Steven S. Segal
In the preceding chapters, we considered blood flow to peripheral capillary beds as if the “periphery” were a single entity. In this chapter, we break that entity down into some of its component parts. Because each organ in the body has its own unique set of requirements, special circulations within each organ have evolved with their own particular features and regulatory mechanisms. Especially for times of great stress to the body, each organ possesses circulatory adaptations that allow it to make the changes appropriate for causing minimal harm to the overall organism. Here, we focus on the circulations of the brain, heart, skeletal muscle, abdominal viscera, and skin. We discuss other special circulations in the context of particular organs—the lungs in Chapter 31, the kidneys in Chapter 34, the placenta in Chapter 56, and the fetal circulation in Chapter 57.
The blood flow to individual organs must vary to meet the needs of the particular organ as well as of the whole body
The blood flow to each tissue must meet the nutritional needs of that tissue’s parenchymal cells while at the same time allowing those cells to play their role in the homeostasis of the whole individual. The way in which the circulatory system distributes blood flow must be flexible so that changing demands can be met. In the process of meeting these demands, the body makes compromises. Consider the circulatory changes that accompany exercise. Blood flow to active skeletal muscle increases tremendously through both an increase and a redistribution of cardiac output. Blood flow to the coronary circulation must also rise to meet the demands of exercise. Furthermore, to dispose of the heat generated during exercise, the vessels in the skin dilate, thereby promoting heat transfer to the environment. As cardiac output is increasingly directed to active muscle and skin, circulation to the splanchnic and renal circulations decreases while blood flow to the brain is preserved.
This chapter focuses on the perfusion of select systemic vascular beds, but keep in mind that the lungs receive the entire cardiac output and therefore must also be able to accommodate any changes in total blood flow.
Neural, myogenic, metabolic, and endothelial mechanisms control regional blood flow
Several mechanisms govern vascular resistance and thus the distribution of blood circulating throughout the body. The extent to which a particular bed depends on a particular blood flow control mechanism varies from organ to organ. We have discussed these mechanisms in the preceding chapters and briefly review them here.
The interplay among these four mechanisms establishes a resting level of vasomotor tone. Vascular smooth muscle cells (VSMCs) and endothelial cells also use gap junctions for electrical and chemical signaling between themselves, thereby coordinating their activity during vasomotor control.
In addition to these mechanisms, which are part of a sophisticated feedback control system, other factors—which are not regulatory in nature—can affect the local circulation. These other factors are all mechanical forces that are external to the blood vessels and that tend either to collapse or to open them (see Chapter 22). For example, in the heart and skeletal muscle, muscle contraction transiently halts blood flow by compressing blood vessels within the tissue.
Neural Mechanisms The resistance vessels of nearly every organ are invested with fibers of the autonomic nervous system (ANS), particularly those of the sympathetic division (see Chapter 23). In addition to its critical role in controlling blood pressure and cardiac output, the ANS modulates local blood flow to meet the needs of particular tissues.
Myogenic Mechanisms Many vessels, particularly the muscular arteries and arterioles that govern vascular resistance, are inherently responsive to changes in transmural pressure. Increased pressure and the accompanying stretch of VSMCs elicit vasoconstriction, whereas decreased pressure elicits vasodilation. This myogenic response plays an important role in the autoregulation that occurs in the vessels of the brain, heart, skeletal muscle, and kidneys. (See Chapter 20.)
Metabolic Mechanisms Throughout the body, the vessels that govern blood flow are sensitive to the local metabolic needs of parenchymal cells. Table 20-8 lists several changes that act synergistically to increase local blood flow. For example, a decrease in PO2 or pH promotes relaxation of VSMCs, thereby causing vasodilation. In response to activity, excitable cells raise extracellular K+ concentration ([K+]o), which also causes vasodilation. Tissues with high energy demands—such as the brain, heart, and skeletal muscle during exercise—rely heavily on such local control mechanisms.
Endothelial Mechanisms Endothelial cells release a variety of vasoactive substances (see Table 20-9). For example, the shear stress exerted by the movement of blood through the vessel lumen stimulates the release of nitric oxide (NO), which relaxes VSMCs and prevents leukocyte adhesion.
Anastomoses at the circle of Willis and among the branches of distributing arteries protect the blood supply to the brain, which is approximately 15% of cardiac output
The brain accounts for only ~2% of the body’s weight, yet it receives ~15% of the resting cardiac output. Of all the tissues in the body, the brain is the least tolerant of ischemia. It depends entirely on oxidative sources of energy production. Each day, the human brain oxidizes ~100 g of glucose, which is roughly equivalent to the amount stored as glycogen in the liver. Interruption of cerebral blood flow for just a few seconds causes unconsciousness. If ischemia persists for even a few minutes, irreversible cellular damage is likely. (See Note: Brain Metabolism)
Arteries Blood reaches the brain through four source arteries—the two internal carotid arteries and the two vertebral arteries (Fig. 24-1). The vertebral arteries join to form the basilar artery, which then splits to form the two posterior cerebral arteries, which in turn are part of the circle of Willis at the base of the brain. The internal carotid arteries are the major source of blood to the circle. Three bilateral pairs of distributing arteries (anterior, middle, and posterior cerebral arteries) arise from the circle of Willis to envelop the cerebral hemispheres. Smaller branches from the vertebral and basilar arteries distribute blood to the brainstem and cerebellum. The distributing arteries give rise to pial arteries that course over the surface of the brain, forming anastomoses, and then branch again into arterioles that penetrate the tissue at right angles to the brain surface. These penetrating arterioles branch centripetally to give rise to capillaries. The anastomoses on the cortical surface provide the collateral circulation that is so important should a distributing artery or one of its branches become occluded. Each of the four source arteries tends to supply the brain region closest to where the source artery joins the circle of Willis. If a stenosis develops in one source artery, other source arteries to the circle of Willis can provide alternative flow. Nevertheless, if flow through a carotid artery becomes severely restricted (e.g., with atherosclerotic plaque), ischemia may occur in the ipsilateral hemisphere, with impairment of function.
Figure 24-1 Vascular anatomy of the brain. The illustration in B, with the temporal lobe pulled away, depicts the major branches of the left middle cerebral artery, one of the distributing arteries. Pial arteries course over the surface of the brain and give rise to penetrating arterioles that supply the microcirculation within the brain.
Veins The veins of the brain are wide, thin-walled structures that are nearly devoid of smooth muscle and have no valves. In general, the veins drain the brain radially, in a centrifugal direction. The intracerebral veins converge into a superficial pial plexus lying under the arteries. The plexus drains into collecting veins, which course over the distributing arteries and empty into the dural sinuses (see Fig. 11-1B). The exception to this radial pattern is the deep white matter of the cerebral hemispheres and basal ganglia; these regions drain centrally into veins that course along the walls of the lateral ventricles to form a deep venous system, which also empties into the dural sinuses. Nearly all of the venous blood from the brain leaves the cranium by way of the internal jugular vein. (See Note: Emissary Veins)
Capillaries One of the most characteristic features of the brain vasculature is the blood-brain barrier (see Chapter 11), which prevents the solutes in the lumen of the capillaries from having direct access to the brain extracellular fluid (BECF). For this reason, many drugs that act on other organs or vascular beds have no effect on the brain. Polar and water-soluble compounds cross the blood-brain barrier slowly, and the ability of proteins to cross the barrier is extremely limited. Only water, O2, and CO2 (or other gases) can readily diffuse across the cerebral capillaries. Glucose crosses more slowly by facilitated diffusion. No substance is entirely excluded from the brain; the critical variable is the rate of transfer. The blood-brain barrier protects the brain from abrupt changes in the composition of arterial blood. In a similar manner, a blood-testis barrier protects the germinal epithelia in males. The blood-brain barrier may become damaged in regions of the brain that are injured, infected, or occupied by tumors. Such damage can be helpful in identifying the location of tumors because tracers that are excluded from healthy central nervous system (CNS) tissue can enter the tumor. In specialized areas of the brain—the circumventricular organs (see Chapter 11)—the capillaries are fenestrated and have permeability characteristics similar to those of capillaries in the intestinal circulation.
