilator hypothesis.
Describes how vascular tone is influenced by prostaglandins, histamine, and bradykinin.
Describes the myogenic response of blood vessels.
Defines active and reactive hyperemia and indicates a possible mechanism for each.
Defines autoregulation of blood flow and briefly describes the metabolic, myogenic, and tissue pressure theories of autoregulation.
Defines neurogenic tone and describes how sympathetic (and parasympathetic) neural influences can alter it.
Describes how vascular tone is influenced by circulating catecholamines, vasopressin, and angiotensin II.
Lists the major influences on venous diameters.
Describes in general how control of flow differs between organs with strong local metabolic control of arteriolar tone and organs with strong neurogenic control of arteriolar tone.

The student knows the dominant mechanisms of flow and blood volume control in the major body organs:

States the relative importance of local metabolic and neural control of coronary blood flow.
Defines systolic compression and indicates its relative importance to blood flow in the endocardial and epicardial regions of the right and left ventricular walls.
Describes the major mechanisms of flow and blood volume control in each of the following specific systemic organs: skeletal muscle, brain, splanchnic organs, skin, and kidney.
States why mean pulmonary arterial pressure is lower than mean systemic arterial pressure.
Describes how pulmonary vascular control differs from that in systemic organs.

Vascular Smooth Muscle

Because the body s metabolic needs are continually changing, the cardiovascular system must continually make adjustments in the diameter of its blood vessels. The purposes of these vascular changes are to (1) control the rate of blood flow through particular tissues (the job of arterioles) and (2) regulate the distribution of blood volume and cardiac filling (the job of veins). These diameter adjustments are made by regulating the contractile activity of vascular smooth muscle cells, which are present in the walls of all vessels except capillaries. The task of vascular smooth muscle is unique because to maintain a certain vessel diameter in the face of the continual distending pressure of the blood within it, vascular smooth muscle must be able to sustain active tension for prolonged periods.

There are many functional characteristics that distinguish smooth muscle from either skeletal or cardiac muscle. For example, when compared with these other muscle types, smooth muscle cells:

1. Contract and relax much more slowly.

2. Develop active tension over a greater range of muscle lengths.

3. Can change their contractile activity as the result of action potentials or changes in resting membrane potential.

4. May change their contractile activity in the absence of changes in membrane potential.

5. Maintain tension for prolonged periods at low energy cost.

6. Can be activated by stretch.

Contractile Machinery

Vascular smooth muscle cells are small (about 5 mm x 50 mm) spindle-shaped cells usually arranged circumferentially or at small helical angles in blood vessel walls. In many but not all vessels, adjacent smooth muscle cells are electrically connected by gap junctions similar to those found in the myocardium.

Just as in other muscle types, smooth muscle force development and shortening are the result of cross-bridge interaction between thick and thin contractile filaments composed of myosin and actin, respectively. In smooth muscle, however, these filaments are not arranged in regular, repeating sarcomere units. As a consequence, "smooth" muscle cells lack the microscopically visible striations characteristic of skeletal and cardiac muscle cells. The actin filaments in smooth muscle are much longer than those in striated muscle. Many of these actin filaments attach to the inner surface of the cell at structures called dense bands. In the interior of the cell, actin filaments do not attach to Z-lines but rather anchor to small transverse structures called dense bodies that are themselves tethered to the surface membrane by cable-like intermediate filaments. Myosin filaments are interspersed between the smooth muscle actin filaments but in a more haphazard fashion than the regular interweaving pattern of striated muscle. In striated muscle, the contractile filaments are invariably aligned with the long axis of the cell whereas in smooth muscle many contractile filaments travel obliquely or even transversely to the long axis of the cell. Despite the absence of organized sarcomeres, changes in smooth muscle length affect its ability to actively develop tension. Perhaps because of the long actin filaments and the lack of sarcomere arrangement, smooth muscle can develop tension over a greater range of length changes than either skeletal or cardiac muscle.

As in striated muscle, the strength of the cross-bridge interaction between thick and thin filaments in smooth muscle is controlled primarily by changes in the intracellular free Ca²⁺ level, which range from about 10⁷M in relaxed muscle to 10⁶M during maximal contraction. However, the sequence of steps linking an increased free Ca²⁺ level to contractile filament interaction is different in smooth muscle than in striated muscle. In smooth muscle:

1. Ca²⁺ first forms a complex with the calcium binding protein calmodulin.

2. The Ca²⁺-calmodulin complex then activates a phosphorylating enzyme called myosin light chain kinase.

3. This enzyme causes phosphorylation by adenosine triphosphate (ATP) of the light chain protein that is a portion of the cross-bridge head of myosin.

4. Myosin light chain phosphorylation enables cross-bridge formation and cycling during which energy from ATP is utilized for tension development and shortening.

Smooth muscle is also unique in that once tension is developed, it can be maintained at very low energy costs, ie, without the need to continually split ATP in cross-bridge cycling. The mechanisms responsible are still somewhat unclear but presumably involve very slowly cycling or even noncycling cross-bridges. This is often referred to as the latch state and may involve light chain dephosphorylation of attached cross-bridges. Also by mechanisms that are yet incompletely understood, it is apparent that vascular smooth muscle contractile activity is regulated not only by changes in intracellular free Ca²⁺ levels but also by changes in the Ca²⁺sensitivity of the contractile machinery. Thus the contractile state of vascular smooth muscle may sometimes change in the absence of changes in intracellular free Ca²⁺ levels.

Membrane Potentials

Smooth muscle cells have resting membrane potentials ranging from 40 to 65 mV and thus are generally lower than those in striated muscle. As in all cells, the resting membrane potential of smooth muscle is determined largely by the cell permeability to potassium. Many types of K⁺ channels have been identified in smooth muscle. The one that seems to be predominantly responsible for determining the resting membrane potential is termed an inward rectifying type K⁺ channel. (Inward rectifying signifies that K⁺ ions move into cells through this channel slightly more easily than they move out through it.) There are also ATP-dependent K⁺ channels that are closed when cellular ATP levels are normal but open if ATP levels fall. Such channels have been proposed to be important in matching organ blood flow to the metabolic state of the tissue.

Smooth muscle cells regularly have action potentials only in certain vessels. When they do occur, smooth muscle action potentials are initiated primarily by inward Ca²⁺ current and are developed slowly like the "slow type" cardiac action potentials (see Figure 2 2). As in the heart, this inward (depolarizing) Ca²⁺ current flows through a voltage-operated calcium channel (VOC); this type of channel is one of several types of calcium channels present in smooth muscle. The repolarization phase of the action potential occurs primarily by an outward flux of potassium ions through both delayed K⁺ channels and calcium-activated K⁺ channels.

Many types of ion channels in addition to those mentioned have been identified in vascular smooth muscle, but in most cases their exact role in cardiovascular function remains obscure. For example, there appear to be nonselective, stretch-sensitive cation channels that may be involved in the response of smooth muscle to stretch. The reader should note, however, that many of the important ion channels in vascular smooth muscle are also important in heart muscle (see Table 2 1).

Electromechanical versus Pharmacomechanical Coupling

In smooth muscle, changes in intracellular free Ca²⁺ levels can occur both with and without changes in membrane potential. The processes involved are called electromechanical coupling and pharmacomechanical coupling, respectively, and are illustrated in Figure 7 1.

