Systemic and Pulmonary Circulation and Oxygen Delivery

Systemic and Pulmonary Circulation and Oxygen Delivery

Elizabeth J. Bridges

Joseph O. Schmelz

The structural and functional characteristics of the systemic circulation determine the continuous adjustments in flow, pressure, and resistance that occur in each vascular bed and that are vital determinants of tissue function. Blood flow and nutrient exchange in various vascular beds are affected by the structural and metabolic characteristics of the vascular bed, the physical factors that affect flow and the exchange of materials across the blood vessel wall, the local factors originating from the metabolically active cells and vascular endothelium that regulate flow to individual vascular beds, and local and systemic neuroendocrine regulation. The combined regulation of cardiac output, blood pressure, and systemic vascular resistance determines tissue blood flow and, ultimately, the survival of each organ system and the body as a whole. This chapter describes the basic anatomy and physiology of the systemic and pulmonary circulation; Chapter 3 describes the overall regulation of cardiac output and blood pressure.


Blood vessels are usually classified in the following manner: aorta, large arteries; main arterial branch, small arteries, arterioles; terminal arterioles, capillaries, postcapillary venules; venules, small veins, main venule branch, large veins, and the vena cava.1, 2, 3 These classifications are based on structural characteristics such as diameter, wall thickness, and the presence of muscle. Although blood vessel diameter is often used to characterize different vessels, it is not an appropriate criterion to use for classification, because differences in vessel size reflect the state of vessel contraction as well as differences between organ systems and species.3,4

With the exception of the capillaries, the systemic vasculature is composed of three layers: the tunica intima or internal layer, which consists of the endothelium and the basal membrane; the tunica media, which consists of smooth muscle and a matrix of collagen, elastin, and glycoproteins; and the tunica adventitia, which consists of connective tissue (Fig. 2-1). The muscularis in the artery is a concentric ring, which allows for vasoconstriction. In contrast, the venous musculature is organized into small bundles at right angles.5 In the larger arteries and veins, the tunica adventitia also contains blood vessels that supply the vessel wall (vasa vasorum).3 The vascular endothelium, which is a metabolically active barrier, is a primary mediator of vascular function and is discussed in detail.


Arteries in which the media contains smooth muscle and elastin are called elastic arteries.3 Because of the considerable amount of elastin, these large conducting arteries are able to distend to twice their unloaded length. The ability of the capacitive arteries to distend is important in cushioning pulsatile flow, such that the blood flow to the organs/tissue is almost a constant flow. During systole, the aorta and proximal large vessels store approximately 50% to 60% of the stroke volume. During diastole, the distended vessels recoil and move the remaining blood to the periphery. This phenomenon is referred to as a “Windkessel function,” which is the transformation of pulsatile flow in the central arteries to constant flow in the periphery.6 As the arteries approach the periphery, they become smaller in diameter, and there is a relative decrease in elastin and a relative increase in smooth muscle in the tunica media.7,8 These peripheral arteries are referred to as muscular arteries.

The small arteries (prearteriolar vessels with a diameter less than 500 mm) receive nervous stimulation primarily from noradrenergic stimuli, with the nerve terminals located in the adventitia. Unlike the larger arteries, in which sympathetic neural constriction is activated by α1 and postsynaptic α2 receptors, the small arteries are noradrenergically constricted mainly by the postsynaptic α2 receptors.8,9 The small arteries are also sensitive to endothelium-derived relaxing and contracting factors. Of clinical importance, abnormal small artery wall structure is an independent predictor of cardiovascular events (e.g., stroke, myocardial infarction, death).10,11 However, it may be possible to reverse these changes with vasodilator therapy.12

Microvascular Bed

The term microcirculation denotes the vascular and lymphatic microcirculation. The vascular microcirculation consists of (1) large and small arterioles (precapillary resistance vessels); (2) terminal arterioles, which in many tissues serve as so-called precapillary sphincters; and (3) other precapillary structures such as capillaries; and (4) nonmuscular venules, known collectively as the exchange vessels, and muscular venules (postcapillary resistance vessels). The term lymphatic microvasculature refers specifically to the terminal lymphatic vessels.


As the vessel diameter decreases from the small arteries to the arterioles, the number of smooth muscle layers decreases from approximately six layers in the 300-μm vessels to a single layer of irregularly dispersed smooth muscle in the 30- to 50-μm vessels.7 At this point, the vessels are referred to as arterioles. The smallest arteriolar branches (8 to 20 μm in diameter) are called the terminal arterioles.13 In some cases, smooth muscle extends beyond the intersection of the terminal arterioles with the nonmuscular capillaries into structures known as precapillary sphincters.14 The terminal arterioles and precapillary sphincters control the distribution of blood supply to the exchange vessels.15

Figure 2-1 Schematic drawing of the major structural characteristics of the principal segments of blood vessels. The relative amounts of elastic tissue and fibrous tissues are largest in the aorta and least in small branches of the arterial tree. Small vessels have more prominent smooth muscle in the media. Capillaries consist only of endothelial cells. The walls of the veins are much like the arterial walls, but are thinner in relation to their caliber. (From iDAMS 3746-08-17.)