Lymphatics The brain lacks lymphatic vessels.
Vascular Volume The skull encloses all of the cerebral vasculature, along with the brain and the cerebrospinal fluid compartments. Because the rigid cranium has a fixed total volume, vasodilation and an increase in vascular volume in one region of the brain must be met by reciprocal volume changes elsewhere within the cranium. Tight control of the cerebral blood volume is essential for preventing elevation of the intracranial pressure. With cerebral edema or hemorrhage, or with the growth of a brain tumor, neurological dysfunction can result from the restriction of blood flow due to vascular compression. An analogous situation can occur in the eyes of patients with glaucoma (see Chapter 15). Pressure buildup within the eye compresses the optic nerve and retinal artery, and blindness can result from the damage caused by diminished blood flow to the retinal cells.
Neural, metabolic, and myogenic mechanisms control blood flow to the brain
Cerebral blood flow averages 50 mL/min for each 100 g of brain tissue and, because of autoregulation, is relatively constant. Nevertheless, regional changes in blood distribution occur in response to changing patterns of neuronal activity (Fig. 24-2).
Figure 24-2 Changes in regional blood flow. The investigators used the washout of 133Xe, measured with detectors placed over the side of the patient’s head, as an index of regional blood flow in the dominant cerebral hemisphere. The turquoise “hot spots” represent regions where blood flow is more than 20% above mean blood flow for the entire brain. At rest, blood flow is greatest in the frontal and premotor regions. The patterns of blood flow change in characteristic ways with the other seven forms of cerebral activity. (Data from Ingvar DH: Functional landscapes of the dominant hemisphere. Brain Res 1976; 107:181-197.)
Neural Control Sympathetic nerve fibers supplying the brain vasculature originate from postganglionic neurons in the superior cervical ganglia and travel with the internal carotid and vertebral arteries into the skull, branching with the arterial supply. The sympathetic nerve terminals release norepinephrine, which causes contraction of VSMCs. Parasympathetic innervation of the cerebral vessels arises from branches of the facial nerve; they elicit a modest vasodilation when activated. The cerebral vessels are also supplied with sensory nerves, whose cell bodies are located in the trigeminal ganglia and whose sensory processes contain substance P and calcitonin gene–related peptide, both of which are vasodilatory neurotransmitters. Local perturbations (e.g., changes in pressure or chemistry) may stimulate the sensory nerve endings to release these vasodilators, an example of an axon reflex. (See Note: Axon Reflex)
Despite this innervation, neural control of the cerebral vasculature is relatively weak. Instead, it is the local metabolic requirements of the brain cells that primarily govern vasomotor activity in the brain.
Metabolic Control Neural activity leads to ATP breakdown and to the local production and release of adenosine, a potent vasodilator. A local increase in brain metabolism also lowers PO2 while raising PCO2 and lowering pH in the nearby BECF. These changes trigger vasodilation and thus a compensatory increase in blood flow. Cerebral VSMCs relax mainly in response to low extracellular pH; these cells are insensitive to increased PCO2 per se, and decreased intracellular pH actually causes a weak vasoconstriction.
How does brain blood flow respond to systemic changes in pH? Lowering of arterial pH at a constant PCO2 (metabolic acidosis; see Chapter 28) has little effect on cerebral blood flow because arterial H+cannot easily penetrate the blood-brain barrier and therefore does not readily reach cerebral VSMCs. On the other hand, lowering of arterial pH by increasing PCO2 (respiratory acidosis; see Chapter 28) rapidly leads to a fall in the pH around VSMCs because CO2 readily crosses the blood-brain barrier. This fall in pH of the BECF evokes pronounced dilation of the cerebral vasculature, with an increase in blood flow that occurs within seconds. The rise in arterial PCO2 caused by inhalation of 7% CO2 can cause cerebral blood flow to double. Conversely, the fall in arterial PCO2 caused by hyperventilation raises the pH of the BECF, producing cerebral vasoconstriction, decreased blood flow, and dizziness. Clinically, hyperventilation is used to lower cerebral blood flow in the emergency treatment of acute cerebral edema and glaucoma.
A fall in the blood and tissue PO2—from hypoxemia or impaired cardiac output—may also contribute to cerebral vasodilation, although the effects are less dramatic than those produced by arterial hypercapnia. The vasodilatory effects of hypoxia may be direct or may be mediated by release of adenosine, K+, or NO into the BECF. (See Note: Vasodilatory Effect of Hypoxia in the Brain)
Myogenic Control Cerebral resistance vessels are inherently responsive to changes in their transmural pressure. Increases in pressure lead to vasoconstriction, whereas decreases in pressure produce vasodilation.
The neurovascular unit matches blood flow to local brain activity
Neurons, glia, and cerebral blood vessels function as an integrated unit to distribute cerebral blood flow according to local activity within the brain (Fig. 24-2). This “neurovascular coupling” involves several signaling pathways that complement the metabolic control discussed before. Some neurotransmitters and neuromodulators are vasoactive (e.g., acetylcholine, catecholamines, and neuropeptides) and can control blood vessels in the region of synaptic activity. The endfeet of astrocytes (see Fig. 11-9) come into direct contact with the smooth muscle penetrating arterioles and the endothelial cells of capillaries. The release of neurotransmitters (e.g., glutamate and γ-aminobutyric acid) from neurons initiates [Ca2+]i waves in astrocytes as well as in dendrites of adjacent neurons. These [Ca2+]i waves stimulate the release of powerful vasodilators, including NO and metabolites of arachidonic acid. Thus, synaptic activity generates vasoactive mediators in neurons and astrocytes that can produce vasodilation. Concurrent activation of local interneurons with vascular projections helps focus the vasomotor response. The vasodilator signal conducts through gap junctions from cell to cell along the endothelium and smooth muscle cells of penetrating arterioles, retrograde to the pial arteries, which are a major part of vascular resistance. This reduction in proximal resistance directs increased blood flow to the region of increased neural activity.
Autoregulation maintains a fairly constant cerebral blood flow across a broad range of perfusion pressures
The perfusion pressure to the brain is the difference between the systemic arterial pressure (mean pressure, ~95 mm Hg) and intracranial venous pressure, which is nearly equal to the intracranial pressure (<10 mm Hg). A decrease in cerebral blood flow could thus result from a fall in arterial pressure or a rise in intracranial (or venous) pressure. However, the local control of cerebral blood flow maintains a nearly constant blood flow through perfusion pressures ranging from ~70 to 150 mm Hg. This constancy of blood flow—autoregulation (see Chapter 20)—maintains a continuous supply of O2 and nutrients. In patients with hypertension, the cerebral blood flow remains normal because cerebral vascular resistance increases. Conversely, vascular resistance falls with hypotension. This autoregulation of blood flow has both myogenic and metabolic components.
Increases in intracranial pressure compress the brain vasculature and tend to reduce blood flow despite autoregulatory vasodilation. In such cases, the brain regulates its blood flow by inducing reflexive changes in systemic arterial pressure. This principle is exemplified by the Cushing reflex, an increase in arterial pressure that occurs in response to an increase in intracranial pressure. It appears that intracranial compression causes a local ischemia that stimulates vasomotor centers in the medulla. Increased sympathetic nerve activity in the systemic circulation then triggers a rise in total peripheral resistance. The Cushing reflex may occur acutely with the swelling that follows a head injury or more gradually with growth of a brain tumor. Over a considerable pressure range, the Cushing reflex ensures that the perfusion pressure can offset the effects of vascular compression and thereby maintain the constancy of cerebral blood flow.