Electromechanical coupling, shown in the left half of Figure 7 1, occurs because the smooth muscle surface membrane contains voltage-operated channels for calcium (the same VOCs that are involved in action potential generation). Membrane depolarization increases the open-state probability of these channels and thus leads to smooth muscle cell contraction and vessel constriction. Conversely, membrane hyperpolarization leads to smooth muscle relaxation and vessel dilation. Because the VOCs for Ca²⁺ are partially activated by the low resting membrane potential of vascular smooth muscle, changes in resting potential can alter the resting calcium influx rate and therefore the basal contractile state.

With pharmacomechanical coupling, chemical agents (eg, released neurotransmitters) can induce smooth muscle contraction without the need for a change in membrane potential. As illustrated in the right side of Figure 7 1, the combination of a vasoconstrictor agonist (such as norepinephrine) with a specific membrane-bound receptor (such as an ₁-adrenergic receptor) initiates events that cause intracellular free Ca²⁺ levels to increase for two reasons. One, the activated receptor may open surface membrane receptor-operated channels (ROCs) for Ca²⁺ that allow Ca²⁺ influx from the extracellular fluid. Two, the activated receptor may induce the formation of an intracellular "second messenger," inositol trisphosphate (IP₃), that opens specific channels that release Ca²⁺ from the intracellular sarcoplasmic reticulum stores. In both processes, the activated receptor first stimulates specific guanosine triphosphate binding proteins (GTP-binding proteins or "G proteins"). Such receptor-associated G proteins seem to represent a general first step through which most membrane receptors operate to initiate their particular cascade of events that ultimately lead to specific cellular responses.

The reader should not conclude from Figure 7 1 that all vasoactive chemical agents (chemical agents that cause vascular effects) produce their actions on smooth muscle without changing membrane potential. In fact, most vasoactive chemical agents do cause changes in membrane potential because their receptors can be linked, by G proteins or other means, to ion channels of many kinds.

Not shown in Figure 7 1 are the processes that remove Ca²⁺ from the cytoplasm of vascular smooth muscle although they are important as well in determining the free cytosolic Ca²⁺ levels. As in cardiac cells (see Figure 2 7), smooth muscle cells actively pump calcium into the sarcoplasmic reticulum and outward across the sarcolemma. Calcium is also countertransported out of the cell in exchange for sodium.

Mechanisms for Relaxation

Hyperpolarization of the cell membrane is one mechanism for causing smooth muscle relaxation and vessel dilation. In addition, however, there are at least two general mechanisms by which certain chemical vasodilator agents can cause smooth muscle relaxation by pharmacomechanical means. In Figure 7 1, the specific receptor for a chemical vasoconstrictor agent is shown linked by a specific G protein to phospholipase C. In an analogous manner, other specific receptors may be linked by other specific G proteins to other enzymes that produce second messengers other than IP₃. An example is the ₂-adrenergic receptor¹ that is present in arterioles of skeletal muscle and liver. ₂-receptors are not innervated but can sometimes be activated by abnormally elevated levels of circulating epinephrine. The ₂-receptor is linked by a particular G protein (G_s) to adenylate cyclase. Adenylate cyclase catalyzes the conversion of ATP to cyclic adenosine monophosphate (cAMP). Increased intracellular levels of cAMP cause the activation of protein kinase A, a phosphorylating enzyme that in turn causes phosphorylation of proteins at many sites. The overall result is stimulation of Ca²⁺ efflux, membrane hyperpolarization, and decreased contractile machinery sensitivity to Ca²⁺ all of which act synergistically to cause vasodilation. In addition to epinephrine, histamine and vasoactive intestinal peptide are vasodilator substances that act through the cAMP pathway.

In addition to cAMP, cyclic guanosine monophosphate (cGMP) is an important intracellular second messenger that causes vascular smooth muscle relaxation by mechanisms that are not yet clear. Nitric oxide is an important vasodilator substance that operates via the cGMP pathway. Nitric oxide can be produced by endothelial cells and also by nitrates a clinically important class of vasodilator drugs. Nitric oxide is gaseous and easily diffuses into smooth muscle cells, where it activates the enzyme guanylyl cyclase that in turn causes cGMP formation from GTP.

¹ Vascular -receptors are designated ₂-receptors and are pharmacologically distinct from the ₁-receptors found on cardiac cells.

Vascular Tone

Vascular tone is a term commonly used to characterize the general contractile state of a vessel or a vascular region. The "vascular tone" of a region can be taken as an indication of the "level of activation" of the individual smooth muscle cells in that region. Actually, this association is a statistical one because rarely do all the cells in a vessel or all the vessels in a vascular region act in precise unison.

Control of Arteriolar Tone

As described in Chapter 6, the blood flow through any organ is determined largely by its vascular resistance, which is dependent primarily on the diameter of its arterioles. Consequently, an organ's flow is controlled by factors that influence the arteriolar smooth muscle tone.

Basal Tone

Arterioles remain in a state of partial constriction even when all external influences on them are removed; hence they are said to have a degree of basal tone. The understanding of the mechanism is incomplete, but basal arteriolar tone may be a reflection of the fact that smooth muscle cells inherently and actively resist being stretched as they continually are in pressurized arterioles. In any case, this basal tone establishes a baseline of partial arteriolar constriction from which the external influences on arterioles exert their dilating or constricting effects. These influences can be separated into three categories: local influences, neural influences, and hormonal influences.

Local Influences on Arterioles

Local Metabolic Influences

The arterioles that control flow through a given organ lie within the organ tissue itself. Thus, arterioles and the smooth muscle in their walls are exposed to the chemical composition of the interstitial fluid of the organ they serve. The interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Interstitial oxygen levels, for example, fall whenever the tissue cells are using oxygen faster than it is being supplied to the tissue by blood flow. Conversely, interstitial oxygen levels rise whenever excess oxygen is being delivered to a tissue from the blood. In nearly all vascular beds, exposure to low oxygen reduces arteriolar tone and causes vasodilation, whereas high oxygen levels cause arteriolar vasoconstriction.² Thus, a local feedback mechanism exists that automatically operates on arterioles to regulate a tissue's blood flow in accordance with its metabolic needs. Whenever blood flow and oxygen delivery fall below a tissue's oxygen demands, the oxygen levels around arterioles fall, the arterioles dilate, and the blood flow through the organ appropriately increases.

Many substances in addition to oxygen are present within tissues and can affect the tone of vascular smooth muscle. When the metabolic rate of skeletal muscle is increased by exercise, for example, not only do tissue levels of oxygen decrease, but those of carbon dioxide, H⁺, and K⁺ increase. Muscle tissue osmolarity also increases during exercise. All of these chemical alterations cause arteriolar dilation. In addition, with increased metabolic activity or oxygen deprivation, cells in many tissues may release adenosine, which is an extremely potent vasodilator agent.

At present, it is not known which of these (or possibly other) metabolically related chemical alterations within tissues are most important in the local metabolic control of blood flow. It appears likely that arteriolar tone depends on the combined action of many factors.

