Circulation

6.6.1 Capillary Circulation/Microcirculation

The capillary bed is the main portion of the microcirculation disposed between arterioles and venules, where the exchange or transport of nutrients and waste occurs.

6.6.1.1 Functional Anatomy and Types

On the basis of the completeness of their endothelial walls, capillaries are classified into three types as continuous, dis­continuous, and fenestration capillaries.

Continuous capillaries with complete endothelial walls and basement membranes are found in adipose tissue; smooth, skeletal, and cardiac muscle; placenta; lungs; and central ner­vous system. They have pinocytic vesicles (60-70 nm in diam­eter) along their luminal and basal borders, form tight junctions with adjacent cells, and have pores or intercellular clefts between cells that allow the passage of water-soluble ions and molecules across the capillary wall. Many of these capillaries also possess gap junctions that allow for cell-to-cell communi­cation along the capillary wall.

Discontinuous capillaries or sinusoids have gaps between the endothelial cells and incomplete or absent basement membranes. They are found in the liver, spleen, and bone marrow and allow passage of whole cells, macromolecules, and particles across the capillary wall. Although capillaries are generally considered passive, contractile properties of endothelial cells have been observed in liver sinusoids.

Fenestrated capillaries contain small openings of 0.1 μm or less in diameter that are closed (except for glomerular capillaries) by a thin diaphragm. These holes or fenestrae allow the rapid diffusion of solutes and water across the capillary wall. Fenestrated capillaries are found in endocrine and exocrine glands, gallbladder, synovial membrane, ciliary body, and choroid plexus and in countercurrent flow systems as found in the renal medulla.

6.6.1.2 Exchange Across Capillary Wall

Velocity of blood flow is least (about 0.05 cm/s) in capillaries. The capillaries have the most important function of exchange of substances between blood and tissues. Oxy­gen, nutrients, and other essential substances enter the tissues from capillary blood; carbon dioxide, other end products of metabolism, and other unwanted substances are removed from the tissues by capillary blood. Exchange of materials across the capillary endothelium occurs by the processes of diffusion, filtration, and pinocytosis.

Diffusion is the main process for exchange of gases, water, glucose, sodium, urea, and many other substances. These substances diffuse through the intercellular clefts in the endothelial wall of the capillaries because of concentra­tion gradient. Filtration occurs through the slit pores present in capillary endothelium, which depends upon the net filtra­tion pressure. Larger molecules are transported across the capillary endothelium in the form of vesicles by the process of pinocytosis.

6.6.1.3 Capillary Pressure and Regulatory Factors Blood pressure decreases from the arterial to the venous end of the capillary, while capillary diameter usually increases. In systemic capillaries, pressures are 35 and 15 mmHg, respec­tively. The mean hydrostatic blood pressure for systemic capillaries is about 25 mmHg.

Capillary blood flow is controlled by both nervous and chemical factors. Capillaries are mainly supplied by the sym­pathetic vasoconstrictor fibers. Many chemical factors such as excess of carbon dioxide, lack of oxygen, increased hydro­gen ion concentration, histamine, and metabolites like lactic acid cause dilatation of capillaries. Serotonin causes constric­tion of capillaries.

6.6.2 Lymphatic Circulation

6.6.2.1 Organization of Lymphatic System

Lymphatic system arises from tissue spaces as a meshwork of delicate vessels called lymph capillaries. Lymph capillaries start from tissue spaces as enlarged blind-ended terminals called capillary bulbs, which are surrounded by muscle fibers.

The fluid flow through the lymphatic vessels that roughly parallels the venous circulation is one-way because of the presence of valves. Moreover, because it is not pressurized, the lymph is dependent on passive movement and some impact of changes in the diaphragm. These vessels with branches coming from throughout the body progressively coalesce and empty into the general circulation in the cranial vena cava. The beginnings of this circulatory pathway are essentially thin, blind-ended pouches that collect interstitial fluid that drains to localized tissue lymph nodes and the regional nodes and large lymph vessels that parallel the trunk of the body. Lymph drainage from the forelimbs, neck, and head also drains into the venous blood via the thoracic and right lymphatic ducts.

The lymphatic fluid, containing the plasma proteins, flows to the thorax, where the fluid reenters the bloodstream at the subclavian veins. The role of lymphatic flow in counteracting the accumulation of excessive interstitial fluid is especially important in the lungs. Lung capillaries are more permeable to plasma proteins than are most capillaries in the systemic circulation.

6.6.2.2 Formation of Lymph

The blood vascular system transports compounds such as nutrients and metabolites to and from the blood-tissue exchange system at the capillary level. The interstitium filled with gel-like matrix and the lymphatics constitute an extra- vascular flow system on which the blood capillary-tissue exchanges depend. The steady state of the interstitium depends on the passage of materials in and out of the blood capillaries and the passage of materials into the lymph system and then back to the bloodstream. The excess of capillary filtration over reabsorption is normally balanced by lymph flow. Lymph is formed from interstitial fluid, due to the permeability of lymph capillaries. As the blood passes via tissue capillaries, 9/10th of fluid passes into the venous end of capillaries from the arterial end and the remaining 1/10th of the fluid passes into lymph capillaries.

Large molecules, such as plasma proteins, cannot be reabsorbed into the capillaries against their concentration gradients that enter the lymphatic system. The blind beginnings of the lymph vessels are adapted for the intake of large molecules, and concentration and pressure gradients favor this route. Water-insoluble fats are absorbed from the intestine into the lymphatics. Lymphocytes enter the circula­tion principally through the lymphatics, which play a role in the immune mechanism also.

6.6.2.3 Regulation of Lymphatic Circulation

Lymph progresses through the channels by contractions of the lymph vessels and by a massaging action of muscles that overlie lymph vessels. Forward movement of lymph lowers the pressure in the part of the vessel evacuated and, because there is no backflow of lymph, entry of lymph from the backward parts is favored.

Hormones, vasoactive substances, and nerves affect the rate and strength of contraction in lymph vessels. Norepi­nephrine, epinephrine, and α-adrenergic sympathetic nerves stimulate motor activity and local lymph flow. Stimulation of β-adrenergic receptors results in the opposite effect. Simi­larly, a decrease in contractile activity is observed in response to stimulation with acetylcholine, which causes nitric oxide synthesis by endothelial cells. Certain endotoxins can para­lyze lymphatics. Ordinarily, gravity has little effect on lymph flow because the column of fluid in the lymphatic is not continuous and a hydrostatic gradient is not present as it is in veins.

6.6.2.4 Functions of Lymph

Lymph is a clear and colorless fluid composed of 96% water and 4% solids. Lymph returns the proteins from tissue spaces into blood and is responsible for redistribution of fluid in the body. Bacteria, toxins, and other foreign bodies are removed from tissues via lymph, and it plays an important role in immunity by transport of lymphocytes. Lymph flow is responsible for the maintenance of structural and functional integrity of tissue. Obstruction to lymph flow affects various tissues, particularly myocardium, nephrons, and hepatic cells. Lymphatic flow serves as an important route for intestinal fat absorption.

6.6.2.5 Edema

Edema is an abnormal accumulation of interstitial fluid accompanied by swelling. Factors that result in edema are an increase in capillary pressure, increased capillary perme­ability, a decrease in the concentration of plasma proteins, and obstruction of the lymphatic vessels.