The coronary circulation receives 5% of the resting cardiac output from the left side of the heart and mostly returns it to the right side of the heart
The heart receives ~5% of the resting cardiac output, although it represents less than 0.5% of total body weight. The heart normally uses oxidative phosphorylation to generate the ATP required to pump blood. However, of all the O2that the heart consumes, no more than 40% reflects the oxidation of carbohydrate. More than 60% of myocardial O2 consumption in the fasting state is due to the oxidation of fatty acids. The myocardium readily oxidizes ketone bodies (see Chapter 51), which can provide considerable energy during starvation or during diabetic ketoacidosis. When the O2 supply is adequate, the heart takes up and oxidizes both lactate and pyruvate, as do red (i.e., oxidative) skeletal muscle fibers, although the arterial concentration of pyruvate is usually low. When the energetic demand for ATP exceeds the supply of O2, the heart can no longer take up lactate but instead releases lactate by breaking down its own glycogen stores. In this manner, the heart can continue to function for a short time when it is deprived of O2. If hypoxia develops in the myocardium, nociceptive fibers trigger the sensation of referred pain, known as angina pectoris. More severe or prolonged insults damage the myocardial tissue, which eventually becomes necrotic (myocardial infarction).
The entire blood supply to the myocardium derives from the right and left coronary arteries, which originate at the root of the aorta behind the cusps of the aortic valves (Fig. 24-3). Although anatomy is subject to individual variation, the right coronary artery generally supplies the right ventricle and atrium, and the left coronary artery supplies the left ventricle and atrium. The left coronary artery divides near its origin into two principal branches: the left circumflex artery sends branches to the left atrium and ventricle, and the left anterior descending artery descends to the apex of the heart and branches to supply the interventricular septum and a portion of the right as well as the left ventricle. These arteries course over the heart, branching into segments that penetrate into the tissue and dividing into capillary networks. Capillary density in histological sections of the human heart exceeds 3000/mm2(skeletal muscle has only ~400/mm2). The small diameter of cardiac muscle fibers (<20 μm), less than half that of skeletal muscle (~50 μm), facilitates O2 diffusion into the cardiac cells, which have a high energetic demand.
Figure 24-3 Heart and coronary circulation.
Once blood passes through the capillaries, it collects in venules, which drain outward from the myocardium to converge into the epicardial veins. These veins empty into the right atrium through the coronary sinus. Other vascular channels drain directly into the cardiac chambers. These include the thebesian veins, which drain capillary beds within the ventricular wall. Because the deoxygenated blood carried by the thebesian veins exits predominantly into the ventricles, this blood flow bypasses the pulmonary circulation. Numerous collateral vessels among branches of the arterial vessels and throughout the venous system act as anastomoses; these provide alternative routes for blood flow should a primary vessel become occluded.
Extravascular compression impairs coronary blood flow during systole
In other systemic vascular beds, blood flow roughly parallels the pressure profile in the aorta, rising in systole and falling in diastole (see Fig. 22-3A). However, in the coronary circulation, flow is somewhat paradoxical. Although the heart is the source of its own perfusion pressure, myocardial contraction effectively compresses its own vascular supply. Therefore, the profile of blood flow through the coronary arteries depends on both the perfusion pressure in the aorta (Fig. 24-4, top panel) and the extravascular compression resulting from the contracting ventricles, particularly the left ventricle.
Figure 24-4 Coronary blood flow cycle. Bands at beginning of systole and diastole reflect isovolumetric contraction and relaxation, respectively.
Blood flow in the left coronary artery may actually reverse transiently in early systole (Fig. 24-4, middle panel), as the force of the left ventricle’s isovolumetric contraction compresses the left coronary vessels, while the aortic pressure has not yet begun to rise (i.e., aortic valve is still closed). As aortic pressure increases later during systole, coronary blood flow increases but never reaches peak values. However, early during diastole, when the relaxed ventricles no longer compress the left coronary vessels and aortic pressure is still high, left coronary flow rises rapidly to extremely high levels. All told, ~80% of total left coronary blood flow occurs during diastole.
In contrast, the profile of flow through the right coronary artery (Fig. 24-4, lower panel) is very similar to the pressure profile of its feed vessel, the aorta. Here, systole contributes a greater proportion of the total flow, and systolic reversal does not occur. The reason for this difference is the lower wall tension developed by the right side of the heart, which pumps against the low resistance of the pulmonary circulation and does not occlude the right coronary vessels during contraction.
The impact of systolic contraction on the perfusion of the left coronary vessels is highlighted by the effect of ventricular fibrillation (see Fig. 21-14I). At the onset of this lethal arrhythmia, left coronary perfusion transiently increases, reflecting the loss of mechanical compression of the vasculature.
Changes in heart rate, because they affect the duration of diastole more than that of systole, also affect coronary flow. During tachycardia, the fraction of the cardiac cycle spent in diastole decreases, minimizing the time available for maximal left coronary perfusion. If the heart is healthy, the coronary vessels can adequately dilate in response to the metabolic signals generated by increased cardiac work, which offsets the negative effects of the shorter diastole. On the other hand, a high heart rate can be dangerous when severe coronary artery disease restricts blood flow. (See Note: Adverse Effects of Tachycardia on Left Coronary Perfusion)
Coronary blood flow not only varies in time during the cardiac cycle, it also varies with depth in the wall of the heart. Blood flows to cardiac myocytes through arteries that penetrate from the epicardium toward the endocardium. During systole, the intramuscular pressure is greatest near the endocardium and least near the epicardium. All things being equal, the perfusion of the endocardium would therefore be less than that of the epicardium. However, total blood flows to the endocardial and epicardial halves are approximately equal because the endocardium has a lower intrinsic vascular resistance and thus a greater blood flow during diastole. When the diastolic pressure at the root of the aorta is pathologically low (e.g., aortic regurgitation) or coronary arterial resistance is high (e.g., coronary artery occlusion), endocardial blood flow falls below the epicardial flow. Thus, the inner wall of the left ventricle often experiences the greatest damage with atherosclerotic heart disease.
Myocardial blood flow parallels myocardial metabolism
A striking feature of the coronary circulation is the nearly linear correspondence between myocardial O2 consumption and myocardial blood flow. This relationship persists in isolated heart preparations, emphasizing that metabolic signals are the principal determinants of O2 delivery to the myocardium. In a resting individual, each 100 g of heart tissue receives 60 to 70 mL/min of blood flow. Normally, the heart extracts 70% to 80% of the O2 content of arterial blood (normally ~20 mL/dL blood), thereby producing an extremely low venous O2 content (~5 mL/dL). Therefore, the myocardium cannot respond to increased metabolic demands by extracting much more O2 than it already does when the individual is at rest. The heart can meet large increases in O2 demand only by increasing coronary blood flow, which can exceed 250 mL/min per 100 g with exercise.
Because blood pressure normally varies within fairly narrow limits, the only way to substantially increase blood flow through the coronary circulation during exercise is by vasodilation. The heart relies primarily on metabolic mechanisms to increase the caliber of its coronary vessels. Adenosine has received particular emphasis in this regard. An increased metabolic activity of the heart, an insufficient coronary blood flow, or a fall in myocardial PO2results in adenosine release. Adenosine then diffuses to the VSMCs, activating purinoceptors to induce vasodilation by lowering [Ca2+]i (see Table 20-7). Thus, inadequate perfusion to a region of tissue would elevate interstitial adenosine levels, causing vasodilation and restoration of flow to the affected region.
When cardiac demand outstrips the blood supply, a transient rise in [K+]o may also contribute to the initial increase in coronary perfusion (see Table 20-8). However, it is unlikely that K+ mediates sustained elevations in blood flow. When O2 demand exceeds O2 supply, a rise in the PCO2 and a fall in PO2 may also lower coronary vascular resistance.
Coronary blood flow is relatively stable between perfusion pressures of ~70 mm Hg and more than 150 mm Hg. Thus, like that of the brain, the blood flow to the heart exhibits autoregulation. In addition to the myogenic response, fluctuations in adenosine and PO2 contribute to coronary autoregulation.