For conceptual purposes, Figure 7 2 summarizes current understanding of local metabolic control. Vasodilator factors enter the interstitial space from the tissue cells at a rate proportional to tissue metabolism. These vasodilator factors are removed from the tissue at a rate proportional to blood flow. Whenever tissue metabolism is proceeding at a rate for which the blood flow is inadequate, the interstitial vasodilator factor concentrations automatically build up and cause the arterioles to dilate. This, of course, causes blood flow to increase. The process continues until blood flow has risen sufficiently to appropriately match the tissue metabolic rate and prevent further accumulation of vasodilator factors. The same system also operates to reduce blood flow when it is higher than required by the tissue's metabolic activity, because this situation causes a reduction in the interstitial concentrations of metabolic vasodilator factors.

Local metabolic mechanisms represent by far the most important means of local flow control. By these mechanisms, individual organs are able to regulate their own flow in accordance with their metabolic needs. As indicated below, several other types of local influences on blood vessels have been identified. However, many of these represent fine-tuning mechanisms and many are important only in certain, usually pathological, situations.

² An important exception to this rule occurs in the pulmonary circulation and will be discussed later in this chapter.

Local Influences from Endothelial Cells

Endothelial cells cover the entire inner surface of the cardiovascular system. A large number of studies have shown that blood vessels respond very differently to certain vascular influences when their endothelial lining is missing. Acetylcholine, for example, causes vasodilation of intact vessels but causes vasoconstriction of vessels stripped of their endothelial lining. This and other similar results have led to the realization that endothelial cells respond to various stimuli by producing a local factor that can decrease the tone of the overlying smooth muscle layers. Originally called EDRF (endothelial derived relaxing factor), this substance has now been identified as nitric oxide. It is produced within endothelial cells from the amino acid, L-arginine, by the action of an enzyme, nitric oxide synthase. Nitric oxide synthase is activated by a rise in the intracellular level of the Ca²⁺. Nitric oxide is a small lipid-soluble molecule that, once formed, easily diffuses into adjacent smooth muscle cells where it causes relaxation by stimulating cGMP production as mentioned previously.

Acetylcholine and several other agents (including bradykinin, vasoactive intestinal peptide, and substance P) stimulate endothelial cell nitric oxide production because their receptors on endothelial cells are linked to receptor-operated Ca²⁺ channels. Probably more importantly from a physiological standpoint, flow-related shear stresses on endothelial cells stimulates their nitric oxide production presumably because stretch-sensitive channels for Ca²⁺ are activated. Such flow-related endothelial cell nitric oxide production probably explains why, for example, exercise and increased blood flow through muscles of the lower leg can cause dilation of the blood-supplying femoral artery at points far upstream of the exercising muscle itself.

Agents that block nitric oxide production by inhibiting nitric oxide synthase cause significant increases in the vascular resistances of most resting organs. For this reason, it is believed that endothelial cells are normally always producing some nitric oxide that is importantly involved, along with other factors, in reducing the normal net resting tone of arterioles throughout the body.

Endothelial cells have also been shown to produce several other locally acting vasoactive agents including the vasodilators "endothelial-derived hyperpolarizing factor" (EDHF) and prostacyclin (PGI₂) and the vasoconstrictor endothelin. The roles of these agents in the overall scheme of normal checks and balances on local flow control is speculative at present.

Other Local Chemical Influences

In addition to the local metabolic influences on vascular tone, many specific locally produced and locally acting chemical substances have been identified that have vascular effects and therefore could be important in local vascular regulation in certain instances. In most cases, however, definite information about the relative importance of these substances in cardiovascular regulation is lacking.

Prostaglandins and thromboxane are a group of several chemically related products of the cyclooxygenase pathway of arachidonic acid metabolism. Certain prostaglandins are potent vasodilators while others are potent vasoconstrictors. Despite the vasoactive potency of the prostaglandins and the fact that most tissues (including endothelial cells and vascular smooth muscle cells) are capable of synthesizing prostaglandins, it has not been demonstrated convincingly that prostaglandins play a crucial role in normal vascular control. It is clear, however, that vasodilator prostaglandins are involved in inflammatory responses. Consequently, inhibitors of prostaglandin synthesis, such as aspirin, are effective anti-inflammatory drugs. Prostaglandins produced by platelets and endothelial cells are important in the hemostatic (flow stopping, antibleeding) vasoconstrictor and platelet-aggregating responses to vascular injury. Hence, aspirin is often prescribed to reduce the tendency for blood clotting especially in patients with potential coronary flow limitations. Arachidonic acid metabolites produced via the lipoxygenase system (eg, leukotrienes) also have vasoactive properties and may influence blood flow and vascular permeability during inflammatory processes.

Histamine is synthesized and stored in high concentrations in secretory granules of tissue mast cells and circulating basophils. When released, histamine produces arteriolar vasodilation (via the cAMP pathway) and increases vascular permeability, which leads to edema formation and local tissue swelling. Histamine increases vascular permeability by causing separations in the junctions between the endothelial cells that line the vascular system. Histamine release is classically associated with antigen-antibody reactions in various allergic and immune responses. Many drugs and physical or chemical insults that damage tissue also cause histamine release. Histamine can stimulate sensory nerve endings to cause itching and pain sensations. While clearly important in many pathological situations, it seems unlikely that histamine participates in normal cardiovascular regulation.

Bradykinin is a small polypeptide that has about 10 times the vasodilator potency of histamine on a molar basis. It also acts to increase capillary permeability by opening the junctions between endothelial cells. Bradykinin is formed from certain plasma globulin substrates by the action of an enzyme, kallikrein, and is subsequently rapidly degraded into inactive fragments by various tissue kinases. Like histamine, bradykinin is thought to be involved in the vascular responses associated with tissue injury and immune reactions. It also stimulates nocioceptive nerves and may thus be involved in the pain associated with tissue injury.

Transmural Pressure

The passive elastic mechanical properties of arteries and veins and how changes in transmural pressure affect their diameters were discussed in Chapter 6. The effect of transmural pressure on arteriolar diameter is more complex because arterioles respond both passively and actively to changes in transmural pressure. For example, a sudden increase in the internal pressure within an arteriole produces (1) first an initial slight passive mechanical distention (slight because arterioles are relatively thick-walled and muscular), and (2) then an active constriction that, within seconds, may completely reverse the initial distention. A sudden decrease in transmural pressure elicits essentially the opposite response, ie, an immediate passive decrease in diameter followed shortly by a decrease in active tone which returns the arteriolar diameter to near that which existed before the pressure change. The active phase of such behavior is referred to as a myogenic response, because it seems to originate within the smooth muscle itself. The mechanism of the myogenic response is not known for certain, but stretch-sensitive ion channels on arteriolar vascular smooth muscle cells are likely candidates for involvement.

All arterioles have some normal distending pressure to which they probably are actively responding. Therefore, the myogenic mechanism is likely to be a fundamentally important factor in determining the basal tone of arterioles everywhere. Also, for obvious reasons and as will be soon discussed, the myogenic response is potentially involved in the vascular reaction to any cardiovascular disturbance that involves a change in arteriolar transmural pressure.

Flow Responses Caused by Local Mechanisms

In organs with a highly variable metabolic rate, such as skeletal and cardiac muscle, the blood flow closely follows the tissue's metabolic rate. For example, skeletal muscle blood flow increases within seconds of the onset of muscle exercise and returns to control values shortly after exercise ceases. This phenomenon, which is illustrated in Figure 7 3A, is known as exercise or active hyperemia (hyperemia means high flow). It should be clear how active hyperemia could result from the local metabolic vasodilator feedback on arteriolar smooth muscle. As alluded to previously, once initiated by local metabolic influences on small resistance vessels, endothelial flow-dependent mechanisms may assist in propagating the vasodilation to larger vessels upstream, which helps promote the delivery of blood to the exercising muscle.