Peripheral edema: Peripheral edema in horses is caused by a reduced venous massage to aid in the return of venous blood from pendant blood capillaries and inability of the lymphatic system to remove this excessive interstitial fluid. With exercise, muscle massage decreases venous pressure and aids in lymph return. With exercise, stocking edema soon disappears. The lymphatics ordinarily handle minor increases in tissue flow, preventing the formation of edema. The edema that occurs in immunologically

mediated tissue reactions (e.g., urticaria) and in various renal diseases is apparently caused by damage to the capillary basement membrane.

Pulmonary edema: In the lungs, where edema is particularly dangerous, the rapid removal of capillary filtrate by the lymph system plays an important role in preventing fluid accumulation in the alveoli when capillary hydrostatic pressure increases or when plasma protein concentration decreases. One of the most common causes of pulmonary edema is left-sided heart failure or mitral valvular disease. This results in a large increase in pulmonary venous pressure and pulmonary capillary pressure and flooding of the interstitial spaces and alveoli with fluid. Another common cause of pulmonary edema is damage to the capillary membrane by infections such as pneumonia. This results in the rapid leakage of both plasma protein and fluid out of the capillaries into the interstitial spaces and the alveoli.

6.6.3 Venous Circulation

The venous system completes the circulatory circuit. Blood leaving the capillary beds enters the venous system and is transported back to the heart. At the microcirculatory level, capillaries drain into venules, which progressively converge to form small veins that exit the organ. In contrast to the arterioles, venules have little tone and resistance. Extensive communication takes place via chemical signals between venules and nearby arterioles. This venoarteriolar signaling is vital for matching capillary inflow and outflow within an organ. Veins have a large radius, so they offer little resistance to flow. Furthermore, because the total cross-sectional area of the venous system gradually decreases as smaller veins con­verge into progressively fewer but larger vessels, blood flow speeds up as blood approaches the heart. In addition to serving as low-resistance pathways to the returning blood from the tissues to the heart, systemic veins also serve as a blood reservoir. Because of their storage capacity, veins are often called capacitance vessels. Veins have thinner walls with less smooth muscle than arteries do. Also, in contrast to arteries, veins have little elasticity because venous connec­tive tissue contains considerably more collagen fibers than elastin fibers and also venous smooth muscle has little inher­ent myogenic tone. Because of these features, veins are highly distensible, or stretchable, and have little elastic recoil. They easily distend to accommodate additional volumes of blood with only a small increase in venous pressure. Veins containing an extra volume of blood simply stretch to accom­modate the additional blood without tending to recoil. In this way, veins serve as a blood reservoir. Under resting conditions, the veins contain more than 60% of the total blood volume. When the body is at rest and many of the capillary beds are closed, the capacity of the venous reservoir is increased as extra blood bypasses the closed capillaries and enters the veins. When this extra volume of blood stretches the veins, the blood moves forward through the veins more slowly because the total cross-sectional area of the veins has been increased as a result of the stretching. Therefore, the blood spends more time in the veins. As a result of this slower transit time through the veins, the veins essentially store the extra volume of blood because it is not moving forward as quickly to the heart to be pumped out again.

When the stored blood is needed, such as during exercise, extrinsic factors reduce the venous reservoir capacity and drive the extra blood from the veins to the heart so that it can be pumped to the tissues. Increased venous return leads to an increased stroke volume, in accordance with the Frank- Starling law of the heart. In contrast, if too much blood pools in the veins instead of being returned to the heart, cardiac output gets abnormally diminished.

The term venous return refers to the volume of blood per minute entering each atrium from the veins. By the time the blood enters the venous system, blood pressure averages only 17 mmHg. However, because atrial pressure is near 0 mmHg, a small but adequate driving pressure still exists to promote the flow of blood through the large-radius, low-resistance veins.

In addition to the driving pressure imparted by cardiac contraction, other factors also enhance venous return: sym­pathetically induced venous vasoconstriction, skeletal muscle pump, venous valves, respiratory pump, and cardiac suction. Additionally, low pressure in the veins, unidirectional blood flow by valves, higher intra-abdominal pressure, and tonicity of the skeletal muscles aid in the venous return.

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Venous Return Aided by Extrinsic Pumping Involv­ing Skeletal and Connective Elements

Some mammals with hooves (Perissodactyls such as rhinoceros and horse) have a cartilaginous plate, the “frog” or cuneus ungulae, at the base of the hoof that is flexed upward with each footstep. This flexing pushes on an overlying elastic cushioning tissue that is com­pressed and moves outward, expanding nearby carti­lage and hoof walls. It also compresses nearby veins, sending blood into the leg above. When the foot is lifted, elastic rebound of these tissues draws blood into the local veins. This pumping action is particularly important in horses, with their long, thin legs, because they do not have enough skeletal muscle mass below the knee to act as extrinsic muscle pumps.

6.6.3.1 Sympathetically Induced Venous Vasoconstriction

Veins are not very muscular and have little inherent tone, but venous smooth muscles are abundantly supplied with sym­pathetic nerve fibers. Hence, sympathetic stimulation produces venous vasoconstriction, which modestly elevates venous pressure; this, in turn, increases the pressure gradient to drive more of the stored blood from the veins into the right atrium, thus enhancing venous return. Since veins often have such a broad radius, the mild vasoconstriction caused by sympathetic activation barely affects flow resistance. Veins still have a significant radius and are low-resistance conduits even when they are restricted.

Arteriolar vasoconstriction immediately reduces flow through these vessels because of their increased resistance, whereas venous vasoconstriction immediately increases flow through these vessels and causes increased venous return. The increased venous return initiated by sympathetic stimu­lation leads to increased cardiac output because of the increase in end-diastolic volume. Sympathetic stimulation of the heart also increases cardiac output by increasing the heart rate and increasing the heart’s contractility.

6.6.3.2 Skeletal Muscle Pump

Many large veins in the extremities are located between the skeletal muscles, so muscle contraction compresses the veins. This external venous compression reduces venous capacity and increases venous pressure, in effect squeezing blood in the veins forward toward the heart. This pumping action, known as the skeletal muscle pump, is another way in which extra blood stored in the veins is returned to the heart during exercise. The skeletal muscle pump also counters the effect of gravity on the venous system.

6.6.3.3 Venous Valves

Venous vasoconstriction and external venous compression both drive blood toward the heart, which is aided by the venous valves. Large veins are equipped with one-way valves spaced at 2-4 cm intervals; these valves let blood move forward toward the heart but keep it from moving back toward the tissues. These venous valves also play a role in counteracting the gravitational effects of upright posture by helping to minimize the backflow of blood that tends to occur when an animal stands up and by temporarily supporting portions of the column of blood when the skeletal muscles are relaxed.

6.6.3.4 Respiratory Pump

The pressure within the chest cavity averages 5 mmHg less than atmospheric pressure due to the respiratory activity. Blood is exposed to this subatmospheric pressure when it passes through the chest cavity on its way to the heart from the lower parts of the body. An externally applied pressure gradient exists between the lower veins (at atmospheric pressure) and the chest veins because the venous system in the limbs and abdomen is susceptible to normal atmospheric pressure (at less than atmospheric pressure). This pressure difference pushes blood from the lower veins to the chest veins, promoting increased venous return. This mechanism of facilitating venous return through respiratory activity is called the respiratory pump. Increased respiratory activity, skeletal muscle pump, and venous vasoconstriction, all enhance venous return during exercise.

