Chapter 33: Circulation Through Special Regions

After studying this chapter, you should be able to:

• Define the special features of the circulation in the brain, coronary vessels, skin, and fetus, and how these are regulated.

• Describe how cerebrospinal fluid (CSF) is formed and reabsorbed, and its role in protecting the brain from injury.

• Understand how the blood-brain barrier impedes the entry of specific substances into the brain.

• Delineate how the oxygen needs of the contracting myocardium are met by the coronary arteries, and the consequences of their occlusion.

• List the vascular reactions of the skin and the reflexes that mediate them.

• Understand how the fetus is supplied with oxygen and nutrients in utero, and the circulatory events required for a transition to independent life after birth.

The distribution of the cardiac output to various parts of the body at rest in a normal man is shown in Table 33–1. The general principles described in preceding chapters apply to the circulation of all these regions, but the vascular supplies of many organs have additional special features that are important to their physiology. The portal circulation of the anterior pituitary is discussed in Chapter 18; the pulmonary circulation in Chapter 34; the renal circulation in Chapter 37; and the circulation of the splanchnic area, particularly the intestines and liver, in Chapters 25 and 28. This chapter is concerned with the special circulations of the brain, the heart, and the skin, as well as the placenta and fetus.

VESSELS

The principal arterial inflow to the brain in humans is via four arteries: two internal carotid arteries and two vertebral arteries. In humans, the carotid arteries are quantitatively the most significant. The vertebral arteries unite to form the basilar artery, and the basilar artery and the carotids form the circle of Willis below the hypothalamus. The circle of Willis is the origin of the six large vessels supplying the cerebral cortex. Substances injected into one carotid artery are distributed almost exclusively to the cerebral hemisphere on that side. Normally no crossing over occurs, probably because the pressure is equal on both sides. Even when it is not, the anastomotic channels in the circle do not permit a very large flow. Occlusion of one carotid artery, particularly in older patients, often causes serious symptoms of cerebral ischemia. There are precapillary anastomoses between the cerebral vessels, but flow through these channels is generally insufficient to maintain the circulation and prevent infarction when a cerebral artery is occluded.

Venous drainage from the brain by way of the deep veins and dural sinuses empties principally into the internal jugular veins in humans, although a small amount of venous blood drains through the ophthalmic and pterygoid venous plexuses, through emissary veins to the scalp, and down the system of paravertebral veins in the spinal canal.

The cerebral vessels have a number of unique anatomic features. In the choroid plexuses, there are gaps between the endothelial cells of the capillary wall, but the choroid epithelial cells that separate them from the cerebrospinal fluid (CSF) are connected to one another by tight junctions. The capillaries in the brain substance resemble nonfenestrated capillaries in muscle (see Chapter 31), but there are tight junctions between the endothelial cells that limit the passage of substances via the paracellular route. In addition, there are relatively few vesicles in the endothelial cytoplasm, and presumably little vesicular transport. However, multiple transport systems are present in the capillary cells. The brain capillaries are surrounded by the endfeet of astrocytes (Figure 33–1). These endfeet are closely applied to the basal lamina of the capillaries, but they do not cover the entire capillary wall, and gaps of about 20 nm occur between endfeet (Figure 33–2). However, the endfeet induce the tight junctions in the capillaries (see Chapter 31). The protoplasm of astrocytes is also found around synapses, where it appears to isolate the synapses in the brain from one another.

INNERVATION

Three systems of nerves innervate the cerebral blood vessels. Postganglionic sympathetic neurons have their cell bodies in the superior cervical ganglia, and their endings contain norepinephrine. Many also contain neuropeptide Y. Cholinergic neurons that probably originate in the sphenopalatine ganglia also innervate the cerebral vessels, and the postganglionic cholinergic neurons on the blood vessels contain acetylcholine. Many also contain vasoactive intestinal peptide (VIP) and peptide histidyl methionine (PHM-27) (see Chapter 7). These nerves end primarily on large arteries. Sensory nerves are found on more distal arteries. They have their cell bodies in the trigeminal ganglia and contain substance P, neurokinin A, and calcitonin gene-related peptide (CGRP). Substance P, CGRP, VIP, and PHM-27 cause vasodilation, whereas neuropeptide Y is a vasoconstrictor. Touching or pulling on the cerebral vessels causes pain.

FORMATION & ABSORPTION

CSF fills the ventricles and subarachnoid space. In humans, the volume of CSF is about 150 mL and the rate of CSF production is about 550 mL/d. Thus the CSF turns over about 3.7 times a day. In experiments on animals, it has been estimated that 50–70% of the CSF is formed in the choroid plexuses and the remainder is formed around blood vessels and along ventricular walls. Presumably, the situation in humans is similar. The CSF in the ventricles flows through the foramens of Magendie and Luschka to the subarachnoid space and is absorbed through the arachnoid villi into veins, primarily the cerebral venous sinuses. The villi consist of projections of the fused arachnoid membrane and endothelium of the sinuses into the venous sinuses. Similar, smaller villi project into veins around spinal nerve routes. These projections may contribute to the outflow of CSF into venous blood by a process known as bulk flow, which is unidirectional. However, recent studies suggest that, at least in animals, a more important route for CSF reabsorption into the bloodstream in health is via the cribriform plate above the nose and thence into the cervical lymphatics. However, reabsorption via one-way valves (of uncertain structural basis) in the arachnoid villi may assume a greater role if CSF pressure is elevated. Likewise, when CSF builds up abnormally, aquaporin water channels may be expressed in the choroid plexus and brain microvessels as a compensatory adaptation.

