Physiology_Levy

Physiology_Levy. Arterial compliance (Ca), the ratio of blood volume to mean blood pressure (see Eq. 19.1 ), also affects pulse pressure. This relationship is illustrated in Fig. 17.16 . When cardiac output and TPR are constant, a decrease in arterial compliance results in an increase in pulse pressure. Diminished arterial compliance also imposes a greater workload on the left ventricle (i.e., increased afterload), even if stroke volume, TPR, and Pa are equal in the two individuals. As previously discussed, if the heart rate and stroke volume remain constant, an increase in TPR causes Pa to increase. •Fig. 17.15 Effect of a Change in Stroke Volume on Pulse Pressure in a System in Which Arterial Compliance Remains Constant Over the Prevailing Range of Pressures and Volumes. Alargerincrementinbloodvolume,whereby(V4− V3)> (V2− V1),resultsingreatermeanbloodpressure(PB > PA)andagreaterpulsepressure,sothat(P4− P3)> (P2− P1).


Physiology_Levy

Physiology_Levy. When arterial compliance is constant, an increase in TPR leads to proportional increases in systolic and diastolic pressure so that the pulse pressure is unchanged (Fig. 17.17A ). However, arterial compliance is not linear. As Pa increases and the artery is stressed, compliance decreases (see Fig. 17.17B ). Because of the decrease in arterial compliance with increased Pa, pulse pressure increases when Pa is elevated. Effect of Arterial Compliance on Myocardial Energy Consumption The increased cardiac energy requirement imposed by a rigid arterial system is illustrated in Fig. 17.18 . In the data depicted in


Physiology_Levy

Physiology_Levy. Effect of Arterial Compliance on Myocardial Energy Consumption The increased cardiac energy requirement imposed by a rigid arterial system is illustrated in Fig. 17.18 . In the data depicted in Fig. 17.18 , the cardiac output from the left ventricle either was allowed to flow through the natural route (the aorta) or was directed through a stiff plastic tube to the peripheral arteries. In this experiment, the TPR values were virtually identical, regardless of which pathway •Fig. 17.16 Foragivenvolumeincrement(V2− V1),reducedarterialcompliance(complianceB[LowCa]< complianceA[HighCa])resultsinincreasedpulsepressure,whereby(P4− P1)> (P3− P2).Pa,meanarterialpressure.


Physiology_Levy

Physiology_Levy. •Fig. 17.17 Comparisonoftheeffectsofagivenchangeinperipheralresistanceonpulsepressure(P)whenthepressure-volumecurveforthearterialsystemiseitherrectilinear(A) orcurvilinear(B). Theincrementinarterialvolumeisthesameforbothconditions;thatis,(V4−V3)=(V2−V1).PressureABVolumeP1V1V2V3V4P3P6P4P2–P5–PressureP1V1V2V3V4P3P6P4P2–P5– •Fig. 17.18 Therelationshipbetweenmyocardialoxygencon-sumption(1mL/100g/beat)andstrokevolume(inmilliliters)inananesthetizeddogwhosecardiacoutputcouldbepumpedbytheleftventricleeitherthroughtheaortaorthroughastiffplastictubetotheperipheralarteries.(ModifiedfromKellyRP,TuninR,KassDA.Circ Res. 1992;71:490.)Plastic tubing Native aorta Stroke volume (mL) 5 0 0.05 O 2 consumption (mL) O2/100 g/beat)0.1 10 15 was selected. The results showed that for any given stroke volume, myocardial oxygen consumption was substantially greater when the blood was diverted through the plastic tubing than when it flowed through the aorta. The increased oxygen consumption indicates that the


Physiology_Levy

Physiology_Levy. oxygen consumption was substantially greater when the blood was diverted through the plastic tubing than when it flowed through the aorta. The increased oxygen consumption indicates that the left ventricle has to expend significantly more energy to pump blood through a less compliant conduit than through a more compliant conduit.


Physiology_Levy

Physiology_Levy. Arterialpulsepressureprovidesvaluableinformationaboutaperson’sstrokevolume,providedthatarterialcomplianceisessentiallynormal.Patientswhohaveseverecongestiveheartfailureorwhohavesufferedaseverehemorrhagearelikelytohaveaverylowarterialpulsepressurebecausetheirstrokevolumesareabnormallysmall.Conversely,individualswithlargestrokevolumes,asinaorticvalveregurgitation,arelikelytohaveanincreasedarterialpulsepressure.Similarly,well-trainedathletesatresttendtohavelargestrokevolumesbecausetheirheartratesareusuallylow.Theprolongedventricularfillingtimesintheseindividualsinducetheventriclestopumpalargestrokevolume,andhencetheirpulsepressureislarge. The radial stretch of the ascending aorta brought about by left ventricular ejection initiates a pressure wave that is propagated down the aorta and its branches. The pressure wave travels much faster (≈4 to 12 m/second) than the blood itself does. This pressure wave is the “pulse” that can be detected through palpation of a peripheral artery.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Most commonly, blood pressure is estimated indirectly by means of a sphygmomanometer. In hospital intensive care units, needles or catheters may be introduced into the peripheral arteries of patients to measure arterial blood pressure directly by means of strain gauges. When blood pressure readings are taken from the arm, systolic pressure may be estimated by palpation of the radial artery at the wrist (palpatory method). While pressure in the cuff exceeds the systolic level, no pulse is perceived. As pressure falls just below the systolic level ( Fig. 17.20A ), a spurt of blood passes through the brachial artery under the cuff during the peak of systole, and a slight pulse is felt at the wrist.


Physiology_Levy

Physiology_Levy. Fig. 17.20A ), a spurt of blood passes through the brachial artery under the cuff during the peak of systole, and a slight pulse is felt at the wrist. The auscultatory method is a more sensitive and therefore more precise technique for measuring systolic pressure, and it also enables diastolic pressure to be estimated. The practitioner listens with a stethoscope applied to the skin of the antecubital space over the brachial artery. While the pressure in the cuff exceeds systolic pressure, the brachial artery is occluded, and no sounds are heard (see Fig. 17.20B ). When the inflation pressure falls just below the systolic level (120 mm Hg in


Physiology_Levy

Physiology_Levy. Fig. 17.20A ), a small spurt of blood escapes the occluding pressure of the cuff, and slight tapping sounds (called Korotkoff sounds) are heard with each heartbeat. The pressure at which the first sound is detected •Fig. 17.19 Pulse Pressure Curves Recorded From Various Sites in the Arterial Trees of Humans at Different Ages. Inthe24-yearold,thearterialpulsedisplaysstrikingchangesinthepulsepressureamplitudeandcontourasitpassesdownthearterialtree.Thepulsepressurewaveinthe68-year-oldshowslittleamplificationandisrelativelyunchangedasthepulsetravelsbecausethereislesswavereflection.(ReproducedbypermissionofHodderEducationfromNicholsWW,O’RourkeM,eds.McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. 5thed.London:Arnold;2005.) represents systolic pressure. It usually corresponds closely to the directly measured systolic pressure. As the inflation pressure of the cuff continues to fall, more blood escapes under the cuff per beat and the sounds become louder.