Effect of Cardiac Suction on Venous Return During ven­tricular contraction, the AV valves are drawn downward, enlarging the atrial cavities. As a result, atrial pressure tran­siently drops below 0 mmHg, thus increasing the vein-to- atria pressure gradient so that venous return is enhanced. In addition, rapid expansion of the ventricular chambers during ventricular relaxation creates a transient negative pressure in the ventricles so that blood is “sucked in” from the atria and veins, that is, the negative ventricular pressure increases the vein-to-atria-to-ventricle pressure gradient, further enhancing venous return. Thus, the heart functions as a suction pump to facilitate cardiac filling.

6.6.3.5 Venous Pressure and Flow

The pressure in the venules is 12-18 mmHg. In the larger veins, it decreases gradually to roughly 5.5 mmHg in the major veins outside the thorax. The pressure in the great veins at their entrance into the right atrium (central venous pressure) averages 4.6 mmHg but fluctuates with respiration and heart action. Peripheral venous pressure, like arterial pressure, is affected by gravity. Thus, on a proportional basis, gravity has a greater effect on venous than on arterial pressures. When blood flows from the venules to the large veins, its average velocity increases, as the total cross­sectional area of the vessels decreases. In the great veins, the velocity of blood is about one-fourth that in the aorta, averaging about 10 cm/s.

6.6.4 Special Circulations

6.6.4.1 Cerebral Circulation

The brain receives 15% of the cardiac output. Brain tissues need adequate blood supply continuously, and stoppage of blood flow to the brain for 5 s leads to unconsciousness and for 5 min leads to irreparable damage to the brain cells in contrast to the other tissues, which can be deprived of a blood supply for extended periods and recover to normal function when blood supply resumes. The tolerance of an adult brain to hypoxia is much lower than the tolerance of a newborn brain.

Anatomic considerations: The main blood supply to the brain comes from the paired internal carotid artery in horses and cats and from maxillary artery in the ruminants. The internal carotid artery in the horse and dog and the cerebral carotid artery in the other domestic mammals penetrate the dura mater and form a vascular ring located ventral to the hypothalamus called as cerebral arterial circle or circulus arteriosus cerebri or circle of Willis.

In dogs, where the circle of Willis is complete, blood flow to the brain is maintained even in the face of an obstruction at any single point in the vascular circle. In ruminants and cats, the internal carotid arteries connect with other vessels in the head before entering the arterial circle. These vas­cular connections form a complex network of vessels, the rete mirabile. The rete mirabile facilitates maintenance of a constant brain temperature in the face of either high or low temperature stress.

Blood-brain barrier: One of the most characteristic features of the brain vasculature is the blood-brain barrier, which prevents the solutes in the lumen of capillaries from hav­ing direct access to the brain extracellular fluid as these capillaries have very limited permeability. The blood­brain barrier consists mainly of tight junctions that seal together the endothelial cells of brain capillaries, along with a thick basement membrane around the capillaries. The astrocytes’ processes press up on the capillaries and produce substances that keep the tight junctions ’ perme­ability properties constant. Lipid-soluble substances, such as oxygen, carbon dioxide, alcohol, and most anesthetic agents, can readily diffuse across the cerebral capillaries. Glucose crosses more slowly via facilitated diffusion. Polar and water-soluble compounds cross the blood­brain barrier slowly, and the ability of proteins to cross the barrier is extremely limited. However, trauma, tumors, certain toxins, and inflammation can cause a breakdown of the blood-brain barrier. In specialized areas of the brain,

i. e., the circumventricular organs including median emi­nence, pineal gland, area postrema, and posterior pituitary, the capillaries are fenestrated and have permeability characteristics similar to those of capillaries in the intesti­nal circulation.

6.6.4.1.1 Blood Flow Dynamics and Regulatory Mechanisms

Local control mechanisms: As the brain is extremely intol­erant to ischemia; cerebral blood flow is regulated primar­ily by local mechanisms, particularly in response to changing levels of local metabolism as well as systemic alterations in blood gases. Neural activity and increased metabolism result in reductions in ATP accompanied by adenosine release as well as decreases in tissue PO₂, increased PCO₂, and decreased pH contributing to cere­bral vasodilation.

Autonomic vascular regulatory mechanisms play only a sec­ondary and comparatively minor role. Coupling of flow to metabolism in the brain involves a unique interaction among neural activity, cerebral vasculature, and action of astrocytes. Astrocytes contact neurons, and their endfeet form a discontinuous sheath around capillaries. Neurotransmitters such as glutamate activate astrocytes, ultimately producing vasodilation due to direct relaxation of vascular smooth muscle as well as release of vasodilators such as NO and metabolites of arachidonic acid.

Hypoxia-stimulated cerebral vasodilation: Cerebral blood flow increases in response to hypoxia, due to increased concentrations or release of a wide variety of vasodilators, including adenosine, potassium and hydrogen ions, prostaglandins, excitatory amino acids, and NO. Addition­ally, hypoxia also has direct effects on cerebrovascular myocytes, including modest reductions in ATP, activation of the KATP, and other potassium channels which cause cerebral vasodilation. The relative importance of the many mechanisms leading to cerebral vasodilation depends sig­nificantly on the size of the vessel.

Hypercapnia-stimulated cerebral vasodilation: Carbon dioxide is one of the most potent dilators of cerebral vessels, and cerebral resistance vessels are extremely sen­sitive to even minor elevations in arterial pCO₂. For example, breathing 7% CO₂ is capable of doubling cere­bral flow. NO plays a role in hypercapnia-induced cerebral vasodilation, although it may be permissive and modula­tory rather than primary in nature. CO₂-induced changes in cerebral flow appear to be related primarily to alterations of pH in extracellular fluid within the brain.

Neural control factors: Cerebral blood vessels are innervated primarily by the sympathetic nervous system, which mediates vasoconstriction due to release of norepineph­rine and also neuropeptide Y (NPY). Sympathetic control of cerebral blood vessels is relatively weak due to low density of adrenergic receptor in cerebral blood vessels. Parasympathetic nervous system has a minor effect on blood flow. The distal cerebral vessels are innervated by sensory nerves containing substance P and calcitonin gene-related peptide (CGRP), which are potent vasodilators. Local perturbations result in their reflex release from perivascular nerves, through activating ATP-sensitive potassium channels, thereby producing hyperpolarization and relaxation of cerebral arteries.

Brain ischemia elicits the Cushing reflex, which involves a large increase in sympathetic nerve activity, peripheral vasoconstriction, and arterial blood pressure, presumably in an attempt to increase cerebral flow.