CSF is formed continuously by the choroid plexus in two stages. First, plasma is passively filtered across the choroidal capillary endothelium. Next, secretion of water and ions across the choroidal epithelium provides for active control of CSF composition and quantity. Bicarbonate, chloride, and potassium ions enter the CSF via channels in the epithelial cell apical membranes. Aquaporins provide for water movement to balance osmotic gradients. The composition of CSF (Table 33–2) is essentially the same as that of brain extracellular fluid (ECF), which in living humans makes up 15% of the brain volume. In adults, free communication appears to take place between the brain interstitial fluid and CSF, although the diffusion distances from some parts of the brain to the CSF are appreciable. Consequently, equilibration may take some time to occur, and local areas of the brain may have extracellular microenvironments that are transiently different from CSF.

Lumbar CSF pressure is normally 70–180 mm H₂O. Up to pressures well above this range, the rate of CSF formation is independent of intraventricular pressure. However, absorption is proportional to the pressure (Figure 33–3). At a pressure of 112 mm H₂O, which is the average normal CSF pressure, filtration and absorption are equal. Below a pressure of approximately 68 mm H₂O, absorption stops. Large amounts of fluid accumulate when the capacity for CSF reabsorption is decreased (external hydrocephalus, communicating hydrocephalus). Fluid also accumulates proximal to the block and distends the ventricles when the foramens of Luschka and Magendie are blocked or there is obstruction within the ventricular system (internal hydrocephalus, noncommunicating hydrocephalus).

PROTECTIVE FUNCTION

The most critical role for CSF (and the meninges) is to protect the brain. The dura is attached firmly to bone. Normally, there is no “subdural space,” with the arachnoid being held to the dura by the surface tension of the thin layer of fluid between the two membranes. As shown in Figure 33–4, the brain itself is supported within the arachnoid by the blood vessels and nerve roots and by the multiple fine fibrous arachnoid trabeculae. The brain weighs about 1400 g in air, but in its “water bath” of CSF it has a net weight of only 50 g. The buoyancy of the brain in the CSF permits its relatively flimsy attachments to suspend it very effectively. When the head receives a blow, the arachnoid slides on the dura and the brain moves, but its motion is gently checked by the CSF cushion and by the arachnoid trabeculae.

The pain produced by spinal fluid deficiency illustrates the importance of CSF in supporting the brain. Removal of CSF during lumbar puncture can cause a severe headache after the fluid is removed, because the brain hangs on the vessels and nerve roots, and traction on them stimulates pain fibers. The pain can be relieved by intrathecal injection of sterile isotonic saline.

HEAD INJURIES

Without the protection of the spinal fluid and the meninges, the brain would probably be unable to withstand even the minor traumas of everyday living; but with the protection afforded, it takes a fairly severe blow to produce cerebral damage. The brain is damaged most commonly when the skull is fractured and bone is driven into neural tissue (depressed skull fracture), when the brain moves far enough to tear the delicate bridging veins from the cortex to the bone, or when the brain is accelerated by a blow on the head and is driven against the skull or the tentorium at a point opposite where the blow was struck (contrecoup injury).

The tight junctions between capillary endothelial cells in the brain and between the epithelial cells in the choroid plexus effectively prevent proteins from entering the brain in adults and slow the penetration of some smaller molecules as well. An example is the slow penetration of urea (Figure 33–5). This uniquely limited exchange of substances into the brain is referred to as the blood-brain barrier, a term most commonly used to encompass this barrier overall and more specifically the barrier in the choroid epithelium between blood and CSF.

Passive diffusion across the tight cerebral capillaries is very limited, and little vesicular transport takes place. However, there are numerous carrier-mediated and active transport systems in the cerebral capillaries. These move substances out of as well as into the brain, though movement out of the brain is generally freer than movement into it.

PENETRATION OF SUBSTANCES INTO THE BRAIN

Water, CO₂, and O₂ penetrate the brain with ease, as do the lipid-soluble free forms of steroid hormones, whereas their protein-bound forms and, in general, all proteins and polypeptides do not. The rapid passive penetration of CO₂ contrasts with the regulated transcellular penetration of H⁺ and HCO₃^– and has physiologic significance in the regulation of respiration (see Chapter 35).

Glucose is the major ultimate source of energy for nerve cells. Its diffusion across the blood-brain barrier would be very slow, but the rate of transport into the CSF is markedly enhanced by the presence of specific transporters, including the glucose transporter 1 (GLUT1). The brain contains two forms of GLUT1: GLUT1 55K and GLUT1 45K. Both are encoded by the same gene, but they differ in the extent to which they are glycosylated. GLUT1 55K is present in high concentration in brain capillaries (Figure 33–6). Infants with congenital GLUT1 deficiency have low CSF glucose concentrations in the presence of normal plasma glucose, and they have seizures and delayed development. In addition, transporters for thyroid hormones; several organic acids; choline; nucleic acid precursors; and neutral, basic, and acidic amino acids are present at the blood-brain barrier.