Although sympathetic stimulation directly constricts coronary vessels, accompanying metabolic effects predominate, producing an overall vasodilation
Sympathetic nerves course throughout the heart, following the arterial supply. Stimulation of these nerves causes the heart to beat more frequently and more forcefully. β1 Adrenoceptors on the cardiac myocytes mediate these chronotropic and inotropic responses. As discussed in the preceding section, the increased metabolic work of the myocardium leads to coronary vasodilation through metabolic pathways. However, during pharmacological inhibition of the β1 receptors on the cardiac myocytes, which prevents the increase in metabolism, sympathetic nerve stimulation causes a coronary vasoconstriction. This response is the direct effect of sympathetic nerve activity on α adrenoceptors on the VSMCs of the coronary resistance vessels. Thus, blocking of β1 receptors “unmasks” adrenergic vasoconstriction. However, under normal circumstances (i.e., no β blockade), the tendency of the metabolicpathways to vasodilate far overwhelms the tendency of the sympathetic pathways to vasoconstrict.
Activation of the vagus nerve has only a mild vasodilatory effect on the coronary resistance vessels. This muted response is not due to insensitivity of the resistance vessels to acetylcholine, which elicits a pronounced vasodilation when it is administered directly. Rather, the release of acetylcholine from the vagus nerve is restricted to the vicinity of the sinoatrial node. Thus, the vagus nerve has a much greater effect on heart rate than on coronary resistance.
Collateral vessel growth can provide blood flow to ischemic regions
When a coronary artery or one of its primary branches becomes abruptly occluded, ischemia can produce necrosis (i.e., a myocardial infarct) in the region deprived of blood flow. However, if a coronary artery narrows gradually over time, collateral blood vessels may develop and at least partially ameliorate the reduced delivery of O2 and nutrients to the compromised area, preventing or at least diminishing tissue damage. Collateral vessels originate from existing branches that undergo remodeling with the proliferation of endothelial and smooth muscle cells. Stimuli for collateral development include angiogenic molecules (see Chapter 20) released from the ischemic tissue and changes in mechanical stress in the walls of vessels supplying the affected region.
Vasodilator drugs may compromise myocardial flow through “coronary steal”
A variety of drugs can promote vasodilation of the coronary arteries. These are typically prescribed for patients suffering from angina pectoris, the chest pain associated with inadequate blood flow to the heart (see box titled Treating Coronary Artery Disease). If the buildup of atherosclerotic plaque—which underlies angina pectoris—occurs in the large epicardial arteries, the increased resistance lowers the pressure in the downstream microvessels. Under such conditions, the physician should be cautious in using pharmacological agents to dilate the coronary vessels. In an ischemic area of the myocardium downstream from a stenosis, metabolic stimuli may have already maximally dilated the arterioles. Administration of a vasodilator can then only increase the diameter of blood vessels in nonischemic vascular beds that are parallel to the ischemic ones. The result is coronary steal, a further reduction in the pressure downstream from the site of stenosis and further compromise of the blood flow to the ischemic region. When vasodilator therapy relieves angina, the favorable result is more likely to be attributable to the vasodilation of the noncoronary systemic vessels, which reduces peripheral resistance, thereby reducing the afterload during systole and thus the work of the heart.
THE SKELETAL MUSCLE
Perhaps the most impressive characteristic of the blood flow to skeletal muscle is its extreme range. Muscle blood flow at rest is 5 to 10 mL/min for each 100 g of tissue. With maximal aerobic exercise, it may increase 50-fold, reaching 250 mL/min or more for each 100 g of active muscle. The linear correspondence among work rate, O2 consumption, and muscle blood flow implies a “coupling” between muscle fiber activity and O2 delivery to capillaries. Muscle blood flow during exercise is the subject of Chapter 60. Here we discuss the key features of the organization of the skeletal muscle vasculature and the integration of its blood flow control mechanisms.
A microvascular unit is the capillary bed supplied by a single terminal arteriole
The vascular supply to skeletal muscle begins external to the tissue in the feed arteries. These muscular vessels are the last branches of the arterial supply, located just before entry into the tissue. As much as 30% to 50% of the total resistance to blood flow through skeletal muscle resides in these feed arteries. Therefore, an important site of blood flow control is located proximal to the microvessels that are in direct contact with skeletal muscle fibers.
The arteriolar network originates from the site at which a feed artery enters the muscle. Within the muscle, arterioles branch through several orders (Fig. 24-5A) until reaching the terminal arterioles (Fig. 24-5B), which are the last branches to contain smooth muscle and therefore the last branches still able to control blood flow. Thus, the terminal arteriole is the functional equivalent of the precapillary sphincter (see Chapter 20). The group of capillaries supplied by a terminal arteriole represents one microvascular unit, which is the smallest functional unit of blood flow control in skeletal muscle. Each unit consists of 15 to 20 capillaries that run parallel to the muscle fibers in each direction, for a distance of 1 mm or less, ending in a collecting venule.
Figure 24-5 Microvascular units in skeletal muscle. A, A feed artery (FA) branches into primary arterioles, which after two more orders of branching gives rise to transverse arterioles (3A), which in turn gives rise to terminal arterioles (4A). B, The terminal arteriole supplies a microvascular unit (1 mm in length).
Owing to the profound differences in length between capillaries (≤1 mm) and muscle fibers (centimeters), many microvascular units are required to span the distance of each muscle fiber. When a muscle fiber contracts, blood flow must increase throughout all of the microvascular units that supply that fiber to provide O2 and to remove metabolites.
Metabolites released by active muscle trigger vasodilation and an increase in blood flow
When skeletal muscle is at rest, its vascular resistance is high, blood flow is low, and the venous O2 content is only a few milliliters per deciliter lower than the arterial O2 content. As exercise begins, the terminal arterioles (those closest to the capillaries) dilate first. This vasodilation increases blood flow through capillaries that are already conducting blood and also opens up quiescent capillaries, thus increasing the number of perfused capillaries and decreasing the effective intercapillary distance. If total blood flow has not yet increased very much, the increased muscle demand for O2 produces a large increase in the O2 extraction ratio (see Chapter 20). As metabolic demand later increases, additional O2 delivery is required. The vasculature meets this demand by progressively dilating the terminal arterioles, then the more proximal arteriolar branches and feed arteries. Thus, vasodilation “ascends” the resistance network.
A coordinated vasodilation throughout the resistance network is essential when segments having substantial resistance are organized in series with each other. Dilation of the downstream arterioles, without dilation of the proximal arterioles and feed arteries, would result in only a limited ability to increase muscle blood flow because of the high resistance of upstream vessels. Thus, when feed arteries dilate in concert with arterioles, the increase in muscle blood flow is profound.
The primary stimulus triggering vasodilation is the release of vasodilator substances (e.g., adenosine, CO2, K+) from active muscle fibers in proportion to the energy expenditure. These metabolites diffuse locally and—acting either directly on VSMCs or indirectly on adjacent endothelial cells—relax the VSMCs of resistance vessels, thereby increasing blood flow in proportion to local demand. Although a variety of substances released by muscle fibers can contribute to the hyperemia, no single stimulus yet explains the integrated response of blood-flow control to muscle contraction. Furthermore, the hyperemic response to increased muscle activity begins within a second or two of the onset of exercise. In contrast, it would take several seconds for these substances to be produced by the skeletal muscle fibers, to reach the interstitium, and to diffuse to the arteriolar VSMCs in sufficient concentration to elicit vasodilation.