Capillaries branch from terminal arteriolar segments. The capillary wall consists of endothelial cells and basal lamina; there is no tunica media or adventitia. Capillary diameter is 4 to 8 mm, which is just large enough to allow the deformable red blood cells to pass through.14,16 Not all exchange vessels in an area are simultaneously open. During periods of increased metabolism, capillary recruitment increases the number of open and perfused exchange vessels, thereby decreasing the distances for diffusion between exchange blood vessels and cells, as well as increasing the total surface area for exchange between the capillaries and cells.13

In microvascular beds located in the ears, fingers, and toes in humans and many other mammals, there are arteriovenous vascular channels that bypass the exchange vessels and allow blood to flow directly from arterioles to venules.13 These arteriovenous anastomoses, which are richly innervated by the sympathetic nervous system, are important in local temperature control in these areas and even of the whole body in some conditions.17

Exchange Vessel Endothelium

The endothelium of exchange vessels in various organs contains at least four different structures that determine the rate of filtration and bulk transport of water and solutes and the exchange of larger molecules (Fig. 2-2). The structure of the membrane (continuous, fenestrated, discontinuous and tight junction) varies depending on the location of the vascular bed.18 All four types of endothelium have a continuous basement membrane, with the exception of the discontinuous endothelium.

Continuous endothelium is found in skin; skeletal, smooth, and cardiac muscle; and the lungs. There are several mechanisms by which substances pass through continuous endothelium. Water and solutes pass through intercellular junctions (40 to 1 Å) driven predominantly by a pressure gradient (ΔP) driving fluid out of the vessels. This outward flow is partly counterbalanced by forces drawing water back into the vessels. Lipid-soluble substances (CO2, O2) pass directly through the cell by diffusion; cytoplasmic vesicles transport solutes and water back and forth through the endothelium; and vesicles intermittently fuse to create channels in the cell. The junctions between the cells are responsible for the high permeability of the membrane to “ultrafiltrate,” or proteinfree fluid, and for the rapid diffusion of small ions. The continuous endothelium is relatively impermeable to plasma proteins and large molecules.

Fenestrated vascular endothelium is located in the gastrointestinal mucosa, glands, renal glomerular capillaries, and peritubular capillaries. The endothelium has openings (fenestrae) that expose the basement membrane (renal glomerular capillaries) or are covered by a thin diaphragm (gastrointestinal mucosa, renal peritubular capillaries). The fenestrated endothelium has a higher permeability to water and small solute molecules than continuous endothelium, whereas its permeability to plasma proteins is low, similar to continuous endothelium.13

Discontinuous endothelium is located in the hepatic cells, bone marrow, and splenic sinusoids. Discontinuous endothelium contains gaps in the endothelium and basement membrane and is permeable to proteins and other large molecules.

Figure 2-2 Different types of endothelial cells, their distribution to different organs and specific functional roles (bm, basal membrane, tj, tight junction, f, fenestrae, p, pores. (From Priese, K. R., & Kuebler, W. M. [2006]. Normal endothelium. Handbook of Experimental Pharmacology, 176[Pt. 1], 1-40.)

Tight-junction endothelium is located in the central nervous system and retina. It is the least permeable. The endothelial cells are connected by tight junctions that effectively restrict passage of all substances. Water- and lipid-soluble molecules pass directly through the endothelium, whereas ions and lipid-insoluble substances, such as glucose and amino acids, are transported by membrane carriers.19


Venous capillaries extend to the postcapillary venules (nonmuscular, 7 to 50 μm) and collecting venules. Along with the capillaries, the nonmuscular venules act as exchange vessels. Smooth muscle reappears in venules that are approximately 30 to 50 μm in diameter. These venules, which receive adrenergic innervation, are referred to as the muscular venules, postcapillary resistance vessels, or capacitance vessels.2,13,16 As discussed later in the section on microcirculation, postcapillary resistance tends to be far less than precapillary resistance and has almost no effect on overall systemic vascular resistance. The veins contain approximately 70% of total blood volume, with approximately 25% of this volume in the venules.2


In general, veins have a larger diameter and thinner, more compliant walls than arteries at equivalent branches of the vascular tree.2 However, the thickness of the venous walls is variable. For example, the veins in the legs and feet, which withstand the high hydrostatic pressure associated with standing, are thick-walled, whereas the veins near or above the level of the heart are thin-walled. The veins contain all three vascular layers found in the arteries; however, these layers are often indistinct.3 Superficial veins form a rich anastomosis with deeper veins via vessels that perforate the muscles. These perforating veins allow venous return from cold skin to be diverted to warm muscle, providing a thermal short circuit, and they are particularly important for function of the muscle pump, which is described in Chapter 3.

