Structure and Function of the Cardiovascular and Lymphatic Systems

From the SA node, the impulse that begins systole spreads throughout the right atrium at a conduction velocity of about 35 cm/s.8 The action potential is delayed in the region of the AV node, possibly because of electrophysiologic differences in the cells that comprise the AV region. Conduction velocity within the node is about 10 cm/s, markedly slower than conduction through the atria. The delay between atrial and ventricular excitation permits an additional boost to ventricular filling by atrial contraction (atrial kick). From the AV node the impulse travels from the AV bundle and through the bundle branches to the Purkinje fibers. Conduction velocities in the AV and Purkinje fibers are the most rapid in the heart.

Ventricular activation occurs sequentially in three phases: (1) septal activation, (2) apical activation, and (3) basal (upper) and posterior activation. The first areas of the ventricles to be excited are portions of the interventricular septum. The septum is activated from both the RBB and the LBB, although the impulse travels from left to right. The extensive network of Purkinje fibers promotes the rapid spread of the impulse to the ventricular apexes. Activation traverses the heart wall from the inside outward (from the endocardium to the epicardium). The basal and posterior portions of the ventricles are the last to be activated. Deactivation, which begins in diastole, occurs in the opposite direction, spreading from the outside inward (epicardium to endocardium). All areas of the ventricle recover at about the same time.

Movement of ions into and out of the cell creates an electrical (voltage) difference across the cell membrane, called the membrane potential. The resting membrane potential of myocardial cells is between −80 and −90 mV, whereas that of the SA node is between −50 and −60 millivolts and that of the AV node is between −60 and −70 mV.8 During depolarization, the inside of the cell becomes less negatively charged as positive ions move inside. In cardiac cells, as in other excitable cells, when the resting membrane potential (in millivolts) becomes less negative with depolarization and reaches the threshold potential for cardiac cells, a cardiac action potential is fired. The various phases of the cardiac action potential are related to changes in the permeability of the cell membrane to sodium, potassium, chloride, and calcium. Threshold is the point at which the cell membrane's selective permeability to these ions is temporarily disrupted, leading to an “all or nothing” depolarization. Drugs that alter the movement of these ions (e.g., calcium) have profound effects on the action potential and can alter heart rate. If the resting membrane potential becomes more negative because of a decrease in the extracellular potassium concentration (hypokalemia), it is termed hyperpolarization.

Normal myocardial cell depolarization and repolarization occur in five phases numbered 0 through 4 (Fig. 31.8). Phase 0 consists of depolarization. This phase lasts 1 to 2 ms and represents rapid sodium entry into the cell. Phase 1 is early repolarization, in which calcium slowly enters the cell. Phase 2, also called the plateau, is a continuation of repolarization, with slow entry of calcium and sodium into the cell. Potassium is moved out of the cell during phase 3, with a return to resting membrane potential in phase 4.⁸ The time between action potentials corresponds to diastole.

Illustration A depicts the action potential of a ventricle indicating four phases and points are as follows. (0, minus 40), (1, 20), (3, minus 40), (4, minus 90). All data are approximate. Illustration B depicts the action potential of S A node indicating two phases and points are as follows. (4, minus 60), (0, 30), (3, minus 40). All data are approximate. Illustration C depicts the action potential of the atrium indicating four phases and points are as follows. (0, minus 30), (1, 10), (3, minus 40), (4, minus 80). All data are approximate.

The phases of depolarization and repolarization occur somewhat differently in the SA and AV node cells, a difference that enables these cells to generate cardiac action potentials independently. The cells of the Purkinje fibers, atria, and ventricles begin with a negative resting membrane potential and proceed to a rapid upstroke, or depolarization (phase 0), a rapid early repolarization (phase 1), a plateau (phase 2), and a rapid later repolarization (phase 3) (see Fig. 31.8 A and C). The fast inward current of phase 0 is mediated by sodium ions flowing through “fast channels” in the cell membrane and causes the rapid upstroke of the action potential in Purkinje fibers, atria, and ventricles. In contrast, the cells of the SA and AV nodes begin with a less negative resting membrane potential, proceed to a slow upstroke (phase 0), and usually lack a plateau (phase 2) (see Fig. 31.8B). The slow inward current, mediated by calcium through transient and long-lasting channels and sodium ions flowing through “slow channels” of the cell membrane, is responsible for the action potential of the SA node and the AV node. Hence, drugs that block calcium have profound effects on the slow inward current and can alter heart rate. Slow channel-blocking drugs, such as verapamil, are used to treat a variety of cardiovascular disorders.

The absolute refractory period, during which no new cardiac action potential can be initiated by a stimulus, no matter the strength, follows depolarization. The absolute refractory period corresponds to the time needed for the reopening of channels that permit sodium and calcium influx (phase 0 through half of phase 3). A relative refractory period occurs near the end of repolarization. During this time, the membrane can be depolarized again but only by a greater than normal stimulus. Abnormal refractory periods as a result of disease can cause abnormal heart rhythms or dysrhythmias, including ventricular fibrillation and cardiac arrest (see Chapter 32).