Physiology_Levy

Physiology_Levy. corresponds closely to the directly measured systolic pressure. As the inflation pressure of the cuff continues to fall, more blood escapes under the cuff per beat and the sounds become louder. When the inflation pressure approaches the diastolic level, the Korotkoff sounds become muffled. When the inflation pressure falls just below the diastolic level (80 mm Hg in


Physiology_Levy

Physiology_Levy. Fig. 17.20A ), the sounds disappear; the pressure reading at this point indicates diastolic pressure. The origin of the Korotkoff sounds is related to the discontinuous spurts of blood that pass under the cuff and meet a static column of blood beyond the cuff; the impact and turbulence generate audible vibrations. Once the inflation pressure is less than diastolic pressure, flow is continuous in the brachial artery, and sounds are no longer heard (see Fig. 17.20C The Venous System Veins are elements of the circulatory system that return blood to the heart from tissues. Moreover, veins constitute a very large reservoir that contains up to 70% of the blood in the circulation. The reservoir function of veins makes them able to adjust the volume of blood returning to the heart,


Physiology_Levy

Physiology_Levy. Theankle-brachialindex(ABI)istheratioofsystolicbloodpressuresattheankle(dorsalispedisartery)tothatinthebrachialartery.TheABI,whichisobtainedbysimplemeasurements,isanindicatorofpossibleperipheralarterydisease.TheABIhasalsobeenproposedasapredictorofriskforcardiovascularandcerebrovasculardisease.PeoplewithanormalABIratioof1.1to1.4havealowerincidenceofeithercoronaryorcerebrovasculareventsthandothosewitharatioof0.9orlower.Inaddition,astherateofABIincreaseswithtime,theincidencesofcardiovascularmorbidityandmortalityalsoincrease. or preload, so that the needs of the body can be matched when cardiac output is altered (see Chapter 19). This high capacitance is an important property of veins.


Physiology_Levy

Physiology_Levy. or preload, so that the needs of the body can be matched when cardiac output is altered (see Chapter 19). This high capacitance is an important property of veins. The hydrostatic pressure in postcapillary venules is approximately 20 mm Hg, and it decreases to approximately 0 mm Hg in the thoracic venae cavae and right atrium. Hydrostatic pressure in the thoracic venae cavae and right atrium is also termed central venous pressure. Veins are very distensible and have very low resistance to blood flow. Such low resistance allows movement of blood from Consider that the arterial blood pressure is being measured in a patient whose blood pressure is 120/80 mm Hg. The pressure (represented by the oblique line) in a cuff around the patient’s arm is allowed to fall from greater than 120 mm Hg (point B) to below 80 mm Hg (point C) in about 6 seconds.


Physiology_Levy

Physiology_Levy. When the cuff pressure exceeds the systolic arterial pressure (120 mm Hg), no blood progresses through the arterial segment under the cuff, and no sounds can be detected by a stethoscope bell placed on the arm distal to the cuff. When the cuff pressure falls below the diastolic arterial pressure, arterial flow past the region of the cuff is continuous, and no sounds are audible. When the cuff pressure is between 120 and 80 mm Hg, spurts of blood traverse the artery segment under the cuff with each heartbeat, and the Korotkoff sounds are heard through the stethoscope. •Fig. 17.20 A toC, Measurementofarterialbloodpressurewithasphygmomanometer. peripheral veins to the heart with only small reductions in central venous pressure. Moreover, veins control filtration and absorption by adjusting postcapillary resistance (see the section “ ”) and assist in the cardiovascular adjustments that accompany changes in body position.


Physiology_Levy

Physiology_Levy. The ability of veins to participate in these various functions depends on their distensibility, or compliance. Venous compliance varies with the position in the body in such a way that veins in the lower limb are less compliant than those at or above the level of the heart. Veins in the lower limbs are also thicker than those in the brain or upper limbs. The compliance of veins, like that of arteries, decreases with age, and the vascular thickening that occurs is accompanied by a reduction in elastin and an increase in collagen content. Variations in venous return are achieved by adjustments in venomotor tone, respiratory activity (see Chapter 19), and orthostatic stress or gravity.


Physiology_Levy

Physiology_Levy. Variations in venous return are achieved by adjustments in venomotor tone, respiratory activity (see Chapter 19), and orthostatic stress or gravity. Gravitational forces influence the amount of blood in the venous system and therefore may profoundly affect cardiac output. For example, soldiers standing at attention for a long time may faint because gravity causes blood to pool in the dependent blood vessels, which reduces cardiac output. Warm ambient temperatures interfere with the compensatory vasomotor reactions, and the absence of muscular activity exaggerates these effects. Gravitational effects are amplified in airplane pilots during pullout from dives. The centrifugal force in the footward direction may be several times greater than the force of gravity. Pilots characteristically black out momentarily during the pullout maneuver as blood is drained from the cephalic regions and pooled in the lower parts of the body.


Physiology_Levy

Physiology_Levy. Some explanations have been advanced to explain the gravitationally induced reduction in cardiac output, but they are inaccurate. For example, it has been argued that when an individual is standing, the force of gravity impedes venous return to the heart from the dependent regions of the body. This explanation is incomplete because it does not account for the gravitational counterforce on the arterial side of the same vascular circuit, and this counterforce facilitates venous return. Moreover, it does not account for the effect of gravity in causing venous pooling. When a person is standing upright, gravity causes blood to accumulate in the lower extremities and distend both the arteries and veins. Because venous compliance is so much greater than arterial compliance, this distention occurs more on the venous side than on the arterial side of the circuit.


Physiology_Levy

Physiology_Levy. The hemodynamic effects of such venous distention (venous pooling) resemble those caused by the hemorrhage of an equivalent volume of blood from the body. When an adult shifts from a supine position to a relaxed standing position, 300 to 800 mL of blood pools in the legs. This pooling may reduce cardiac output by approximately 2 L/min. The compensatory adjustments made to assume a standing position are similar to the adjustments to blood loss (see also ): There are reflex increases in heart rate and cardiac contractility. In addition, both arterioles and veins constrict; the arterioles are affected to a greater extent than are the veins. When a recumbent person stands but remains at rest, the pressure in the veins rises in the dependent regions of the body (


Physiology_Levy

Physiology_Levy. When a recumbent person stands but remains at rest, the pressure in the veins rises in the dependent regions of the body ( Fig. 17.21 ). The Pv in the legs increases gradually and does not reach an equilibrium value until almost 1 minute after the person begins standing. The slowness of this rise in Pv is attributable to the venous valves, which allow flow only toward the heart. When a person stands, the valves prevent blood in the veins from falling toward the feet. Hence, the column of venous blood is supported at numerous levels by these valves. Because of these valves, the venous column can be thought of as consisting of many discontinuous segments. However, blood continues to enter the column from many venules and small tributary veins, and the pressure continues to rise. As soon as the pressure in one segment exceeds that in the segment just above it, the intervening valve is forced open. Ultimately, all the valves are open, and the column is continuous.


Physiology_Levy

Physiology_Levy. •Fig. 17.21 Meanpressures(±95%confidenceintervals)inthefootveinsofhumansubjectsduringquietstanding,duringwalking,andduringrunning.(FromStickC,etal.J Appl Physiol. 1992;72:2063.)100 80 60 40 20 0 Venous pressure (mm Hg) Walking (3 km/hr) Walking (6 km/hr) Running (10 km/hr) Standing Someofthedrugsusedtotreatchronichypertensioninterferewiththereflexadaptationtostanding.Similarly,astronautsexposedtoweightlessnesslosetheiradaptationstogravityafterafewdaysinspace,andtheyexperiencepronounceddifficultieswhentheyfirstreturntoearth.Whensuchastronautsandotherindividualswithimpairedreflexadaptationsstand,theirbloodpressuremaydropsubstantially.Thisresponseiscalledorthostatic hypotension, whichmaycauselightheadednessorfainting.