Autoregulation: Autoregulation is a significant feature of the cerebral circulation. The range of perfusion pressures over which autoregulation occurs is not fixed, and the upper limit of autoregulation is promoted by increased activity of cervical sympathetic nerves. Cerebral flow autoregulation during arterial hypotension is achieved by vasodilation, and the autoregulation ability is diminished by hypercapnia. Calcitonin gene-related peptide, adeno­sine, endothelium-dependent hyperpolarizing factor, vasoactive intestinal peptide (VIP), cyclic AMP, prostacy­clin, and norepinephrine-stimulated β-adrenoceptors also vasodilate cerebral vessels, via activation of KATP channels. Despite the importance of metabolic factors, none of these can completely account for autoregulation of cerebral blood flow. Thus, myogenic mechanisms con­tribute importantly to cerebral autoregulation. Resistance vessels in the cerebral circulation respond robustly to increases in pressure with vasoconstriction and to decreases in pressure with relaxation.

6.6.4.2 Coronary Circulation

6.6.4.2.1 Anatomical Considerations

Cardiac muscles are supplied by two coronary arteries, viz. right and left coronary arteries, which arise from the aorta at the level of the sinus of Valsalva (aortic sinus), thus compris­ing the first branches of aorta. As these arteries encircle the heart in the pattern of a crown, the coronary arteries derive their name from the Latin word corona meaning crown.

The main coronary arteries lie on the heart surface, and smaller arteries penetrate from the surface into the cardiac muscle mass. The myocardium receives its nutritive blood supply almost entirely through these arteries, and the inner 1/10 mm of the endocardial surface receives nutrition directly from the blood inside the cardiac chambers, which contributes only to a minuscule amount. The coronary circu­lation outlay is as shown in Fig. 6.5.

6.6.4.2.1.1 Branches of Coronary Arteries

Coronary arteries divide and subdivide into smaller branches, which run all along the heart surface. Smaller branches are called epicardiac arteries and give rise to further smaller branches known as final arteries or intramural vessels. Final arteries run at the right of the wall of the heart.

The right coronary artery supplies the right atrium and ventricle, while the left coronary artery supplies primarily the left atrium and ventricle and interventricular septum, although there can be overlap. The majority of cardiac veins drains into the right atrium through the coronary sinus.

6.6.4.2.1.2 Venous Drainage

Venous drainage from the heart muscle is by four types of vessels, coronary sinus, anterior coronary veins, arteriosinusoidal vessels, and Thebesian veins.

Fig. 6.5 Coronary circulation showing the blood flow in the coronary vessels and back to the heart chambers

Most of the venous blood is returned to the heart through the coronary sinus and anterior cardiac veins, which drain into the right atrium.

Coronary sinus is the larger vein draining 75% of the total coronary flow. It drains blood from the left side of the heart and opens into right atrium near the tricuspid valve.

Anterior coronary veins drain blood from the right side of the heart and open directly into the right atrium. In addition, there are other vessels that empty directly into the heart chambers.

Arteriosinusoidal vessels are sinusoidal capillary-like vessels that connect arterioles to the chambers.

Thebesian veins connect capillaries to the chambers and drain deoxygenated blood from myocardium, directly into the concerned chamber of the heart.

A few arterioluminal vessels which are small arteries drain directly into the chambers. A few anastomoses occur between the coronary arterioles and extracardiac arterioles, especially around the mouths of the great veins. Anastomoses between coronary arterioles in humans only pass particles less than 40 m in diameter, but these channels enlarge and increase in number in patients with coronary artery disease.

6.6.4.2.2 Species Variation

Cattle—Coronary sinus blood consists of a mixture of venous blood from the heart and from the azygous vein, which carries venous blood from noncardiac tissues and empties into the great cardiac vein.

Dog—More than 80% of coronary sinus blood arises entirely from the left ventricle, with the remaining 20% originating from other parts of the heart. Consequently, the collection and analysis of coronary sinus blood have been a valuable tool for the study of left ventricular metabolism. However, caution must be used in extending this technique to other species because of anatomic differences.

Venous coronary blood from the right ventricle of the dog heart predominantly drains into the right atrium through the right cardiac vein. Only a very small amount of venous blood drains from myocardial tissue directly into the cardiac chambers, primarily into the right atrium and ventricle, through the very small Thebesian vein.

6.6.4.2.3 Collateral Coronary Arteries

The coronary arteries lack collateral arteries in most species, i.e., vessels connecting major arteries without an intervening capillary bed are absent. However, there are species, within- species, and breed variation.

Coronary collateral arteries in the dog heart are typically thin-walled vessels of very small diameter and therefore conduct only a very low volume of collateral coronary blood flow. However, collateral coronary arteries are absent or so small in size or number that collateral blood flow is inadequate to prevent infarction following sudden coronary occlusion.

The purebred Beagle dog tends to have an extensive collateral coronary circulation. Similarly, the guinea pig has abundant collateral arteries, so that tissue perfusion is maintained following abrupt occlusion of a coronary artery, preventing myocardial infarction (an area of necrosis resulting from inadequate coronary arterial flow) or tissue damage. Non-canine species vary widely in their ability to develop coronary collateral vessels and in the location and nature of these collateral vessels. In humans and pig, collateral vessels arise as microvascular connections between capillary beds of an occluded and a nonoccluded artery and are located within the myocardium or in the subendocardium. The development of collateral vessels in porcine and human hearts occurs through a process of angiogenesis or the sprouting of new capillaries from preexisting capillaries. Capillaries develop in response to factors such as vascular endothelial growth factor (VEGF), which is stimulated by hypoxia, in part via hypoxia-mediated adenosine release.

For example, most of the mammals can develop collateral coronary arteries if a major coronary artery is occluded slowly and gradually, as occurs in atherosclerosis even though they lack significant preexisting coronary collateral circulation. Initially, this newly developed collateral circula­tion has little reserve capacity or ability to increase flow in response to an increase in myocardial oxygen demand. How­ever, collateral development and expansion continue well beyond the time of occlusion, so collateral flow capacity 6 months after occlusion may approach that of the coronary artery prior to occlusion.

Collateral coronary arteries in the dog heart develop through a process of enlargement and expansion of preexisting epicardial arterioles (arteriogenesis). Arteriogenesis is stimulated by shear stress due to increased flow velocity proximal to the occlusion and involves partici­pation of adhesion molecules and growth factors. The process of collateral development by arteriogenesis is not signifi­cantly influenced by the presence or absence of physical exercise.

6.6.4.2.4 Control of Coronary Blood Flow

Normal blood flow through coronary circulation is about 200 mL/min. It is about 65-70 mL/min/100 g of cardiac muscle or about 225 mL/min, which is about 4-5% of the total cardiac output.

6.6.4.2.4.1 Basal Tone

The heart exhibits a high level of oxygen extraction; yet, coronary blood flow in most mammals is relatively high at rest (around 100 mL/min per 100 g of tissue). While α-adrenergic stimulation can produce coronary vasoconstric­tion, the importance of neural mechanisms in establishing or maintaining basal coronary tone is minimal as compared to tissues such as skin and gastrointestinal vascular beds.

6.6.4.2.5 Regulatory Mechanisms

6.6.4.2.5.1 Autoregulation

Heart also has the capacity to regulate its own blood flow by autoregulation like any other organ. Coronary blood flow is not affected when mean arterial pressure varies between 60 and 150 mmHg. Coronary blood flow is regulated mainly by local vascular response to the needs of cardiac muscle.