An electrocardiogram originates from myocardial cell electrical activity as recorded by skin electrodes and is the summation of all the cardiac action potentials (Fig. 31.9). The P wave represents atrial depolarization. The PR interval is a measure of time from the onset of atrial activation to the onset of ventricular activation. The PR interval represents the time necessary for electrical activity to travel from the sinus node through the atrium, AV node, and His-Purkinje system to activate ventricular myocardial cells. The QRS complex represents the sum of all ventricular muscle cell depolarization. The configuration and amplitude of the QRS complex may vary considerably among individuals. During the ST interval, the entire ventricular myocardium is depolarized. The QT interval is sometimes called the electrical systole of the ventricles but the time it takes varies inversely with the heart rate. The T wave represents ventricular repolarization.

Illustration A depicts the tracing for E C G deflections. The horizontal represents the time given in seconds and the vertical axis represents the voltage in millivolt. The E C G tracing comprises P which indicates the atrial depolarization, QRS which indicates the ventricular depolarization and atrial depolarization, and T which indicates the ventricular repolarization. Illustration B depicts the tracing for E C G which shows the E C G intervals among P, QRS, and T waves. The horizontal represents the time given in seconds and the vertical axis represents the voltage in millivolt. The E C G tracing shows the P R interval between 0.12 to 0.20 s, Q R S under 0.10 s, S T interval, and T Illustration B depicts the relationship between cardiac electrical activity and E C G which shows the S A node in right atrium and A V node in left atrium relates to P, depolarization of right ventricle relates to S T, and repolarization of left ventricular relates to T.

Sympathetic and parasympathetic nerve fibers innervate all parts of the atria and ventricles and the SA and AV nodes. Efferent sympathetic and parasympathetic fibers join at the cardiac plexus, a neural junction located at the root of the aorta in front of the trachea. The cardiovascular center in the brainstem responds to input from higher brain centers and from sensory receptors in the periphery and modulates sympathetic and parasympathetic nerve activation (Fig. 31.10) In general, sympathetic stimulation increases electrical conductivity and the strength of myocardial contraction, and vagal parasympathetic nerve activity does the opposite, slowing the conduction of action potentials through the heart and reducing the strength of contraction. Thus the sympathetic and parasympathetic nerves affect the speed of the cardiac cycle (heart rate, or beats per minute). Sympathetic nervous activity enhances myocardial performance. Stimulation of the SA node by the sympathetic nervous system rapidly increases heart rate. The sympathetic nervous system may also induce an increased influx of calcium (Ca²⁺), which increases the contractile strength of the heart and the speed of electrical impulses through the heart muscle and the nodes. Finally, sympathetic nerves influence the diameter of the coronary vessels. Increased sympathetic discharge dilates the coronary vessels by causing the release of vasodilating metabolites resulting from increased myocardial contraction.

A right lateral illustration of the brain highlights the cardiovascular (C V) center at the base of the brain. The inputs to the cardiovascular center (nerve impulses) are as follows. • From higher brain centers: cerebral cortex, limbic system, and hypothalamus. • From sensory receptors: Proprioceptors-monitor movements, chemoreceptors-monitor blood chemistry, and baroreceptors-monitor blood pressure. The outputs to the heart (increased frequency of nerve impulses) are as follows. • Cardiac accelerator nerves (sympathetic): Increased rate of spontaneous depolarization in S A node (and A V node) increases heart rate. Increased contractility of atria and ventricles increases stroke volume. • Vagus nerves (cranial nerve X, parasympathetic): Decreased rate of spontaneous depolarization in S A node (and A V node) decreases heart rate.

The parasympathetic nervous system affects the heart through the vagus nerve, which releases acetylcholine. Receptors for acetylcholine are found in the myocardium and coronary vessels of the heart. Acetylcholine causes a decreased heart rate, slows conduction through the AV node, and reduces myocardial contraction strength.

Sympathetic neural stimulation of the myocardium and coronary vessels depends on the presence of G-protein–coupled adrenergic receptors, which bind specifically with neurotransmitters of the sympathetic nervous system. The effects of sympathetic stimulation depend on whether the α- or β-adrenergic receptors are most plentiful on cells of the effector tissue and whether the neurotransmitter is norepinephrine or epinephrine. Individual variations in receptor structure also influence receptor responsiveness.9 There are five types of adrenergic receptors: β₁, β₂, β₃, α₁, and α₂. (Each of the α-adrenergic receptors also has three subtypes, so some sources indicate that there are nine types of adrenergic receptors.) Overall, cardiovascular structures have more β- than α-receptors; therefore, effects mediated by the β-receptors predominate. Norepinephrine is released by postsynaptic sympathetic nerve endings in the heart, whereas epinephrine is mainly released by the adrenal medulla and reaches the heart through the bloodstream.