Physiology_Levy

Physiology_Levy. Precise measurement reveals that the final level of Pv in the feet during quiet standing is only slightly greater than that in a static column of blood extending from the right atrium to the feet. This finding indicates that the pressure drop caused by blood flow from the foot veins to the right atrium is very small. Because of this very low resistance, all the veins can be viewed as having a common venous compliance in the model of the circulatory system illustrated in . When an individual who has been standing quietly begins to walk, Pv in the legs decreases appreciably (see


Physiology_Levy

Physiology_Levy. Fig. 17.21 ). Because of the intermittent venous compression exerted by the contracting leg muscles, and because of the operation of the venous valves, blood is forced from the veins toward the heart. Hence, muscular contraction lowers the mean Pv in the legs and serves as an auxiliary pump. Furthermore, muscular contraction prevents venous pooling and lowers capillary hydrostatic pressure. In this way, muscular contraction reduces the tendency for edematous fluid to collect in the feet during standing.


Physiology_Levy

Physiology_Levy. The circulatory system supplies the tissues with blood in amounts that meet the body’s requirements for O2 and nutrients. The capillaries, whose walls consist of a single layer of endothelial cells, allow rapid exchange of gases, water, and solutes with interstitial fluid. The muscular arterioles, which are the major resistance vessels, regulate regional blood flow to the capillary beds. Venules and veins serve primarily as collecting channels and storage vessels. The lymphatic system is composed of lymphatic vessels, nodes, and lymphoid tissue. This system collects the fluid and proteins that have escaped from blood and transports them back into the veins for recirculation in blood. In this section, the network of the smallest blood vessels of the body, as well as the lymphatic vessels, are examined in detail.


Physiology_Levy

Physiology_Levy. The microcirculation is defined as the circulation of blood through the smallest vessels of the body: arterioles, capillaries, and venules. Arterioles (5 to 100 µm in diameter) have a thick smooth muscle layer, a thin adventitial layer, and an endothelial lining (see Fig. 15.2 ). Arterioles give rise directly to capillaries (5 to 10 µm in diameter) or, in some tissues, to metarterioles (10 to 20 µm in diameter), which then give rise to capillaries ( Fig. 17.22 ). Metarterioles can bypass the capillary bed and connect to venules, or they can connect directly to the capillary bed. Arterioles that give rise directly to capillaries regulate flow through these capillaries by constriction or dilation. The capillaries form an interconnecting network of tubes with an average length of 0.5 to 1 mm. Functional Properties of Capillaries


Physiology_Levy

Physiology_Levy. Functional Properties of Capillaries In metabolically active organs, such as the heart, skeletal muscle, and glands, capillary density is high. In less active tissues, such as subcutaneous tissue or cartilage, capillary density is low. Capillary diameter also varies. Some capillaries have diameters smaller than those of erythrocytes. Passage through these tiny vessels requires the erythrocytes to become temporarily deformed. Fortunately, normal erythrocytes are quite flexible. Blood flow in capillaries depends chiefly on the contractile state of arterioles. The average velocity of blood flow •Fig. 17.22 Composite Schematic Illustration of the Microcirculation. Thecircular structures onthearterioleandvenulerepresentsmoothmusclefibers,andthebranching solid lines representsympatheticnervefibers.Thearrows indicatethedirectionofbloodflow.AV,arteriovenous.


Physiology_Levy

Physiology_Levy. in capillaries is approximately 1 mm/second; however, it can vary from zero to several millimeters per second in the same vessel within a brief period. These changes in capillary blood flow may be random or rhythmic. The rhythmic oscillatory behavior of capillaries is caused by contraction and relaxation (vasomotion) of the precapillary vessels (i.e., the arterioles and small arteries).


Physiology_Levy

Physiology_Levy. Vasomotion is an intrinsic contractile behavior of vascular smooth muscle and is independent of external input. Changes in transmural pressure (intravascular pressure minus extravascular pressure) also influence the contractile state of precapillary vessels. An increase in transmural pressure, caused either by an increase in Pv or by dilation of arterioles, results in contraction of the terminal arterioles. A decrease in transmural pressure causes precapillary vessel relaxation. Humoral and possibly neural factors also affect vasomotion. For example, when increased transmural pressure causes the precapillary vessels to contract, the contractile response can be overridden and vasomotion abolished. This effect is accomplished by metabolic (humoral) factors when the O2 supply becomes too low for the requirements of parenchymal tissue, as occurs in skeletal muscle during exercise.


Physiology_Levy

Physiology_Levy. Although a reduction in transmural pressure relaxes the terminal arterioles, blood flow through the capillaries cannot increase if the reduction in intravascular pressure is caused by severe constriction of the upstream microvessels. Large arterioles and metarterioles also exhibit vasomotion. However, their contraction usually does not completely occlude the lumen of the vessel and arrest blood flow, whereas contraction of the terminal arterioles may arrest blood flow. Thus the flow rate in capillaries may be altered by contraction and relaxation of small arteries, arterioles, and metarterioles. Blood flow through the capillaries has been called nutritional flow because it provides for exchange of gases and solutes between blood and tissue. Conversely, blood flow that bypasses the capillaries as it passes from the arterial to the venous side of the circulation via metarterioles has been termed nonnutritional, or shunt, flow (see


Physiology_Levy

Physiology_Levy. Fig. 17.22 ). In some areas of the body (e.g., fingertips, ears), true AV shunts exist (see Fig. 17.37 ). However, in many tissues, such as muscle, anatomical shunts are lacking. Even in the absence of these shunts, nonnutritional flow can occur. In tissues with metarterioles, nonnutritional flow may be continuous from arteriole to venule during low metabolic activity, when many precapillary vessels are closed. When metabolic activity increases in these tissues, more precapillary vessels open to allow capillary perfusion. True capillaries lack smooth muscle and are therefore incapable of active constriction. Nevertheless, the endothelial cells that form the capillary wall contain actin and myosin, and they can alter their shape in response to certain chemical stimuli. Because of its narrow lumen (i.e., small radius), a thin-walled capillary can withstand high internal pressures without bursting. This property can be explained in terms of the law of Pierre-Simon Laplace:


Physiology_Levy

Physiology_Levy. Equation 17.16 T = tension in the vessel wall r = radius of the vessel Laplace’s equation applies to very thin-walled vessels, such as capillaries. Wall tension opposes the distending force (ΔPr) that tends to pull apart a theoretical longitudinal slit in the vessel (


Physiology_Levy

Physiology_Levy. Fig. 17.23 ). Transmural pressure in a blood vessel in vivo is essentially equal to intraluminal pressure because extravascular pressure is generally negligible. To calculate wall tension, pressure in mm Hg is converted to dynes per square centimeter according to the equation P = hρg, where h is the height of an Hg column in centimeters, ρ is the density of Hg in g/cm3, and g is gravitational acceleration in cm/s2. For a capillary with a pressure of 25mmHg and a radius of 5 × 10−4 cm, the pressure (2.5 cm Hg × 13.6 g/cm3 × 980 cm/sec2) is 3.33 × 104 •Fig. 17.23 Diagram of a Small Blood Vessel to Illustrate the Law of Laplace. T=Pr,whereP=intraluminalpressure,r=radiusofthevessel,andT=walltensionastheforceperunitlengthtangentialtothevesselwall.Walltensionpreventsrupturealongatheoreticallongitudinalslitinthevessel.


Physiology_Levy

Physiology_Levy. dyne/cm2. Wall tension is then 16.7 dyne/cm. For an aorta with a pressure of 100 mm Hg and a radius of 1.5 cm, wall tension is 2 × 105 dyne/cm. Thus at the pressures normally found in the aorta and capillaries, the wall tension of the aorta is approximately 12,000 times greater than that of the capillaries. In a person standing quietly, capillary pressure in the feet may reach 100 mm Hg. Even under such conditions, capillary wall tension increases to a value that is still only one three-thousandth of the wall tension in the aorta at the same internal pressure.