That is, whenever the vigor of cardiac contraction is increased, the rate of coronary blood flow also increases. Conversely, decreased heart activity is accompanied by decreased coronary flow. The factors regulating coronary blood flow are:

1. Oxygen demand

2. Metabolic factors

3. Coronary perfusion pressure

4. Nervous factors

1. Oxygen demand: Blood flow in the coronary arteries usually is regulated almost exactly in proportion to the oxygen need by the cardiac musculature. Normally, about 70% of the oxygen in the coronary arterial blood is removed as the blood flows through the heart muscle. Because not much oxygen is left, very little additional oxygen can be supplied to the heart musculature unless the coronary blood flow increases. Fortunately, the coro­nary blood flow does increase almost in direct proportion to any additional metabolic consumption of oxygen by the heart. Muscle cells release vasodilator molecules when the oxygen content in the heart drops, and these compounds widen the arterioles. Amount of blood passing through coronary circulation is directly proportional to the con­sumption of oxygen by cardiac muscle. Even in resting condition, a large amount of oxygen, i.e., 70-80%, is consumed from the blood by heart muscle than by any other tissues. In conditions associated with increased car­diac activity, the need for oxygen increases enormously. Thus, the need for oxygen, i.e., hypoxia, immediately causes coronary vasodilatation and increases the blood flow to heart. Asphyxia and hypoxia increase coronary blood flow 200-300% in denervated as well as intact hearts, and the feature common to these three stimuli is hypoxia of the myocardial fibers. Oxygen is the most important factor maintaining blood flow through the coro­nary blood vessels.

2. Metabolic factors: Coronary vasodilatation during hyp­oxic conditions occurs because of some metabolic products, which increase the coronary blood flow by vasodilatation.

Reactive Hyperemia

Reactive hyperemia is the increase in blood flow due to the vasodilator effects of metabolites.

Metabolic products increase the coronary blood flow.

Adenosine is a potent vasodilator, and it increases the blood flow to cardiac muscle. In the presence of very low concentrations of oxygen in the muscle cells, a large proportion of the cell’s ATP degrades to adeno­sine monophosphate; then small portions of this are further degraded and release adenosine into the tissue fluids of the heart muscle, with resultant increase in local coronary blood flow. After the adenosine causes vasodilation, much of it is reabsorbed into the cardiac cells to be reused.

Other substances which increase the coronary blood flow by vasodilatation are potassium, hydrogen, carbon dioxide, lactate, and prostaglandins.

3. Coronary perfusion pressure: Perfusion pressure is the balance between mean arterial pressure and venous pres­sure. Thus, coronary perfusion pressure is the balance between mean arterial pressure in aorta and right atrial pressure. Since right arterial pressure is low, the mean arterial pressure becomes the major factor that maintains the coronary blood flow.

4. Nervous control of coronary blood flow: The coronary circulation is relatively independent of central neural reg­ulation; however; coronary blood vessels are innervated by both sympathetic and parasympathetic nervous system. Sympathetic stimulation, by releasing norepinephrine and epinephrine, increases both heart rate and heart contractil­ity and increases the rate of metabolism of the heart. In turn, increased metabolism of the heart sets off local blood flow regulatory mechanisms for dilating the coronary vessels, and the blood flow increases approximately in proportion to the metabolic needs of the heart muscle. In contrast, vagal stimulation, with its release of acetylcho­line, slows the heart and has a slight depressive effect on heart contractility. These effects in turn decrease cardiac oxygen consumption and, therefore, indirectly constrict the coronary arteries.

When the systemic blood pressure falls, the overall effect of the reflex increase in noradrenergic discharge causes increased coronary blood flow secondary to the metabolic changes in the myocardium at a time when the cutaneous, renal, and splanchnic vessels are constricted. In this way, the circulation of the heart, like that of the brain, is preserved when flow to other organs is compromised. Thus, sympa­thetic nervous system stimulation generally produces a mild α-receptor-mediated vasoconstriction in the coronary circu­lation. Parasympathetic effects on the coronary vasculature are minor, and vagal activation primarily has an effect to decrease heart rate.

An unusual feature of the coronary circulation is the effect of mechanical compression of the blood vessels during sys­tole in the cardiac cycle. This compression causes a brief period of occlusion and reduction of blood flow. When the period of occlusion (i.e., systole) is over, reactive hyperemia occurs to increase blood flow and oxygen delivery and to repay the oxygen debt that was incurred during the compression.

6.6.4.3 Splanchnic Circulation

6.6.4.3.1 Anatomic Considerations

The splanchnic circulation includes the vascular beds of the gastrointestinal tract, spleen, pancreas, and liver. The splanchnic circulation contains approximately 15% of the total blood volume, with the majority contained in the liver. Blood flow to the splanchnic bed has two primary functions. It is important both in supplying oxygen and nutrients to the tissues and in supporting the absorption of substances from the gastrointestinal tract. This circulation is unique in that it contains two capillary beds in series; venous flow from the capillary beds of the gastrointestinal tract, spleen, and pan­creas combines to provide a major source of blood flow, through the portal vein, to the liver capillaries.

6.6.4.3.2 Intestinal Circulation

The celiac artery is the primary blood supply to the stomach, pancreas, and spleen. The superior and inferior mesenteric arteries supply the large and small intestines, as well as parts of the stomach and pancreas. The superior mesenteric artery is the largest of all the splanchnic branches from the aorta, carrying >10% of the cardiac output. Extensive interconnections between the arterial branches provide mul­tiple collateral pathways through which blood can reach each portion of the intestines. Small arteries course through the various muscle layers and reach the submucosa as arterioles, and then some enter into the intestinal villi. The incoming arteriole courses up the center of the villus, branching into many capillaries along the way to the tip of the villus. Capillaries converge into venules and carry blood back to the base of the villus. Capillaries also interconnect the arteri­ole and the venule all along the villus. These microvessels of villi are highly permeable to solutes of low molecular weight, thereby facilitating the absorption of nutrients, and this coun­tercurrent exchange system enables permeable solutes to move from the arteriole to the venule without having to traverse the entire length of the villus, particularly when blood flow to the villi is low.

Because the capillaries in the villi are fenestrated and have a large surface area, they are well suited for absorbing nutrients from the intestinal lumen. The venous blood carries away the majority of water-soluble nutrients absorbed from the gut, eventually delivering them to the portal vein.

Intestinal blood flow is directly linked to metabolic activ­ity. Flow is low in unfed animals but can increase as much as eightfold, following food ingestion (postprandial hyperemia). Throughout the gastrointestinal tract, blood flow in each layer of the gut wall closely correlates with the local metabolic activity occurring during digestion and absorption. Intestinal blood flow at rest, in the fasting state, is typically 30 mL/min for each 100 g of tissue. However, flow can reach 250 mL/ min for each 100 g during peak hyperemia after a meal. These activities consume O₂ and produce vasodilator metabolites (e.g., adenosine and CO₂) that increase blood flow locally. Digestive activity increases metabolism, increasing concentrations of local vasodilator mediators such as adeno­sine and CO₂ and, consequently, augmenting blood flow. Further, the absorption of nutrients generates hyperosmolality in both the blood and lymphatic vessels of the villus, which stimulates an increase in blood flow. Also, during digestion, the gastrointestinal tract releases several hormones, such as cholecystokinin and neurotensin, that promote intestinal blood flow. The intestinal epithelium also releases various kinins (e.g., bradykinin and kallidin), which are powerful vasodilators. In the case of ruminants, various products of rumen fermentation, such as CO₂ and fatty acids, also act as vasodilators of the rumen circulation. Mechanical stimulation of the small intestine of the cat increases blood flow through the release of serotonin from enterochromaffin cells. Serotonin, in turn, stimulates the release of the vasodilator VIP from nerve endings. Addition­ally, under specific circumstances, especially during inflam­mation or noxious stimulation of the gut lumen, a wide variety of other chemical mediators such as substance P and CGRP released from neurons cause vasodilation.