Venous Valves

With the exception of the intrathoracic and intracerebral veins, the medium-sized veins contain valves that are oriented in the direction of blood flow, thus preventing retrograde blood flow into the muscle.2 The presence of competent valves, in conjunction with the muscle pump in the lower extremities, is crucial to the ability to stand erect and in maintaining a reasonably low capillary pressure, because the valves interrupt the hydrostatic column that extends from the right atrium to the feet after each leg muscle contraction.20 After humans with normal valvular function stand up, the valves in dependent veins initially interrupt the hydrostatic column. However, over a period of approximately 2 to 3 minutes, as the veins fill with blood, the valves can no longer interrupt the hydrostatic column as volume continues to accumulate. At this time, there is a displacement of approximately 600 mL of blood from the central circulation into the legs and pelvic organs.21 In conditions in which blood flow is high, the hydrostatic effects associated with the loss of valvular function occur within 2 to 3 seconds. If the hydrostatic effects are not overcome by the muscle pump in the lower extremities, arterial hypotension, and syncope result. This phenomenon is readily seen in the soldier who faints while standing motionless at attention. There is also some evidence that there are microscopic venous valves located in the small veins and also in the post-capillary venules.22 These microscopic valves may play a protective role against venous hypertension when there is valvular insufficiency in larger veins.


In contrast to the arteries, not all veins constrict when exposed to norepinephrine. For example, the postcapillary venules ranging from 0.007 to 2 mm in diameter do not have smooth muscle and therefore cannot constrict.23 Most of the larger venules and small veins (including veins in the skeletal muscle) contain some smooth muscle,2 but they are sparsely innervated and are not considered sites of vasoconstriction. The lack of venoconstriction in the skeletal muscle is important because the leg veins do not constrict in orthostasis. The splanchnic organs (liver, gastrointestinal tract, pancreas, and spleen) are the exception because they are richly innervated by sympathetic noradrenergic fibers and are capable of venoconstriction. In addition, the veins in the skin respond to thermoregulatory reflexes. In humans, significant venoconstriction occurs only in the splanchnic circulation; in response to thermoregulatory reflexes, the veins in the skin constrict and dilate.17,24,25


The lymphatics are a system of thin-walled vessels that collect and conduct lymph through active contraction of the lymphatic microvasculature to the central circulation.26, 27, 28 Lymph consists primarily of ultrafiltrate and proteins that have been filtered from exchange vessels. The initial lymphatic vessels (also known as terminal lymphatics or lymph capillaries), which consist of endothelialized tubes, originate in large, blind-terminal bulbs located in the connective tissue of most organ systems.29 The lymphatic capillaries empty into collecting lymphatics, which in turn empty into transporting lymphatic vessels (Fig. 2-3). The central lymphatic vessels empty into the left and right lymphatic ducts, which empty into the subclavian veins.

A very small and transient pressure gradient between the interstitium and the terminal lymphatics promotes fluid movement into the lymphatics. Beginning at the level of the collecting capillaries, there are bicuspid valves, and the larger lymphatics contain smooth muscle that spontaneously contracts in a rhythmic manner.30 The primary mechanism underlying the peristaltic like lymphatic flow is the intrinsic contraction of the lymphangions, which are the functional unit of lymphatic vessels, consisting of the valve and portion of the vessel surrounding the valve. The intrinsic contraction remains active during rest, anesthesia, and immobilization.31 Lymphatic flow is also facilitated by lymph formation, skeletal muscle contractions (e.g., walking, foot flexing), respiration, fluctuations of central venous pressure, gastrointestinal peristalsis, and arterial pulsations.32

Figure 2-3 Steady-state distribution and circulation of fluid (ultrafiltrate) and plasma proteins in a normal human (weight, 65 kg). The doubledashed line between plasma and interstitial fluid represents exchange vessel endothelium. The weights at the bottoms of the boxes represent the total content of each. (From Renkin, E. M. [1986]. Some consequences of capillary permeability to macromolecules: Starling’s hypothesis reconsidered. American Journal of Physiology, 250, H706-H710.)