Physiology_Levy

Physiology_Levy. The diameter of the resistance vessels (arterioles) is determined from the balance between the contractile force of the vascular smooth muscle and the distending force produced by intraluminal pressure. The greater the contractile activity of the vascular smooth muscle of an arteriole, the smaller its diameter. In small arterioles, contraction can continue to the point at which the vessel is completely occluded. Occlusion is caused by infolding of the endothelium and by trapping of blood cells in the vessel.


Physiology_Levy

Physiology_Levy. With a progressive reduction in intravascular pressure, vessel diameter decreases (as does vessel wall tension, according to the law of Laplace) and blood flow eventually ceases, although pressure within the arteriole is still greater than tissue pressure. The pressure that causes flow to cease has been called the critical closing pressure, and its mechanism is still unclear. The critical closing pressure is low when vasomotor activity is reduced by inhibition of sympathetic nerve activity in the vessel and is increased when vasomotor tone is enhanced by activation of the vascular sympathetic nerve fibers.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Vasoactive Role of the Capillary Endothelium The endothelium is an important source of substances that cause contraction or relaxation of vascular smooth muscle. One of these substances is prostacyclin, or prostaglandin I2 (PGI2). PGI2 can relax vascular smooth muscle via an increase in cyclic adenosine monophosphate (cAMP; Fig. 17.24 ). PGI2 is formed in the endothelium from muscle; its action is not endothelium mediated. Vasodilator agents such as adenosine, H+, CO2, and K+ may be released from parenchymal tissue and act locally on resistance vessels (see Fig. 17.24 Lumen Endothelium Interstitial space Relaxation Basement membrane ATP ADP AMP Adenosine Parenchymal tissue cAMP RelaxationcGMP NO NP ACh GCyc L-arg. Vascular smooth muscle Cyc OxPGI2Syn PGI2 AA H+, CO2, K+


Physiology_Levy

Physiology_Levy. arachidonic acid, and the process is catalyzed by PGI2 synthase. The mechanism that triggers synthesis of PGI2 is not known. However, PGI2 may be released by an increase in shear stress caused by accelerated blood flow. The primary function of PGI2 is to inhibit platelet adherence to the endothelium and platelet aggregation and thus prevent intravascular clot formation. PGI2 also causes relaxation of vascular smooth muscle. Of far greater importance in endothelium-mediated vascular dilation is the formation and release of nitric oxide (NO), a component of endothelium-derived relaxing factor (see


Physiology_Levy

Physiology_Levy. Of far greater importance in endothelium-mediated vascular dilation is the formation and release of nitric oxide (NO), a component of endothelium-derived relaxing factor (see Fig. 17.24 ). When endothelial cells are stimulated by acetylcholine or other vasodilator agents (e.g., adenosine triphosphate [ATP], bradykinin, serotonin, substance P, histamine), NO is released. These agents do not cause vasodilation in blood vessels lacking the endothelium. NO (synthesized from L-arginine) activates guanylyl cyclase in vascular smooth muscle to increase the concentration of cyclic guanosine monophosphate (cGMP), which produces relaxation by decreasing myofilament sensitivity to [Ca++]. Release of NO can be stimulated by the shear stress of blood flow on the endothelium. The drug nitroprusside also increases cGMP by acting directly on vascular smooth


Physiology_Levy

Physiology_Levy. Acetylcholine also stimulates the release of an endothelium-dependent hyperpolarizing factor that underlies the relaxation of adjacent smooth muscle. Although arachidonic acid metabolites have been suggested, the factor remains unknown. Moreover, how the factor reaches vascular smooth muscle (diffusion through the extracellular space or passage via myoepithelial junctions) is unclear. Nevertheless, there are diverse ways by which endothelial cells communicate with vascular smooth muscle. The endothelium can also synthesize endothelin, a potent vasoconstrictor peptide. Endothelin affects vascular tone and blood pressure and may be involved in pathological states, including atherosclerosis, pulmonary hypertension, congestive heart failure, and renal failure. Passive Role of the Capillary Endothelium


Physiology_Levy

Physiology_Levy. Passive Role of the Capillary Endothelium Solvent and solute move across the capillary endothelial wall by three processes: diffusion, filtration, and pinocytosis. Diffusion is the most important process for transcapillary exchange, and pinocytosis is the least important. Diffusion. Under normal conditions, only approximately 0.06 mL of water per minute moves across the capillary wall per 100 g of tissue as a result of filtration. In contrast, 300 mL of water per minute per 100 g of tissue moves across the capillary wall by diffusion. Thus diffusion is the key factor in providing exchange of gases, substrates, and waste products between capillaries and tissue cells. The process of diffusion is described by Fick’s law (see also Equation 17.17 J = quantity of a substance moved per unit time A = cross-sectional area of the diffusion pathway


Physiology_Levy

Physiology_Levy. ΔC = concentration gradient of the solute •Fig. 17.25 Flowand Diffusion-Limited Transport From Capillaries (Cap) to Tissue. A, Flow-limitedtransport.Thesmallestwater-solubleinerttracerparticles(blue dots) reachnegligibleconcentrationsafterpassingonlyashortdistancedownthecapillary.Largerparticles(brown dots) withsimilarpropertiestravelfartheralongthecapillarybeforereachinganinsignificantintracapillaryconcentration.Bothsubstancescrosstheinterstitialfluid(ISF)andreachtheparenchymaltissue(Cell).Becauseoftheirsize,moreofthesmallerparticlesaretakenupbythetissuecells.Thelargestparticles(red circles) cannotpenetratethecapillaryporesandhencedonotescapefromthecapillarylumenexceptbypinocytoticvesicletransport.Anincreaseinthevolumeofbloodfloworanincreaseincapillarydensityincreasestissuesupplyofthediffusiblesolutes.Notethatcapillarypermeabilityisgreateratthevenousendofthecapillary(alsointhevenule,notshown)becauseofthelargernumberofporesinthisregion.B,


Physiology_Levy

Physiology_Levy. For diffusion across a capillary wall, Fick’s law can also be expressed as Equation 17.18 P = capillary permeability by the substance Co = concentration of the substance outside the Ci = concentration of the substance inside the capillary The PS product provides a convenient expression of available capillary surface area because the intrinsic permeability of the capillary is rarely altered much under physiological conditions. However, in pathological conditions, as with a bee sting, capillary permeability may be altered.


Physiology_Levy

Physiology_Levy. In capillaries, diffusion of lipid-insoluble molecules is restricted to water-filled channels or pores. Movement of solute across the capillary endothelium is complex and involves corrections for attractions between solute and solvent molecules, interactions between solute molecules, pore configuration, and charge on the molecules in relation to charge on the endothelial cells. Such solute motion is not simply a matter of random thermal movement of molecules that seemingly run down a concentration gradient. For small molecules, such as water, NaCl, urea, and glucose, the capillary pores offer little restriction to diffusion (i.e., they have a low reflection coefficient; see the section “ ”). Diffusion of these substances is so rapid that the mean concentration gradient across the capillary endothelium is extremely small. The larger the lipid-insoluble molecules are, the more restricted is their diffusion through capillaries. Diffusion eventually becomes minimal when the molecular


Physiology_Levy

Physiology_Levy. endothelium is extremely small. The larger the lipid-insoluble molecules are, the more restricted is their diffusion through capillaries. Diffusion eventually becomes minimal when the molecular weight of the molecules exceeds approximately 60,000. With small molecules, the only limitation to net movement across the capillary wall is the rate at which blood flow transports the molecules to the capillary. Transport of these molecules is said to be flow limited.


