10.1 Course of the Circulation
Figure 10.1 is an overview of the circulation. Its course is as follows:
– Blood from the superior and inferior vena cavae enters the right atrium.
– It then passes to the right ventricle through the tricuspid valve.
– From the right ventricle, it passes to the pulmonary artery through the pulmonic valve and into the lungs, where it is oxygenated.
– Oxygenated blood from the lungs enters the pulmonary vein and travels to the left atrium.
– It then passes to the left ventricle through the mitral valve.
– Blood is ejected from the left ventricle into the aorta through the aortic valve.
– It then travels through arteries to the tissues.
– Mixed venous blood from the tissues then drains into the vena cavae.
Atrial septal defect
Atrial septal defect (ASD) is a hole between the two atria of the heart that allows blood to shunt between these chambers. It is often not detected until adulthood, when it presents with cyanosis (bluish or purplish tinge to the skin and mucous membranes, caused by lack of oxygen to the blood), dyspnea (especially on exertion), fatigue, palpitations, and edema (a collection of excess fluid in the cavities or tissues of the body). Signs of ASD include arrhythmias (especially atrial fibrillation), a split second heart sound, and a pulmonary ejection systolic murmur that is appreciated best at the second intercostal space at the left sternal edge. Complications may include heart failure and shunt reversal. Small ASDs may heal spontaneously, but larger defects require surgical closure with a patch. Medications (e.g., β-blockers and digoxin) may be required for symptomatic control. Anticoagulant therapy (e.g., warfarin) may be required to reduce the risk of stroke.
Ventricular septal defect
Ventricular septal defect (VSD) is a hole between the two ventricles of the heart that allows blood to shunt between these chambers. This is the most common congenital heart defect and is often associated with Down syndrome, tetralogy of Fallot (see p. 101), and Turner syndrome. VSD may also occur due to septal rupture following a myocardial infarction (MI). Signs and symptoms include cyanosis, dyspnea (shortness of breath), fatigue, edema, tachycardia, and pansystolic murmur, which is appreciated best at the fourth intercostal space. Complications include Eisenmenger syndrome (pulmonary hypertension and shunt reversal), endocarditis (due to turbulent blood flow in a high-pressure system), stroke, and heart failure. Small VSDs may heal spontaneously, but larger defects require surgical closure with a patch. Medications (e.g., β-blockers and digoxin) may be required for symptomatic control. Diuretics may be used to reduce preload in heart failure.
Tetralogy of Fallot
Tetralogy of Fallot is a rare combination of four cardiac defects: pulmonary valve stenosis, overriding aorta, VSD, and right ventricular hypertrophy. Symptoms include cyanosis, dyspnea, fainting, finger clubbing, fatigue, and prolonged crying in infants. Signs include systolic murmur appreciated at the left sternal base, thrill (palpable mur-mur), and an abnormal second heart sound. Treatment includes corrective surgery in infancy. This usually involves intracardiac repair of the VSD with a patch and repair of the stenosed pulmonary valve. Complications following surgery, such as arrhythmias, can be treated with the appropriate antiarrhythmic agent or by implantation of a pacemaker or internal defibrillator.
Fig. 10.1 Circulation.
Red: Oxygenated blood. Blue: Deoxygenated blood.
From Atlas of Anatomy, © Thieme 2008, Illustration by Markus Voll.
10.2 Vascular Components of the Circulatory System
Refer to Fig 10.2.
– Arteries are high-pressure vessels that carry oxygenated blood from the heart to the rest of the body.
– They have thick walls that are composed of elastic tissue (elastin, collagen, and connective tissue) and smooth muscle.
Fig. 10.2 Characteristics of vessels.
The diameters of vessels leaving and entering the heart are large, whereas the diameters of capillaries are very small. The aggregated cross-sectional area of capillaries is large because they are an order of magnitude more numerous than arteries and veins. The holding capacity of veins is much greater than arteries or capillaries. Because they are extremely compliant, veins can expand to permit great increases in blood volume. (TPR, total peripheral resistance)
– The large arteries, particularly the aorta, expand elastically to contain the stroke volume and produce a continuous flow.
– Arterioles control blood flow and distribute blood into the capillary beds.
– Their walls are composed primarily of smooth muscle.
– They are the major sites of controllable resistance in the systemic circulation. Resistance is controlled by multiple factors, including local metabolism, vasoactive substances such as angiotensin II, and the sympathetic nervous system acting at α1 receptors (producing vasoconstriction) or β2 receptors (producing vasodilation).
– Capillaries facilitate the exchange of gases, fluid, and nutrients between the blood and the interstitial space.
– Their walls are thin, consisting of a single layer of endothelial cells surrounded by a basal lamina. In most tissues, the endothelial cells have small pores or gaps between cells that permit trans-capillary exchange of small water-soluble substances by diffusion. Large water-soluble substances can cross capillary endothelial cell membranes by transcytosis in vesicles.
– The cumulative cross-sectional area of the capillaries is high.
– Venules are small veins that collect blood from the capillaries.
– Veins are low-pressure vessels that return blood back to the heart via the venae cavae. They also act as expandable reservoirs.
– They passively relax or actively constrict under sympathetic adrenergic stimulation of α1 receptors.