The β₁-receptors are found mostly in the heart, specifically the conduction system (AV and SA nodes, Purkinje fibers) and the atrial and ventricular myocardium. The β₂-receptors are found in the heart and also on vascular smooth muscle. Stimulation of both the β₁- and β₂-receptors results in an increase in heart rate (chronotropy) and force of myocardial contraction (inotropy).⁶ In addition, stimulation of the β₂-receptors results in vasodilation because of the location of the receptors on vascular smooth muscle. Overall β₁ and β₂ stimulation enables the heart to pump more blood, and β₂ stimulation also increases coronary blood flow. In the heart, stimulation of β₃-receptors found in the myocardium and coronary vessels opposes the effects of β₁- and β₂-receptor stimulation and decreases myocardial contractility (negative inotropic effect).⁹ Thus, β₃-receptors may provide a “safety mechanism” to prevent overstimulation of the heart by the sympathetic nervous system.

Norepinephrine binding with α₁-receptors, all of which are postsynaptic in the systemic and coronary arteries, causes smooth muscle contraction and thus vasoconstriction. One of the subtypes of α₂-receptors is located on the sympathetic ganglia and nerve terminals. The effect of norepinephrine on these receptors is to inhibit release of more norepinephrine, which promotes vasodilation, thus providing another safety mechanism to prevent excess blood pressure elevation. Dysfunction of α- and β-adrenergic receptors can occur in many conditions (e.g., diabetes, hypertension) and has been implicated in the pathogenesis of many cardiac diseases, including heart failure, myocardial ischemia, and dysrhythmias (see Chapter 32).

Within each myocardial sarcomere are myosin and actin molecules that are grouped together to form filaments. Myosin molecules resemble golf clubs with two large, ovoid heads at one end of the shaft (see Fig. 31.12D). The bi-lobed heads contain an actin-binding site and a site of ATPase activity. About 200 myosin molecules are bundled together with their heads facing outward, forming a single thick filament. Actin molecules resemble beads, and they are strung into two chains that wind around each other, forming a thin filament (see Fig. 31.12C).

Several proteins are also present in the sarcomere. A tropomyosin molecule (a relaxing protein) lies alongside actin molecules. Troponin, another relaxing protein, associates with the tropomyosin molecule. The troponin complex itself has three components. Troponin T aids in binding of the troponin complex to actin and tropomyosin; troponin I inhibits the ATPase of actomyosin; and troponin C contains binding sites for the calcium ions involved in contraction. Troponin T and I molecules are released into the bloodstream during myocardial injury. They can be measured to evaluate if a myocardial infarction or other damage has occurred. The sarcomere also contains a giant elastic protein, titin, which attaches myosin to the Z line, acts as a spring, and influences myocardial stiffness. The titin structure affects myocardial diastolic filling and has been found to play a role in heart failure.¹¹

Where thick filaments overlap with thin filaments, a central dark band is formed, called the anisotropic band, or A band (see Fig. 31.12B). The light bands of the sarcomere, called isotropic bands or I bands, contain only actin molecules and no myosin. The center of the sarcomere is a less dense region called the H band, which contains only myosin molecules and no actin. Thick filaments are held together by M-protein molecules that form a central thin, dark M line.⁷ Thin filaments of actin extend from each side of the Z line, a dense fibrous structure at the center of each I band. The area from one Z line to the next Z line defines one sarcomere.

The coronary arteries deliver oxygen (O₂) to the myocardium. Approximately 70% to 75% of this O₂ is used immediately by cardiac muscle, leaving little O₂ in reserve. Because the O₂ content of the blood and the amount of O₂ extracted from the blood cannot be increased under normal circumstances, any increased energy needs can be met only by increasing coronary blood flow. The MV̇O₂ increases with exercise and decreases with hypotension and hypothermia. As myocardial metabolism and consumption of O₂ increase, the concentration of local vasoactive metabolic factors increases. Some of these (e.g., adenosine, nitric oxide, and prostaglandins) dilate coronary arterioles, thus increasing coronary blood flow. Aging reduces the efficiency of myocardial metabolism and may contribute to the development of heart failure.12

The ovoid head-end of the myosin contains a binding site for actin and a separate enzymatic site that catalyzes the breakdown of ATP to adenosine diphosphate (ADP) and inorganic phosphate (P_i) (see Fig. 31.13). This reaction releases the chemical energy stored in ATP. The splitting of ATP occurs on the myosin molecule before it attaches to actin, but the ADP and inorganic phosphate released remain bound to the active site on myosin.

The binding of this high-energy myosin-actin to form a cross-bridge releases the energy stored in myosin (i.e., ADP and P_i), producing the force necessary for movement of the cross-bridge. With the attachment of actin to myosin at the cross-bridge, the myosin head molecule undergoes a position change, exerting traction on the rest of the myosin bridge, causing the thin filaments to slide past the thick filaments (see Fig. 31.13D). During contraction each cross-bridge undergoes several cycles of attachment, movement, and dissociation from the thin filaments. The rate of cross-bridge cycling is linked to systolic function and cardiac output.¹³

Calcium entering the cell triggers the release of additional calcium from the two storage sites within the sarcomere. Calcium ions then diffuse toward the myofibrils, where they bind with troponin. The calcium-troponin complex interaction facilitates the contraction process (see Fig. 31.13). In the resting state, troponin is bound to actin and the tropomyosin molecule covers the sites where the myosin heads bind to actin, thereby preventing interaction between actin and myosin. Calcium binds to troponin, which ultimately results in tropomyosin moving troponin, thus uncovering the binding sites. Myosin and actin can now form cross-bridges, and ATP can be dephosphorylated to adenosine diphosphate (ADP). Under these circumstances, sliding of the thick and thin filaments can occur, and the muscle contracts.