Reactive or postocclusion hyperemia is a higher than normal blood flow that occurs transiently after the removal of any restriction that has caused a period of lower than normal blood flow. The phenomenon is illustrated in Figure 7 3B. For example, flow through an extremity is higher than normal for a period after a tourniquet is removed from the extremity. Both local metabolic and myogenic mechanisms may be involved in producing reactive hyperemia. The magnitude and duration of reactive hyperemia depend on the duration and severity of the occlusion as well as the metabolic rate of the tissue. These findings are best explained by an interstitial accumulation of metabolic vasodilator substances during the period of flow restriction. However, unexpectedly large flow increases can follow arterial occlusions lasting only 1 or 2 seconds. These may be explained best by a myogenic dilation response to the reduced intravascular pressure and decreased stretch of the arteriolar walls that exists during the period of occlusion.

Except when displaying active and reactive hyperemia, nearly all organs tend to keep their blood flow constant despite variations in arterial pressure ie, they autoregulate blood flow. As shown in Figure 7 4A, an abrupt increase in arterial pressure is normally accompanied by an initial abrupt increase in organ blood flow that then gradually returns toward normal despite the sustained elevation in arterial pressure. The initial rise in flow with increased pressure is expected from the basic flow equation ( = P/R). The subsequent return of flow toward the normal level is caused by a gradual increase in active arteriolar tone and resistance to blood flow. Ultimately, a new steady state is reached with only slightly elevated blood flow because the increased driving pressure is counteracted by a higher than normal vascular resistance. As with the phenomenon of reactive hyperemia, blood flow autoregulation may be caused by both local metabolic feedback mechanisms and myogenic mechanisms. The arteriolar vasoconstriction responsible for the autoregulatory response shown in Figure 7 4A, for example, may be partially due to (1) a "washout" of metabolic vasodilator factors from the interstitium by the excessive initial blood flow and (2) a myogenic increase in arteriolar tone stimulated by the increase in stretching forces that the increase in pressure imposes on the vessel walls. There is also a tissue pressure hypothesis of blood flow autoregulation for which it is assumed that an abrupt increase in arterial pressure causes transcapillary fluid filtration and thus leads to a gradual increase in interstitial fluid volume and pressure. Presumably the increase in extravascular pressure would cause a decrease in vessel diameter by simple compression. This mechanism might be especially important in organs such as the kidney and brain whose volumes are constrained by external structures.

Although not illustrated in Figure 7 4A, autoregulatory mechanisms operate in the opposite direction in response to a decrease in arterial pressure below the normal value. One important general consequence of local autoregulatory mechanisms is that the steady state blood flow in many organs tends to remain near the normal value over quite a wide range of arterial pressure. This is illustrated in the graph of Figure 7 4B. As will be discussed later, the inherent ability of certain organs to maintain adequate blood flow despite lower than normal arterial pressure is of considerable importance in situations such as shock from blood loss.

Neural Influences on Arterioles

Sympathetic Vasoconstrictor Fibers

These neural fibers innervate arterioles in all systemic organs and provide by far the most important means of reflex control of the vasculature. Sympathetic vasoconstrictor nerves are the backbone of the system for controlling total peripheral resistance and thus are essential participants in global cardiovascular tasks such as regulating arterial blood pressure.

Sympathetic vasoconstrictor nerves release norepinephrine from their terminal structures in amounts generally proportional to their electrical activity.^3,4 Norepinephrine causes an increase in the tone of arterioles after combining with an a₁-adrenergic receptor on smooth muscle cells. Norepinephrine appears to increase vascular tone primarily by pharmacomechanical means. The mechanism involves G protein linkage of a-adrenergic receptors to phospholipase C and subsequent Ca²⁺ release from intracellular stores by the action of the second messenger IP₃, as was illustrated in the pharmacomechanical section of Figure 7 1.

Sympathetic vasoconstrictor nerves normally have a continual or tonic firing activity. This tonic activity of sympathetic vasoconstrictor nerves makes the normal contractile tone of arterioles considerably greater than their basal tone. The additional component of vascular tone is called neurogenic tone. When the firing rate of sympathetic vasoconstrictor nerves is increased above normal, arterioles constrict and cause organ blood flow to fall below normal. Conversely, vasodilation and increased organ blood flow can be caused by sympathetic vasoconstrictor nerves if their normal tonic activity level is reduced. Thus, an organ's blood flow can either be reduced below normal or be increased above normal by changes in the sympathetic vasoconstrictor fiber firing rate.

³ Pharmacological studies indicate that the amount of norepinephrine released from sympathetic nerves at a given level of electrical activity can be modulated by presynaptic influences from a variety of agents. Norepinephrine release from sympathetic nerves is inhibited by high extracellular K⁺, adenosine, certain prostaglandins, acetylcholine, and by norepinephrine itself. The latter effect is mediated by ₂-adrenergic receptors located on the sympathetic nerves. These receptors are pharmacologically distinct from the ₁-adrenergic receptors on smooth muscle cells. Angiotensin can enhance norepinephrine release from sympathetic nerves. Whether such effects are important in physiological situations is unclear at present.

⁴ In addition to norepinephrine, sympathetic vasoconstrictor nerves to some tissues are now thought to also release some ATP and neuropeptide Y as "cotransmitters." Like norepinephrine, these agents promote vessel constriction.

Other Neural Influences

Blood vessels, as a general rule, do not receive innervation from the parasympathetic division of the autonomic nervous system. However, parasympathetic vasodilator nerves, which release acetylcholine, are present in the vessels of the brain and the heart but their influence on arteriolar tone in these organs appears to be inconsequential. Parasympathetic vasodilator nerves are also present in the vessels of the salivary glands, pancreas, gastric mucosa, and external genitalia. In the latter, they are responsible for the vasodilation of inflow vessels responsible for erection.

Hormonal Influences on Arterioles

Under normal circumstances hormonal influences on blood vessels are generally thought to be of minor consequence in comparison to the local metabolic and neural influences. However, it should be emphasized that the understanding of how the cardiovascular system operates in many situations is incomplete. Thus, the hormones discussed below may play more important roles in cardiovascular regulation than is now appreciated.

Circulating Catecholamines

During activation of the sympathetic nervous system, the adrenal glands release the catecholamines epinephrine and norepinephrine into the bloodstream. Under normal circumstances, the blood levels of these agents are probably not high enough to cause significant cardiovascular effects. However, circulating catecholamines may have cardiovascular effects in situations (such as vigorous exercise or hemorrhagic shock) that involve high activity of the sympathetic nervous system. In general, the cardiovascular effects of high levels of circulating catecholamines parallel the direct effects of sympathetic activation which have already been discussed; both epinephrine and norepinephrine can activate cardiac ₁-adrenergic receptors to increase heart rate and myocardial contractility and can activate vascular -receptors to cause vasoconstriction. Recall that in addition to the ₁-receptors that mediate vasoconstriction, arterioles in a few organs also possess ₂-adrenergic receptors that mediate vasodilation. Because vascular ₂-receptors are more sensitive to epinephrine than are vascular ₁-receptors, moderately elevated levels of circulating epinephrine can cause vasodilation whereas higher levels cause ₁-receptor-mediated vasoconstriction. Vascular ₂-receptors are not innervated and therefore are not activated by norepinephrine released from sympathetic vasoconstrictor nerves. The physiological importance of these vascular ₂-receptors is unclear because adrenal epinephrine release occurs during periods of increased sympathetic activity when arterioles would simultaneously be undergoing direct neurogenic vasoconstriction. Again, under normal circumstances, circulating catecholamines are not an important factor in cardiovascular regulation.