– The contractile state of large veins is critically important in setting central venous pressure, which determines the preload of the right ventricle. In turn, this has a major effect on cardiac output, as the heart cannot pump more blood than is delivered to it by venous return.
Aneurysms are bulges in arteries, especially serious in the aortic arch, descending abdominal aorta, and the brain. Increasing dilatation causes increasing tension in the wall of the artery by the law of Laplace, which states that wall tension is proportional to pressure times radius. The increased tension contributes to increased diameter of a vessel and risk of rupture which is usually fatal. Aneurysms more than two inches wide are surgically repaired by inserting a synthetic graft into the vessel.
10.3 Circulatory Hemodynamics
Blood flow is defined as the volume of blood moving through a vessel per unit of time. It is expressed by
Q = v × A
where Q is blood flow (mL/min), v is velocity (cm/sec), and A is cross-sectional area (cm2).
– Blood flow is proportional to the product of velocity and cross-sectional area.
– The velocity of blood flow is faster through vessels with a low cross-sectional area; for example, the velocity of blood flow is faster in the aorta (small cross-sectional area) than in the capillaries (large cumulative cross-sectional area).
Relationship of Pressure and Resistance to Blood Flow
Blood flow through vessels is related to the driving pressure and the resistance to flow, as expressed by
Q = ΔP/R
where Q is blood flow (mL/min), ΔP is pressure gradient (mm Hg), and R is resistance (mm Hg/mL/min).
– Blood flow is directly proportional to the driving pressure gradient and inversely proportional to resistance.
– The greater the driving pressure gradient, the greater the blood flow.
– The greater the resistance, the lower the blood flow.
Resistance is derived from Poiseuille’s equation, as expressed by
R = 8ηL/πr4
where R is resistance, r is radius of the blood vessel, η is viscosity of the fluid, and L is length of the blood vessel.
– Resistance is directly proportional to the viscosity of blood, which is mainly determined by the concentration of cellular elements and proteins. If viscosity increases, then resistance increases, and blood flow will decrease. The converse is also true.
– Resistance is directly proportional to the length of the vessel.
– Because viscosity and the length of the vessels are relatively constant in the circulatory system, which is a closed system, the principal variable controlling resistance to blood flow is the radius of the vessel. Resistance is inversely proportional to the fourth power of the radius. Therefore, small changes in radius cause large changes in resistance. For example, a 19% increase in radius would halve the resistance.
Parallel and series resistance
Resistance to flow in a network of vessels depends on the characteristics of the individual vessels and how they are connected.
– When vessels are connected end to end (all the blood flows through each vessel in series), the resistance of a network is the sum of the individual vessel resistances and is greater than the resistance of any one vessel. This can be expressed as
Rtotal = R1 + R2 + R3 + …
– When vessels are connected in parallel (the blood divides among the different vessels), the resistance of a network varies in an inverse relationship. The total resistance is less than that of any one vessel. This can be expressed as
Rtotal = 1/(1/R1 + 1/R2 + 1/R3 + …)
Example: Two vessels each have a resistance value of 3 units. When connected in series, their combined resistance is 3 + 3 = 6 resistance units. When connected in parallel, their combined resistance is 1/(⅓ + ⅓) = 1.5 resistance units.
Laminar and turbulent flow
– Laminar flow is streamlined and is the most efficient way to move blood. Maximum flow velocity occurs in the center of the bloodstream in nonturbulent vessels; minimum velocity occurs next to the wall of vessels.
– Turbulent flow, where the flow pattern is chaotic, causes bruits (audible vibrations). The tendency for turbulent flow increases with
– ↑velocity of blood flow (e.g., stenosed [narrowed] vessels or cardiac valves)
– ↓ blood viscosity (e.g., severe anemia)
Regulation of Blood Flow
Blood flow through peripheral tissues is under multiple controls. Most controls can be broadly grouped into local control mechanisms and central control mechanisms that act via the sympathetic nervous system. In the majority of tissues, particularly the coronary and cerebral circulations, local control is the dominant influence. Central control is dominant in a few tissues (e.g., in the skin). There are other circulating regulatory mediators whose levels may increase sharply in pathological situations.
Local control keeps blood flowing through a given vascular bed at a level appropriate for its metabolic activity, rising during high metabolic activity and falling during low metabolic activity. Local control reflects the interplay between numerous vasoactive substances produced by local tissues and the endothelium.
Autoregulation is the process where tissues adjust the resistance of their arterioles to maintain blood flow constant in the face of changes in blood pressure (mean arterial pressure). Without autoregulation, flow would vary in parallel with mean arterial pressure, which varies throughout the day, and would often be too high or too low.
Active and reactive hyperemia
Active hyperemia is an increase in local blood flow in response to an increase in local metabolism, as occurs during muscle contraction or glandular secretion. Reactive hyperemia is a transient increase in blood flow following release of an occlusion.
Mechanisms of Local Control
Arteriolar smooth muscle stretches in response to an increase in arterial pressure (Fig. 10.3). This opens stretch-gated channels, leading to depolarization, an influx of Ca2+, and contraction that reduces blood flow back to its previous level. Conversely, a fall in arterial pressure relaxes arteriolar smooth muscle, allowing flow to rise to its previous level.