A variety of drugs and peptides actually cross the cerebral capillaries but are promptly transported back into the blood by a multidrug nonspecific transporter in the apical membranes of the endothelial cells. This P-glycoprotein is a member of the family of adenosine triphosphate (ATP) binding cassettes that transport various proteins and lipids across cell membranes (see Chapter 2). In the absence of this transporter in mice, much larger proportions of systemically administered doses of various chemotherapeutic drugs, analgesics, and opioid peptides are found in the brain than in controls. If pharmacologic agents that inhibit this transporter can be developed, they could be of value in the treatment of brain tumors and other central nervous system (CNS) diseases in which it is difficult to introduce adequate amounts of therapeutic agents into the brain.

CIRCUMVENTRICULAR ORGANS

When dyes that bind to proteins in the plasma are injected, they stain many tissues but spare most of the brain. However, four small areas in or near the brainstem do take up the stain. These areas are (1) the posterior pituitary (neurohypophysis) and the adjacent ventral part of the median eminence of the hypothalamus, (2) the area postrema, (3) the organum vasculosum of the lamina terminalis (OVLT, supraoptic crest), and (4) the subfornical organ (SFO).

These areas are referred to collectively as the circumventricular organs (Figure 33–7). All have fenestrated capillaries, and because of their permeability they are said to be “outside the blood-brain barrier.” Some of them function as neurohemal organs; that is, areas in which polypeptides secreted by neurons enter the circulation. Others contain receptors for many different peptides and other substances, and function as chemoreceptor zones in which substances in the circulating blood can act to trigger changes in brain function without penetrating the blood-brain barrier. For example, the area postrema is a chemoreceptor trigger zone that initiates vomiting in response to chemical changes in the plasma (see Chapter 27). It is also concerned with cardiovascular control, and in many species circulating angiotensin II acts on the area postrema to produce a neurally mediated increase in blood pressure. Angiotensin II also acts on the SFO and possibly on the OVLT to increase water intake. In addition, it appears that the OVLT is the site of the osmoreceptor controlling vasopressin secretion (see Chapter 38), and evidence suggests that circulating interleukin-1 (IL-1) produces fever by acting here too.

The subcommissural organ (Figure 33–7) is closely associated with the pineal gland and histologically resembles the circumventricular organs. However, it does not have fenestrated capillaries, is not highly permeable, and has no established function. Conversely, the pineal and the anterior pituitary do have fenestrated capillaries and are outside the blood-brain barrier, but both are endocrine glands and are not part of the brain.

FUNCTION OF THE BLOOD-BRAIN BARRIER

The blood-brain barrier strives to maintain the constancy of the environment of the neurons in the CNS (Clinical Box 33–1). Even minor variations in the concentrations of K⁺, Ca²⁺, Mg²⁺, H⁺, and other ions can have far-reaching consequences. The constancy of the composition of the ECF in all parts of the body is maintained by multiple homeostatic mechanisms (see Chapters 1 and 38), but because of the sensitivity of the cortical neurons to ionic change, it is not surprising that an additional defense has evolved to protect them. Other functions of the blood-brain barrier include protection of the brain from endogenous and exogenous toxins in the blood and prevention of the escape of neurotransmitters into the general circulation.

DEVELOPMENT OF THE BLOOD-BRAIN BARRIER

In experimental animals, many small molecules penetrate the brain more readily during the fetal and neonatal period than they do in the adult. On this basis, it is often stated that the blood-brain barrier is immature at birth. Humans are more mature at birth than rats and various other experimental animals, and detailed data on passive permeability of the human blood-brain barrier are not available. However, in severely jaundiced infants with high plasma levels of free bilirubin and an immature hepatic bilirubin-conjugating system, free bilirubin enters the brain and, in the presence of asphyxia, damages the basal ganglia (kernicterus). The counterpart of this situation in later life is the Crigler-Najjar syndrome in which there is a congenital deficiency of glucuronyl transferase. These individuals can have very high free bilirubin levels in the blood and develop encephalopathy. In other conditions, free bilirubin levels are generally not high enough to produce brain damage.

KETY METHOD

According to the Fick’s principle (see Chapter 30), the blood flow of any organ can be measured by determining the amount of a given substance (Q_x) removed from the bloodstream by the organ per unit of time and dividing that value by the difference between the concentration of the substance in arterial blood and the concentration in the venous blood from the organ ([A_x] – [V_x]). Thus:

This can be applied clinically using inhaled nitrous oxide (N₂O) (Kety method). The average cerebral blood flow in young adults is 54 mL/100 g/min. The average adult brain weighs about 1400 g, so the flow for the whole brain is about 756 mL/min. Note that the Kety method provides an average value for perfused areas of brain because it gives no information about regional differences in blood flow. It also can only measure flow to perfused parts of the brain. If the blood flow to a portion of the brain is occluded, the measured flow does not change because the nonperfused area does not take up any N₂O.

In spite of the marked local fluctuations in brain blood flow with neural activity, the cerebral circulation is regulated in such a way that total blood flow remains relatively constant. The factors involved in regulating the flow are summarized in Figure 33–8.