6.6.4.3.3 Neural Control Factors

Reciprocal changes in the autonomic nervous system also contribute to postprandial hyperemia. Feeding and digestion are associated with increased parasympathetic nervous sys­tem activity, leading to increased secretory activity, motility, and metabolism in gastrointestinal tissues and increased release of acetylcholine, which indirectly produces vasodila­tion. Concomitantly, there is diminished sympathetic nerve activity, thereby reducing α-adrenoceptor-mediated vasocon­striction. Splanchnic blood flow is autoregulated despite fluctuations in arterial blood pressure by mediators such as adenosine, K⁺, and increased osmolality and via myogenic response.

6.6.4.3.4 Hepatic Circulation

The total blood supply and blood volume contained in the liver constitute approximately 25% of cardiac output, and the liver accounts for 20% of total body oxygen consumption. The hepatic circulation is characterized by a dual blood supply from the hepatic artery and the portal vein, which supplies approximately 75% of its flow. Another unique aspect of the hepatic circulation is that the capillary network in the liver is composed of sinusoids, which converge to form hepatic venules. The sinusoids are highly fenestrated and hence very permeable, allowing rapid exchange between the blood and hepatocytes. However, they are also very sensitive to changes in central venous pressure that alter capillary pressure and thus produce large alterations in fluid exchange through the sinusoids. For example, the increase in central venous pressure that occurs in right-sided heart failure produces substantial movement of fluid across the sinusoids into the peritoneal cavity, resulting in ascites.

6.6.4.3.4.1 Autoregulation

Hepatic artery blood flow is autoregulated mainly by adeno­sine in an effort to maintain total hepatic perfusion at a constant rate. The liver is unique in that it responds to increased metabolic demand through increased oxygen extraction rather than increased blood flow.

6.6.4.3.5 Functional Significance of Splanchnic Circulation

The splanchnic circulation serves as an important blood reservoir and site of vascular resistance, thus contributing to cardiovascular homeostasis. The splanchnic vascular bed of the dog normally contains more than 20% of the blood volume, particularly on the venous side of the circulation. Sympathetic α-adrenoceptor stimulation significantly reduces venous capacitance, without a change in hepatic arterial blood flow, and may mobilize up to half of this volume in response to severe hypoxia, heavy exercise, or hemorrhage. The spleen, particularly in species such as the dog, horse, sheep, cat, and guinea pig, is an important com­ponent of this response and transfers red cell-rich blood to the central circulation. Splenic contraction associated with heavy exercise in the dog, horse, and sheep increases the hemoglo­bin concentration of circulating blood by 20-50%, with a corresponding increase in oxygen-carrying capacity. Sympa­thetic vasoconstriction of the splanchnic bed also contributes significantly to circulatory adjustments to exercise and hem­orrhage by redistributing the flow to other vascular beds such as brain and cardiac and skeletal muscle.

6.6.4.4 Skeletal Muscle Circulation

Skeletal muscles receive 15% of the cardiac output at rest. Skeletal muscles are well supplied with blood vessels, and an artery and one or two veins supply a skeletal muscle. Capillaries are plentiful in muscular tissue. Blood vessels within skeletal muscle receive both sympathetic adrenergic and sympathetic cholinergic innervation. The cholinergic system, acting directly via muscarinic receptors, relaxes vas­cular smooth muscle cells and causes rapid vasodilation. This vasodilation in skeletal muscle occurs in the fight-or-flight response and during the anticipatory response in exercise caused by extensive activation of the sympathetic division. Blood flow to skeletal muscle varies with muscle fiber type. For example, slow-twitch high oxidative muscle exhibits greater flow and capillary density compared with fast-twitch glycolytic muscle in conscious mammals. Blood flow is low at rest in most muscles, although it is relatively high in postural muscles of animals maintaining posture (standing). An important aspect of the skeletal muscle circulation is that the volume of blood flow to skeletal muscle is intimately linked to the level of muscle metabolic activity. Muscle blood flow can increase by 100-fold during strenuous exercise.

Autoregulation is a characteristic feature of the skeletal muscle circulation at rest and during exercise that appears to depend on several mechanisms, with the significance of each mechanism varying from rest to exercise and with the level of exercise. For example, the myogenic response appears to play an important role in autoregulation in the skeletal muscle circulation at rest, while metabolic factors play a greater role during exercise.

6.6.4.5 Pulmonary Circulation

The pulmonary circulation is a relatively short, low-resistance, low-pressure system, which conducts blood to and from a single but very dense capillary bed enveloping the pulmonary alveoli. It consists of the right ventricle, pul­monary arteries, pulmonary capillaries, pulmonary veins, and left atrium. Because the pulmonary vessels are very distensi­ble, they serve not only as a channel but also as a reservoir between the right and left ventricles. The pulmonary vascu­lature is unique in that it accommodates a blood flow that is almost equal to that of all the other organs in the body. The pulmonary capillaries are large, and there are multiple anastomoses, so that each alveolus sits in a capillary basket.

6.6.4.5.1 Anatomical Consideration

The special considerations in the pulmonary circulation are

(1) the position within the negative but rhythmically variable pressure of the thorax; (2) the position between the right ventricle and the left atrium; and (3) the relatively great distensibility and collapsibility of the vessels. There are spe­cies differences in the morphology of the pulmonary vessels that are extremely important in the response to the inspired hypoxia found at altitude.

The mean pressure in the pulmonary artery is approxi­mately one-sixth that of the systemic arteries. This low-pressure system has two major advantages: (1) it minimizes the work of the right heart and (2) allows a very thin blood-gas barrier suitable for high rates of gas exchange. The pressures vary with age as well as with species. The short lengths and large radii of the pulmonary arteries yield a small value for resistance, approximately one-fifth to one-tenth of the resistance to flow observed in the systemic arteries.

Approximately 9% of total blood volume is contained in the pulmonary vessels. It is distributed about equally among the arteries, capillaries, and veins. Increases in pulmonary blood volume of 25-50% may occur when the pulmonary circulation serves a reservoir function to accommodate increases in total blood volume or when extensive systemic arterial and venous constriction causes a shift of blood vol­ume from the systemic to the pulmonary circuit.

Capillary pressures within the lung are low compared with the systemic circulation. Capillary hydrostatic pressure is influenced by gravity, being lower at the apex and higher at the base (mean value of 9 mmHg). Because of the prevailing negative intrathoracic pressures, generally the lung interstitial fluid pressure is subatmospheric (about -12 mmHg).