Vascular Smooth Muscle

Vascular smooth muscle contains the contractile filaments, actin and myosin; however, unlike striated smooth muscle (cardiac), the filaments are not organized in any fashion.33 Although the sarcoplasmic reticulum is not as prominent in vascular smooth muscle as in cardiac muscle, it serves as the primary intracellular source of calcium.34 Additionally, the amount of myosin in smooth muscle is approximately one-fifth that found in striated muscle. Despite this lower amount of myosin, smooth muscle develops higher force per cross-sectional area than striated muscle. Vascular smooth muscle also usually contracts more slowly than striated muscle, and it maintains tonic contractions with lower energy [adenosine triphosphate (ATP)] expenditure.

Smooth muscle is characterized as “phasic” and “tonic.” Phasic vascular smooth muscle, which is capable of high shortening velocities, is located in the portal veins. Tonic vascular smooth muscle is located in most of the small arteries and arterioles and has a slower shortening velocity, but it is capable of maintaining sustained vascular tone.35 As in cardiac and skeletal muscle, contraction of vascular smooth muscle is related to the formation and release of crossbridges by the cyclic attachment and detachment of the heads of the contractile protein myosin with actin (see Chapter 1). Tonic contractions allow for the maintenance of a basal vascular tone, which is crucial for the maintenance of arterial blood pressure. These tonic contractions are the result of a “latch bridge,” which is a slowing in the cross-bridge cycling rate. Other possible mechanisms for the tonic contraction include increased calcium sensitivity and inhibition by agonists of proteins (e.g., caldesmon) that bind actin and interfere with the inhibitory effects of calcium-calmodulin.36


In addition to the systemic factors that affect vascular resistance, there are local factors that control resistance. These factors include autacoids, endothelium-derived vasoactive substances, local metabolic factors that match blood flow (oxygen transport) to metabolism, autoregulation (see Chapter 3), and local heating and cooling.


The autacoids (vasoactive substances) include histamine, serotonin, prostaglandin, and bradykinin. These factors most often compete with adrenergic (vasoconstrictive) effects and exert a local vasodilatory effect, which can improve tissue perfusion. The autacoids are not involved in systemic regulation of blood pressure or total peripheral resistance; however, they initiate or modify the vascular response to other stimuli.

Endothelium-Derived Vasoactive Substances

The vascular endothelium, which is a single layer of squamous cells in the tunica intima that lines the entire vascular tree, modulates vascular tone by secreting dilator and constrictor substances. In addition, the endothelium affects platelet adhesion and aggregation and under basal conditions substances secreted by the endothelium affect the clotting cascade.37 The endothelium is also involved in the regulation of vascular smooth muscle proliferation.37 The proposed functions of the vascular endothelium (Table 2-1) require an intact endothelium.38 The control of vascular tone involves cross talk between the vasodilators nitric oxide (NO), prostaglandins, and endothelial-derived hyperpolarizing factor (EDHF) and the vasoconstrictors endothelin-1 and prostacyclin (Fig. 2-4). A discussion of each of these factors related to vascular control follows. A summary of the stimuli that cause the release of each of the factors is presented in Table 2-2.

Endothelium-Derived Relaxing Factors

The seminal observation that endothelium is a key mediator of vascular reactivity was made in 1980.38 The ability of the artery to relax was attributed to the elusive substance, EDRF, which was later identified as NO.39,40 Although NO is the major EDRF, other relaxing factors such as prostacyclin [prostaglandin I2 (PGI2)] EDHF are also produced.



Factors Responsible

Release of vasodilatory agents

Nitric oxide
Endothelium-derived hyperpolarizing factor

Release of vasoconstrictor agents

Angiotensin/angiotensin II
Prostaglandin H2
Thromboxane A2
Superoxide anions

Antiaggregatory effects

Nitric oxide
Thromboresistant endothelium

Nitric Oxide.

NO is a gas with an extremely short half-life (seconds) that diffuses into vascular smooth muscle cells and causes vasodilation.40, 41, 42 NO production is stimulated by the enzyme nitric oxide synthase (NOS). There are two constitutive forms of NOS: endothelial NOS (eNOS) and neurological NOS (nNOS). Inducible NOS (iNOS), which is present only under pathological conditions, generates 100- to 1000-fold more NO than the constitutive forms.