Physiology_Levy

Physiology_Levy. With flow-limited small molecules, the concentration of the molecule in blood reaches equilibrium with its concentration in interstitial fluid at a location near the origin of the capillary from its parent arteriole. Its concentration falls to negligible levels near the arterial end of the capillary ( Fig. 17.25A ). If the flow is large, the small molecule can still be present at a distant locus downstream in the capillary. A somewhat larger molecule moves farther along the capillary before it reaches an insignificant concentration in blood. Furthermore, the number of still larger molecules that enter the arterial end of the capillary but cannot pass through the capillary pores equals the number that leaves the venous end of the capillary (see Fig. 17.25A


Physiology_Levy

Physiology_Levy. Fig. 17.25A With large molecules, diffusion across the capillaries becomes the limiting factor (diffusion limited); that is, the permeability of a capillary to a large solute molecule limits its transport across the capillary wall. Diffusion of small lipid-insoluble molecules is so rapid that diffusion limits blood-tissue exchange only when distances between capillaries and parenchymal cells are great (e.g., as in tissue edema or very low capillary density; see Fig. 17.25B Movement of lipid-soluble molecules across the capillary wall is not limited to capillary pores (only ≈0.02% of the capillary surface); it also occurs directly through the lipid membranes of the entire capillary endothelium. Consequently, lipid-soluble molecules move rapidly between blood and tissue. The degree of lipid solubility (oil-to-water partition coefficient) provides a good index of the ease of transfer of lipid molecules through the capillary endothelium.


Physiology_Levy

Physiology_Levy. Both O2 and CO2 are lipid soluble, and they readily pass through endothelial cells. Calculations based on (1) the diffusion coefficient for O2, (2) capillary density and diffusion distances, (3) blood flow, and (4) tissue O2 consumption indicate that the O2 supply of normal tissue at rest and during activity is not limited by diffusion or by the number of open capillaries.


Physiology_Levy

Physiology_Levy. Measurements of the partial pressure of O2 (PO2) and O2 saturation of blood in microvessels indicate that in many tissues, O2 saturation at the entrance of capillaries has decreased to approximately 80% as a result of diffusion of O2 from arterioles and small arteries. Moreover, CO2 loading and the resulting intravascular shifts in the oxyhemoglobin dissociation curve occur in the precapillary vessels. Hence, in addition to gas exchange at the capillaries, O2 and CO2 pass directly between adjacent arterioles and venules and possibly between arteries and veins (countercurrent exchange). The countercurrent exchange represents a diffusional shunting of gas away from the capillaries; this shunting may limit the supply of O2 to the tissue at low blood flow rates.


Physiology_Levy

Physiology_Levy. Capillary Filtration. The permeability of the capillary endothelial membrane is not uniform. For example, liver capillaries are quite permeable, and albumin escapes from them at a rate several times greater than that from the less permeable muscle capillaries. Furthermore, permeability is not uniform along the length of the capillary. The venous ends are more permeable than the arterial ends, and permeability is greatest in the venules, a property attributed to the greater number of pores in these regions. Where does filtration occur? Some water passes through the capillary endothelial cell membranes, but most flows through apertures (pores) in the endothelial walls of the capillaries (


Physiology_Levy

Physiology_Levy. Where does filtration occur? Some water passes through the capillary endothelial cell membranes, but most flows through apertures (pores) in the endothelial walls of the capillaries ( Figs. 17.26 17.27 ). The pores in skeletal and cardiac muscle capillaries have diameters of approximately 4 nm. There are clefts between adjacent endothelial cells in cardiac muscle, and the gap at the narrowest point is approximately 4 nm. The clefts (pores) are sparse and represent only approximately 0.02% of the capillary surface area. Pores are absent in cerebral capillaries, where the blood-brain barrier blocks the entry of many small molecules. In addition to clefts, some of the more porous capillaries (e.g., those in the kidneys and intestines) contain fenestrations 20 to 100 nm wide, whereas other capillaries (e.g., those in the liver) have a discontinuous endothelium (see


Physiology_Levy

Physiology_Levy. Fig. 17.27 ). Fenestrations and discontinuous endothelia allow the passage of molecules that are too large to pass through the intercellular clefts of the endothelium. The direction and magnitude of water movement across the capillary wall can be estimated as the algebraic sum of the hydrostatic and osmotic pressure that exists across the wall. An increase in intracapillary hydrostatic pressure favors movement of fluid from the vessel interior to the interstitial space, whereas an increase in the concentration CHAPTER 17 Properties of the Vasculature of osmotically active particles within vessels favors movement of fluid into the vessels from the interstitial space ( Fig. 17.28


Physiology_Levy

Physiology_Levy. CHAPTER 17 Properties of the Vasculature of osmotically active particles within vessels favors movement of fluid into the vessels from the interstitial space ( Fig. 17.28 Hydrostatic Forces. Hydrostatic pressure (blood pressure) within capillaries is not constant. Instead, it depends on arterial and venous pressure and on precapillary resistance (in the arterioles) and postcapillary resistance (in the venules and small veins). An increase in arterial or venous pressure elevates capillary hydrostatic pressure, whereas a reduction in arterial or venous pressure has the opposite effect. An increase in arteriolar resistance or closure of arteries reduces capillary pressure, whereas a greater resistance to flow in venules and veins increases capillary pressure.


Physiology_Levy

Physiology_Levy. Hydrostatic pressure is the principal force in capillary filtration. A given change in Pv produces a greater effect on capillary hydrostatic pressure than does the same change in Pa. Approximately 80% of an increase in Pv is transmitted back to the capillaries. Capillary hydrostatic pressure (Pc) varies from tissue to tissue. Average values, obtained from direct measurements in human skin, are approximately 32 mm Hg at the arterial end of capillaries and approximately 15 mm Hg at the venous end of capillaries at the level of the heart (see Fig. 17.28 ). As discussed previously, when a person stands, hydrostatic pressure increases in the legs and decreases in the head. Tissue pressure, or, more specifically, interstitial fluid pressure (Pi) outside the capillaries, opposes capillary filtration. The difference between Pc and Pi constitutes the driving force for filtration. Normally, Pi is close to zero, and so Pc essentially represents the hydrostatic driving force.