In the lung capillaries, the net outward forces slightly exceed the inward force, causing a very small excess of fluid to filter out of the capillaries. This is returned to the circulation through the lymphatics. The exceptionally rich lymphatic network prevents pulmonary edema until capillary hydrostatic pressure exceeds 25 mmHg. The negative inter­stitial fluid pressure favors passage of fluid across the alveo­lar membranes into the interstitial fluid spaces, thus preventing accumulation of fluid in the alveoli. The lym­phatic vessels, which are contractile, serve as skimming pumps for maintaining the extravascular fluid volume. The alveolar epithelial membrane keeps fluid from entering the alveolar gas spaces. The alveolar epithelium is less permeable than the capillary endothelium, and therefore fluid does not leak into the alveoli unless the epithelium is damaged.

6.6.4.5.2 Regulatory Mechanisms

6.6.4.5.2.1 Autoregulation

Autoregulation is well developed in the pulmonary vascular system and helps match blood flow to ventilation. The major vasomotor activity of resistance vessels depends on local autoregulatory mechanisms rather than central neural reflex systems. The action of alveolar hypoxia is limited to very short segments of arteries/arterioles less than 200 μm in diameter that are immediately adjacent to the alveolus. Car­bon dioxide acts on longer segments. It is the effect that PCO₂ has on the local hydrogen ion concentration rather than the PCO₂ per se, which stimulates vasoconstriction. The site of action is important in that it renders autoregulation effective down to the level of the alveoli.

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Left-Right Difference in Ventricle Pumping Force

The pulmonary circulation is a low-pressure, low-resistance system, whereas the systemic circula­tion is a high-pressure, high-resistance system. There­fore, even though the right and left sides of the heart pump the same amount of blood, the left side performs more work because it pumps an equal volume of blood at a higher pressure into a higher resistance system.

6.6.4.5.2.2 Vasoactive Substances

A wide variety of vasoactive substances are synthesized, stored, or activated by cells of the lung. Histamine, widely distributed in mast cells, is a powerful but rapidly inactivated pulmonary vasoconstrictor, although it has a vasodilator action on the neonatal bovine circulation. Serotonin (5-hydroxytryptamine) is found in mast cells and blood platelets and is also a potent vasoconstrictor. Angiotensin II, formed from angiotensin I by a lung-converting enzyme, is also a vasoconstrictor. Bradykinin, a vasodilator, is both generated and destroyed in the lungs. The prostaglandin vasodilators PGE1 and PGE2 are synthesized and stored in the lungs, but the vasoconstrictor PGF2α is most abundant in lung parenchyma. Nitric oxide (NO) is a vascular smooth muscle-relaxing factor produced by the action of nitric oxide synthase within vascular endothelial cells.

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Story of Nitric Oxide Leading to the Nobel Prize

Ferid Murad, an American physician and pharma­cologist, studied how nitroglycerin activated an enzyme that formed cyclic guanosine monophosphate (cGMP), which in turn caused blood vessels to expand, and in 1976, he was able to show that nitroglycerin produced this effect by emitting nitric oxide (NO). The discovery represented a new principle for transferring signals between cells; a gas as a signal-transferring molecule had never been observed before. Robert Furchgott, Louis Ignarro, and Ferid Murad jointly received the Nobel Prize in 1998 for their discovery that nitric oxide signals blood vessels to dilate.

6.6.4.5.2.3 Vasomotor Nerves

The small pulmonary vessels have muscular coats and dual nerve supply, sympathetic and parasympathetic; however, the predominant supply is via adrenergic sympathetic vaso­constriction. Stimulation of the sympathetic pulmonary nerves increases the pulmonary vascular resistance and hence pulmonary blood pressure. Stimulation of baroreceptors results in increased pulmonary blood flow and decreased pulmonary arterial pressure. The capacious pulmonary vessels constitute one of the body’s blood reservoirs, and the vasoconstrictor fibers function more in the reflex mobilization of blood (e.g., in hemorrhage) than in pressor or depressor pulmonary responses. Small doses of epinephrine produce either minimal vasoconstriction or vaso­dilatation. Larger doses produce definite vasoconstriction.

6.6.4.5.2.4 High Altitude

Unlike most other blood vessels, the vessels of the lungs constrict in response to hypoxia. At high altitudes, airway or ventilatory hypoxia occurs in the absence of any hyper­capnic acidosis or CO₂ retention. Ventilatory hypoxia elicits pulmonary arterial vasoconstriction and consequently an ele­vated pulmonary arterial pressure. Alveolar hypoxia, but not pulmonary arterial hypoxemia, causes this response. The hypertension is reversible when the hypoxia is relieved. The magnitude of the pressor response varies among species, being most pronounced in those (such as calves and pigs) having the most vascular smooth muscle. A local hypoxia (e.g., as occurs when a bronchiole is partially or wholly occluded, decreasing or preventing ventilation to the depen­dent lung region) is helpful in regulating the distribution of blood flow by causing vasoconstriction, which would divert blood from the anoxic region to vessels in better aerated parts of the lung.

6.6.4.5.3 Clinical Correlations

Emphysema (heaves) in horses: Chronic obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic emphysema, and bronchitis, are characterized by increased hindrance to airflow out of the lungs. The primary lung disease results in destruction of vessels and thus a reduction in the overall radius of the pulmonary vascular system. Increased vascular resistance, pulmonary hypertension, and an apparent decrement in the density of capillaries occur in emphysematous horses. In emphysema, airway hypoxia and hypercapnia result from ventilation-perfusion mismatch that favors pulmo­nary vasoconstriction.

Heartworm disease in dogs: Pulmonary hypertension is characteristic of heartworm disease in dogs. Right-heart failure is common in dogs infested with Dirofilaria immitis. Mature worms may be found in the venae cavae, lumens of the right atrium and ventricle, and orifices of the tricuspid and pulmonary semilunar valves. They obstruct flow into and out of the right side of the heart and hinder normal function of cardiac valves. Pul­monary vascular resistance is increased due to obstruction, narrowing, or closure of pulmonary vascular pathways. In large vessels, mature worms occlude their lumens. In smaller vessels, mechanical obstruction is caused by thrombi containing fragments of disintegrating parasites, by emboli, and by fibroplasia involving the walls of arteries.

Exercise-induced pulmonary hemorrhage: Exercise- induced pulmonary hemorrhage (EIPH) occurs in racehorses during sprint racing and is characterized by pulmonary hypertension, edema in the gas-exchange region of the lung, rupture of the pulmonary capillaries, intra-alveolar hemorrhage, and presence of blood in the airways. The enormous cardiac output demanded by the racehorse associated with maximal recruitment and dis­tension of the pulmonary capillaries also contributes to hypertension. During maximal exercise, the pulmonary arterial pressures may exceed 120 mmHg in thoroughbred, and it is observed that the exercise-induced pulmonary hemorrhage occurs above a mean pulmonary artery pres­sure of about 90 mmHg.