Shear stress and vasoactive substances are the primary factors involved in the release of NO for control of vasomotor tone (Fig. 2-5). The activation of eNOS is different for these two mechanisms. Shear stress through G proteins (Gs) leads to eNOS activation, which via the inositol triphosphate (IP3) pathway causes hyperpolarization of the endothelial cells, which allows calcium to flow into the cell.43,44 The increased intracellular calcium binds to calmodulin, which releases eNOS from the inhibitory protein calveolin. The eNOS catalyzes the conversion of L-arginine to NO. After NO is formed in the endothelial cells, it diffuses out of the endothelial cell to the vascular smooth muscle and as described below causes vasodilation. Nitric oxide also has secondary vasodilatory effects through the inhibition of the release of the vasoconstrictor endothelin-1 (ET1), although this beneficial effect decreases with age.45,46

Autocoids and hormones cause the release of NO from the endothelium (Fig. 2-6).47 These substances (Table 2-2) cause the release of IP3, which leads to an increase in intracellular calcium and subsequently stimulates the release of NO. Additionally, NO decreases sympathetic vasoconstriction by inhibiting the release of norepinephrine at the supraspinal, spinal, and synaptic levels.48 Clinically, nitrovasodilators (e.g., nitroglycerin and sodium nitroprusside) cause vasodilation by the donation of NO or NO-like compound.49,50 Of note, nitroglycerin-induced coronary artery vasodilation does not require the presence of an intact endothelium. In addition, ACE inhibitors, calcium channel blockers, statins, and phosphodiesterase inhibitors indirectly stimulate NO release or enhance its bioavailability.51

Nitric oxide also inhibits platelet activation, aggregation, and adhesion (i.e., anticoagulant/profibrinolytic phenotype), leukocyte adhesion,52 vascular smooth muscle proliferation, and it inhibits endothelial cell apoptosis but stimulates vascular smooth muscle apoptosis (Fig. 2-6).37,53 With aging there is a decrease in NO production and increased endothelial cell apoptosis, which leads to a decrease in the protective effect of NO against platelet aggregation and vasoconstriction decreases. There is also diminished NO production with disease processes (e.g., hypertension, diabetes, postmyocardial infarction reperfusion injuries) and altered defense mechanisms.44,54 The loss of the protective endothelium, decreased NO production, and increased NO degradation may foster increased platelet aggregation and vascular proliferation, which are keys to the development of atherosclerosis,55 intimal hyperplasia that causes restenosis after a vascular intervention such as bypass surgery or angioplasty,53 and the procoagulant state seen in septic shock.37 The cytokine-induced increase in NO synthesis by iNOS may be responsible for the decreased vascular tone, vascular hyporeactivity, and hypotension observed in septic shock.56 Nitric oxide also inhibits cytochrome c oxidase, which may be one factor associated with cytopathic hypoxia in sepsis.57,58


Prostacyclin (PGI2) is a cyclooxygenase (COX) dependent vasodilator prostaglandin, which is released transiently by stimulation of endothelial-specific receptors. Prostacyclin receptor stimulation causes an increase in intracellular calcium,
which activates phospholipase A2 and subsequently releases arachidonic acid. Under basal conditions the arachidonic acid is then metabolized by COX-1, which results in the production of prostaglandin H2 (PGH2) and subsequently PGI2.59 Prostacylin binds to receptors on vascular smooth muscle and platelets and through G-protein mediated activation of adenylate cyclase increases cyclic adenosine monophosphate (cAMP) (Fig. 2-7). Increased cAMP stimulates potassium-induced cellular hyperpolarization and the phosphorylation of protein kinase A (PKA), which increases calcium extrusion from the cell and causes vasodilation and also inhibits platelet activation.59 Prostacylin also act through peroxisome proliferator-activated receptor (PPAR)β/δ, which causes a decrease in intracellular calcium and subsequent vasodilation and platelet inhibition through mechanisms that are still being studied. There is cross talk between PGI2 and NO and they have synergistic vasodilatory and antithrombotic actions. Prostacyclin increases NO release and, concomitantly, NO prolongs the effect of prostacyclin by inhibiting its breakdown.59,60

Figure 2-4 Activation of endothelial receptors can stimulate NO synthase (NOS, with the production of nitric oxide [NO]) and cyclooxygenase (COX), which produces prostacyclin (PGI2) from arachidonic acid (AA) and can lead to the release of EDHF. NO causes relaxation by activating the formation of cyclic GMP (cGMP) from guanosine triphosphate (GTP) by soluble guanylate cyclase (GC). PGI2 causes relaxation by activating adenylate cyclase (AC) leading to the formation of cyclic AMP (cAMP). EDHF causes hyperpolarization and relaxation by opening K+ channels. Any increase in cytosolic calcium (including that induced by calcium ionophore A23187) causes the release of relaxing factors. In certain blood vessels, contracting substances can be released from the endothelial cells, which include superoxide anions (O2), thromboxane A2 (TXA2), endoperoxides, and possibly ET1. Thromboxane A2 and endoperoxides activate specific receptors (TX/Endo) on the vascular smooth muscle, as does ET1. Such activation causes an increase in intracellular Ca2+ leading to contraction. The production of ET1 (catalyzed by endothelin converting enzyme [ECE]) can be augmented by angiotensin II (ATII), vasopressin (VP), or thrombin (T). The neurohumoral mediators that cause the release of endothelium-derived relaxing factors (and sometimes contracting factors) through activation of specific endothelial receptors (circles) include acetylcholine (ACh), adenosine diphosphate (P), bradykinin (BK), endothelin (ET), adrenaline (α), serotonin (5HT), T, and VP. (From Vanhoutte, P. M. [1999]. How to assess endothelial function in human blood vessels. Journal of Hypertension, 17, 1047-1058.)