The initiation of muscle fiber contraction leads to a release of K+ that may hyperpolarize the nearby VSMCs (see Table 20-8). Once triggered, this hyperpolarization causes the small proximal arterioles to dilate, and the electrical signal spreads from cell to cell through gap junctions along the endothelium and into VSMCs, conducting upstream to the larger vessels and causing them to dilate in concert. This mechanism of conducted vasodilation, together with the action of the muscle pump, probably contributes to the rapid onset of hyperemia (discussed later). Increases in levels of other metabolites (e.g., adenosine and CO2 levels) or decreases in PO2 contribute to and sustain the hyperemic response. (See Note: Vasodilation Caused by Increases in [K+]o)
Treating Coronary Artery Disease
For many patients with gradual narrowing of their coronary arteries by atherosclerotic plaque, the first sign of disease may be the development of angina pectoris. Pain results when the metabolic demands of a region of myocardium exceed the ability of the compromised blood supply to satisfy those needs. Attacks of angina are often accompanied by characteristic changes on the electrocardiogram. If the diagnosis is in doubt—the chest pain of angina can sometimes be mimicked by gastroesophageal reflux, hyperventilation, costochondritis, and other clinical entities—an exercise test may stress the heart sufficiently to bring on the pain, to induce electrocardiographic changes, or to alter coronary blood flow as monitored by a thallium scan (see Chapter 17). Some patients with significant coronary artery narrowing never experience angina and are said to have silent ischemia. In these patients, only an astute clinician may detect the coronary disease.
Many patients with a stable anginal pattern respond well to medication. Nitrates induce vasodilation by releasing NO (see Chapter 3). The nitrates dilate peripheral veins, reducing venous return and thus the preload to the heart (see Chapter 22); they also dilate the arteries and arterioles, reducing blood pressure and therefore the afterload. Finally, nitrates may increase coronary collateral flow to the involved region of myocardium (see discussion of coronary steal). Beta blockers prevent the sympathetic nervous system from stimulating myocardial β1receptors, thereby reducing both heart rate and contractility and thus metabolic demand. Calcium channel blockers lessen the contractility of the heart muscle and the vascular smooth muscle. These interventions all reduce the metabolic demands of the heart.
In patients for whom medication cannot control the angina or who develop a pattern of unstable angina with an increasing frequency and severity of anginal attacks, mechanical revascularization may be required. For a long time, the only option was coronary artery bypass grafting, but percutaneous transluminal coronary angioplasty may now often be successful. A cardiologist can perform this procedure at the same time as a diagnostic coronary artery catheterization. The physician advances a balloon-tipped catheter through a peripheral artery into the left ventricle and then loops the catheter back out the left ventricle to have a favorable angle for entering the coronary vessels from the aorta. Inflation of the balloon at the site of the obstruction flattens the plaque into the wall of the vessel and restores blood flow. Recurrence of the obstruction may be due to proliferation of VSMCs. Refinements in the technique, placement of stents at the treated site, and use of aggressive anticoagulation have all contributed to the technique’s growing success. Variants of this technique, in which lasers are used, are coming under study increasingly.
Given the continued prevalence of coronary artery disease, a great deal of research has been aimed at developing alternatives to medication and mechanical revascularization. Among the most promising of these is the use of angiogenesis promoters that promote the growth of new blood vessels (see Chapter 20).
Sympathetic innervation increases the intrinsic tone of resistance vessels
Sympathetic nerve fibers invest the entire resistance network, from feed arteries to terminal arterioles. The release of norepinephrine by these nerve terminals leads to vasoconstriction. Increased transmural pressure results in increased myogenic tone, also producing vasoconstriction. On the other hand, the shear stress of blood flowing past the endothelial cells produces vasodilators, such as NO. The interactions among these vasoconstrictor and vasodilatory mechanisms maintain the intrinsic basal tone of the VSMCs. Venules also constrict in response to sympathetic nerve stimulation but are not directly innervated and instead respond to norepinephrine that diffuses from the nearby arterioles.
With nearly one third of total body mass composed of muscle, the sympathetic control of vasomotor tone to skeletal muscle is an integral component of the regulation of both systemic arterial pressure (through total peripheral resistance) and cardiac filling (through venous capacitance and return). This principle is particularly true during maximal aerobic exercise, when more than 80% of the cardiac output flows to the active skeletal muscles.
The basal firing rate of the sympathetic nerves to skeletal muscle is 1 to 2 Hz, which contributes only modestly to the resting vasomotor tone. However, when high-pressure baroreceptors detect a fall in blood pressure (see Chapter 23), sympathetic firing to skeletal muscle may increase to 8 to 16 Hz. This degree of sympathetic nerve activity can close the lumens of arterioles in skeletal muscle.
During exercise, the proportion of cardiac output flowing through skeletal muscle increases. This redistribution of systemic blood flow occurs for two reasons. First, an increase in sympathetic tone constricts splanchnic circulation (see later), renal circulation (see Chapter 34), and the vessels of inactive skeletal muscle. Indeed, only the brain and heart are spared. Second, the metabolites released by active skeletal muscle overcome the vasoconstriction that sympathetic activity would otherwise produce. In addition, substances released during muscle fiber contraction (e.g., NO and adenosine) may inhibit norepinephrine release from sympathetic neurons.
The vasodilatory effects of the metabolites notwithstanding, sympathetic vasoconstrictor activity can be overwhelming, particularly when another large mass of muscle is active simultaneously and requires a substantial portion of cardiac output. Thus, during “whole-body” exercise, each muscle group may receive only a fraction of the blood flow it would otherwise get if it were the only active group in the body. It is at the level of the feed arteries—which are external to the muscle and thus physically removed from the direct influence of the vasoactive products of muscular activity—that sympathetic vasoconstriction puts an upper limit on blood flow during intense aerobic exercise. At the same time, dilation of arterioles within the active muscle maximizes O2 extraction by promoting capillary perfusion.
Rhythmic contraction promotes blood flow through the muscle pump
During exercise, skeletal muscle undergoes rhythmic changes in length and tension, giving rise to mechanical forces within the tissue analogous to those of the beating heart. The contraction of muscle forces venous blood out of the muscle and impedes arterial inflow (Fig. 24-6). Because valves in the veins prevent backflow of blood, each muscle contraction squeezes and empties the veins, driving blood toward the heart (see Chapter 22). During the subsequent relaxation, the reduction in venous pressure increases the driving force for capillary perfusion. In addition, peak arterial inflow occurs during relaxation between contractions. This pumping action of skeletal muscle on the vasculature imparts substantial kinetic energy to the blood, thereby reducing the work of the heart. Remarkably, the skeletal muscle pump may generate up to half of the energy required to circulate blood, an essential contribution for achieving the high blood flows experienced during maximal aerobic exercise. By contrast, use of drugs to dilate blood vessels of inactive muscle can increase blood flow to a lesser extent than is observed with rhythmic contractions.
Figure 24-6 Muscle pump.
THE SPLANCHNIC CIRCULATION
The splanchnic circulation includes the blood flow through the stomach, small intestine, large intestine, pancreas, spleen, and liver (Fig. 24-7A). The majority of flow to the liver occurs through the portal vein, which carries the venous blood draining from all of these organs except the liver itself.
Figure 24-7 Splanchnic circulation.
The vascular supply to the gut is highly interconnected
The celiac artery is the primary blood supply to the stomach, pancreas, and spleen. The superior and inferior mesenteric arteries supply the large and small intestines as well as parts of the stomach and pancreas. The superior mesenteric artery is the largest of all the splanchnic branches from the aorta, carrying more than 10% of the cardiac output. The extensive interconnections between the arcading arterial branches (Fig. 24-7B) provide multiple collateral pathways through which blood can reach each portion of the intestines. This arrangement lessens the risk that the intestines may become ischemic should one of the arteries become occluded.
The microvascular network in the small intestine (Fig. 24-7C) is representative of that throughout the gastrointestinal tract. After penetrating the wall of the intestine, small arteries course through the various muscle layers and reach the submucosa, where they branch into arterioles. Some arterioles remain in the submucosa to form a submucosal vascular plexus. Others project toward the intestinal lumen and into the mucosa, including the villi. Still others project away from the mucosa and course along the smooth muscle bundles. Venules emerging from the villi and mucosal and muscularis layers converge into veins. These exit the intestinal wall, paralleling the arterial supply.