Vasopressin

This polypeptide hormone, also known as antidiuretic hormone (ADH), plays an important role in extracellular fluid homeostasis and is released into the bloodstream from the posterior pituitary gland in response to low blood volume and/or high extracellular fluid osmolarity. Vasopressin acts on collecting ducts in the kidneys to decrease renal excretion of water. Its role in body fluid balance has some very important indirect influences on cardiovascular function, which will be discussed in more detail in Chapter 9. Vasopressin, however, is also a potent arteriolar vasoconstrictor. While it is not thought to be significantly involved in normal vascular control, direct vascular constriction from abnormally high levels of vasopressin may be important in the response to certain disturbances such as severe blood loss through hemorrhage.

Angiotensin II

Angiotensin II is a circulating polypeptide that regulates aldosterone release from the adrenal cortex as part of the system for controlling body sodium balance. This system, to be discussed in greater detail in Chapter 9, is very important in blood volume regulation. Angiotensin II is also a very potent vasoconstrictor agent. Although it should not be viewed as a normal regulator of arteriolar tone, direct vasoconstriction from angiotensin II seems to be an important component of the general cardiovascular response to severe blood loss. There is also strong evidence suggesting that direct vascular actions of angiotensin II may be involved in intrarenal mechanisms for controlling kidney function. In addition, angiotensin II may be partially responsible for the abnormal vasoconstriction that accompanies many forms of hypertension. Again, it should be emphasized that knowledge of many pathological situations including hypertension is incomplete. These situations may well involve vascular influences that are not yet recognized.

Control of Venous Tone

Before considering the details of the control of venous tone, recall that venules and veins play a much different role in the cardiovascular system than do arterioles. Arterioles are the inflow valves that control the rate of nutritive blood flow through organs and individual regions within them. Appropriately, arterioles are usually strongly influenced by the current local metabolic needs of the region in which they reside, whereas veins are not. Veins do, however, collectively regulate the distribution of available blood volume between the peripheral and central venous compartments. Recall that central blood volume (and therefore pressure) has a marked influence on stroke volume and cardiac output. Consequently, when one considers what peripheral veins are doing, one should be thinking primarily about what the effects will be on central venous pressure and cardiac output.

Veins contain vascular smooth muscle that is influenced by many of the things that influence vascular smooth muscle of arterioles. Constriction of the veins (venoconstriction) is largely mediated through activity of the sympathetic nerves that innervate them. As in arterioles, these sympathetic nerves release norepinephrine, which interacts with ₁-receptors and produces an increase in venous tone and a decrease in vessel diameter. There are, however, several functionally important differences between veins and arterioles. Compared with arterioles, veins normally have little basal tone. Thus, veins are normally in a dilated state. One important consequence of the lack of basal venous tone is that vasodilator metabolites that may accumulate in the tissue have little effect on veins.

Because of their thin walls, veins are much more susceptible to physical influences than are arterioles. The large effect of internal venous pressure on venous diameter was discussed in Chapter 6 and is evident in the pooling of blood in the veins of the lower extremities that occurs during prolonged standing (as will be discussed further in Chapter 10).

Often external compressional forces are an important determinant of venous volume. This is especially true of veins in skeletal muscle. Very high pressures are developed inside skeletal muscle tissue during contraction and cause venous vessels to collapse. Because veins and venules have one-way valves, the blood displaced from veins during skeletal muscle contraction is forced in the forward direction toward the right heart. In fact, rhythmic skeletal muscle contractions can produce a considerable pumping action, often called the skeletal muscle pump, which helps return blood to the heart during exercise.

Summary of Primary Vascular Control Mechanisms

Vessels are subject to a wide variety of influences, and special influences often apply to particular organs. Certain general factors, however, dominate the control of the peripheral vasculature when it is viewed from the standpoint of overall cardiovascular system function; these influences are summarized in Figure 7 5. Basal tone, local metabolic vasodilator factors, and sympathetic vasoconstrictor nerves acting through ₁-receptors are the major factors controlling arteriolar tone and therefore the blood flow rate through peripheral organs. Sympathetic vasoconstrictor nerves, internal pressure, and external compressional forces are the most important influences on venous diameter and therefore on peripheral-central distribution of blood volume.

Vascular Control in Specific Organs

As will become evident in the remaining sections of this chapter, many details of vascular control vary from organ to organ. However, with regard to flow control, most organs can be placed somewhere in a spectrum that ranges from almost total dominance by local metabolic mechanisms to almost total dominance by sympathetic vasoconstrictor nerves.

The flow in organs like the brain, heart muscle, and skeletal muscle is very strongly controlled by local metabolic control whereas the flow in the kidneys, skin, and splanchnic organs is very strongly controlled by sympathetic nerve activity. Consequently, some organs are automatically forced to participate in overall cardiovascular reflex responses to a greater extent than are other organs. The overall plan seems to be that in cardiovascular emergency, flow to the brain and heart will be preserved at the expense of everything else if need be.

Coronary Blood Flow

The major right and left coronary arteries that serve the heart tissue are the first vessels to branch off the aorta. Thus the driving force for myocardial blood flow is the systemic arterial pressure, just as it is for other systemic organs. Most of the blood that flows through the myocardial tissue returns to the right atrium by way of a large cardiac vein called the coronary sinus.

Local Metabolic Control

As emphasized before, coronary blood flow is controlled primarily by local metabolic mechanisms and thus it responds rapidly and accurately to changes in myocardial oxygen consumption. In a resting individual, the myocardium extracts 70 75% of the oxygen in the blood that passes through it. Coronary sinus blood normally has a lower oxygen content than blood at any other place in the cardiovascular system. Myocardial oxygen extraction cannot increase significantly from its resting value. Consequently, increases in myocardial oxygen consumption must be accompanied by appropriate increases in coronary blood flow.

The issue of which metabolic vasodilator factors play the dominant role in modulating the tone of coronary arterioles is unresolved at present. Many believe that adenosine, released from myocardial muscle cells in response to increased metabolic rate, may be an important local coronary metabolic vasodilator influence. Regardless of the specific details, myocardial oxygen consumption is the most important influence on coronary blood flow.

Systolic Compression

Large forces and/or pressures are generated within the myocardial tissue during cardiac muscle contraction. Such intramyocardial forces press on the outside of coronary vessels and cause them to collapse during systole. Because of this systolic compression and the associated collapse of coronary vessels, coronary vascular resistance is greatly increased during systole. The result, at least for much of the left ventricular myocardium, is that coronary flow is lower during systole than during diastole, even though systemic arterial pressure (ie, coronary perfusion pressure) is highest during systole. This is illustrated in the left coronary artery flow trace shown in Figure 7 6. Systolic compression has much less effect on flow through the right ventricular myocardium, as is evident from the right coronary artery flow trace in Figure 7 6. This is because the peak systolic intraventricular pressure is much lower for the right heart than for the left, and the systolic compressional forces in the right ventricular wall are correspondingly less than those in the left ventricular wall.