– This mechanism explains autoregulation but not active or reactive hyperemia.
Local tissue metabolic factors
Metabolizing tissue produces vasodilator metabolites (e.g., CO2, H+, and adenosine) and consumes O2. Arteriolar smooth muscle dilates in response to an increase in vasodilator metabolites and fall in local O2 concentration. These changes occur during a rise in local metabolism or a decrease in local blood flow.
– These factors are responsible for active and reactive hyperemia and for part of autoregulation.
The endothelium that lines the arterioles is a source of substances that relax or constrict the surrounding smooth muscle. These substances are the following:
– Nitric oxide (NO). This is the most important endothelium-derived vasoactive factor. It is produced constitutively and increases in response to increased shear stress (faster blood velocity). NO acts by stimulating the production of cyclic guanosine monophosphate (cGMP), which activates a kinase whose actions inhibit smooth muscle contraction, causing vasodilation. NO is also an important inhibitor of platelet aggregation.
– Prostacyclin (PGI2). PGI2 is an eicosanoid that acts via cyclic adenosine monophosphate (cAMP) and protein kinase A to inhibit smooth muscle contraction, causing vasodilation.
– Endothelium-derived hyperpolarizing factor (EDHF). This factor relaxes vascular smooth muscle, causing vasodilation by opening K+channels. This hyperpolarizes vascular muscle cells which decreases their cystolic Ca2+concentration.
– Endothelin. This is a peptide that causes potent vasoconstriction of vascular smooth muscle.
– Vasoconstriction of blood vessels and subsequent decrease in blood flow occur as a result of norepinephrine binding to α1-adrenergic receptors.
Fig. 10.3 Vasoconstriction and vasodilation.
Neuronal regulation of blood flow is controlled by the sympathetic nervous system (1a,b). Vasoconstriction is achieved by norepinephrine binding to α1-adrenergic receptors on blood vessels. Vasodilation is achieved by decreasing the tone of the sympathetic system. The salivary glands and the genitals dilate in response to parasympathetic stimuli to which vasoactive substances (bradykinin and nitric oxide [NO], respectively) act as the mediators. Local control of blood flow (2a,b) occurs in response to myogenic effects and a change in oxygen concentration in tissues. Vasodilation may also occur in response to an increase in metabolic products (e.g., CO2, H+, adenosine diphosphate [ADP], adenosine monophosphate [AMP], adenosine, and K+). Vasoactive hormones (3a,b) either have a direct effect on the vascular musculature (e.g., epinephrine) or lead to the local release of vasoactive substances (e.g., NO and endothelin) that exert local paracrine effects. NO acts as a vasodilatory agent. It is released from the endothelium when acetylcholine (via M receptors), endothelin-1 (via ETB receptors), or histamine (via H1 receptors) binds with an endothelial cell. NO then diffuses to and relaxes vascular muscle cells in the vicinity. Endothelin-1 causes vasodilation by causing the release of NO. It can also cause vasoconstriction in the vascular musculature. When substances such as angiotensin II and antidiuretic hormone (ADH) bind to the endothelial cells, they release endothelin-1, which diffuses to and constricts the adjacent vascular muscles (via ETA receptors). High concentrations of epinephrine have a vasoconstrictive effect (via α1-adrenergic receptors), whereas low concentrations exert vasodilatory effects (via β2-adrenergic receptors). Eicosanoids: prostaglandin F2α (PGF2α) and thromboxane A2 (released from platelets) have vasoconstrictive effects, whereas prostacyclin (PGI2), released from endothelium, and prostaglandin E2 (PGE2) have vasodilatory effects. Endothelium-derived hyperpolarizing factor (EDHF) causes vasodilation by opening K+ channels in vascular muscle cells, hyperpolarizing them, leading to a drop in cytosolic Ca2+ concentration. Bradykinin and kallidin are vasodilatory agents cleaved from kininogens in plasma by the enzyme kallikrein. (ATP, adenosine triphosphate)
– Vasodilation of blood vessels and subsequent increase in blood flow occur due to a decrease in sympathetic tone.
Nitrates are vasodilator drugs that break down or are metabolized in the body to produce nitric oxide (NO). Their sites of action depend on how and where this occurs. Some, such as nitroglycerin, act primarily in the venous system to reduce central venous pressure. This reduces cardiac preload and cardiac work and decreases the coronary demand for oxygen (O2), which is one reason why they help relieve angina. Others have a more global action; for example, sodium nitroprusside spontaneously forms NO throughout the body and greatly reduces total peripheral resistance, thereby lowering blood pressure. The nitrates in general are shortacting drugs because they are metabolized quickly and because NO itself has a lifetime of only seconds.
Collateral circulation is a type of long-term local blood flow regulation. When normal blood flow becomes partially or completely blocked, small collateral vessels enlarge and assume the major role in supplying blood to that region. At first, these vessels can supply only a small fraction of the normal blood supply, but with sufficient time, they can return flow to near-normal levels. Regular aerobic exercise may promote collateral vessel development in coronary arteries.
Angiogenesis is an increase in the number and size of the vessels supplying local vascular beds in response to a decrease in perfusion pressure. It is a mechanism for long-term regulation of blood flow. Cancer cells can trigger angiogenesis, causing nearby blood vessels to branch into them to provide nutrients and oxygen.