The mechanical function of the heart is characterized by a number of length-tension curves (Fig. 31.15). Factors that increase contractility, such as sympathetic nerve stimulation, cause the heart to operate on a higher length-tension curve (curve A in Fig. 31.15). A higher tension or increase in ventricular stroke volume is generated without a necessary change in left ventricular end-diastolic volume (LVEDV) or fiber length. Heart failure (curve C in Fig. 31.15) is characterized by a lower length-tension curve. The Frank-Starling law of the heart may not apply to dilated or failing hearts because their fibers are already stretched beyond their optimal length. The failing heart responds to increased filling or stretch with a progressive decline in the force of contraction. Thus at the same left ventricular end-diastolic volume (LVEDV) as curves A and B (see Fig. 31.15), the force of contraction of stroke volume is decreased (Fig. 31.15C).

A graph shows the effect of changes in myocardial contractility on the Frank-Starling curve. The horizontal axis represents the ventricular end-diastolic volume given in milliliters. The vertical axis represents the cardiac output or stroke volume or stroke work or systolic muscle tension, ranging from 0 to 200. The curve shifts downward and to the right as contractility is decreased. Stroke volume in response to increased left ventricular end-diastolic volume in heart failure.

The cross-bridge arrangement with the sarcomere partially accounts for the length-tension mechanism of cardiac muscle. According to the Frank-Starling law, the longer the initial resting length of the cardiac muscle fiber (optimal length is between 2.2 and 2.4 mm), the greater the strength of contraction. At 2.2 mm an optimal number of active cross-bridges exist between actin and myosin. However, if the fibers are stretched beyond 2.2 to 2.4 mm, the force of contraction decreases because actin and myosin become partially disengaged, disrupting many of the cross-bridges. Excessive stretching, to about 3.65 mm, causes actin and myosin to become completely disengaged so that tension (force of contraction) drops to zero. The relationship between stretch and contraction can be compared with that of a rubber band. Up to a certain point, the more the rubber band is stretched the farther it will fly when one end is released; beyond that point, however, the rubber band will break but, of course, the myocardium does not actually break.

Many pathophysiologic factors are linked to decreased HRV, including neurologic disease (e.g., parkinsonian syndrome, multiple sclerosis), cardiovascular disease (e.g., coronary artery disease, heart failure), inflammation, alcohol and drug consumption, occupational exposures, exposure to electromagnetic fields, air pollution, and others.15 Recent studies have documented the relationship between psychological stress, lack of effective coping mechanisms, and mental health disorders with decreased heart rate variability.¹⁶ A decrease in HRV may indicate that the individual is vulnerable to complications from their underlying conditions. For example, a decrease in HRV is associated with a higher risk of cardiovascular events and mortality in individuals with cardiovascular disease.¹⁷

Thyroid hormone, specifically triiodothyronine, causes increases in both heart rate and contractility, resulting in an increase in cardiac output; it also decreases systemic vascular resistance. Triiodothyronine acts directly on the cardiac myocytes to cause gene transcription and cellular changes that result in more calcium release from the sarcoplasmic reticulum.18 Awareness of these changes helps to understand the cardiovascular changes that occur with thyroid diseases. Growth hormone, working together with insulin-like growth factor-1 (IGF-1), also has been shown to increase myocardial contractility.¹⁹ Decreases in levels of growth hormone or thyroid hormone may result in bradycardia (heart rate below 60 beats/min), reduced cardiac output, and low blood pressure. (Other hormones are discussed in the Regulation of Blood Pressure section.)

An artery is a thick-walled, pulsating blood vessel transporting blood away from the heart. In the systemic circulation, arteries carry oxygenated blood. When the iron in hemoglobin is oxygenated, it turns bright red, which is why arterial vessels are often color-coded red in illustrations (see Fig. 31.17). Arterial walls are composed of elastic connective tissue, fibrous connective tissue, and smooth muscle. There are two types of arteries: elastic and muscular. Elastic arteries have a thick tunica media with more elastic fibers than smooth muscle fibers. Elastic arteries are located close to the heart and include the aorta and its major branches and the pulmonary trunk. Elasticity allows the vessel to absorb energy and stretch as blood is ejected from the heart during systole. During diastole, elasticity promotes recoil of the arteries, maintaining blood pressure within the vessels.

Muscular arteries, consisting of the medium and small size arteries, are farther from the heart than the elastic arteries. They contain more muscle fibers and fewer elastic fibers than the elastic arteries and they function to distribute blood to arterioles throughout the body (see Fig. 31.17). Because their smooth muscle can contract or relax, they play a role in blood flow control and in directing flow to body parts with the highest need at any point in time. For example, during exercise more blood is sent to the skeletal muscles, while after a meal more blood is directed to the gut and liver. Contraction narrows the vessel lumen (the internal cavity of the vessel), which diminishes flow through the vessel (vasoconstriction). When the smooth muscle layer relaxes, more blood flows through the vessel lumen (vasodilation).