ROLE OF INTRACRANIAL PRESSURE

In adults, the brain, spinal cord, and spinal fluid are encased, along with the cerebral vessels, in a rigid bony enclosure. The cranial cavity normally contains a brain weighing approximately 1400 g, 75 mL of blood, and 75 mL of spinal fluid. Because brain tissue and spinal fluid are essentially incompressible, the volume of blood, spinal fluid, and brain in the cranium at any time must be relatively constant (Monro-Kellie doctrine). More importantly, the cerebral vessels are compressed whenever the intracranial pressure rises. Any change in venous pressure promptly causes a similar change in intracranial pressure. Thus, a rise in venous pressure decreases cerebral blood flow both by decreasing the effective perfusion pressure and by compressing the cerebral vessels. This relationship helps compensate for changes in arterial blood pressure at the level of the head. For example, if the body is accelerated upward (positive g), blood moves toward the feet and arterial pressure at the level of the head decreases. However, venous pressure also falls and intracranial pressure falls, so that the pressure on the vessels decreases and blood flow is much less severely compromised than it would otherwise be. Conversely, during acceleration downward, force acting toward the head (negative g) increases arterial pressure at head level, but intracranial pressure also rises, so that the vessels are supported and do not rupture. The cerebral vessels are protected during the straining associated with defecation or delivery in the same way.

AUTOREGULATION

As seen in other vascular beds, autoregulation is prominent in the brain (Figure 33–9). This process, by which the flow to many tissues is maintained at relatively constant levels despite variations in perfusion pressure, is discussed in Chapter 31. In the brain, autoregulation maintains a normal cerebral blood flow at arterial pressures of 65–140 mm Hg.

ROLE OF VASOMOTOR & SENSORY NERVES

The innervation of large cerebral blood vessels by postganglionic sympathetic and parasympathetic nerves and the additional distal innervation by sensory nerves have been described above. The nerves may also modulate tone indirectly, via the release of paracine substances from astrocytes. The precise role of these nerves, however, remains a matter of debate. It has been argued that noradrenergic discharge occurs when the blood pressure is markedly elevated. This reduces the resultant passive increase in blood flow and helps protect the blood-brain barrier from the disruption that could otherwise occur (see above). Thus, vasomotor discharges affect autoregulation. With sympathetic stimulation, the constant-flow, or plateau, part of the pressure-flow curve is extended to the right (Figure 33–9); that is, greater increases in pressure can occur without an increase in flow. On the other hand, the vasodilator hydralazine and the angiotensin-converting enzyme (ACE) inhibitor captopril reduce the length of the plateau. Finally, neurovascular coupling may adjust local perfusion in response to changes in brain activity (see below).

BLOOD FLOW IN VARIOUS PARTS OF THE BRAIN

A major advance in recent decades has been the development of techniques for monitoring regional blood flow in living, conscious humans. Among the most valuable methods are positron emission tomography (PET) and related techniques in which a short-lived radioisotope is used to label a compound and the compound is injected. The arrival and clearance of the tracer are monitored by scintillation detectors placed over the head. Because blood flow is tightly coupled to brain metabolism, local uptake of 2-deoxyglucose is also a good index of blood flow (see below and Chapter 1). If the 2-deoxyglucose is labeled with a short half-life positron emitter such as ¹⁸F, ¹¹O, or ¹⁵O, its concentration in any part of the brain can be monitored.

Another valuable technique involves magnetic resonance imaging (MRI). MRI is based on detecting resonant signals from different tissues in a magnetic field. Functional magnetic resonance imaging (fMRI) measures the amount of blood in a tissue area. When neurons become active, their increased discharge alters the local field potential. A still unsettled mechanism triggers an increase in local blood flow and oxygen. The increase in oxygenated blood is detected by fMRI. PET scanning can be used to measure not only blood flow but the concentration of molecules, such as dopamine, in various regions of the living brain. On the other hand, fMRI does not involve the use of radioactivity. Consequently, it can be used at frequent intervals to measure changes in regional blood flow in a single individual.

In resting humans, the average blood flow in gray matter is 69 mL/100 g/min compared with 28 mL/100 g/min in white matter. A striking feature of cerebral function is the marked variation in local blood flow with changes in brain activity. An example is shown in Figure 33–10. In persons who are awake but at rest, blood flow is greatest in the premotor and frontal regions. This is the part of the brain that is believed to be concerned with decoding and analyzing afferent input and with intellectual activity. During voluntary clenching of the right hand, flow is increased in the hand area of the left motor cortex and the corresponding sensory areas in the postcentral gyrus. Especially when the movements being performed are sequential, the flow is also increased in the supplementary motor area. When persons talk, there is a bilateral increase in blood flow in the face, tongue, and mouth-sensory and motor areas and the upper premotor cortex in the categorical (usually the left) hemisphere. When the speech is stereotyped, Broca and Wernicke areas do not show increased flow, but when the speech is creative—that is, when it involves ideas—flow increases in both these areas. Reading produces widespread increases in blood flow. Problem solving, reasoning, and motor ideation without movement produce increases in selected areas of the premotor and frontal cortex. In anticipation of a cognitive task, many of the brain areas that will be activated during the task are activated beforehand, as if the brain produces an internal model of the expected task. In right-handed individuals, blood flow to the left hemisphere is greater when a verbal task is being performed and blood flow to the right hemisphere is greater when a spatial task is being performed (Clinical Box 33–2).

UPTAKE & RELEASE OF SUBSTANCES BY THE BRAIN

If the cerebral blood flow is known, it is possible to calculate the consumption or production by the brain of O₂, CO₂, glucose, or any other substance present in the bloodstream by multiplying the cerebral blood flow by the difference between the concentration of the substance in arterial blood and its concentration in cerebral venous blood (Table 33–3). When calculated in this manner, a negative value indicates that the brain is producing the substance.