Systolic compressional forces on coronary vessels are greater in the endocardial (inside) layers of the left ventricular wall than in the epicardial layers.⁵ Thus, the flow to the endocardial layers of the left ventricle is impeded more than the flow to epicardial layers by systolic compression. Normally, the endocardial region of the myocardium can make up for the lack of flow during systole by a high flow in the diastolic interval. However, when coronary blood flow is limited for example, by coronary disease and stenosis the endocardial layers of the left ventricle are often the first regions of the heart to have difficulty maintaining a flow sufficient for their metabolic needs. Myocardial infarcts (areas of tissue killed by lack of blood flow) occur most frequently in the endocardial layers of the left ventricle.

⁵ Consider that the endocardial surface of the left ventricle is exposed to intraventricular pressure ( 120 mmHg during systole), while the epicardial surface is exposed only to intrathoracic pressure ( 0 mmHg).

Neural Influences on Coronary Flow

Coronary arterioles are densely innervated with sympathetic vasoconstrictor fibers, yet when the activity of the sympathetic nervous system increases, the coronary arterioles normally vasodilate rather than vasoconstrict. This is because an increase in sympathetic tone increases myocardial oxygen consumption by increasing heart rate and contractility. The increased local metabolic vasodilator influence apparently outweighs the concurrent vasoconstrictor influence due to an increase in the activity of sympathetic vasoconstrictor fibers that terminate on coronary arterioles. It has been experimentally demonstrated that a given increase in cardiac sympathetic nerve activity causes a greater increase in coronary blood flow after the direct vasoconstrictor influence of sympathetic nerves on coronary vessels has been eliminated with -receptor blocking agents. However, sympathetic vasoconstrictor nerves do not appear to influence coronary flow enough to affect the mechanical performance of normal hearts. Whether these coronary vasoconstrictor fibers might be functionally important in certain pathological situations is an open question.

Skeletal Muscle Blood Flow

Collectively, the skeletal muscles constitute 40 45% of body weight more than any other single body organ. Even at rest, about 15% of the cardiac output goes to skeletal muscle, and during strenuous exercise skeletal muscle may receive more than 80% of the cardiac output. Thus, skeletal muscle blood flow is an important factor in overall cardiovascular hemodynamics.

Because of a high level of intrinsic tone of the resistance vessels in resting skeletal muscles, the blood flow per gram of tissue is quite low when compared with that of other organs such as the kidneys. However, resting skeletal muscle blood flow is still substantially above that required to sustain its metabolic needs. Resting skeletal muscles normally extract only 25 30% of the oxygen delivered to them in arterial blood. Changes in the activity of sympathetic vasoconstrictor fibers do alter resting muscle blood flow. For example, maximum sympathetic discharge rates can decrease blood flow in a resting muscle to less than one fourth its normal value, and conversely, if all neurogenic tone is removed, resting skeletal muscle blood flow may double. This is a modest increase in flow compared with the 20-fold increase in flow that can occur in an exercising skeletal muscle. Nonetheless, because of the large mass of tissue involved, changes in the vascular resistance of resting skeletal muscle brought about by changes in sympathetic activity are very important in the overall reflex regulation of arterial pressure.

A particularly important characteristic of skeletal muscle is its very wide range of metabolic rates. During heavy exercise, the oxygen consumption rate of and oxygen extraction by skeletal muscle tissue can reach the high values typical of the myocardium. In most respects, the factors that control blood flow to exercising muscle are similar to those that control coronary blood flow. Local metabolic control of arteriolar tone is very strong in exercising skeletal muscle, and muscle oxygen consumption is the most important determinant of blood flow in exercising skeletal muscle.

As will be discussed in Chapter 10, the cardiovascular response to muscle exercise involves a general increase in sympathetic activity. This of course reduces flow to susceptible organs, which include non-exercising muscles. In exercising muscles, the increased sympathetic vasoconstrictor nerve activity is not evident as outright vasoconstriction but does limit the degree of metabolic vasodilation. One important function that this seemingly counterproductive process may serve is that of preventing an excessive reduction in total peripheral resistance (TPR) during exercise. Indeed, if arterioles in most of the skeletal muscles in the body were allowed to dilate to their maximum capacity simultaneously, TPR would be so low that the heart could not possibly supply enough cardiac output to maintain arterial pressure.

As in the heart, muscle contraction produces large compressional forces within the tissue, which can collapse vessels and impede blood flow. Strong, sustained (tetanic) skeletal muscle contractions may actually stop muscle blood flow. About 10% of the total blood volume is normally contained within the veins of skeletal muscle, and during rhythmic exercise the "skeletal muscle pump" is very effective in displacing blood from skeletal muscle veins. Blood displaced from skeletal muscle into the central venous pool is an important factor in the hemodynamics of strenuous whole body exercise.

The veins in skeletal muscle are rather sparsely innervated with sympathetic vasoconstrictor fibers, and the rather small volume of blood that can be mobilized from skeletal muscle by sympathetic nerve activation is probably not of much significance to total body hemodynamics. This is in sharp contrast to the large displacement of blood from exercising muscle by the muscle pump mechanism.

Cerebral Blood Flow

Adequate cerebral blood flow is of paramount importance for survival because unconsciousness occurs very rapidly after an interruption in flow. One rule of overall cardiovascular system function is that, in all situations, measures are taken that are appropriate to preserve adequate blood flow to the brain.

The brain as a whole has a nearly constant rate of metabolism that, on a per gram basis, is nearly as high as that of myocardial tissue. Cerebral blood flow appears to be regulated almost entirely by local mechanisms. Flow through the cerebrum is autoregulated very strongly and is little affected by changes in arterial pressure unless it falls below about 60 mmHg. When arterial pressure decreases below 60 mmHg, brain blood flow decreases proportionately. It is presently unresolved whether metabolic mechanisms or myogenic mechanisms or both are involved in the phenomenon of cerebral autoregulation.

Presumably because the overall average metabolic rate of brain tissue shows little variation, total brain blood flow is remarkably constant over nearly all situations. The cerebral activity in discrete locations within the brain, however, changes from situation to situation. As a result, blood flow to discrete regions is not constant but closely follows the local neuronal activity. The mechanisms responsible for this strong local control of cerebral blood flow are as yet undefined, but H⁺, K⁺, oxygen, and adenosine seem most likely to be involved.

Cerebral blood flow does increase whenever the partial pressure of carbon dioxide (PCO₂) is raised above normal in the arterial blood. Conversely, cerebral blood flow decreases whenever arterial blood PCO₂ falls below normal. It appears that cerebral arterioles respond not to changes in PCO₂ but to changes in the extracellular H⁺ concentration (ie, pH) caused by changes in PCO₂. Cerebral arterioles also vasodilate whenever the partial pressure of oxygen (PO₂) in arterial blood falls significantly below normal values. Higher than normal arterial blood PO₂, such as that caused by oxygen inhalation, produces little decrease in cerebral blood flow.

Although cerebral vessels receive both sympathetic vasoconstrictor and parasympathetic vasodilator fiber innervation, cerebral blood flow is influenced very little by changes in the activity of either under normal circumstances. Sympathetic vasoconstrictor responses may, however, be important in protecting cerebral vessels from excessive passive distention following large, abrupt increases in arterial pressure.