An artery becomes an arteriole where the diameter of its lumen narrows to less than 0.5 mm. Arterioles are mainly composed of smooth muscle and regulate the flow of blood into the capillaries by constricting or dilating to either slow or increase the flow of blood into the capillaries (Fig. 31.18). The thick smooth muscle layer of the arterioles is a major determinant of the resistance blood encounters as it flows through the systemic circulation.

Left panel, A. An illustration shows the arteriole, the capillary bed, and the venule. The endothelium and smooth muscle fiber of the arteriole are labeled. Blood flow from the heart and through the arteriole. The capillary bed comprises precapillary sphincters (relaxed), true capillary, and thoroughfare channel. The endothelium and the smooth fiber of the venule are labeled. Blood from the venule flows to the heart. Blood flows from arteriole to metarteriole followed by capillary bed. Right panel, B. An illustration shows the arteriole, the metarteriole, and the venule. The endothelium and the smooth muscle fiber of the arteriole are labeled. Blood from the heart flows through the arteriole, into the venule and to the heart. The endothelium and the smooth muscle fiber of the venule are labeled. Precapillary sphincters (contracted) and thoroughfare channel.

The capillary network is composed of connective channels called metarterioles and “true” capillaries (see Fig. 31.18). Metarterioles have discontinuous smooth muscle cells in their tunica media, whereas capillaries have no smooth muscle cells. There is a ring of smooth muscle called the precapillary sphincter at the point where capillaries branch from metarterioles. As the sphincters contract and relax, they regulate blood flow through the capillary beds. The precapillary sphincters help to maintain arterial pressure and regulate selective flow to vascular beds.

Capillaries are composed solely of a layer of endothelial cells surrounded by a basement membrane (see Fig. 31.17). Their thin walls and unique structure make possible the rapid exchange of water; small soluble molecules; some larger molecules, such as albumin; and cells of the innate and adaptive components of the immune system between the blood and the interstitial fluid. Based on their structure, three types of capillaries have been described: continuous, sinusoid, and fenestrated. In the renal glomerulus, for example, the endothelial cells contain oval windows or pores termed fenestrations, which are covered by a thin diaphragm. Sinusoid capillaries are found in the liver and bone marrow.

Substances pass between the capillary lumen and the interstitial fluid (1) through junctions between endothelial cells, (2) through fenestrations in endothelial cells, (3) in vesicles moved by active transport across the endothelial cell membrane, or (4) by diffusion through the endothelial cell membrane (Fig. 31.19B). A single capillary may be only 0.5 to 1 mm in length and 0.01 mm in diameter, but the capillaries are so numerous their total surface area may be more than 600 m² (about 100 football fields).

Left panel, A. The illustration shows a cutaway view of a blood vessel and identifies the following layers from the inside to the outside: endothelium, basement membrane, tunic intima, tunica media, tunica adventitia, nerve, and vasa vasorum. Right panel, B. The illustration shows a cross-section of the blood vessel. The structure identified on the illustration are as follows: plasma membrane, water-filled pore, interstitial fluid, plasma, cytoplasm, and endothelial cell. The functions of the endothelium are as follows. Plasma protein generally cannot cross the capillary wall. Exchangeable proteins are moved across by vesicular transport. Small water-soluble substances pass through the pores. Lipid-soluble substances pass through the endothelial cells.

The vascular endothelium, or blood vessel lining, is important to several body functions and is sometimes considered a separate endocrine organ. All tissues depend on a blood supply, and the blood supply depends on endothelial cells, which form the lining, or endothelium, of the blood vessel (see Fig. 31.19). In addition to substance transport, the vascular endothelium has important roles in coagulation, antithrombogenesis, and fibrinolysis; immune system function; tissue and vessel growth and wound healing; and vasomotion, the contraction and relaxation of vessels. Table 31.3 summarizes some of the more important endothelial functions. Because of its varying roles, the actual structure of the endothelium may vary in different vascular beds. For example, within lymph nodes the endothelial cells of specialized venules, called high endothelial venules, are uniquely structured to support the movement of lymphocytes from the blood into the lymph node.²⁰ Endothelial injury and dysfunction are central processes in many of the most common and serious cardiovascular disorders, including hypertension and atherosclerosis (see Chapter 32).

Compared with arteries, veins are thin walled with more fibrous connective tissue and have a larger diameter (see Fig. 31.17). A given vein is larger than the artery that lies within the same sheath. Veins also are more numerous than arteries. The smallest venules downstream from the capillaries have an endothelial lining and are surrounded by connective tissue. The largest venules have some smooth muscle fibers in their thin tunica media. The venous tunica externa has less elastic tissue than that in arteries, so veins do not recoil as much or as rapidly after distention. Like arteries, veins receive nourishment from tiny vasa vasorum.

Some veins, typically in the legs, contain valves to facilitate the one-way flow of blood toward the heart (Fig. 31.20). These valves are folds of the tunica intima and resemble the semilunar valves of the heart. Backflow in veins of the legs is stopped as the flaps of the valves fill with blood and block the vessel. The position of the valves also facilitates blood flow in the proper direction during venous compression. When a person stands up, contraction of the skeletal muscles of the legs compresses the deep veins of the legs and assists the flow of blood toward the heart and against the force of gravity. This important mechanism of venous return is called the muscle pump (see Fig. 31.20B).