OXYGEN CONSUMPTION

O₂ consumption by the human brain (cerebral metabolic rate for O₂, CMRO₂) averages approximately 20% of the total body resting O₂ consumption (Table 33–1). The brain is extremely sensitive to hypoxia, and occlusion of its blood supply produces unconsciousness in a period as short as 10 s. The vegetative structures in the brainstem are more resistant to hypoxia than the cerebral cortex, and patients may recover from accidents such as cardiac arrest and other conditions causing fairly prolonged hypoxia with normal vegetative functions but severe, permanent intellectual deficiencies. The basal ganglia use O₂ at a very high rate, and symptoms of Parkinson disease as well as intellectual deficits can be produced by chronic hypoxia. The thalamus and the inferior colliculus are also very susceptible to hypoxic damage (Clinical Box 33–3).

ENERGY SOURCES

Glucose is the major ultimate source of energy for the brain; under normal conditions, 90% of the energy needed to maintain ion gradients across cell membranes and transmit electrical impulses comes from this source. Glucose enters the brain via GLUT1 in cerebral capillaries (see above). Other transporters then distribute it to neurons and glial cells.

Glucose is taken up from the blood in large amounts, and the RQ (respiratory quotient; see Chapter 26) of cerebral tissue is 0.95–0.99 in normal individuals. Importantly, insulin is not required for most cerebral cells to utilize glucose. In general, glucose utilization at rest parallels blood flow and O₂ consumption. This does not mean that the total source of energy is always glucose. During prolonged starvation, appreciable utilization of other substances occurs. Indeed, evidence indicates that as much as 30% of the glucose taken up under normal conditions is converted to amino acids, lipids, and proteins, and that substances other than glucose are metabolized for energy during convulsions. Some utilization of amino acids from the circulation may also take place even though the amino acid arteriovenous difference across the brain is normally minute.

The consequences of hypoglycemia in terms of neural function are discussed in Chapter 24.

GLUTAMATE & AMMONIA REMOVAL

The brain’s uptake of glutamate is approximately balanced by its output of glutamine. Glutamate entering the brain associates with ammonia and leaves as glutamine. The glutamate-glutamine conversion in the brain—the opposite of the reaction in the kidney that produces some of the ammonia entering the tubules—serves as a detoxifying mechanism to keep the brain free of ammonia. Ammonia is very toxic to nerve cells, and ammonia intoxication is believed to be a major cause of the bizarre neurologic symptoms in hepatic coma (see Chapter 28).

ANATOMIC CONSIDERATIONS

The two coronary arteries that supply the myocardium arise from the sinuses behind two of the cusps of the aortic valve at the root of the aorta (Figure 33–11). Eddy currents keep the valves away from the orifices of the arteries, and they are patent throughout the cardiac cycle. Most of the venous blood returns to the heart through the coronary sinus and anterior cardiac veins (Figure 33–12), which drain into the right atrium. In addition, there are other vessels that empty directly into the heart chambers. These include arteriosinusoidal vessels, sinusoidal capillary-like vessels that connect arterioles to the chambers; thebesian veins that connect capillaries to the chambers; and a few arterioluminal vessels that are small arteries draining directly into the chambers. A few anastomoses occur between the coronary arterioles and extracardiac arterioles, especially around the mouths of the great veins. Anastomoses between coronary arterioles in humans only pass particles less than 40 μm in diameter, but evidence indicates that these channels enlarge and increase in number in patients with coronary artery disease.

PRESSURE GRADIENTS & FLOW IN THE CORONARY VESSELS

The heart is a muscle that, like skeletal muscle, compresses its blood vessels when it contracts. The pressure inside the left ventricle is slightly higher than in the aorta during systole (Table 33–4). Consequently, flow occurs in the arteries supplying the subendocardial portion of the left ventricle only during diastole, although the force is sufficiently dissipated in the more superficial portions of the left ventricular myocardium to permit some flow in this region throughout the cardiac cycle. Because diastole is shorter when the heart rate is high, left ventricular coronary flow is reduced during tachycardia. On the other hand, the pressure differential between the aorta and the right ventricle, and the differential between the aorta and the atria, are somewhat greater during systole than during diastole. Consequently, coronary flow in those parts of the heart is not appreciably reduced during systole. Flow in the right and left coronary arteries is shown in Figure 33–13. Because no blood flow occurs during systole in the subendocardial portion of the left ventricle, this region is prone to ischemic damage and is the most common site of myocardial infarction. Blood flow to the left ventricle is decreased in patients with stenotic aortic valves because the pressure in the left ventricle must be much higher than that in the aorta to eject the blood. Consequently, the coronary vessels are severely compressed during systole. Patients with aortic stenosis are particularly prone to develop symptoms of myocardial ischemia, in part because of this compression and in part because the myocardium requires more O₂ to expel blood through the stenotic aortic valve. Coronary flow is also decreased when the aortic diastolic pressure is low. The rise in venous pressure in conditions such as heart failure reduces coronary flow because it decreases effective coronary perfusion pressure (Clinical Box 33–4).