The arrangement of microvessels within a villus is like a fountain (Fig. 24-7D). The incoming arteriole courses up the center of the villus, branching into many capillaries along the way to the tip of the villus. Capillaries converge into venules and carry blood back to the base of the villus. Capillaries also interconnect the arteriole and the venule all along the villus. These microvessels are permeable to solutes of low molecular weight or high lipid solubility.
The arrangement just described can create a countercurrent exchange system that enables permeable solutes to move from the arteriole to the venule without having to traverse the entire length of the villus, particularly under conditions of low flow. With prolonged transit times, blood-borne O2 can diffuse from the arteriole to the venule before reaching the tip of the villus, which makes it susceptible to anoxic damage. The situation is just the opposite for solutes (e.g., Na+) that the villus epithelium absorbs during digestion. These solutes enter capillaries and then pass into venules. As the venous blood travels toward the base of the villus, the solute can diffuse out of the venules, into the interstitium, and then into the arterioles. In this way, the solute concentration in the arterial blood increases as the blood flows to the tip of the villus. This “trapping” process increases the interstitial osmolarity near the tip of the villus, in a manner analogous to the mechanism that maintains high osmolality at the tip of the renal medulla (see Chapter 38).
In contrast, when the intestinal mucosa is adequately perfused (e.g., at rest and particularly after a meal), the tips of the villi are well oxygenated (as in Fig. 24-7D), the effects of countercurrent exchange are reduced, and the osmolality within the villi falls.
Because the capillaries in the villi are fenestrated (i.e., they have large pores) and have a large surface area, they are well suited for absorbing nutrients from the intestinal lumen. The venous blood carries away the majority of water-soluble nutrients absorbed from the gut, eventually delivering them to the portal vein. Lipophilic nutrients absorbed from the intestinal lumen enter the central lacteal of the villus (Fig. 24-7D), which merges with the intestinal lymphatics. The lymph then delivers these substances into the bloodstream through the thoracic duct.
Blood flow to the gastrointestinal tract increases up to eight-fold after a meal (postprandial hyperemia)
Throughout the gastrointestinal tract, blood flow in each layer of the gut wall closely correlates with the local metabolism (which reflects digestive and absorptive activity). Intestinal blood flow at rest, in the fasting state, is typically 30 mL/min for each 100 g of tissue. However, flow can reach 250 mL/min for each 100 g during peak hyperemia after a meal. The increase in blood flow with the ingestion and digestion of a meal reflects a complex interplay of several factors.
First, the CNS initiates an “anticipatory” response that increases splanchnic blood flow with the mere thought of food—corresponding to the “cephalic phase” of gastric (see Chapter 42) and pancreatic (see Chapter 43) secretion.
Second, mucosal metabolic activity during digestion and absorption primarily depends on the rate of active transport of substances across the epithelium. These activities consume O2 and produce vasodilator metabolites (e.g., adenosine and CO2) that increase blood flow locally.
Third, the absorption of nutrients generates hyperosmolality in both the blood and the lymphatic vessels of the villus. Hyperosmolality itself stimulates an increase in blood flow.
Fourth, during digestion, the gastrointestinal tract releases several hormones, some of which are vasoactive. Of these, cholecystokinin and neurotensin (see Table 41-1) may reach high enough concentrations in the local circulation to promote intestinal blood flow. The intestinal epithelium also releases various kinins (e.g., bradykinin and kallidin), which are powerful vasodilators. The magnitude of the postprandial hyperemia further depends on the nature of the luminal content. Bile acids and partially digested fats are particularly effective in promoting hyperemia by acting on chemoreceptors in the intestinal mucosa. (See Note: Vasoactive Enteric Hormones)
The circulatory system does not distribute the increased splanchnic blood flow equally to all digestive organs, nor does it distribute the flow equally throughout the wall of even one segment of bowel. During and after a meal, blood flow increases sequentially along the gastrointestinal tract, first in the stomach and then in more distal segments of the intestine as digestion proceeds. In all segments, blood flow through the muscularis layers primarily provides nutrition for the smooth muscle cells. However, flow through the villi and submucosal vessels supports the absorption of foodstuffs as well as the secretion of electrolytes, fluids, and enzymes. After a meal, splanchnic blood flow is elevated for 2 to 4 hours, primarily reflecting the vasodilation in the mucosal layer.
As in the heart and skeletal muscle, muscle contraction in the intestine (i.e., peristalsis) decreases blood flow, probably as a result of the compression applied by the muscularis in conjunction with the distending pressure of the luminal contents.
Sympathetic activity directly constricts splanchnic vessels, whereas parasympathetic activity indirectly dilates them
The gastrointestinal tract is endowed with its own division of the ANS, the enteric nervous system (ENS; see Chapters 14 and 41). At one level, the ENS is its own independent nervous system, with sensory neurons, the capacity to integrate and to process sensory data, and motor neurons. One of the components of the ENS, the myenteric (or Auerbach) plexus, releases vasoactive neurotransmitters. However, this plexus probably achieves its major influence on blood flow by controlling the peristaltic activity of the intestinal smooth muscle.
The enteric division sends sensory information upstream to the peripheral ganglia and to the CNS. The ENS also receives important input from the sympathetic and parasympathetic divisions of the ANS. Postganglionic sympathetic neurons originate in the celiac, superior mesenteric, and inferior mesenteric ganglia and send nerve fibers that travel along the corresponding major arteries to all splanchnic organs. Except for the capillaries, all splanchnic blood vessels receive sympathetic innervation. The predominant neural influence is sympathetic vasoconstriction, mediated by norepinephrine acting on α adrenoceptors on VSMCs. The vasoconstriction occurs to a similar extent in both the muscularis and mucosal layers, without redistribution of flow between the layers. Vasoconstriction elicited by sympathetic nerve activity can reduce blood flow to less than 10 mL/min per 100 g of tissue (i.e., ~25% of resting values).
Parasympathetic preganglionic fibers travel to the intestine through vagal or pelvic nerves, which contact postganglionic parasympathetic neurons in the intestinal wall. The effect of parasympathetic activity on blood flow is indirect. Parasympathetic activity stimulates intestinal motility and glandular secretion, which in turn increases intestinal metabolism, thereby enhancing blood flow to the gut.
Changes in the splanchnic circulation regulate total peripheral resistance and the distribution of blood volume
The splanchnic circulation serves both as a site of adjustable resistance and as a major reservoir of blood. During exercise, when blood flow increases to active skeletal muscle, sympathetic constriction of the splanchnic resistance vessels decreases the proportion of cardiac output directed to the viscera. Therefore, abdominal cramping can result from attempts to exercise too soon after eating, when the gastrointestinal tract still demands blood flow to support its digestive and absorptive activities.
The splanchnic circulation contains ~15% of the total blood volume, with the majority contained in the liver; sympathetic constriction of the capacitance vessels can rapidly mobilize about half of this blood volume. During increases in sympathetic tone, splanchnic arteriolar constriction reduces perfusion, resulting in the passive collapse of the splanchnic veins. Blood contained in these veins moves into the inferior vena cava, thus increasing the circulating blood volume. With a greater increase in sympathetic activity, as would occur with intense exercise or severe hemorrhage, active venoconstriction mobilizes even more venous blood, thereby helping to maintain arterial pressure. (See Note: The Spleen as a Blood Reservoir)
Exercise and hemorrhage can substantially reduce splanchnic blood flow
A reduction in blood flow leads to the production of vasodilator metabolites (e.g., adenosine and CO2), which stimulate arteriolar dilation and increase O2 delivery. Nevertheless, during maximal exercise or severe hemorrhage, blood flow through the gut may fall to less than 25% of its resting value. Fortunately, temporary reductions in splanchnic flow can occur without serious O2 deprivation; at rest, the viscera normally extract only ~20% of the O2 carried in the blood, so that extraction can increase several-fold. However, extended periods of compromised splanchnic blood flow can irreversibly damage the intestinal parenchyma.