Vasodilating Factors

Nitric oxide

Acetylcholine, histamine, arginine vasopressin, epinephrine, norepinephrine, bradykinin, adenosine diphosphate, serotonin (from aggregating platelets), thrombin (from coagulation cascade)

Endothelium-derived relaxing factor


Endothelium-derived hyperpolarizing factor

Vasoconstricting Factors

Endothelium-derived contracting factor

Physical stimuli (mechanical stretch), arachidonic acid (endothelial injury and platelet aggregation), serotonin, adenosine platelet diphosphate



Superoxide anions

Thrombin, interleukin-1, epinephrine, angiotensin II, arginine vasopressin

Endothelin-1, endothelial membrane damage

Physical stress (e.g., shear stress, postischemic reperfusion), chemical endothelial stimulants (bradykinin, cytokines)

Figure 2-5 Nitric oxide messenger system. Proposed role in stimulating soluble guanylate cyclase and cyclic guanosine 3,5′-monophosphate to cause vasodilation and possibly a negative inotropic effect. Antianginal nitrates cause coronary vasodilation by this mechanism. M1, muscarinic receptor, subtype 1. (From Opie, L. H. [2004]. Heart physiology: From cell to circulation. Philadelphia: Lippincott.)

Endothelium-Derived Hyperpolarizing Factors.

Vasodilation of arterioles is also mediated by non-NO/non-prostanoid EDHFs.61,62 EDHF may be the predominant mechanism for vasodilation in smaller diameter vessels (i.e., resistance arteries <300 μm) in contrast to larger vessels where NO is the dominant vasodilator.63 There are four putative EDHFs: the enzyme cytochrome p450 monooxygenase (cytochrome P-450), potassium, hydrogen peroxide, and C-type natriuretic peptide.62 EDHFs, which may be considered a mechanism as much as a factor,63 are synthesized in response to wall shear stress or the binding of bradykinin and acetylcholine or substance P to endothelial cell receptors. EDHF diffuses from the endothelium to the vascular smooth muscle where it
causes endothelium-dependent hyperpolarization, which in turn decreases cytosolic calcium and causes vasorelaxation through the various mediator-specific pathways (Fig. 2-8).61

Figure 2-6 Postulated signal transduction processes in a normal endothelial cell. Activation of the cell causes the release of NO, which has important protective effects in the vascular wall. α, alpha-adrenergic; 5-HT, serotonin receptor; EDHF, endothelium-derived hyperpolarizing factor; ET, endothelin receptors; B, bradykinin receptor; P, purinoreceptor; G, coupling proteins; cAMP, cyclic adenosine monophosphate; NO, nitric oxide; LDL, low-density lipoproteins; +, activation; −, inhibition. (Modified from Vanhoutte, P. M. [1999]. Endothelial dysfunction and vascular disease. In J. A. Panza, & R. O. Cannon (Eds.), Endothelium, nitric oxide and atherosclerosis. New York: Futura Publishing.)

Figure 2-7 Schematic summarizing the release of relaxing factors from endothelial cells and their effect on vascular smooth muscle cells. Ach, acetylcholine; A23187, calcium ionophore A21837; BK, bradykinin; B2, bradykinin B2 receptor; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; EDHF, endothelium-derived hyperpolarizing factor; EET, epoxyeicosatrienoic acid; K+; potassium channel; M1, M3, muscarinic M1 or M3 receptor subtypes; NOS, nitric oxide synthase; PGI2, prostacyclin; P450, cytochrome P450 monooxygenase; TBA, tetrabutylammonium; TEA, tetraethylammonium. The broken line indicates the action of an inhibitor or an antagonist. (From Mombouli, J. V., & Vanhoutte, P. M. [1999]. Endothelial dysfunction: From physiology to therapy. Journal of Molecular Cell Cardiology, 31, 61-74.)