Coronary blood flow has been measured by inserting a catheter into the coronary sinus and applying the Kety method to the heart on the assumption that the N₂O content of coronary venous blood is typical of the entire myocardial effluent. Coronary flow at rest in humans is about 250 mL/min (5% of the cardiac output). A number of techniques utilizing radionuclides, radioactive tracers that can be detected with radiation detectors over the chest, have been used to study regional blood flow in the heart and to detect areas of ischemia and infarct as well as to evaluate ventricular function. Radionuclides such as thallium-201 (²⁰¹Tl) are pumped into cardiac muscle cells by Na⁺, K⁺ ATPase and equilibrate with the intracellular K⁺ pool. For the first 10–15 min after intravenous injection, ²⁰¹Tl distribution is directly proportional to myocardial blood flow, and areas of ischemia can be detected by their low uptake. The uptake of this isotope is often determined soon after exercise and again several hours later to bring out areas in which exertion leads to compromised flow. Conversely, radiopharmaceuticals such as technetium-99m stannous pyrophosphate (^99mTc-PYP) are selectively taken up by infarcted tissue by an incompletely understood mechanism and make infarcts stand out as “hot spots” on scintigrams of the chest. Coronary angiography can be combined with measurement of ¹³³Xe washout (see above) to provide detailed analysis of coronary blood flow. Radiopaque contrast medium is first injected into the coronary arteries, and radiographs are used to outline their distribution. The angiographic camera is then replaced with a scintillation camera, and ¹³³Xe washout is measured.

VARIATIONS IN CORONARY FLOW

At rest, the heart extracts 70–80% of the O₂ from each unit of blood delivered to it (Table 33–1). O₂ consumption can only be increased significantly by increasing blood flow. Therefore, it is not surprising that blood flow increases when the metabolism of the myocardium is increased. The caliber of the coronary vessels, and consequently the rate of coronary blood flow, is influenced not only by pressure changes in the aorta but also by chemical and neural factors. The coronary circulation also shows considerable autoregulation.

CHEMICAL FACTORS

The close relationship between coronary blood flow and myocardial O₂ consumption indicates that one or more of the products of metabolism cause coronary vasodilation. Factors suspected of playing this role include a lack of O₂ and increased local concentrations of CO₂, H⁺, K⁺, lactate, prostaglandins, adenine nucleotides, and adenosine. Likely several or all of these vasodilator metabolites act in an integrated manner, redundant manner, or both. Asphyxia, hypoxia, and intracoronary injections of cyanide all increase coronary blood flow 200–300% in denervated as well as intact hearts, and the feature common to these three stimuli is hypoxia of the myocardial fibers. A similar increase in flow is produced in the area supplied by a coronary artery if the artery is occluded and then released. This reactive hyperemia is similar to that seen in the skin (see below). Evidence suggests that in the heart it is due to release of adenosine.

NEURAL FACTORS

The coronary arterioles contain α-adrenergic receptors, which mediate vasoconstriction, and β-adrenergic receptors, which mediate vasodilation. Activity in the noradrenergic nerves to the heart and injections of norepinephrine cause coronary vasodilation. However, norepinephrine increases the heart rate and the force of cardiac contraction, and the vasodilation is due to production of vasodilator metabolites in the myocardium secondary to the increase in its activity. When the inotropic and chronotropic effects of noradrenergic discharge are blocked by a β-adrenergic blocking drug, stimulation of the noradrenergic nerves or injection of norepinephrine in unanesthetized animals elicits coronary vasoconstriction. Thus, the direct effect of noradrenergic stimulation is constriction rather than dilation of the coronary vessels. On the other hand, stimulation of vagal fibers to the heart dilates the coronaries.

When the systemic blood pressure falls, the overall effect of the reflex increase in noradrenergic discharge is increased coronary blood flow secondary to the metabolic changes in the myocardium at a time when the cutaneous, renal, and splanchnic vessels are constricted. In this way the circulation of the heart, like that of the brain, is preserved when flow to other organs is compromised.

The amount of heat lost from the body is regulated to a large extent by varying the amount of blood flowing through the skin. The fingers, toes, palms, and earlobes contain well-innervated anastomotic connections between arterioles and venules (arteriovenous anastomoses; see Chapter 31). Blood flow in response to thermoregulatory stimuli can vary from 1 to as much as 150 mL/100 g of skin/min, and it has been postulated that these variations are possible because blood can be shunted through the anastomoses. The subdermal capillary and venous plexus is a blood reservoir of some importance, and the skin is one of the few places where the reactions of blood vessels can be observed visually.

WHITE REACTION

When a pointed object is drawn lightly over the skin, the stroke lines become pale (white reaction). The mechanical stimulus apparently initiates contraction of the precapillary sphincters, and blood drains out of the capillaries and small veins. The response appears in about 15 s.