6.6.4.6 Cutaneous Circulation

The major functions of the skin include thermoregulation, storage of blood, protection, cutaneous sensations, excretion and absorption, and synthesis of vitamin D. The dermis has an extensive network of blood vessels that carry 8-10% of the total blood flow in resting state, thus acting as a blood reservoir. In skin, capillaries reach only as superficially as the dermis; the epidermis does not have a blood supply. The venules that are part of a plexus of vessels near the dermal- epidermal border contain an appreciable volume of blood. Total blood flow through the cutaneous circulation is com­posed of both nutritional flow perfusing the capillary beds of the skin and flow directed through arteriovenous anastomoses (AVAs), which shunt flow between arteries and veins. The skin is normally overperfused in relation to its nutritional requirements. Thus, local metabolic control of skin blood flow is of little functional importance. Local vasodilator metabolites, sympathetic neuronal regulation mediated by α1 adrenoceptors, and sensory cues (e.g., temperature, touch, pain), all work together to regulate local nutrient flow through the precapillary sphincters and capillaries.

The skin is classified into apical and nonapical skin based on the blood flow. The apical skin at the extremities of the body has a very high surface-to-volume ratio that favors heat loss. Circulation to these apical regions has an unusual fea­ture of arteriovenous anastomosis (AV) called glomus bod­ies. Glomus bodies of the skin are tiny nodules found in many parts of the body, including the ears, the pads of the fingers and toes, and the nail beds.

The AV anastomoses, which are involved in heat exchange, are in parallel with the capillaries of the skin, which are involved in nutrient exchange. The anastomotic vessels are under neural control, rather than the control of local metabolites. In these apical regions, blood flow is under the control of sympathetic fibers that release norepinephrine and thereby constrict the arterioles, anastomotic vessels, and venules. Therefore, the increase in sympathetic tone that occurs in response to decreases in core temperature elicits vasoconstriction in the AV anastomoses mediated by both α1 and α2 adrenoceptors, a fall in blood flow, and a reduction in heat loss. On the other hand, when the core temperature rises, the withdrawal of sympathetic tone leads to passive vasodi­lation; there is no active vasodilation. Thus, sympathetic tone to the vasculature of apical skin is substantial at rest under cool environments to minimize heat loss.

6.6.4.6.1 Nonapical Skin

The nonapical skin almost completely lacks AV anastomoses, and there are two types of sympathetic neurons innervating the vessels of the skin which release norepineph­rine and acetylcholine. Vasoconstriction occurs in response to the release of norepinephrine. Vasodilation in nonapical skin occurs in response to sympathetic neurons that release acetylcholine. The acetylcholine stimulates eccrine sweat glands to release kallikrein, a protease that converts kininogens to kinins, and these kinins act in a paracrine fashion on nearby blood vessels to relax the vascular smooth muscle cells. Cholinergic sympathetic neurons may cause vasodilation by means of a second pathway involving the co-release of vasodilatory neurotransmitters (e.g., calcitonin gene-related peptide, vasoactive intestinal peptide) that act directly on vascular smooth muscle cells (VSMCs), indepen­dently of sweat gland activity. In addition to sympathetic nerve fibers, mammalian skin contains small-diameter unmy­elinated and thinly myelinated nerve fibers with nociceptive receptors that can contribute to vasodilation in response to pain or injurious stimuli. Activation of these receptors mark­edly increases CGRP release, which contributes to local vasodilation. In addition to neurally mediated effects, the cutaneous circulation dilates or constricts in response to local heating or cooling, respectively.

6.6.4.7 Placental and Fetal Circulation

6.6.4.7.1 Circulation in Fetus

The placenta has a low vascular resistance and receives 45% of the cardiac output through the umbilical arteries in the umbilical cord to the placenta, which serves as the “fetal lung.” The umbilical veins drain the placenta toward the liver. The fetal circulation is capable of considerable regula­tion, particularly as the fetus matures. Fetal hypoxia can stimulate vasoconstriction in the skeletal tissues, gut, kidneys, and vasodilation in the heart and brain. If the fetus is hypoxic, there is severe constriction in the fetal pulmonary circulation to divert more blood through the ductus arteriosus to the systemic tissues.

The fetal circulation has three shunts; two of these shunts, the foramen ovale and the ductus arteriosus, cause the fetal right and left ventricles to operate as parallel pumps rather than pumps in series as in the adult.

The third shunt in the fetal circulation is the ductus venosus, a low-resistance channel that allows a significant fraction of relatively oxygenated blood in the umbilical vein to bypass the fetal liver and directly enter the caudal vena cava.

In species such as sheep, a low-resistance pathway, the foramen ovale, connects the right and left atria, and a structure known as the crista dividens directs the better oxygenated blood from the posterior vena cava through the foramen ovale to the left atrium. The poorly oxygenated blood returning to the right atrium in the cranial vena cava is directed into the right atrium and right ventricle. Most of the right ventricular output does not go through the lungs, however, because fetal lungs have a high vascular resis­tance. Another low-resistance channel, the ductus arteriosus, connects the pulmonary artery with the aorta and allows blood to bypass the lungs. The better oxygenated blood enters the left ventricle, from which it reaches the brachycephalic vessels and the front of the animal. The less well-oxygenated blood from the ductus arteriosus enters the aorta downstream from the brachyce­phalic vessels.

Relatively oxygenated blood from the ductus venosus joins blood from the lower extremities and hepatic veins in the caudal vena cava and continues to the heart. Pressure in the fetal right atrium is normally higher than pressure in the left atrium, allowing blood to flow through an open flap in the foramen ovale from the right to the left atrium. Anatomically, the foramen ovale lies in the pathway of blood from the caudal vena cava carrying the relatively well-oxygenated blood from the ductus venosus. The tendency for this rela­tively oxygenated blood from the caudal vena cava to prefer­entially stream toward the foramen ovale is further accentuated by the crista dividens of the interatrial septum. Consequently, the majority of blood from the caudal vena cava is directed through the foramen ovale into the left atrium and subsequently into the left ventricle. As a result, the PO₂ and oxygen saturation of blood in the fetal left ventricle is relatively high. In contrast, oxygen saturation of blood in the cranial vena cava is much lower due to high oxygen con­sumption in the developing brain. The anatomic location of the entry of the cranial vena cava into the right atrium leads to preferential streaming of the majority of the cranial vena cava blood into the right ventricle. Consequently, oxygen satura­tion of blood in the right ventricle is lower than that in the left ventricle.

The ductus arteriosus forms a vascular conduit between the pulmonary artery and aorta. In the fetus, the ductus arteriosus allows blood to flow from the high-pressure pul­monary artery to the lower pressure aorta. Physiologically, the ductus arteriosus provides a pathway for blood in the fetal pulmonary artery to bypass the high-resistance vascular bed of the fetal lung and instead to flow into the aorta distal to the origin of the coronary arteries and the brachiocephalic trunk. In fact, only 10-12% of the blood flows through the lungs in the fetus.

The roles of the foramen ovale and ductus arteriosus in the fetus are closely interrelated. During ventricular systole, the relatively well-oxygenated blood in the left ventricle is ejected into the aortic root. The first vessels arising from the aorta include the coronary arteries and the brachiocephalic trunk, and they primarily receive this flow, so that the devel­oping heart and brain benefit from receiving comparatively well-oxygenated blood. This relationship would seem teleo­logically to be advantageous to these organs, but it is not essential for fetal survival or continued development, since fetuses lacking this preferential direction of flow due to congenital malformations continue to develop to term. The foramen ovale is also important for normal left ventricular development. By increasing the volume provided to the left ventricle, flow through the foramen ovale is important in promoting the normal growth and development of the fetal left ventricle.

6.7