Vascular compliance, or capacitance, describes the distensibility (ability to stretch) of blood vessels. It is expressed by
C = ΔV/ΔP
where C is compliance, ΔV is change in the volume of a vessel (mL), and ΔP is change in pressure (mm Hg).
– The large veins are highly compliant, which allows them to accommodate changes in blood volume with relatively small changes in pressure.
– The order of compliance from high to low is veins > aorta > arteries > arterioles.
10.4 Arterial Pressure
Note: By convention, blood pressure, if not otherwise specified, refers to arterial pressure.
Systolic and Diastolic Pressure
Each cardiac ejection raises pressure in the aorta and major arteries, reaching a peak value called the systolic pressure. It begins to fall in late systole and continues to fall throughout diastole until the beginning of the next ejection. The value at that point is called the diastolic pressure. Figure 10.4 illustrates how blood pressure is measured with a sphygmomanometer.
Pulse pressure is the difference between the systolic and diastolic pressures.
– Stroke volume is the main determinant of pulse pressure. The capacitance of arteries is relatively low compared with veins; therefore, any increase in stroke volume during ventricular systole will increase systolic pressure. Diastolic pressure remains unchanged throughout systole, so the increase in systolic pressure will equal the increase in pulse pressure.
Mean Arterial Pressure
Mean arterial pressure (MAP) is the average pressure measured throughout the cardiac cycle. A typical value is ~95 mm Hg.
At rest, diastole occupies about two-thirds of the cardiac cycle, and systole occupies about one-third of the cycle; therefore, MAP is always less than their arithmetic average. It can be estimated from the following:
MAP = diastolic pressure + ⅓ pulse pressure
MAP is a function of cardiac output (CO) and total peripheral resistance (TPR):
MAP = CO × TPR
– CO is determined by stroke volume and heart rate.
– TPR is determined by the series/parallel combination of the vessels in peripheral tissues.
Hypertension is abnormally high blood pressure. Essential hypertension is the term used when the cause is unknown. It accounts for 90% of all cases. The other 10% of hypertension cases are secondary to diseases such as renal artery stenosis, polycystic kidneys, pyelonephritis, glomer ulonephritis, diabetes mellitus, Cushing syndrome, Conn syndrome, pheochromocytoma, hyperparathyroidism, coarctation of the aorta, and preeclampsia. Pain can also be a cause of hypertension. Chronic hypertension can lead to end-organ damage, including left ventricular hypertrophy, renal failure, peripheral vascular disease, stroke, transient ischemic attacks (TIAs), MI, congestive heart failure, and cerebral encephalopathy. Drug treatment of hypertension includes diuretics (mainly thiazides), angiotensin antagonists (ACE inhibitors, angiotensin II inhibitors, and rennin inhibitors), β-blockers, Ca2+-channel blockers, α1-adrenergic receptor blockers, α2-adrenergic receptor agonists, and direct vasodilators.
Fig. 10.4 Blood pressure (BP) measurement with a sphygmomanometer.
The BP is routinely measured at the level of the heart by a sphygmomanometer. An inflatable cuff is snugly wrapped around the arm, and a stethoscope is placed over the brachial artery. While reading the manometer, the cuff is inflated to a pressure higher than the expected systolic pressure (Ps; the radial pulse disappears). The air in the cuff is then slowly released (~2−4 mm Hg/s). The first sounds synchronous with the pulse (Korotkoff sounds) indicate that the pulse has fallen below the Ps. This value is read from the manometer. These sounds first become increasingly louder, then more quiet and muffled, and eventually disappear when the cuff pressure falls below the diastolic pressure (Pd; second reading).
Neural Regulation of Arterial Pressure
The baroreceptor reflex allows the body to compensate rapidly for changes in arterial pressure. It is mediated by receptors sensitive to mechanical stretch that are located in the carotid sinuses and in the walls of the aortic arch.
Carotid sinus massage
Carotid sinus massage slows the heart rate via the baroreceptor reflex. It is a useful noninvasive procedure for termination of supraventricular tachycardia (SVT). It is also useful for differentiating SVT from ventricular tachycardia (VT), as VT will be unaffected by carotid sinus massage.
Jugular venous pressure
The internal jugular vein passes medial to the clavicular head of the sternocleidomastoid muscle up behind the angle of the mandible. It is a reliable manometer of right atrial pressure. It is not normally visible or palpable but may become distended in right ventricular failure.
The mechanism of the baroreceptor reflex is as follows:
– Decreased arterial pressure causes carotid sinus baroreceptors to undergo a reduced amount of stretch. This decreases the rate of action potential firing in the carotid sinus nerve, a branch of the glossopharyngeal nerve (cranial nerve [CN] IX). The aortic arch baroreceptors are innervated by branches of the vagus nerve (CN X) and acts in a similar manner. Impulses from these baroreceptors are relayed to the vasomotor center in the medulla oblongata, which increases sympathetic outflow to the heart and blood vessels and reduces parasym-pathetic outflow to the heart. This results in the following:
– ↑ heart rate
– ↑ contractility, stroke volume, and cardiac output
– ↑ venoconstriction (Fig. 10.5). This reduces the compliance of veins, resulting in an increase in venous return to the heart. According to the Frank–Starling mechanism, increased venous return increases filling pressures (preload) such that CO is increased.