TRIPLE RESPONSE

When the skin is stroked more firmly with a pointed instrument, instead of the white reaction there is reddening at the site that appears in about 10 s (red reaction). This is followed in a few minutes by local swelling and diffuse, mottled reddening around the injury. The initial redness is due to capillary dilation, a direct response of the capillaries to pressure. The swelling (wheal) is local edema due to increased permeability of the capillaries and postcapillary venules, with consequent extravasation of fluid. The redness spreading out from the injury (flare) is due to arteriolar dilation. This three-part response—the red reaction, wheal, and flare—is called the triple response and is part of the normal reaction to injury (see Chapter 3). It persists after total sympathectomy. On the other hand, the flare is absent in locally anesthetized skin and in denervated skin after the sensory nerves have degenerated, but it is present immediately after nerve block or section above the site of the injury. This, plus other evidence, indicates that it is due to an axon reflex, a response in which impulses initiated in sensory nerves by the injury are relayed antidromically down other branches of the sensory nerve fibers (Figure 33–14). This is the one situation in the body in which there is substantial evidence for a physiologic effect due to antidromic conduction. The transmitter released at the central termination of the sensory C fiber neurons is substance P (see Chapter 7), and substance P and CGRP are present in all parts of the neurons. Both dilate arterioles and, in addition, substance P causes extravasation of fluid. Effective nonpeptide antagonists to substance P have been developed, and they reduce the extravasation. Thus, it appears that substance P produces the wheal.

REACTIVE HYPEREMIA

A response of the blood vessels that occurs in many organs but is visible in the skin is reactive hyperemia, an increase in the amount of blood in a region when its circulation is reestablished after a period of occlusion. When the blood supply to a limb is occluded, the cutaneous arterioles below the occlusion dilate. When the circulation is reestablished, blood flowing into the dilated vessels makes the skin become fiery red. O₂ in the atmosphere can diffuse a short distance through the skin, and reactive hyperemia is prevented if the circulation of the limb is occluded in an atmosphere of 100% O₂. Therefore, the arteriolar dilation is apparently due to a local effect of hypoxia.

GENERALIZED RESPONSES

Noradrenergic nerve stimulation and circulating epinephrine and norepinephrine constrict cutaneous blood vessels. No known vasodilator nerve fibers extend to the cutaneous vessels, and thus vasodilation is brought about by a decrease in constrictor tone as well as the local production of vasodilator metabolites. Skin color and temperature also depend on the state of the capillaries and venules. A cold blue or gray skin is one in which the arterioles are constricted and the capillaries dilated; a warm red skin is one in which both are dilated.

Because painful stimuli cause diffuse noradrenergic discharge, a painful injury causes generalized cutaneous vasoconstriction in addition to the local triple response. When the body temperature rises during exercise, the cutaneous blood vessels dilate in spite of continuing noradrenergic discharge in other parts of the body. Dilation of cutaneous vessels in response to a rise in hypothalamic temperature overcomes other reflex activity. Cold causes cutaneous vasoconstriction; however, with severe cold, superficial vasodilation may supervene. This vasodilation is the cause of the ruddy complexion seen on a cold day.

Shock is more profound in patients with elevated temperatures because of cutaneous vasodilation, and patients in shock should not be warmed to the point that their body temperature rises. This is sometimes a problem because well-meaning laymen have read in first-aid books that “injured patients should be kept warm,” and they pile blankets on accident victims who are in shock.

UTERINE CIRCULATION

The blood flow of the uterus parallels the metabolic activity of the myometrium and endometrium and undergoes cyclic fluctuations that correlate with the menstrual cycle in nonpregnant women. The function of the spiral and basilar arteries of the endometrium in menstruation is discussed in Chapter 22. During pregnancy, blood flow increases rapidly as the uterus increases in size (Figure 33–15). Vasodilator metabolites are undoubtedly produced in the uterus, as they are in other active tissues. In early pregnancy, the arteriovenous O₂ difference across the uterus is small, and it has been suggested that estrogens act on the blood vessels to increase uterine blood flow in excess of tissue O₂ needs. However, even though uterine blood flow increases 20-fold during pregnancy, the size of the conceptus increases much more, changing from a single cell to a fetus plus a placenta that weighs 4–5 kg at term in humans. Consequently, more O₂ is extracted from the uterine blood during the latter part of pregnancy, and the O₂ saturation of uterine blood falls. Corticotrophin-releasing hormone appears to play an important role in up-regulating uterine blood flow, as well as in the eventual timing of birth.

PLACENTA

The placenta is the “fetal lung” (Figures 33–16 and 33–17). Its maternal portion is in effect a large blood sinus. Into this “lake” project the villi of the fetal portion containing the small branches of the fetal umbilical arteries and vein (Figure 33–16). O₂ is taken up by the fetal blood and CO₂ is discharged into the maternal circulation across the walls of the villi in a manner analogous to O₂ and CO₂ exchange in the lungs (see Chapter 35). However, the cellular layers covering the villi are thicker and less permeable than the alveolar membranes in the lungs, and exchange is much less efficient. The placenta is also the route by which all nutritive materials enter the fetus and by which fetal wastes are discharged to the maternal blood.

FETAL CIRCULATION

The arrangement of the circulation in the fetus is shown diagrammatically in Figure 33–17. Fifty-five percent of the fetal cardiac output goes through the placenta. The blood in the umbilical vein in humans is believed to be about 80% saturated with O₂, compared with 98% saturation in the arterial circulation of the adult. The ductus venosus (Figure 33–18) diverts some of this blood directly to the inferior vena cava, and the remainder mixes with the portal blood of the fetus. The portal and systemic venous blood of the fetus is only 26% saturated, and the saturation of the mixed blood in the inferior vena cava is approximately 67%. Most of the blood entering the heart through the inferior vena cava is diverted directly to the left atrium via the patent foramen ovale. Most of the blood from the superior vena cava enters the right ventricle and is expelled into the pulmonary artery. The resistance of the collapsed lungs is high, and the pressure in the pulmonary artery is several mm Hg higher than it is in the aorta, so that most of the blood in the pulmonary artery passes through the ductus arteriosus to the aorta. In this manner, the relatively unsaturated blood from the right ventricle is diverted to the trunk and lower body of the fetus, while the head of the fetus receives the better-oxygenated blood from the left ventricle. From the aorta, some of the blood is pumped into the umbilical arteries and back to the placenta. The O₂ saturation of the blood in the lower aorta and umbilical arteries of the fetus is approximately 60%.