Left panel, A. The illustration shows a vein when the muscles are relaxed. The vein is normal with blood from high-pressure zone flowing through the opening and into the low-pressure zone. Right panel, B. The illustration shows a vein when the muscles are contracted. The vein is constricted with blood from the high-pressure zone flowing through the opening and into the low-pressure zone.

Resistance to flow through a system of vessels, or total resistance, depends not only on characteristics of individual vessels, but also on whether the vessels are arranged in series (end to end) or in parallel (side to side) and on the total cross-sectional area of the system. Vessels arranged in parallel provide less resistance than vessels arranged in series. Blood flowing through the distributing arteries, beginning with branches off the aorta and ending at arterioles in the capillary bed, encounters more resistance than blood flowing through the capillary bed itself, where flow is distributed among many short, tiny branches arranged in parallel (Fig. 31.21). The total cross-sectional area of the arteriolar system is greater than that of the arterial system, yet the greater number of arterioles arranged in series leads to great resistance to flow in the arteriolar system. In contrast, the capillary system has a larger number of vessels arranged in parallel than the arteriolar system, and the total cross-sectional area is much greater; thus there is lower resistance overall through the capillary system. The resulting slow velocity of flow in each capillary is optimal for capillary-tissue exchange.

Top panel, A. An illustration compares the size of the arteries, capillaries, and veins. Arteries and arterioles: small cross-sectional area, high velocity. Capillaries: large cross-sectional area, low velocity. Veins and venules: small cross-sectional area (larger than that of arteries and arterioles), high velocity. Arrows from the left to the right, along the vessels represent the flow. Bottom panel, B. An illustration shows and labels the following structures, from the left to the right: aorta, arteries, arterioles, capillaries, venules, veins, and vena cava. The upper part of the illustration represents total cross-sectional area. The lower part of the illustration represents velocity of blood flow in milliliters per second. The curve is high and stable initially, falls and is roughly stable for a while, and rises to stabilize at the original level.

Blood velocity, or speed, is the distance blood travels in a unit of time, usually centimeters per second (cm/s). It is directly related to blood flow (the amount of blood moved per unit of time) and inversely related to the cross-sectional area of the vessel in which the blood is flowing (see Fig. 31.21). As blood moves from the aorta to the capillaries, the total cross-sectional area of the vessels increases and the velocity decreases.

Flow through a tubular system can be either laminar or turbulent. Blood flow through the vessels, except where vessels split or branch, is usually laminar. In laminar flow, concentric layers of molecules move “straight ahead,” with each layer flowing at a slightly different velocity (Fig. 31.22A). The cohesive attraction between the fluid and the vessel wall prevents the molecules of blood that are in contact with the wall from moving at all. The next thin layer of blood is able to slide slowly past the stationary layer and so on until, at the center, the blood velocity is greatest. Large vessels have room for a large center layer; therefore they have less resistance to flow and greater flow and velocity than smaller vessels.

Top panel, A. The illustration shows a linear tube tracing a parabolic-shaped velocity profile. Bottom panel, B. The illustration shows a branched tube tracing a parabolic-shaped velocity profiles at the trunk and random velocity profiles in the branches.

Where flow is obstructed, the vessel turns or branches, or blood flows over rough surfaces, the flow becomes turbulent with whorls or eddy currents that produce noise, causing a bruit (vascular murmur) to be heard on auscultation (see Fig. 31.22B). Resistance increases with turbulence, which frequently occurs in areas with atherosclerotic plaque (e). Wall shear stress (WSS) is the complex interaction between the vessel wall's endothelial layer and blood hemodynamics. Much investigation is on the consequences of lower WSS and the promotion of atherosclerotic plaque development distal to an induced stenosis.²¹ Clarifying WSS and the perivascular changes with inflammation, macrophage activation, medial thinning, and plaque disruption is critical to understanding the pathogenesis of atherosclerosis.

The arterial blood pressure is determined by the cardiac output multiplied by the peripheral resistance (Fig. 31.23). The systolic blood pressure is the highest arterial blood pressure after ventricular contraction or systole. The diastolic blood pressure is the lowest arterial blood pressure that occurs during ventricular filling or diastole. The mean arterial pressure (MAP), which is the average pressure in the arteries throughout the cardiac cycle, depends on the elastic properties of the arterial walls and the mean volume of blood in the arterial system. MAP can be approximated from the measured values of the systolic (P_s) and diastolic (P_d) pressures as follows:

An equation and an accompanying flowchart show the factors regulating blood pressure. The equation reads: blood pressure equals cardiac output (heart rate multiplied with stroke volume) multiplied with peripheral resistance (P R) or hypertension equals increased C O and or increased P R. • In hypertension increased preload leads to increased fluid volume and venous constriction. • Increased contractility affects the cardiac output. • Vessel diameter (arteriolar) and blood viscosity impact the peripheral resistance. The flowchart shows the following pathways. 1. Humoral regulation (vasodilators and vasoconstrictors). Interrelated with 2. Leads to 3. 2. Local regulation, ionic factors (oxygen, potassium ions, carbon dioxide, and hydrogen), autoregulation. Leads to 3. 3. Vessel diameter (arteriolar). Impacts the peripheral resistance. 4. Sympathetic nervous activity. Leads to 3, 5, and 6. 5. Constrictor (alpha). 6. Dilator (beta, only to skeletal muscle arterioles). Vasodilators include natriuretic peptides, nitric oxide, adrenomedullin, endothelins, and prostacyclin. Vasoconstrictors include epinephrine, norepinephrine, angiotensin 2, and vasopressin.