– ↑ vasoconstriction of arterioles. This increases TPR and therefore arterial pressure.
There are additional baroreceptors in the walls of the heart, particularly the atria, and in the pulmonary vessels. These are called cardiopulmonary or low-pressure baroreceptors (because the pressures they detect are lower than arterial pressure). Their role is to detect fullness of the vascular system; that is, they serve as de facto blood volume detectors. Mechanistically, they work the same way as the arterial baroreceptors.
Fig. 10.5 Blood pressure regulation via vascular smooth muscle.
Postsynaptic sympathetic fibers release norepinephrine, which acts at α1-adrenergic receptors, causing contraction of vascular smooth muscle, thus increasing blood pressure. Conversely, circulating epinephrine acts at β2 adrenergic receptors to cause dilation of vascular smooth muscle. Postsynaptic parasympathetic fibers do not innervate vascular smooth muscle.
From Atlas of Anatomy, © Thieme 2008, Illustration by Markus Voll.
Table 10.1 summarizes the vasomotor response to the baroreceptor reflex.
Hormonal Control of Arterial Pressure
The renin–angiotensin−aldosterone system (RAS) is involved in the longer-term regulation of arterial pressure by modulating blood volume (Fig. 10.6).
Fig. 10.6 Renin–angiotensin−aldosterone system (RAS).
If the mean renal blood pressure acutely drops below 100 mm Hg, renal baroreceptors will trigger the release of renin into the systemic circulation. Renin is a peptidase that catalyzes the cleavage of angiotensin I from angiotensinogen. Angiotensin-converting enzyme (ACE) cleaves two amino acids from angiotensin I to produce angiotensin II. Angiotensin II and aldosterone are the most important effectors of the RAS. Angiotensin II stimulates the release of aldosterone by the adrenal cortex. Both hormones directly and indirectly lead to normalization of plasma volume and arterial blood pressure. They also inhibit renin release via negative feedback. (GFR, glomerular filtration rate; RBF, renal blood flow)
The response of the RAS to a decrease in arterial pressure is as follows:
– A decrease in arterial pressure causes a subsequent decrease in renal perfusion pressure and an increase in sympathetic stimulation of the kidney. Both influences stimulate juxtaglomer ular cells of afferent arterioles to secrete the enzyme renin.
– Renin is secreted into the bloodstream, where it catalyzes the conversion of angiotensinogen to angiotensin I.
– Angiotensin I is transported throughout the peripheral vasculature, where it is converted to angiotensin II by the action of angiotensin-converting enzyme (ACE). Angiotensin II is physiologically active and causes
– Vasoconstriction of arterioles, which increases arterial pressure by increasing TPR
– Increased synthesis and secretion of aldosterone by the adrenal cortex. Aldosterone increases Na+ (and water) reabsorption in the distal nephron. This increases arterial pressure by expanding blood volume, which increases CO.
– Increased reabsorption of Na+ and water by promoting Na+−H+ exchange in the proximal tubule.
Other Factors Involved in the Regulation of Arterial Pressure
Whereas the changes in sympathetic and parasympathetic outflow that control blood pressure originate within vasomotor centers in the brain, the normal detectors of blood pressure are in the vasculature outside the brain. However, severe ischemia of the vasomotor centers (e.g., due to extremely low arterial pressure or to cerebral edema that compresses cerebral blood vessels) can excite the vasomotor centers directly. The result is a sharp rise in arterial pressure, known as the Cushing reflex.
Chemoreceptors: Carotid and Aortic Bodies
Carotid and aortic bodies contain sensory receptors that are sensitive to a reduction in the partial pressure of oxygen (PO2).
– When PO2 falls, impulses from these receptors are relayed to the vasomotor center, which increase sympathetic outflow. This leads to vasoconstriction of arterioles causing an increase in TPR and arterial pressure.
The secretion of antidiuretic hormone (ADH, or vasopressin) from the posterior pituitary is mainly controlled by plasma osmolality. However, the hypothalamic neurons that stimulate ADH secretion also receive input from baroreceptors. ADH is released by the posterior pituitary when arterial pressure or blood volume falls too low, such as with severe hemorrhage.
– It acts via V1 receptors to cause direct arteriolar vasoconstriction, thus increasing TPR and arterial pressure.
– It also acts via V2 receptors to promote the reabsorption of water in the collecting duct of the kidney. This increases blood volume, which, in turn, slowly increases CO and arterial pressure.
Atrial Natriuretic Peptide
Atrial natriuretic peptide (ANP) is released in response to the stretch of low-pressure mechanoreceptors located at the venoatrial junction of the heart. These atrial receptors are stretched by increased venous return.
– ANP causes vasodilation of arterioles, which decreases TPR and reduces arterial pressure.
– Vasodilation of renal arterioles by ANP increases renal blood flow and the glomerular filtration rate. This results in increased excretion of Na+ and water, which reduces blood volume and CO and thus helps return arterial pressure to normal.
Note: Stretching of low-pressure mechanoreceptors also causes an increase in heart rate (Bain-bridge reflex). This, in turn, increases CO and renal perfusion.