FETAL RESPIRATION

The tissues of fetal and newborn mammals have a remarkable but poorly understood resistance to hypoxia. However, the O₂ saturation of the maternal blood in the placenta is so low that the fetus might suffer hypoxic damage if fetal red cells did not have a greater O₂ affinity than adult red cells (Figure 33–19). The fetal red cells contain fetal hemoglobin (hemoglobin F), whereas the adult cells contain adult hemoglobin (hemoglobin A). The cause of the difference in O₂ affinity between the two is that hemoglobin F binds 2, 3-DPG less effectively than hemoglobin A does. The decrease in O₂ affinity due to the binding of 2, 3-DPG is discussed in Chapter 31.

CHANGES IN FETAL CIRCULATION & RESPIRATION AT BIRTH

Because of the patent ductus arteriosus and foramen ovale (Figure 33–18), the left heart and right heart pump in parallel in the fetus rather than in series as they do in the adult. At birth the circulation has to change from a parallel to a serial system and from placental to pulmonary gas exchange. This has to be largely completed within minutes of birth, although the complete changes may not be achieved for many hours. The essential element initiating the changes is the fall in the pulmonary vascular resistance when the lungs are first filled with a gas. The pulmonary vascular resistance falls to less than 20% of the value in utero after the lungs are expanded by the first few breaths.

The stimulus for the baby to initiate breathing after birth is not fully understood. In a normal labor, there is no evidence that hypoxia plays a significant role and it is likely that the sudden exposure to light, sound, cold air, and other tactile stimuli are the most important triggers. Oxygen is a strong vasodilator of the pulmonary vascular tree, operating through the production of nitric oxide (NO). The high arterial oxygen tension and bradykinin, which is released from the lungs during their initial inflation, are vasoconstrictors for the umbilical arteries and ductus arteriosus.

Blood returning from the lungs raises the pressure in the left atrium, closing the foramen ovale by pushing the valve that guards it against the interatrial septum. The ductus arteriosus constricts and this, together with the fall in pulmonary vascular resistance, directs most of the output of the right ventricle through the lungs. The ductus arteriosus is functionally closed within a few hours of birth and permanent anatomic closure follows in the next 24–48 h due to extensive intimal thickening. In addition, relatively high concentrations of vasodilators are present in the ductus in utero—especially prostaglandin F_2α—and synthesis of this prostaglandin is blocked by inhibition of cyclooxygenase at birth. In many premature infants the ductus fails to close spontaneously but closure can be produced by drugs that inhibit cyclooxygenase. NO may also be involved in maintaining ductal patency in this setting.

After established pulmonary respiration, highly oxygenated blood containing pulmonary bradykinin reaches the umbilical arteries, initiating constriction. Further constriction is also stimulated by cold and handling of the cord and the arteries are completely constricted within three to five minutes after birth. Venous flow continues as a result of the increased placental pressure within the contracted uterus and the negative intrathoracic pressure of the baby’s respiratory efforts (initially −30 to −50 mm Hg). Within 5 minutes, flow ceases within the umbilical cord and there is little residual blood remaining within the placenta. This redistribution of blood within the fetoplacental circulation after birth is called the “placental transfusion.”

Finally, in the fetal circulation the right ventricular output is slightly greater than that of the left. This is possible because of the parallel pump system and the shunts. After birth the serial system requires both ventricular outputs to be equal before the shunts can close.

• Cerebrospinal fluid is produced predominantly in the choroid plexus of the brain, in part via active transport mechanisms in the choroid epithelial cells. Fluid is reabsorbed into the bloodstream to maintain appropriate pressure in the setting of continuous production.

• The permeation of circulating substances into the brain is tightly controlled. Water, CO₂, and O₂ permeate freely. Other substances (such as glucose) require specific transport mechanisms, whereas entry of macromolecules is negligible. The effectiveness of the blood-brain barrier in preventing entry of xenobiotics is bolstered by active efflux mediated by P-glycoprotein.

• The coronary circulation supplies oxygen to the contracting myocardium. Metabolic products and neural input induce vasodilation as needed for oxygen demand. Blockage of coronary arteries may lead to irreversible injury to heart tissue.

• Control of cutaneous blood flow is a key facet of temperature regulation, and is underpinned by varying levels of shunting through arteriovenous anastomoses. Hypoxia, axon reflexes, and sympathetic input are all important determinants of flow through the cutaneous vasculature.

• The fetal circulation cooperates with that of the placenta and uterus to deliver oxygen and nutrients to the growing fetus, as well as carrying away waste products. Unique anatomic features of the fetal circulation as well as biochemical properties of fetal hemoglobin serve to ensure adequate O₂ supply, particularly to the head. At birth, the foramen ovale and the ductus arteriosus close such that the neonatal lungs now serve as the site for oxygen exchange.