Brain capillaries are unique in that they are considerably less porous than those in other organs, and they greatly restrict the transcapillary movement of all polar particles. The diffusional restriction and other specific metabolic mechanisms associated with the endothelial cells of brain capillaries constitute what is known as the blood-brain barrier.⁶ Because of the blood-brain barrier, the extracellular space of the brain represents a special fluid compartment in which the chemical composition is regulated separately from that in the plasma and general body extracellular fluid compartment. The extracellular compartment of the brain encompasses both interstitial fluid and cerebrospinal fluid (CSF) which surrounds the brain and spinal cord and fills the brain ventricles. The CSF is formed from plasma by selective secretion (not simple filtration) by specialized tissues, the choroid plexes, located within the ventricles. These processes regulate the chemical composition of the CSF. The interstitial fluid of the brain takes on the chemical composition of CSF through free diffusional exchange.

The blood-brain barrier serves to protect the cerebral cells from ionic disturbances in the plasma. Also, by exclusion and/or endothelial cell metabolism, it prevents many circulating hormones (and drugs) from influencing the parenchymal cells of the brain and the vascular smooth muscle cells in brain vessels.

⁶ Brain capillaries have a special carrier system for glucose and present no barrier to oxygen and carbon dioxide diffusion. Thus, the blood-brain barrier does not restrict nutrient supply to the brain tissue.

Splanchnic Blood Flow

A number of abdominal organs, including the gastrointestinal tract, spleen, pancreas, and liver, are collectively supplied with what is called the splanchnic blood flow. Splanchnic blood flow is supplied to these abdominal organs through many arteries, but it all ultimately passes through the liver and returns to the inferior vena cava through the hepatic veins.

The organs of the splanchnic region receive about 25% of the resting cardiac output and moreover contain more than 20% of the circulating blood volume. Thus adjustments in either the blood flow or the blood volume of this region have extremely important effects on the cardiovascular system.

There is a great diversity of function among individual organs and even regions within organs in the splanchnic region. Blood flow is required to support secretory and absorptive processes as well as muscular contractions of the gastrointestinal tract. The mechanisms of vascular control in specific areas of the splanchnic region are not well understood but are likely to be quite varied. Nonetheless, since most of the splanchnic organs are involved in the digestion and absorption of food from the gastrointestinal tract, splanchnic blood flow increases after food ingestion. A large meal can elicit a 30 100% increase in splanchnic flow, but individual organs in the splanchnic region probably have higher percentage increases in flow at certain times because they are involved sequentially in the digestion-absorption process.

Collectively, the splanchnic organs have a relatively high blood flow and extract only 15 20% of the oxygen delivered to them in the arterial blood. In general, sympathetic nerves play a major role in vascular control. The arteries and veins of all the organs involved in the splanchnic circulation are richly innervated with sympathetic vasoconstrictor nerves. Maximal activation of sym-

pathetic vasoconstrictor nerves can produce an 80% reduction in flow to the splanchnic region and also cause a large shift of blood from the splanchnic organs to the central venous pool. In humans, a large fraction of the blood mobilized from the splanchnic circulation during periods of sympathetic activation comes from the constriction of veins in the liver. In many other species, the spleen acts as a major reservoir from which blood is mobilized by sympathetically mediated contraction of smooth muscle located in the outer capsule of the organ.

Renal Blood Flow

The kidneys normally receive approximately 20% of the cardiac output of a resting individual, and since this can be reduced to practically zero during strong sympathetic activation, the control of renal blood flow is important to overall cardiovascular function. However, because the kidneys are such small organs, changes in renal blood volume are inconsequential to overall cardiovascular hemodynamics.

Increases in sympathetic vasoconstrictor activity can markedly reduce total renal blood flow by increasing the neurogenic tone of renal resistance vessels. In fact, extreme situations involving intense and prolonged sympathetic vasoconstrictor activity can lead to renal failure.

It has long been known that experimentally isolated kidneys (ie, kidneys deprived of their normal sympathetic input) autoregulate their flow quite strongly. The mechanism responsible for this phenomenon has not been definitely established but myogenic, tissue pressure, and metabolic hypotheses have been advanced. The real question is what purpose such a strong local mechanism plays in the intact organism where it seems to be largely overridden by reflex mechanisms. In an intact individual, renal blood flow is not constant but is highly variable, depending on the prevailing level of sympathetic vasoconstrictor nerve activity. In extreme situations, such as severe blood loss, highly elevated sympathetic nerve activity can reduce renal blood flow to such a low value that permanent kidney damage can occur.

The mechanisms responsible for the intrinsic regulation of renal blood flow and kidney function have not been established. While studies suggest that prostaglandins and some intrarenal renin-angiotensin system may be involved, the whole issue of local renal vascular control remains quite obscure. Renal function is itself of paramount importance to overall cardiovascular function, as will be described in Chapter 9.

Cutaneous Blood Flow

The metabolic activity of body cells produces heat, which must be lost in order for the body temperature to remain constant. The skin is the primary site of exchange of body heat with the external environment. Alterations in cutaneous blood flow in response to various metabolic states and environmental conditions provide the primary mechanism responsible for temperature homeostasis. (Other mechanisms such as shivering, sweating, and panting also participate in body temperature regulation under more extreme conditions.)

Cutaneous blood flow, which is about 6% of the resting cardiac output, can decrease to about one twentieth of its normal value when heat is to be retained (eg, in a cold environment, during the development stages of a fever). In contrast, cutaneous blood flow can increase up to seven times its normal value when heat is to be lost (eg, in a hot environment, accompanying a high metabolic rate, after a fever breaks).

The anatomic interconnections between microvessels in the skin are highly specialized and extremely complex. An extensive system of interconnected veins called the venous plexus normally contains the largest fraction of cutaneous blood volume, which, in individuals with lightly pigmented skin, gives the skin a reddish hue. To a large extent, heat transfer from the blood takes place across the large surface area of the venous plexus. The venous plexus is richly innervated with sympathetic vasoconstrictor nerves. When these fibers are activated, blood is displaced from the venous plexus, and this helps reduce heat loss and also lightens the skin color. Since the skin is one of the largest body organs, venous constriction can shift a considerable amount of blood into the central venous pool.

Cutaneous resistance vessels are also richly innervated with sympathetic vasoconstrictor nerves, and since these fibers have a normal tonic activity, cutaneous resistance vessels normally have a high degree of neurogenic tone. When body temperature rises above normal, skin blood flow is increased by reflex mechanisms. In certain areas (such as the hands, ears, and nose) vasodilation appears to result entirely from the withdrawal of sympathetic vasoconstrictor tone. In other areas (such as the forearm, forehead, chin, neck, and chest) the cutaneous vasodilation that occurs with body heating greatly exceeds that which occurs with just the removal of sympathetic vasoconstrictor tone. This "active" vasodilation is closely linked to the onset of sweating in these areas. The sweat glands in human cutaneous tissue are innervated by cholinergic sympathetic fibers that release acetylcholine. Activation of these nerves elicit sweating and an associated marked cutaneous vasodilation. The exact mechanism for this sweating-related cutaneous vasodilation remains unclear because it is not abolished by agents that block acetylcholine's vascular effects. It has long been thought that it was caused by local bradykinin formation secondary to the process of sweat gland activation. Newer evidence suggests that instead the cholinergic sympathetic nerves to sweat glands may release not only acetylcholine but also other vasodilator cotransmitters. While these special sympathetic nerves are very important to temperature regulation, they do not participate in the normal, moment-to-moment, regulation of the cardiovascular system.