10.5 Microcirculation and Lymph
Capillary Exchange of Lipid and Water-soluble Substances
– Lipid-soluble substances (e.g., O2 and carbon dioxide [CO2]) cross the membranes of capillary endothelial cells by simple diffusion. They do not depend on the presence of pores.
– Small water-soluble substances (e.g., Na+, Cl−, glucose, and urea) move through the pores of capillary walls by diffusion.
– Large water-soluble substances (e.g., albumin and immunoglobulins) can cross capillary endothelial cell membranes by transcytosis in vesicles.
Capillary Exchange of Fluid
Fluid movement (filtration) across capillary membranes or through membrane pores is driven by differences in plasma and interstitial hydrostatic and osmotic pressures. These pressures are known as Starling forces (Fig. 10.7).
Capillary Hydrostatic Pressure
Capillary hydrostatic pressure (Pc) is the pressure of fluid within blood vessels. It is the most important factor in the capillary exchange of fluids.
– Filtration out of the capillary will increase with increasing Pc.
– Pc depends on changes in arterial blood pressure, capillary flow, and the ratio of the resistance in arterioles to that in venules.
– Pc is the only force that varies significantly between the proximal and distal ends of the capillary: 35 mm Hg at the arterial end, 15 mm Hg at the venous end.
Increases in venous pressure increase filtration into interstitial fluid much more than a comparable increase in arterial blood pressure.
Thin-walled capillaries are able to withstand a hydrostatic pressure of 35 mm Hg because of their small radius (the tension in their walls is also small by the law of Laplace).
Fig. 10.7 Starling forces across a capillary wall.
At the arterial end of a capillary hydrostatic pressure causes net filtration of fluids out of the capillary into interstitial fluid. Hydrostatic pressure reduces progressively throughout the capillary. At the venous end plasma oncotic pressure is the driving force for fluid reabsorption into the capillary.
Pc, capillary hydrostatic pressure; Pi, interstitial fluid hydrostatic pressure; πc, plasma oncotic pressure; πi, interstitial fluid oncotic pressure.
Interstitial Fluid Hydrostatic Pressure
Interstitial fluid hydrostatic pressure (Pi) is the pressure in the interstitial fluid.
– Pi is 1 to 2 mm Hg (or maybe slightly negative), so its contribution to capillary exchange is normally small.
– It is determined by the volume of interstitial fluid and by the distensibility of the interstitial space.
– Pi increases with lymphatic blockage and increased capillary permeability.
Plasma Oncotic Pressure
Plasma oncotic pressure (πc) is the component of osmotic pressure contributed by macromolecules such as plasma proteins.
– It is ~25 mm Hg.
– It is the most important pressure opposing hydrostatic pressure.
– It decreases when plasma protein concentration is lower than normal.
Interstitial Fluid Oncotic Pressure
Interstitial fluid oncotic pressure (πi) is proportional to the concentration of plasma proteins that are in the interstitial fluid.
– Interstitial fluid oncotic pressure is 1 to 2 mm Hg because the concentration of proteins in interstitial fluid is usually low.
– An increase in this oncotic pressure enhances the filtration of fluid out of the capillaries.
– If proteins leak out of the capillaries, then this pressure increases.
Net fluid movement (Jv) is predicted by the Starling hypothesis, expressed by the f ollowing equation:
Net fluid movement (Jv) = k [(Pc − Pi) − (πc − πi)]
where k is a filtration constant for the capillary membrane (a measure of the permeability of the capillary membrane to water) and is measured in mL/min/mm Hg. Jv is measured in mL/min.
– A positive value indicates that there is net fluid movement out of the capillary (filtration).
– A negative value indicates that there is net fluid movement into the capillary (reabsorption).
Note that for any one capillary the value of k is negligible and therefore in theoretical calculations of fluid movement it can be ignored. The net fluid flow therefore becomes a function of the theoretical net pressures acting across the capillary.
The two interstitial pressures are very low so the net filtration pressure is determined mainly by hydrostatic pressure and plasma oncotic pressure.
Note: Most capillaries have filtration at their arterial end and reabsorption at their venous end.
Net filtration of fluid out of the capillaries usually exceeds net reabsorption of fluid into the capillaries by a slight margin because interstitial fluid hydrostatic pressure and interstitial fluid oncotic pressures are low. This leads to the formation of lymph.
– Lymph is a combination of excess filtered fluid, filtered proteins, and macromolecules (e.g., fats).
– The lymphatic system provides a route for lymph to flow from the interstitial space back into the circulatory system.
– Lymphatic vessels have valves similar to veins that establish unidirectional flow.
Edema is the accumulation of fluid in the interstitial fluid space, often seen as swelling. It is a sign that normal capillary/lymph exchange is disrupted.
– It can result from inadequate drainage of lymph due to obstruction of the lymphatic system or when capillary filtration exceeds capillary reabsorption.
Table 10.2 summarizes many causes of edema.
Lower than normal levels of albumin in the blood (hypoalbuminemia) and hence decreased plasma protein binding may occur in the following conditions: liver disease (e.g., hepatitis, cirrhosis, and hepatocellular necrosis), ascites, nephrotic syndrome, malabsorption syndromes (e.g., Crohn disease), extensive burns, and pregnancy. These all exhibit edema due to decreased plasma oncotic pressure.