After a severe hemorrhage and sustained splanchnic vasoconstriction, the ischemic mucosal epithelia slough off, even after repletion of the blood volume and restoration of blood flow. Sloughing occurs particularly at the tips of the villi, where the epithelial cells are particularly susceptible to ischemia because of countercurrent flow. As these cells slough, it appears that pancreatic enzymes generate “activators” that enter the circulation and produce multiple organ failure. For example, such factors can lead to an irreversible decline in cardiovascular function. In an experimental setting, one can avoid damage to the heart by collecting the blood draining from the gut during the first several minutes of reperfusion, thereby preventing access of these blood-borne substances to the heart. Another major consequence of damage to the epithelium is endotoxic shock, which results from disruption of the barrier that normally prevents bacteria and toxins from escaping the intestinal lumen and entering the systemic circulation and peritoneal cavity.
The liver receives its blood flow from both the systemic and the portal circulations
The liver receives nearly one fourth of resting cardiac output. Of this blood flow, ~25% is arterial blood that arrives by the hepatic artery. The remaining 75% of the hepatic blood flow comes from the portal vein, which drains the stomach, intestines, pancreas, and spleen (Fig. 24-7A). Because the portal venous blood has already given up much of its O2 to the gut, the hepatic artery is left to supply ~75% of the O2used by the liver.
We discuss the anatomy of the hepatic circulation in more detail in Chapter 46. Small branches of the portal vein give rise to terminal portal venules, and branches of the hepatic artery give rise to hepatic arterioles. These two independent sources of blood flow enter the liver lobule at its periphery. Blood flows from these terminal vessels into the sinusoids, which form the capillary network of the liver. The sinusoids converge at the center of the lobule to form terminal hepatic venules (i.e., central veins), which drain into progressively larger branches of the hepatic veins and finally into the inferior vena cava. Within the sinusoids, rapid exchange occurs between the blood and the hepatocytes because the vascular endothelial cells have large fenestrations and gaps and thus do not meet to form interendothelial junctions as in other capillaries. Thus, the liver sinusoids are more permeable to protein than are capillaries elsewhere in the body. The passage of blood from the gastrointestinal tract past the reticuloendothelial cells of the liver (see Chapter 46) also removes bacteria and particulate matter, thereby preventing the access of potentially harmful material to the general circulation.
The mean blood pressure in the portal vein is normally 10 to 12 mm Hg. In contrast, the pressure in the hepatic artery averages 90 mm Hg. These two systems, with very different pressures, feed into the sinusoids (8 to 9 mm Hg). The sinusoids drain into the hepatic veins (~5 mm Hg), and these in turn drain into the vena cava (2 to 5 mm Hg). These remarkable values lead us to three conclusions. First, there must be a very high “precapillary” resistance between the hepatic artery (90 mm Hg) and the sinusoids (8 to 9 mm Hg), causing the arterial pressure to step down to sinusoidal values. If the sinusoidal pressure were as high as in typical capillaries (e.g., 25 mm Hg), blood would flow from the hepatic artery to the sinusoids and then backward into the portal vein. Second, because the pressure in the portal vein (10 to 12 mm Hg) is only slightly higher than that in the sinusoids (8 to 9 mm Hg), the precapillary resistance of the portal inflow (75% of the total flow) must be very low. Third, because the pressure in the sinusoids is only slightly higher than that in the hepatic vein (~5 mm Hg), the resistance of the sinusoids must also be extremely low.
As a result of the unique hemodynamics of the liver, changes in pressure within the hepatic vein have profound effects on fluid exchange across the wall of sinusoids. For example, in right-sided congestive heart failure, an elevated vena cava pressure can result in transudation of fluid from the liver into the peritoneal cavity, a condition known as ascites.
A change in the blood flow through one of the inputs to the liver (e.g., portal vein) leads to a reciprocal change in flow through the other input (i.e., hepatic artery). However, these adjustments do not fully stabilize total hepatic blood flow. For example, if the inflow through the hepatic artery decreases, the pressure inside the sinusoids falls slightly, leading to an increase in flow from the portal vein into the sinusoids. When the inflow through the portal vein decreases, metabolic factors (e.g., decreases in metabolites carried by the portal blood) trigger an increase in flow from the hepatic arteriolar system. The hepatic arterial supply displays autoregulation (see Chapter 20), which is absent in the portal venous system. With changes in O2 delivery, the liver compensates with corresponding changes in O2 extraction ratio. Hence, the liver tends to maintain constant O2 consumption.
The cirrhotic liver is hard, shrunken, scarred, and laced with thick bands of fibrotic tissue. The most common cause of this in the United States is chronic alcoholism, but worldwide, hepatitis B and hepatitis C are also leading causes. Less commonly, inherited diseases, such as hemochromatosis (iron overload) and Wilson disease (altered copper metabolism), can be responsible, as can diseases of unclear etiology, such as biliary cirrhosis and sclerosing cholangitis.
When damage to the liver becomes severe, the clinical consequences of cirrhosis can become life-threatening. The 5-year survival rate is the same as that for primary lung cancer—less than 10%. The three major complications of cirrhosis are metabolic abnormalities, portal hypertension, and hepatic encephalopathy.
The liver’s inability to maintain its normal synthetic activities (see Chapter 46) results in a range of metabolic problems. Both albumin and cholesterol levels fall, and the prothrombin time rises, indicating failure of the liver to manufacture proteins in the coagulation cascade. Decreased plasma levels of K+and Na+ often herald the onset of renal failure, a consequence of the hepatorenal syndrome.
The scarring that accompanies cirrhosis causes increased resistance to blood flow through the liver. When the portal venous pressure rises, the signs and symptoms of portal hypertension can appear. The increased portal venous pressure leads to increased pressure in the splanchnic capillaries. The Starling forces (see Chapter 20) thus promote the filtration and extravasation of fluid. The result is abdominal edema (i.e., fluid accumulation in the interstitium), which can progress to frank ascites (i.e., fluid in the peritoneal cavity). As the portal pressure rises farther, a portion of the portal blood begins to flow through and dilate the portal anastomoses with systemic veins. These anastomoses are present in the lower esophagus, around the umbilicus, at the rectum, and in the retroperitoneum.
Dilation of the vessels in the lower esophagus can lead to the development of esophageal varices. These veins, and similar veins in the stomach, can burst and cause life-threatening hemorrhage. When varices are associated with persistent or recurrent bleeding, the physician can inject sclerosing agents directly into the varices, a procedure called sclerotherapy. However, even after sclerotherapy, recurrent bleeding is not uncommon, and complications include perforation, stricture formation, infection, and aspiration. It is possible to prevent rupture of the varices in some patients by placing an intrahepatic portosystemic shunt. One introduces a catheter through the jugular vein and into the liver and then places a stent between a branch of the hepatic vein and a branch of the portal vein, allowing portal blood to shunt directly into the vena cava.
In some cases of portal hypertension, surgical intervention is necessary. Portacaval shunts (i.e., those linking the portal vein and inferior vena cava) can stop rebleeding and reduce portal hypertension, but hepatic encephalopathy (see next) can occur and overall mortality is not improved. The distal splenorenal shunt is now the more popular choice of treatment. It is effective in preventing rebleeding, and because it diverts only a portion of the blood flow away from the liver (i.e., just the blood exiting the spleen; Fig. 24-7A), it is associated with a much lower incidence of encephalopathy.