Physiology_Levy

Physiology_Levy. Osmotic Forces. The key factor that restrains fluid loss from capillaries is the osmotic pressure of plasma proteins (such as albumin). This osmotic pressure is called colloid osmotic pressure or oncotic pressure (πp). The total osmotic pressure of plasma is approximately 6000 mm Hg (reflecting the presence of electrolytes and other small molecules, as well as plasma proteins), whereas oncotic pressure is only approximately 25 mm Hg. This low level of oncotic pressure is an important factor in fluid exchange across the capillary because plasma proteins are essentially confined to the intravascular space, whereas electrolytes are virtually equal in concentration on both sides of the capillary endothelium. The relative permeability of solute by water influences the actual magnitude of osmotic pressure. The reflection coefficient (σ) is the relative impediment to the passage of a substance through the capillary membrane. The reflection coefficient of water is 0, and that of albumin (to


Physiology_Levy

Physiology_Levy. pressure. The reflection coefficient (σ) is the relative impediment to the passage of a substance through the capillary membrane. The reflection coefficient of water is 0, and that of albumin (to which the endothelium is essentially impermeable) is 1. Filterable solutes have reflection coefficients between 0 and 1. In addition, different tissues have different reflection coefficients for the same molecule. Hence, movement of a given solute across the endothelial wall varies with the tissue. The actual oncotic pressure of the plasma (πp) is defined by the following equation (see also


Physiology_Levy

Physiology_Levy. Equation 17.19 1 µm 0.5 µm 0.1 µm0.1 µm GJTJ CT Nu PC V BM * V A B C D •Fig. 17.26 A, Electronmicrographofacross-sectionofacapillaryinamouseventricle.Theluminaldiameterisapproximately4µm.Inthissection,thecapillarywallisformedbyasingleendothelialcell(Nu,endothelialnucleus).Thethinpericapillaryspaceisoccupiedbyapericyte(PC)andaconnectivetissue(CT)cell(“fibroblast”),whichformsafunctionalcomplex(arrow)withitself.V,plasmalemmalvesicles.B, DetailoftheendothelialcellinA showingplasmalemmalvesicles(V)attachedtotheendothelialcellsurface.Thesevesiclesareespeciallyprominentinvascularendotheliumandareinvolvedintransportofsubstancesacrossthebloodvesselwall.Notethecomplexalveolarvesicle(asterisk). BM,basementmembrane.C, Junctionalcomplexinacapillaryofamouseheart.“Tight”junctions(TJ)typicallyforminthesesmallbloodvesselsandappeartoconsistoffusionsbetweenapposedendothelialcellsurfacemembranes.D,


Physiology_Levy


Physiology_Levy

Physiology_Levy. CHAPTER 17 Properties of the Vasculature 365 Junction of two Discontinuousendothelial cells endothelium • Fig. 17.27 Illustration of an electron micrograph of a capillary in cross-section. With prolonged standing, particularly when associated with elevation of Pv in the legs (such as that caused by pregnancy and congestive heart failure), filtration across capillaries is greatly enhanced, exceeding the capacity of the lymphatic system to remove the filtrate from the interstitial space and thus leading to edema.


Physiology_Levy

Physiology_Levy. The concentration of plasma proteins may change in several pathological states and thus alter the osmotic force and movement of fluid across the capillary membrane. The plasma protein concentration is increased in conditions of dehydration (e.g., water deprivation, prolonged sweating, severe vomiting, diarrhea). In this condition, less water moves by osmotic force from the tissues to the vascular compartment, thereby decreasing the volume of the interstitial fluid. In contrast, the plasma protein concentration is reduced in some renal diseases because of its loss in urine, and edema may occur. When capillary injury is extensive, as in severe burns, intravascular fluid and plasma protein leak into the interstitial space in the damaged tissues. The protein that escapes from the vessel lumen increases the oncotic pressure of the interstitial fluid. This greater osmotic force outside the capillaries leads to additional fluid loss and possibly to severe dehydration.


Physiology_Levy

Physiology_Levy. Balance of Hydrostatic and Osmotic Forces. The pressure sure and the role of these forces in regulating fluid passage across the capillary endothelium were expounded by Frank Starling in 1896. This relationship constitutes Starling’s • Fig. 17.28 Schematic representation of the factors responsible for filtration and absorption across the capillary wall and the formation of lymph.


Physiology_Levy

Physiology_Levy. Albumin is the most important plasma protein that determines oncotic pressure. Its molecular weight is 69,000 D. Albumin exerts an osmotic force greater than can be accounted for solely on the basis of its concentration in plasma. Therefore, it cannot be replaced on a mole-bymole basis by inert substances of appropriate molecular size, such as dextran. This additional osmotic force becomes disproportionately great at high concentrations of albumin (as in plasma), and this force is weak to absent in dilute solutions of albumin (as in interstitial fluid). The reason for this activity of albumin is its negative charge at normal blood pH and the attraction and retention of cations (principally Na+) in the vascular compartment (Gibbs-Donnan effect). hypothesis. It can be expressed as follows:


Physiology_Levy

Physiology_Levy. hypothesis. It can be expressed as follows: Equation 17.20 k = filtration constant for the capillary membrane πi= interstitial fluid oncotic pressure Filtration occurs when the algebraic sum is positive; absorption occurs when it is negative. Traditionally, filtration was thought to occur at the arterial end of the capillary, and absorption was thought to occur at its venous end because of the gradient of hydrostatic pressure along the capillary. This scheme is true for an idealized capillary (see


Physiology_Levy

Physiology_Levy. Fig. 17.28 ). However, in well-perfused capillaries, arteriolar vasoconstriction can reduce Pc in such a way that absorption at the arteriolar end can occur transiently. With continued vasoconstriction, absorption diminishes with time because Pi increases. In some vascular beds (e.g., the renal glomerulus), hydrostatic pressure in the capillary is high enough to cause filtration along the entire length of the capillary. In other vascular beds (e.g., the intestinal mucosa), the hydrostatic and oncotic forces are such that absorption occurs along the whole capillary.


Physiology_Levy

Physiology_Levy. In the steady-state Pa, Pv, postcapillary resistance, hydrostatic and oncotic pressure of interstitial fluid, and oncotic pressure of plasma are relatively constant. Hence, in the normal state, filtration and absorption across the capillary wall are well balanced. However, a change in precapillary resistance influences fluid movement across the capillary wall. Vasoconstriction reduces net filtration, and vasodilation increases filtration.


Physiology_Levy

Physiology_Levy. Capillary Filtration Coefficient. The rate of fluid movement (Qf) across the capillary membrane depends not only on the algebraic sum of the hydrostatic and osmotic forces across the endothelium (ΔP) but also on the area (Am) of the capillary wall available for filtration, the distance (Δx) across the capillary wall, the viscosity (η) of the filtrate, and the filtration constant (k) of the membrane. These factors may be expressed as follows: Equation 17.21 This expression, which describes the flow of fluid through the membrane pores, is essentially Poiseuille’s law for flow through tubes. Because the thickness of the capillary wall and the viscosity of the filtrate are relatively constant, they can be included in the filtration constant k. If the area of the capillary membrane is not known, the rate of filtration can be expressed per unit weight of tissue. Hence, the equation can be simplified as


Physiology_Levy

Physiology_Levy. Equation 17.22 where kt is the capillary filtration coefficient for a given tissue and the units for Qf are milliliters per minute per 100 g of tissue. In any given tissue, the filtration coefficient per unit area of capillary surface, and hence capillary permeability, is not changed by various physiological conditions, such as arteriolar dilation and capillary distention, or by such adverse conditions as hypoxia, hypercapnia, or reduced pH. When capillaries are injured (as by toxins or severe burns), significant amounts of fluid and protein leak out of the capillaries into the interstitial space. This increase in capillary permeability is reflected by an increase in the filtration coefficient.


Physiology_Levy

Physiology_Levy. Because capillary permeability is constant under normal conditions, the filtration coefficient can be used to determine the relative number of open capillaries (i.e., the capillary surface area available for filtration in tissue). For example, the increased metabolic activity of contracting skeletal muscle relaxes the precapillary resistance vessels and hence opens more capillaries. This process, called capillary recruitment, increases the filtering surface area.