In addition to responding reflexly to changes in body temperature, cutaneous vessels also respond to local skin temperature. In general, local cooling leads to local vasoconstriction and local heating causes local vasodilation. The mechanisms for this are unknown. If the hand is placed in ice water, there is initially a nearly complete cessation of hand blood flow accompanied by intense pain. After some minutes, hand blood flow begins to rise to reach values greatly in excess of the normal value, hand temperature increases, and the pain disappears. This phenomenon is referred to as cold-induced vasodilation. With continued immersion, hand blood flow cycles every few minutes between periods of essentially no flow and periods of hyperemia. The mechanism responsible for cold vasodilation is unknown, but it has been suggested that norepinephrine may lose its ability to constrict vessels when their temperature approaches 0 C. Whatever the mechanism, cold-induced vasodilation apparently serves to protect exposed tissues from cold damage.

Tissue damage from burns, ultraviolet radiation, cold injury, caustic chemicals, and mechanical trauma produce reactions in skin blood flow. A classical reaction called the triple response is evoked after vigorously stroking the skin with a blunt point. The first component of the triple response is a red line that develops along the direct path of the abrasion in about 15 seconds. Shortly thereafter, an irregular red flare appears that extends about 2 cm on either side of the red line. Finally, after a minute or two, a wheal appears along the line of the injury. The mechanisms involved in the triple response are unknown, but it seems likely that histamine release from damaged cells is at least partially responsible for the dilation evidenced by the red line and the subsequent edema formation of the wheal. The red flare seems to involve nerves in some sort of a local axon reflex because it can be evoked immediately after cutaneous nerves are sectioned but not after the peripheral portions of the sectioned nerves degenerate.

Pulmonary Blood Flow

The rate of blood flow through the lungs is necessarily equal to cardiac output in all circumstances. When cardiac output increases 3-fold during exercise, for example, pulmonary blood flow must also increase 3-fold. Whereas the flow through a systemic organ is determined by its vascular resistance ( = P/R), the blood flow rate through the lungs is determined simply by the cardiac output ( = CO). Pulmonary vessels do, however, offer some vascular resistance. Although the level of pulmonary vascular resistance does not usually influence the pulmonary flow rate, it is important because it is one of the determinants of pulmonary arterial pressure (P = x R). Recall that mean pulmonary arterial pressure is about 13 mmHg, whereas mean systemic arterial pressure is about 100 mmHg. The reason for the difference in pulmonary and systemic arterial pressures is not that the right heart is weaker than the left heart but rather that pulmonary vascular resistance is inherently much lower than systemic total peripheral resistance. The pulmonary bed has a low resistance because it has relatively large vessels throughout.

A very important distinction between the systemic and pulmonary arteries and arterioles is that the pulmonary vessels are less muscular and more compliant. When pulmonary arterial pressure increases, the pulmonary arteries and arterioles become larger in diameter. Thus an increase in pulmonary arterial pressure decreases pulmonary vascular resistance. This phenomenon is important because it tends to limit the increase in pulmonary arterial pressure that occurs with increases in cardiac output.

The most important active response in the pulmonary vasculature is the hypoxic vasoconstriction of pulmonary arterioles. Recall that systemic arterioles dilate in response to low PO₂. The mechanisms that cause the opposite response in pulmonary vessels are unclear. Current evidence suggests that local prostaglandin synthesis may be involved in pulmonary hypoxic vasoconstriction. Whatever the mechanism, hypoxic vasoconstriction is essential to efficient lung gas exchange because it diverts blood flow away from areas of the lung that are underventilated. Consequently, the best-ventilated areas of the lung also receive the most blood flow. Presumably as a consequence of hypoxic arteriolar vasoconstriction, general hypoxia (such as that encountered at high altitude) causes an increase in pulmonary vascular resistance and pulmonary arterial hypertension.

Both pulmonary arteries and veins receive sympathetic vasoconstrictor fiber innervation, but reflex influences on pulmonary vessels appear to be much less important than the physical and local hypoxic influences. Pulmonary veins serve a blood reservoir function for the cardiovascular system, and sympathetic vasoconstriction of pulmonary veins may be important in mobilizing this blood during periods of general cardiovascular stress.

A consequence of the low mean pulmonary arterial pressure is the low pulmonary capillary hydrostatic pressure of about 8 mmHg (compared with about 25 mmHg in systemic capillaries). Because the plasma oncotic pressure in lung capillaries is near 25 mmHg, as it is in all capillaries, it is likely that the transcapillary forces in the lungs strongly favor continual fluid reabsorption. This cannot be the complete story, however, since the lungs, like other tissues, continually produce some lymph and some net capillary filtration is required to produce lymphatic fluid. This filtration is possible despite the unusually low pulmonary capillary hydrostatic pressure because pulmonary interstitial fluid has an unusually high protein concentration and thus oncotic pressure.

Key Concepts

Continual adjustments of vascular diameter are required to properly distribute the cardiac output to the various systemic tissues (the role of arterioles) and maintain adequate cardiac filling (the role of veins).

Vascular adjustments are made by changes in the tone of vascular smooth muscle.

Vascular smooth muscle has many unique properties that make it sensitive to a wide array of local and reflex stimuli and capable of maintaining tone for long periods of time.

The tone of arterioles, but not veins, can be strongly influenced by local vasodilator factors produced by local tissue metabolism.

In abnormal situations (like tissue injury or severe blood volume depletion), certain local factors like histamine and bradykinin, and hormonal factors like vasopressin and angiotensin have significant vascular influences.

Sympathetic vasoconstrictor nerves provide the primary reflex mechanisms for regulating both arteriolar and venous tone.

Sympathetic vasoconstrictor nerves release norepinephrine, which interacts with

₁-adrenergic receptors on vascular smooth muscle to induce vasoconstriction.

The relative importance of local metabolic versus reflex sympathetic control of arteriolar tone (and therefore blood flow) varies from organ to organ.

In many organs (such as brain, heart muscle, and exercising skeletal muscle), blood flow normally closely follows metabolic rate because of local metabolic influences on arterioles.

In other organs (such as skin and kidneys) blood flow is normally regulated more by sympathetic nerves than by local metabolic conditions.

Study Questions

7 1. Which of the following would increase blood flow through a skeletal muscle?

a. An increase in tissue PCO₂

b. An increase in tissue adenosine

c. The presence of

-receptor blocking drugs

d. Sympathetic activation

7 2. Autoregulation of blood flow implies that arterial pressure is adjusted by local mechanisms to ensure constant flow through an organ. True or false?

7 3. Coronary blood flow will normally increase when

a. Arterial pressure increases

b. Heart rate increases

c. Sympathetic activity increases

d. The heart is dilated

7 4. The arterioles of skeletal muscle would have little or no tone in the absence of normal sympathetic vasoconstrictor fiber activity. True or false?

7 5. A person who hyperventilates (breathes rapidly and deeply) gets dizzy. Why?

7 6. A patient complains of severe leg pains after walking a short distance. The pains disappear after the patient rests (this symptom is called intermittent claudication). What might be the problem?

7 7. How would a stenotic aortic valve influence coronary blood flow?

See answers.