10.6 Properties of Specific Circulations
The renal circulation is discussed in Chapter 15.
Coronary Vascular Anatomy
The left and right coronary arteries, which supply blood to cardiac muscle, are the first two branches that emerge from the ascending aorta. The left coronary artery divides to form the left anterior descending branch and a circumflex branch.
– The left coronary artery supplies mainly the left ventricle.
– The right coronary artery supplies the right ventricle and also a major portion of the posterior wall of the left ventricle.
Seventy-five percent of the coronary venous blood returns to the right atrium via the coronary sinus. Other coronary veins drain directly into the chambers of the heart.
Angina (angina pectoris) is sudden, crushing substernal chest pain that often radiates to the left shoulder and/or neck. It occurs as a result of myocardial ischemia. Classic, typical, stable angina is induced by exercise (typically), stress, cold weather, and heavy meals and is caused by atherosclerosis of the coronary arteries. Variant or unstable angina (angina that is worsening) occurs at rest or with minimal exertion and is due to coronary vasospasm. Other more rare causes of angina include aortic stenosis, hypertrophic obstructive cardiomyopathy, arrhythmias (causing hypoperfusion), and severe anemia. Electrocardiogram (ECG) analysis (performed at rest or during an exercise stress test) may show ST depression and flat or inverted T waves. Medical treatment of angina includes the use of nitrates, β-blockers, calcium channel blockers, and ACE inhibitors. Surgical treatment includes angioplasty with the placement of a stent or coronary artery bypass graft (CABG).
Coronary artery bypass graft (CABG)
CABG is a surgical procedure performed to bypass atherosclerotic narrowings of the coronary arteries that are the cause of anginal pain. These narrowings can eventually occlude if untreated, leading to MI. There are two main coronary arteries, left and right, and these have several branches. A CABG is denoted as single, double, triple, and so on, depending on the number of arteries that are to be bypassed. The internal thoracic artery, which supplies the anterior chest wall and breasts, is usually harvested to use as the bypass artery.
Myocardial infarction (MI)
MI is death of heart muscle. It is caused by complete occlusion of one or more coronary arteries by thrombosis. The pain of an MI is similar to that of angina, but it is more severe and of longer duration. It is also accompanied by nausea, vomiting, diaphoresis (sweating), dyspnea, and a feeling by the individual that he or she is going to die. Common complications of MI include arrhythmias, heart failure, hypertension, and emboli formation. ECG analysis shows ST elevation, T-wave inversion, and Q waves in the leads that “look at” the infarction. Cardiac enzymes are also measured and used as a basis for diagnosis of MI. Immediate treatment of an MI involves the use of thrombolytic drugs such as streptokinase (given as soon as possible after infarction) and aspirin, morphine, and nitrates. Longerterm treatment involves the use of β-blockers and ACE inhibitors. Surgical treatment is the same as for angina.
Several enzymes are released when cardiac muscle cells are damaged: troponin I, creatine kinase, myoglobin, and lactate dehydrogenase. However, troponin I is the only one that is specific for cardiac muscle damage and is routinely measured to help diagnose myocardial infarction (MI).
Coronary Blood Flow
– Coronary blood flow exhibits autoregulation, active hyperemia, and reactive hyperemia.
– Coronary blood flow is predominantly under local metabolic control in response to changes in O2 consumption and adenosine:
– When cardiac activity increases, there is an increase in O2 consumption. To compensate for this, coronary blood flow increases in proportion to the increase in O2 consumption (active hyperemia).
– Adenosine is a vasoactive substance that acts as a coupling agent between O2 consumption and coronary blood flow and is therefore important in active hyperemia. It also plays a role in autoregulation.
– Most coronary flow to the left ventricle occurs during diastole when the muscular wall is relaxed, whereas the right ventricle receives about equal coronary flow in systole and diastole.
Note: Neural influences on vasodilation/vasoconstriction of the coronary vessels are overridden by the effects of the sympathetic system on heart rate and myocardial contractility (by stimulation of β1 receptors), which leads to vasodilation by the metabolic mechanisms discussed above.
Cerebral Vascular Anatomy
The brain is supplied with blood from internal carotid and vertebral arteries. The basilar artery is formed by the convergence of two vertebral arteries. The two internal carotid arteries and the basilar artery enter the circle of Willis, which delivers blood to the brain by six large vessels.
The internal jugular veins provide the majority of the venous drainage via deep veins and dural sinuses.
Cerebral Blood Flow
– The brain exhibits autoregulation, active hyperemia, and reactive hyperemia.
– The distribution of flow to different areas of the brain varies according to their local immediate metabolic needs. The visual cortex, for instance, receives more blood flow during waking hours than during sleep.
– The main factor contributing to local metabolic control is the partial pressure of CO2 (Pco2):
– Increases in arterial Pco2 produce marked vasodilation of cerebral arterioles and increased cerebral blood flow.
– Decreases in arterial Pco2 induce vasoconstriction.
– Vasoactive metabolites, such as adenosine, play a secondary role in the regulation of cerebral blood flow.
– Neural control of cerebral flow is minimal.