Physiology_Levy

Physiology_Levy. Disturbances in Hydrostatic-Osmotic Balance. Relatively small changes in Pa may have little effect on filtration. The change in pressure may be countered by adjustments in precapillary resistance vessels (autoregulation; see ) so that hydrostatic pressure remains constant in the open capillaries. However, a severe reduction in Pa usually evokes arteriolar constriction mediated by the sympathetic nervous system. This response may occur in hemorrhage, and it is often accompanied by a fall in Pv. These changes reduce capillary hydrostatic pressure. However, the lowering of blood pressure in hemorrhage causes a decrease in blood flow (and hence in O2 supply) to the tissue, with the result that vasodilator metabolites accumulate and relax the arterioles. Precapillary vessel relaxation also occurs because of the reduced transmural pressure (autoregulation; see ). Consequently, absorption predominates over filtration, and fluid moves from the interstitium into the capillary. These responses


Physiology_Levy

Physiology_Levy. because of the reduced transmural pressure (autoregulation; see ). Consequently, absorption predominates over filtration, and fluid moves from the interstitium into the capillary. These responses to hemorrhage constitute one of the compensatory mechanisms used by the body to restore blood volume (see


Physiology_Levy

Physiology_Levy. An increase in Pv alone, as occurs in the feet when a person stands up, would elevate capillary pressure and enhance filtration. However, the increase in transmural pressure closes precapillary vessels (myogenic mechanism; see ), and hence the capillary filtration coefficient actually decreases. This reduction in capillary surface available for filtration prevents large amounts of fluid from leaving the capillaries and entering the interstitial space.


Physiology_Levy

Physiology_Levy. In a healthy individual, the filtration coefficient (kt) for the whole body is approximately 0.006 mL/minute/100 g of tissue/mm Hg. For a 70-kg man, an elevation in Pv of 10 mm Hg for 10 minutes would increase filtration from capillaries by 420 mL. Edema does not usually occur because the fluid is returned to the vascular compartment by the lymphatic vessels. When edema develops, it usually appears in the dependent parts of the body, where the hydrostatic pressure is greatest, but its location and magnitude are also determined by the type of tissue. Loose tissues, such as the subcutaneous tissue around the eyes or in the scrotum, are more prone than firm tissues, as in a muscle, or encapsulated structures, as in a kidney, to collect larger quantities of interstitial fluid. Pinocytosis. Some transfer of substances across the capillary wall can occur in tiny pinocytotic vesicles. These vesicles (see


Physiology_Levy

Physiology_Levy. Pinocytosis. Some transfer of substances across the capillary wall can occur in tiny pinocytotic vesicles. These vesicles (see Figs. 17.26 17.27 ), formed by the pinching off of the endothelial cell membrane, can take up substances on one side of the capillary wall, move them across the cell by kinetic energy, and deposit their contents on the other side. This process is termed transcytosis. The amount of material transported in this way is very small in relation to that moved by diffusion. However, pinocytosis may be responsible for the movement of large (30-nm) lipid-insoluble molecules between blood and interstitial fluid. The number of pinocytotic vesicles in endothelium varies among tissues (amount in muscle > amount in lung > amount in brain), and the number increases from the arterial end to the venous end of the capillary.


Physiology_Levy

Physiology_Levy. The terminal vessels of the lymphatic system consist of a widely distributed, closed-end network of highly permeable lymphatic capillaries. These lymphatic capillaries resemble blood capillaries, with two important differences: tight junctions are not present between endothelial cells, and fine filaments anchor lymphatic vessels to the surrounding connective tissue. With muscular contraction, these fine strands pull on the lymphatic vessels to open spaces between the endothelial cells and enable the entrance of protein and large particles into the lymphatic vessels. The lymphatic capillaries drain into larger vessels that finally enter the right and left subclavian veins, where they connect with the respective internal jugular veins.


Physiology_Levy

Physiology_Levy. Only cartilage, bone, epithelia, and tissues of the central nervous system lack lymphatic vessels. These vessels return the plasma capillary filtrate to the circulation. This task is accomplished by means of tissue pressure, and it is facilitated by intermittent skeletal muscle activity, lymphatic vessel contractions, and an extensive system of one-way valves. In this regard, lymphatic vessels resemble veins, although the larger lymphatic vessels do have thinner walls than do the corresponding veins, and they contain only a small amount of elastic tissue and smooth muscle.


Physiology_Levy

Physiology_Levy. The volume of fluid transported through the lymphatic vessels in 24 hours is approximately equal to the body’s total plasma volume. The lymphatic vessels return all of the proteins filtered back to the blood; these proteins account for approximately one fourth to half of the circulating plasma proteins in the blood. The lymphatic vessels are the only means by which the protein that leaves the vascular compartment can be returned to blood. Net backward diffusion of protein into the capillaries cannot occur against the large protein concentration gradient. If the protein were not removed by the lymph vessels, it would accumulate in interstitial fluid and act as an oncotic force that draws fluid from the blood capillaries and produces edema. In addition to returning fluid and protein to the vascular bed, the lymphatic system filters the lymph at the lymph nodes and removes foreign particles such as bacteria. The


Physiology_Levy

Physiology_Levy. In addition to returning fluid and protein to the vascular bed, the lymphatic system filters the lymph at the lymph nodes and removes foreign particles such as bacteria. The CHAPTER 17 Properties of the Vasculature largest lymphatic vessel, the thoracic duct, not only drains the lower extremities but also returns the protein lost through the permeable liver capillaries. Moreover, the thoracic duct carries substances absorbed from the gastrointestinal tract. The principal substance is fat, in the form of chylomicrons.


Physiology_Levy

Physiology_Levy. Lymph flow varies considerably. The flow from resting skeletal muscle is almost nil, and it increases during exercise in proportion to the degree of muscular activity. It is increased by any mechanism that enhances the rate of blood capillary filtration; such mechanisms include increased capillary pressure or permeability and decreased plasma oncotic pressure. When the volume of interstitial fluid exceeds the drainage capacity of the lymphatic vessels, or when the lymphatic vessels become blocked, interstitial fluid accumulates and gives rise to clinical edema. Functional Anatomy of Coronary Vessels


Physiology_Levy

Physiology_Levy. Functional Anatomy of Coronary Vessels The right and left coronary arteries arise at the root of the aorta behind the right and left cusps of the aortic valve, respectively. These arteries provide the entire blood supply to the myocardium. The right coronary artery supplies mainly the right ventricle and atrium. The left coronary artery, which divides near its origin into the anterior descending and the circumflex branches, supplies mainly the left ventricle and atrium. There is some overlap between the regions supplied by the left and right arteries. In humans, the right coronary artery is dominant (supplying most of the myocardium) in approximately 50% of individuals. The left coronary artery is dominant in another 20%, and the flow delivered by each main artery is approximately equal in the remaining 30%. The epicardial distribution of the coronary arteries and veins is illustrated in Fig. 17.29


Physiology_Levy

Physiology_Levy. Coronary arterial blood passes through the capillary beds; most of it returns to the right atrium through the coronary sinus. Of the coronary arteries, epicardial arteries are largest (2 to 5 mm in diameter), large arterioles are medium in size (1.0 to 0.5 mm in diameter), and small arterioles are smallest (<0.1 mm in diameter). Some of the coronary venous blood reaches the right atrium via the anterior coronary veins. In addition, vascular communications directly link the myocardial vessels with the cardiac chambers; these communications are the arteriosinusoidal, arterioluminal, and thebesian vessels. The arteriosinusoidal channels consist of small arteries or arterioles that lose their arterial structure as they penetrate the chamber walls, where they divide into irregular, endothelium-lined sinuses. These sinuses anastomose with other sinuses and with capillaries, and they communicate with the cardiac chambers. The arterioluminal vessels are small arteries or arterioles that open