Even as hepatic scarring increases vascular resistance through the liver, hepatic perfusion continues for a while. However, as we have just seen, eventually some of the portal blood flow shunts around the damaged liver into systemic veins, through preexisting anastomoses. Because the liver is critical for removal and inactivation of naturally occurring toxic metabolites (see Chapter 46) as well as pharmacological agents, toxins that bypass the liver directly enter the systemic veins and can build up in the plasma. If these toxins (e.g., NH3; see Fig. 39-6) cross the blood-brain barrier, they can cause acute delirium.
The skin is the largest organ of the body
The skin is the major barrier between the internal milieu of the body and the unregulated environment of the outside world. The skin is normally overperfused in relation to its nutritional requirements. Thus, local metabolic control of skin blood flow is of little functional importance. However, changes in blood flow to the skin also play a central role in the body’s temperature regulation (see Chapter 59).
In terms of blood flow, we can divide the skin into apical skin (Fig. 24-8A), which is present on the nose, lips, ears, hands, and feet, and nonapical skin (Fig. 24-8B). As in other vascular beds, arterioles break up into capillaries, which reunite to form venules. The capillaries reach only as superficially as the dermis; the epidermis does not have a blood supply. The venules that are part of a plexus of vessels near the dermal-epidermal border (i.e., the most superficial vessels) may contain an appreciable volume of blood, thereby imparting a pinkish hue to individuals with light-colored skin. When cutaneous blood flow decreases, this volume of blood also decreases, lessening the reddish component of skin color (i.e., pallor). Local nutritional flow through the precapillary sphincters and capillaries is under the control of local vasodilator metabolites and sensory stimuli (e.g., temperature, touch, pain). For example, the vascular beds can respond to local thermal changes, largely independent of sympathetic nerve activity: the blood vessels dilate when the skin is directly heated and constrict when it is cooled.
Figure 24-8 Blood flow to the skin. A, In apical skin, glomus bodies (arteriovenous anastomoses) can reach a density of ~500 per cm2 in the nail beds. B, The nonapical skin lacks glomus bodies. Postganglionic sympathetic fibers release norepinephrine (NE), causing the usual vasoconstriction. Preganglionic sympathetic fibers release acetylcholine (ACh) and cause vasodilation, perhaps mediated by formation of bradykinin.
In addition to the effects of local metabolites and local warming and cooling, the blood flow to the skin is under sympathetic neural control. Increases in body core temperature increase blood flow to the skin, leading to a loss of heat. Decreases in core temperature result in the opposite effect of conserving heat. In contrast to other vascular beds, this neural control is far more important than local metabolic control in the overall regulation of skin blood flow.
Specialized arteriovenous anastomoses in apical skin help control heat loss
Apical Skin The apical skin at the extremities of the body has a very high surface-to-volume ratio that favors heat loss. Circulation to these apical regions has an unusual feature—arteriovenous (a-v) anastomoses called glomus bodies. (These glomus bodies are unrelated to the glomus cells of the peripheral chemoreceptors.) Glomus bodies are tiny nodules found in many parts of the body, including the ears, the pads of the fingers and toes, and the nail beds. As the afferent arteriole enters the connective tissue capsule of the glomus body, it becomes a vessel with a small lumen and a thick, muscular wall comprising multiple layers of myoepithelioid cells. These vessels—which have a rich sympathetic innervation—connect with short, thin-walled veins that eventually drain into larger skin veins. The a-v anastomoses, which are involved in heat exchange, are in parallel with the capillaries of the skin, which are involved in nutrient exchange (Fig. 24-8A).
The anastomotic vessels are under neural control, rather than the control of local metabolites, and play a critical role in temperature regulation. In these apical regions, blood flow is under the control of sympathetic fibers that release norepinephrine and thereby constrict the arterioles, anastomotic vessels, and venules. Therefore, the increase in sympathetic tone that occurs in response to decreases in core temperature elicits vasoconstriction in the a-v anastomoses, a fall in blood flow, and a reduction in heat loss. Maximal sympathetic stimulation can completely obliterate the lumen of an anastomotic vessel, thus greatly reducing total blood flow to the skin. On the other hand, when the core temperature rises, the withdrawal of sympathetic tone leads to passive vasodilation; there is no active vasodilation. Indeed, blocking of the sympathetic input to a hand in a neutral thermal environment can increase blood flow 4-fold above basal levels—as much as heat stress can produce. Thus, sympathetic tone to the vasculature of apical skin is substantial at rest.
Nonapical Skin The body uses a very different approach for regulating blood flow in nonapical skin. One important difference is that the vasculature of this skin almost completely lacks a-v anastomoses. A second important difference is that there are two types of sympathetic neurons innervating the vessels of the skin. Some release norepinephrine and some release acetylcholine.
Vasoconstriction occurs in response to the release of norepinephrine. In contrast to the situation in apical skin, blockade of sympathetic innervation to nonapical skin in a thermoneutral environment produces little change in skin blood flow, demonstrating little vasoconstrictor activity at rest.
Vasodilation in nonapical skin occurs in response to sympathetic neurons that release acetylcholine (see Chapter 14). Indeed, blockade of sympathetic innervation to the nonapical skin in a warm environment produces vasoconstriction and a decrease in skin blood flow, demonstrating neurally directed vasodilation before the blockade. The precise mechanism of this vasodilation is obscure. One proposal is that the acetylcholine stimulates eccrine sweat glands, causing the secretion of sweat as well as enzymes that lead to the local formation of vasoactive molecules. For instance, gland cells release kallikrein, a protease that converts kininogens to kinins, one of which is bradykinin (see Chapter 23). These kinins may act in a paracrine fashion on nearby blood vessels to relax VSMCs and thereby increase local perfusion. Cholinergic sympathetic neurons may cause vasodilation by means of a second pathway involving the co-release of vasodilatory neurotransmitters (e.g., calcitonin gene–related peptide, vasoactive intestinal polypeptide) that act directly on VSMCs, independent of sweat gland activity. Evidence for the second pathway is that the vasodilation cannot be blocked by atropine.
Mechanical stimuli elicit local vascular responses in the skin
The White Reaction If the skin is stroked mildly with a sharp instrument, a blanched line appears in the trailing path of the instrument. The immediate response is attributable to passive expulsion of the blood by the external mechanical force. During the next 15 to 60 seconds, the white reaction that ensues is caused by contraction of microvascular VSMCs and pericytes in response to mechanical stimulation. This active response has the effect of emptying the capillary loops, the collecting venules, and the subpapillary venous plexus of blood in a sharply delineated manner.
The Triple Response If a pointed instrument is drawn across the skin more forcefully, a series of reactions ensues that is collectively known as the triple response. Within several seconds, a band of increased redness due to a local dilation and increased perfusion of capillaries and venules appears within the perturbed area. This red reaction is independent of innervation and may persist for one to several minutes. The presumed cause is the local release of a vasodilator substance (e.g., histamine) from cells that were disturbed by the mechanical response.
If the stimulus is sufficiently strong or repeated, the reddening of the skin is no longer restricted to the line that was stroked but spreads to the surrounding region. This flare reaction appears several seconds after the localized redness and is due to dilation of arterioles. The flare reaction depends on a local nervous mechanism, known as the axon reflex, that depends on the branching of a single nerve fiber (see Fig. 15-29). A stimulus applied to one branch (containing the sensory receptor) gives rise to an action potential that travels centrally to the point of fiber branching. From this branch point, the afferent signal travels both orthodromically to the spinal cord and antidromically along the collateral branch. As a result, this collateral branch releases the vasodilating neurotransmitters. Sectioning of the nerve fiber central to the site of the collateral branch eliminates the awareness of the stimulus but does not eliminate the flare reaction until the nerve fiber degenerates. (See Note: Axon Reflexes)
When the stimulus is even more intense, as by the lash of a whip, the skin along the line of injury develops localized swelling known as the wheal. This local edema results from an increase in capillary permeability (e.g., in response to histamine) as filtration exceeds absorption. The wheal is preceded by and ultimately replaces the red reaction, appearing within a few minutes from the time of injury, and it is often surrounded by the flare reaction.
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