The normal range for MAP is 70 to 110 mm Hg. The difference between the systolic pressure and the diastolic pressure (P_s − P_d) is called the pulse pressure and typically is between 40 and 50 mm Hg. The pulse pressure is directly related to arterial wall stiffness and stroke volume.

During a wide range of physiologic conditions, including changes in body position, muscular activity, and circulating blood volume, arterial pressure is regulated within a fairly narrow range to maintain tissue perfusion, or blood supply to the capillary beds. The major factors and relationships that regulate arterial blood pressure are summarized in Fig. 31.23.

The cardiac output (minute volume) of the heart can be changed by alterations in the heart rate, stroke volume (volume of blood ejected during each ventricular contraction), or both. An increase in cardiac output without a decrease in peripheral resistance will cause the MAP and flow rate to increase. The higher arterial pressure increases blood flow through the arterioles. On the other hand, a decrease in the cardiac output causes a drop in the MAP and arteriolar flow if peripheral resistance stays constant (Table 31.4).

Total resistance in the systemic circulation, known as either SVR or TPR, is primarily a function of arteriolar diameter. If cardiac output remains constant, arteriolar constriction raises the MAP by reducing the flow of blood into the capillaries, whereas arteriolar dilation has the opposite effect. Reflex control of total cardiac output and peripheral resistance includes (1) sympathetic stimulation of the heart, arterioles, and veins; and (2) parasympathetic stimulation of the heart (Fig. 31.24). The cardiovascular center in the medulla receives input from arterial baroreceptors and chemoreceptors throughout the vascular system and then modifies vagal and sympathetic output to control heart rate and contractility, plus vascular diameter. Vasoconstriction is regulated by an area of the brainstem that maintains a constant (tonic) output of norepinephrine from sympathetic fibers in the peripheral arterioles. This tonic activity is essential for maintenance of blood pressure.

Top panel, A. An illustration of the brain and the heart shows the baroreceptor reflexes. The reflexes are as follows. • Carotid sinus baroreceptors, through glossopharyngeal nerve (C N 9) to cardiac control center and vasomotor center in medulla. • Carotid sinus baroreceptors, through vagus nerve (C N 10) to cardiac control center and vasomotor center in medulla. • Cardiac control center and vasomotor center in medulla, through vagus nerve (parasympathetic) to heart. • Sympathetic chain to cardiac nerve, sympathetic nerve fibers, and smooth muscle in blood vessel walls. Bottom panel, B. An illustration of the brain and the heart shows the vasomotor chemoreflexes. • Peripheral chemoreceptors (carotid bodies, aortic bodies): decreased oxygen, increased carbon dioxide, decreased p H (increased hydrogen ions) result in decreased parasympathetic impulses. • Medullary chemoreceptors: increased carbon dioxide, decreased oxygen, decreased p H (increased hydrogen ions). • Increase sympathetic impulses. • Cardiac control center through vagus nerve (parasympathetic) to heart. • Sympathetic chain to cardiac nerve, sympathetic nerve fibers, and smooth muscle in blood vessel walls.

Effects of hormones

Hormones influence blood pressure regulation through their effects on vascular smooth muscle and blood volume. By constricting or dilating the arterioles in organs, hormones can (1) increase or decrease the blood flow in response to the body's needs, (2) redistribute blood volume during hemorrhage or shock, and (3) regulate heat loss. The key vasoconstrictor hormones include angiotensin II, antidiuretic hormone (ADH; vasopressin), epinephrine, and norepinephrine. The main vasodilator hormones are the atrial natriuretic hormones, nitric oxide, adrenomedullin, and endothelins. By causing fluid retention or loss, aldosterone, ADH, and the natriuretic hormones can influence stroke volume and thus blood pressure. A variety of other hormones, including adipokines and insulin, may be related to the hypertension that occurs with chronic conditions, such as adiposity and diabetes mellitus. However, these factors have not been clearly demonstrated to play a role in blood pressure regulation in healthy individuals.

Vasoconstrictor hormones

The vasoconstrictor hormones include epinephrine; norepinephrine; angiotensin II, which is part of the renin-angiotensin-aldosterone system (RAAS) (see Chapters 5 and 32); and ADH. Epinephrine, the catecholamine hormone released from the adrenal medulla, causes vasoconstriction in most vascular beds except the coronary, liver, and skeletal muscle circulations. Norepinephrine mainly acts as a neurotransmitter; however, some also is released from the adrenal medulla. When the RAAS is activated, angiotensin II (ANG II) binds to the AT₁ receptor and serves as a potent vasoconstrictor. Other RAAS pathways oppose this action (see Fig. 32.2). High levels of aldosterone also can increase vascular tone.