In hypertension or hypercholesterolemia, when NO-mediated vasodilation is decreased, there may be a compensatory upregulation of EDHF-mediated vasorelaxation.64 Of note, there may be gender-specific EDHF compensatory response, with increased EDHF activity in females but not in males.62 However, oxidative stress associated with atherosclerosis, hyperhomocysteinemia, and possibly poorly controlled diabetes can decrease this compensatory response.64, 65, 66

Endothelium-Derived Contracting Factors

The endothelium-derived contracting factors include ET1, the vasoconstrictor prostanoids, PGH2, the precursor of thromboxane A2 (TXA2); superoxide anions (O2); and components of the reninangiotensin-aldosterone system. These substances are released in response to vasoconstrictive stimuli (see Fig. 2-4). Vasoconstriction also occurs as a result of a decrease in endothelial production of NO.

Figure 2-8 Schematic description of the main hyperpolarizing mechanisms mediated by endothelium-derived hyperpolarizing factor (EDHF). The binding of acetylcholine (Ach), bradykinin (BK), and substance P (SP) to their endothelial receptors and the increase in wall shear stress (τ) promote the synthesis of EDHF. EDHF can then hyperpolarize the smooth muscle cells by three principal pathways. EDHF can passively diffuse from the endothelium to activate calcium-activated potassium (KCa) channels of large conductance (BKCa) located on the smooth muscle cells thereby promoting the release of K+ and membrane hyperpolarization. EDHF can act in an autocrine manner to facilitate the activation of the endothelial KCa channels of small (SKCa) and intermediate (IKCa) conductance directly mediated by Ca2+ inducing the release of K+ and the hyperpolarization of the endothelial cells. Then, the hyperpolarization is transmitted electronically through the myoendothelial gap junctions into the smooth muscle cell layer and/or the K+ released from the endothelial SKCa and IKCa channels into the myoendothelial space activates the Na+/K+ ATPase and the inward rectifying potassium channels (KIR) located on the smooth muscle cells promoting the release of K+ and subsequent hyperpolarization of these cells. EDHF can enhance gap junctional communication. Finally, the smooth muscle cells hyperpolarization decreases the open-state of voltage-gate Ca2+ channels lowering cytosolic Ca2+ and thereby provoking vasorelaxation. (From Bellien, J., Thuillez, C., & Joannides, R. [2008]. Contribution of endothelium-derived hyperpolarizing factors to the regulation of vascular tone in humans. Fundamental of Clinical Pharmacology, 22(4), 363-377.)


In humans there are three isoforms of endothelin.67 ET1, which is the primary isoform in the cardiovascular system, is thought to be the most potent vasoconstrictor known. ET1 is an amino acid peptide that binds to vascular smooth muscle membrane receptors ETA (located on vascular smooth muscle) and ETB (located on vascular smooth muscle and endothelial surfaces). Binding of ET1 to the ETA and ETB receptors on the vascular smooth muscle activates the phospholipase C (PLC)-IP3 pathway, which increases intracellular calcium and the phosphorylation of myosin kinase and causes prolonged muscle contraction. In contrast, under normal resting conditions, the circulating plasma level of ET1 is very low and it acts locally, in a paracrine fashion, to cause vasodilation through the endothelial synthesis of NO and PGI2.68,69 The production of ET1 can be augmented by shear stress, angiotensin II (AII), vasopressin, oxygen free radicals, thrombin, and platelet-derived transforming growth factor and inhibited by NO, atrial natriuretic polypeptide, B-type natriuretic peptide, and prostacylin70 (Fig. 2-9).

The effects of ET1 are important clinically. In pathological conditions such as heart failure, increased ET1 levels are associated with increased morbidity and mortality71 and may play an important role in the disease pathogenesis.64 For example, ET1 stimulates the renin-angiotensin-aldosterone system, which enhances the conversion of angiotensin I to AII, causing a synergistic augmentation of vasoconstriction and sodium retention.70 In addition, in heart failure, ET1 has an negative inotropic effect.68 ET1 may play a role in salt-sensitive hypertension although the mechanism remains unclear.68,72 Unfortunately antagonism of ET1 receptors has not been found to improve outcomes for patients with heart failure or hypertension.73, 74, 75 ET1 levels are increased with hypercholesterolemia and increased ET1 levels may be a marker for endothelial dysfunction. Possible pathological mechanisms for ET1 in atherosclerosis and restenosis after angioplasty include increased fibrous tissue formation, inhibition of eNOS formation, stimulation of platelet aggregation, vascular smooth muscle proliferation, and inflammation of the vessel wall.69,76,77 There is also a link between ET1 and idiopathic pulmonary arterial hypertension and inhibition of ET1 has been shown to improve outcomes for these patients.78,79


Two prostanoids that have vasoconstrictive actions are PGH2 and TXA2. Similar to prostacyclin, arachidonic acid is converted by COX-1 to PGH2. PGH2 is then converted to TXA2 by thromboxane synthase or as discussed above, to prostacyclin.80 TXA2, which acts in a paracrine fashion, causes platelet activation, vasoconstriction, and smooth muscle proliferation, and it is thought to play an important role in the pathogenesis of myocardial infarction. The rationale for the administration of COX-1 antagonists [e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin] in cardiovascular disease is to inhibit platelet production of TXA2, which reduces cardiovascular morbidity and mortality;81,82 however, in patients where there is incomplete TXA2 inhibition, there is still a risk for cardiovascular events.83 A negative side effect of the COX-1 antagonists is that they are toxic to the gastric mucosa.