The pulmonary circulation arises from the right ventricle in the pulmonary artery, which divides into the left and right pulmonary arteries that supply the left and right lungs. The arterial vessels subdivide many times to feed the pulmonary capillaries that surround the alveoli. Venules draining the capillaries recombine to form the pulmonary veins that carry blood to the left atrium.
– Pulmonary blood flow and CO from the left ventricle are always the same except for some of the relatively small amount of blood flowing in bronchial vessels.
– The total resistance of the pulmonary circuit is only ~15% of the TPR, and the corresponding mean pulmonary artery pressure is similarly ~15% of MAP.
– There is virtually no neural control of pulmonary vascular resistance. Resistance falls during elevated CO due to distention of small arterioles and recruitment of closed arterioles.
– Local hypoxia causes vasoconstriction and a subsequent rise in pulmonary vascular resistance. This can occur in the whole lung, as often occurs in people who are not acclimatized to high altitude, or in localized lung regions that are inadequately ventilated. It functions to redistribute blood toward lung regions that can fully participate in gas exchange.
Prenatal Fetal Blood Flow
Oxygenated blood from the placenta travels through the umbilical vein and ductus venosus to the inferior vena cava of the fetus (Fig. 10.8). Upon entering the right atrium, most of this blood travels through the foramen ovale to the left atrium and then into the left ventricle.
– Blood entering the right atrium from the superior vena cava travels preferentially to the right ventricle. Because the pulmonary circulation has very high resistance prior to birth (due to hypoxic vasoconstriction), blood pumped by the right ventricle moves from the pulmonary artery through the ductus arteriosus to the descending aorta.
– Some of the blood from the aorta flows through fetal tissues, but most flows back to the placenta via the umbilical arteries.
Changes in Fetal Blood Flow at Birth
At birth, the vascular resistance in the pulmonary vessels greatly decreases, with a corresponding fall in pulmonary artery pressure. At the same time, there is a large rise in systemic resistance due to the closure of the umbilical arteries. Aortic pressure rises considerably, and left atrial pressure rises slightly above right atrial pressure. The reversal of the pressure gradient in the atria causes the flap covering the foramen ovale to close. Flow through the ductus arteriosus initially reverses, but increased oxygenation causes vasoconstriction, and it eventually closes permanently.
Fig. 10.8 Prenatal circulation.
Red: Oxygenated blood. Blue: Deoxygenated blood.
From Thieme Atlas of Anatomy, Neck and Internal Organs, © Thieme 2006, Illustration by Markus Voll.
Patent foramen ovale
A patent (open) foramen ovale is a small opening between the left and right atria that remains open (pathologically) after birth. It is often asymptomatic and does not require any treatment.
Patent ductus arteriosus
A patent (open) ductus arteriosus (PDA) is an opening between the pulmonary artery and aorta that persists (pathologically) following birth. There may be no symptoms if the defect is small, but larger defects may cause failure to thrive, dyspnea (shortness of breath), fatigue, tachycardia, and cyanosis. Signs of PDA include systolic murmur, collapsing pulse, thrill, and a loud second heart sound. Complications include heart failure, pulmonary hypertension, endocarditis, pneumonia, and arrhythmias. In premature infants, spontaneous closure of a PDA may occur. If not, indomethicin (a nonsteroidal anti inflammatory drug [NSAID]) is used to block prostaglandin E2, which keeps the ductus arteriosus open during fetal development. In full-term infants and in adults, surgical closure of the PDA is necessary.
The splanchnic circulation consists of blood flow through the intestines, spleen, pancreas, and liver. It accounts for ~25% of the cardiac output. Venous drainage from the intestines, spleen, and pancreas flows through the portal vein into the liver. Most of the blood entering the liver comes via the portal vein, and about one-quarter of it is supplied by the hepatic artery.
– At rest, splanchnic blood flow is mainly under local control. It increases during processing of a meal.
– Splanchnic blood flow is also under sympathetic control. During exercise, splanchnic blood flow decreases markedly, freeing up blood to go to working muscle. It also decreases severely in states of major hypovolemia. During hemodynamic shock, the intestines are at risk of damage from sympathetically mediated ischemia.
The primary function of the cutaneous circulation is to regulate heat loss and help maintain body temperature.
Cutaneous blood flow is largely under neural control by sympathetic nerves. It is the most variable of the major vascular beds. It is not controlled by local metabolic factors, as the O2 and nutrient requirements of skin tissue are small.
– When ambient temperature rises, there is vasodilation of cutaneous vessels, allowing heat loss to the environment.
– Trauma leading to the loss of blood (hemorrhage) activates sympathetic vasoconstriction throughout the body, including the skin. As a result, the skin becomes cold and sweaty.
Skeletal Muscle Circulation
– Skeletal muscle blood flow exhibits autoregulation, active hyperemia, and reactive hyperemia.
–Sympathetic control of skeletal blood flow predominates at rest.
– Activation of α1 receptors by norepinephrine causes vasoconstriction, and activation of β2 receptors by epinephrine causes vasodilation.
– Local metabolic control of skeletal blood flow predominates during exercise.
– Exercise increases metabolism in muscles and the production of vasoactive substances, such as lactate and adenosine. These substances are responsible for vasodilation and increased skeletal blood flow. The local vasodilators override sympathetic vasoconstrictive signals.