ADH and aldosterone also affect blood pressure by increasing blood volume through their influence on fluid reabsorption in the kidney and by stimulating thirst. ADH causes the reabsorption of water from tubular fluid in the distal tubule and collecting duct of the nephron. Aldosterone, the end product of the RAAS, stimulates the reabsorption of sodium, chloride, and water from the same locations in the kidney (Fig. 31.25; also see Chapters 3 and 22).

An illustration shows the three mechanisms influencing total plasma volume. • A D H from neurohypophysis triggers the kidney. • A N P and B N P from the heart trigger the kidney. • Fluid and sodium ions loss or retention (urine). • Renin converts angiotensinogen to angiotensin 1 and angiotensin 1 is converted to angiotensin 2 in the presence of A C E which results in vasoconstriction. • R A S S: angiotensin 1 to A C E to angiotensin 2 to adrenal cortex that releases aldosterone to the kidney. • R A S S to vasoconstriction.

Vasodilator hormones

There are numerous vasodilator hormones, most of which have other important effects on blood volume and vascular function. The natriuretic peptides (NPs) include atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin. These hormones function as both vasodilators and regulators of sodium and water excretion (natriuresis and diuresis) (see Chapter 3). ANP and BNP are released from myocytes in heart. Increased pressure or diastolic volume in the heart stimulates the release of these peptide hormones which then stimulate secretion of sodium and water from the kidney (see Fig. 31.25). Serum levels of BNP are increased in many types of cardiac disease including heart failure, hypertension, pulmonary embolism, valvular heart disease, and chronic coronary artery disease, and can be used to predict prognosis. Neprilysin is a drug that prevents the degradation of the natriuretic peptides and can be used in combination with other medications for the treatment of severe acute heart failure (see Chapter 32).²² Many studies are underway to develop other medications that can mimic the positive effects of the natriuretic peptides.²³

Other vasodilating mediators include nitric oxide (NO), adrenomedullin (ADM), the endothelins, and prostacyclin. These mediators are being investigated to determine if they or their inhibitors might be useful drugs for the treatment of cardiovascular diseases or if their levels might be useful in determining the prognosis of persons with known disease. Nitric oxide (NO) is a soluble gas continuously synthesized in endothelial cells by the enzyme nitric oxide synthase (NOS). NO has a wide range of biologic properties that maintain vascular homeostasis, including modulation of vascular dilator tone, regulation of local cell growth, and protection of the vessel from injurious consequences of platelets and cells circulating in blood. NO plays a crucial role in the normal endothelial function. An emerging list of conditions, including those commonly associated as risk factors for atherosclerosis such as hypertension, hypercholesterolemia, smoking, diabetes mellitus, and heart failure, is associated with diminished release of nitric oxide into the arterial wall because of impaired synthesis or excessive oxidative degradation (Fig. 31.26).^24,25 Adrenomedullin (ADM), a peptide with powerful vasodilatory activity, is present in numerous tissues. It has been found to have numerous cardiovascular effects, including a role in fetal cardiovascular system development and vasodilation. ADM is released by endothelial cells in conditions of vascular wall stress and plays a role in controlling vascular tone and blood pressure.²⁶ The endothelins are a family of three structurally similar peptides (ET-1, ET-2, and ET-3) and four receptors produced in cells in the vascular smooth muscle, the endothelium, the kidneys, and other organs. Understanding the physiologic and pathologic roles of these peptides has been complicated by the fact that endothelin binding to some receptors causes vasodilation and natriuresis, whereas binding to other receptors causes the opposite response—vasoconstriction plus sodium and water retention. Inhibitors to ET-1 have been approved for the treatment of pulmonary hypertension (see Chapter 35).

An illustration lists the lifestyle factors associated with reduced bioavailability of nitric oxide: diet, family history, tobacco smoking, diabetes, gender, hyperlipidemia or atherosclerosis, age, sedentary lifestyle, high blood pressure. Reduced nitric oxide also leads to reduced e N O S activity, reduced e N O S expression, arginase upregulation, oxidative stress, endogenous N O S inhibitors, and e N O S uncoupling.

Prostacyclin is a vasodilator that is produced by the actions of cyclooxygenases (COX-1 and COX-2) on arachidonic acid. It has the additional properties of opposing clot formation (antithrombotic), decreasing platelet activity, and inhibiting the release of growth factors from macrophages and the endothelial cells. Nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit these cyclooxygenases have been associated with cardiovascular disease risk in healthy people and in those with a known cardiovascular disease.27

Two other mechanisms that increase venous pressure and venous return to the heart are (1) the skeletal muscle pump and (2) the respiratory pump. During skeletal muscle contraction, the veins within the muscles are partially compressed, causing decreased venous capacity and increased return to the heart (see Fig. 31.20B). The respiratory pump acts during inspiration, when the veins of the abdomen are partially compressed by the downward movement of the diaphragm. Increased abdominal pressure moves blood toward the heart.