Because of the negative side effects of COX-1 antagonists, the use of selective PGH2 or COX-2 inhibitors (coxibs), which are not toxic to the gastrointestinal tract, were evaluated. However, several studies of coxibs found an increased incidence of adverse
serious cardiovascular events, including myocardial infarction and stroke.84,85 This increased risk resulted in the Food and Drug Administration requiring labeling of all selective and nonselective NSAIDs to reflect the possibility of an increased risk for myocardial infarction and stroke with their use.86 It is important to note that the increased risk varies depending on the medication87, 88, 89 and a prospective clinical trial is ongoing to determine the cardiovascular risk of selective and nonselective NSAIDS. The probable mechanism of these adverse effects is that while COX-2 inhibitors do not inhibit thromboxane they do inhibit vascular prostacyclin causing increased systolic blood pressure and platelet activation, which increases the likelihood of thrombus formation.90, 91, 92

Figure 2-9 A. Synthesis of endothelin receptors (ET) and its regulation. The release of active ET1 is controlled via regulation of gene transcription and/or endothelin converting enzyme activity. ET1 synthesis is stimulated by several factors, of which hypoxia seems to be the most important. ET1 formation is down regulated by activators of the NO/cGMP pathway and other factors. B. Vascular actions of ET. In healthy blood vessels, the main action of ET1 is indirect vasodilation mediated by ETB receptors located on endothelial cells. Their activation generates a Ca2+ signal via PLC that turns on the generation of nitric oxide (NO), prostacyclin, adrenomedullin, and other mediators that are powerful relaxants of smooth muscle. On the other hand, binding of ET1 to ETA receptors located on smooth muscle cells will lead to vascular contraction (physiological effect) and/or wall thickening, inflammation, and tissue remodelling (pathological effects). These latter effects may be mediated by vascular ETB2 receptors in certain disease states. Smooth muscle cell signalling involves DAG formation, PKC activation, and extracellular calcium recruited via different cation channels. (From Brunner, F., Bras-Silva, C., Cerdeira, A. S., et al. [2006]. Cardiovascular endothelins: Essential regulators of cardiovascular homeostasis. Pharmacology and Therapeutics, 111(2), 508-531.)

Reactive Oxygen Species.

In response to physical stresses, such as oscillatory shear stress, postischemic reperfusion, and chemical endothelial stimulants (bradykinin, cytokines, AII), the endothelium and vascular smooth muscle produce reactive oxygen species (ROS), which are metabolites of oxygen. Example of ROS include superoxide (O2), hydrogen peroxide, and peroxynitrite (ONOO), which is the product of NO and O2.93 These ROS inhibit NO, EDHF, and prostacyclin pathways and guanalyl cyclase (Fig. 2-10), increase calcium mobilization and the production of the vasoconstrictors PGH2 and TXA2, decrease NO-mediated vasorelaxation, and play a role in endothelial dysfunction.64,93 Pathological effects of ROS that contribute to the development of atherosclerosis include stimulation of vascular smooth muscle proliferation and migration, endothelial apoptosis, altered vasomotor reactivity, oxidation of low-density lipoprotein, which causes cholesterol accumulation in macrophages, the upregulation of adhesion molecules and the creation of a proinflammatory state.94,95 In contrast antioxidant systems, such superoxide dismutase (SOD) and glutathione peroxidase, scavenge, and inactivate ROS. SOD are enzymes that breaks down the free radicals into nontoxic substances and inhibits the breakdown of NO by superoxide anions, inhibits pathologic ET1 production and augments endothelial relaxation.95 Clinically, ACE inhibitors, which prevent angiotensin II from inducing oxidative stress, may improve NO availability,96,97 and statins, which inhibit ROS formation have been found to improve cardiovascular outcomes.98 However, studies and meta-analyses failed to find any beneficial effects from supplemental antioxidants (Vitamin C and Vitamin E) in the reduction of cardiovascular mortality or death.99, 100, 101

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Jan 10, 2021 | Posted by in NURSING | Comments Off on Systemic and Pulmonary Circulation and Oxygen Delivery
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