Physiology_Levy

Physiology_Levy. sinuses. These sinuses anastomose with other sinuses and with capillaries, and they communicate with the cardiac chambers. The arterioluminal vessels are small arteries or arterioles that open directly into the atria and ventricles. The thebesian vessels are small veins that connect capillary beds directly with the cardiac chambers and also communicate with the cardiac veins. All the minute vessels of the myocardium communicate in the form of an extensive


Physiology_Levy

Physiology_Levy. Posterior descending branch of right coronary artery • Fig. 17.29 Illustrations of the anterior and posterior surfaces of the heart, depicting the location and distribution of the principal coronary vessels. plexus of subendocardial vessels. However, the myocardium does not receive significant nutritional blood flow directly from the cardiac chambers. The primary factor responsible for perfusion of the myocardium is aortic pressure. Changes in aortic pressure generally evoke parallel directional changes in coronary blood flow. This is caused in part by changes in coronary perfusion pressure. However, the major factor in the regulation of coronary blood flow is a change in arteriolar resistance engendered by changes in the metabolic activity of the heart. When the metabolic activity of the heart increases, coronary resistance decreases; when cardiac metabolism decreases, coronary resistance increases (see


Physiology_Levy

Physiology_Levy. Blood flow in the heart is autoregulated. If a cannulated coronary artery is perfused by blood from a pressure-controlled reservoir, perfusion pressure can be altered without a change in aortic pressure and cardiac work. The relationship between initial and steady-state blood flow is shown in the experiment depicted in Fig. 17.30 . This is an example of autoregulation of blood flow, which is mediated by a myogenic mechanism in large and small arterioles ( ). The metabolic activity of cardiac muscle in small arterioles and the endothelium modulate autoregulation. The coronary circulation adjusts serial resistances within the microvasculature thereby adapting blood flow to O2 requirements. Blood pressure is kept within narrow 0.2 0.4 0.6 0.8 1 Time (sec) •Fig. 17.30 Pressure-Flow Relationships in the Coronary Vascular


Physiology_Levy

Physiology_Levy. Bed. Asaorticpressurewasheldconstant,thecardiacoutput,heart rate,andcoronaryarteryperfusionpressurewereabruptlyincreased ordecreasedfromthecontrollevel,whichisindicatedbythepointatwhichthetwolinescross.Thesolid circles representtheflowsthat resultedimmediatelyafterthechangeinperfusionpressure;theopen circles representthesteady-stateflowsatthenewpressures.Thereisatendencyforflowtoreturntowardthecontrollevel(autoregulationofbloodflow),andthisismostprominentovertheintermediatepressurerange(≈60to180mmHg).(FromBerneRM,RubioR.Coronarycirculation.InPageE,ed.Handbook of Physiology: Section 2: The Cardiovascular System: The Heart. Vol1.Bethesda,MD:AmericanPhysiologicalSociety;1979.) limits by baroreceptor reflex mechanisms. Hence, changes in coronary blood flow are caused mainly by changes in the diameter of coronary resistance vessels in response to the metabolic demands of the heart.


Physiology_Levy

Physiology_Levy. •Fig. 17.31 Comparison of Phasic Coronary Blood Flow in the Left and Right Coronary Arteries. Extravascularcompressionissogreatduringearlyventricularsystolethatthedirectionofbloodflowinthelargecoronaryarteriessupplyingtheleftventricleisbrieflyreversed.Maximalinflowintheleftcoronaryarteryoccursinearlydiastole,whentheventricleshaverelaxedandextravascularcompressionofthecoronaryvesselsisvirtuallyabsent.Afteraninitialreversalinearlysystole,bloodflowintheleftcoronaryarteryfollowstheaorticpressureuntilearlydiastole,whenitrisesabruptlyandthendeclinesslowlyasaorticpressurefallsduringtheremainderofdiastole. In addition to providing the pressure to move blood through the coronary vessels, the heart also affects its blood supply by the squeezing effect (extravascular compression) of the contracting myocardium on its own blood vessels. The patterns of flow in the left and right coronary arteries are shown in


Physiology_Levy

Physiology_Levy. Fig. 17.31 . In the left ventricle, coronary perfusion pressure is the difference between aortic diastolic pressure and left ventricular end-diastolic pressure. Left ventricular myocardial pressure (pressure within the wall of the left ventricle) is highest near the endocardium and lowest near the epicardium. This pressure gradient does not normally impair endocardial blood flow because the greater blood flow to the endocardium during diastole compensates for the greater blood flow to the epicardium during systole. Measurements of coronary blood flow indicate that the epicardial and endocardial halves of the left ventricle receive approximately equal blood flow under normal conditions. Because extravascular compression is greatest at the endocardial surface of the ventricle, the equality of epicardial and endocardial blood flow indicates that the tone of the endocardial resistance vessels is less than that of the epicardial vessels.


Physiology_Levy

Physiology_Levy. Theminimalextravascularresistanceandabsenceofleftventricularworkduringdiastolecanbeusedtoimprovemyocardialperfusioninpatientswithadamagedmyocardiumandlowbloodpressure.Inamethodcalledcounterpulsation, aninflatableballoonisinsertedintothethoracicaortathroughafemoralartery.Theballoonisinflatedduringeachventriculardiastoleanddeflatedduringeachsystole.Thisprocedureenhancescoronarybloodflowduringdiastolebyraisingdiastolicpressureatatimewhencoronaryextravascularresistanceislowest.Furthermore,itreducescardiacenergyrequirementsbyloweringaorticpressure(afterload)duringventricularejection. The flow pattern in the right coronary artery is similar to that in the left coronary artery (see


Physiology_Levy

Physiology_Levy. The flow pattern in the right coronary artery is similar to that in the left coronary artery (see Fig. 17.31 ). In contrast to the left ventricle, reversal of blood flow does not occur in the right ventricle in early systole because pressure in the thin right ventricle is lower during systole. Hence, systolic blood flow constitutes a much greater proportion of total coronary inflow than it does in the left coronary artery.


Physiology_Levy

Physiology_Levy. •Fig. 17.32 A, Unmaskingoftherestrictingeffectofventricularsystoleonmeancoronarybloodflowbyinductionofventricularfibrillationduringperfusionoftheleftcoronaryarteryatconstantpressure.Withtheonsetofventricularfibrillation,coronarybloodflowincreasesabruptlybecauseextravascularcompressionisremoved.Flowthengraduallyreturnstowardandoftenfallsbelowtheprefibrillationlevel.Thisincreaseincoronaryresistancethatoccursdespitetheremovalofextravascularcompressiondemonstratestheheart’sabilitytoadjustitsbloodflowtomeetitsenergyrequirements.B, EffectofcardiacsympatheticnervestimulationoncoronarybloodflowandonbloodO2tension(PO2)inthecoronarysinusinafibrillatingheartduringperfusionoftheleftcoronaryarteryatconstantpressure.(BerneRM.Unpublishedobservations.) The extent to which extravascular compression restricts coronary inflow can be readily observed when the heart is suddenly arrested in diastole or with the induction of ventricular fibrillation.


Physiology_Levy

Physiology_Levy. The extent to which extravascular compression restricts coronary inflow can be readily observed when the heart is suddenly arrested in diastole or with the induction of ventricular fibrillation. Fig. 17.32A depicts mean left coronary flow when the vessel was perfused with blood at a constant pressure from a reservoir. When ventricular fibrillation was electrically induced, blood flow increased immediately and substantially. A subsequent increase in coronary resistance over a period of many minutes reduced myocardial blood flow to below the level that existed before induction of ventricular fibrillation (see Fig. 17.32B , just before stellate ganglion stimulation).


Physiology_Levy

Physiology_Levy. Fig. 17.32B , just before stellate ganglion stimulation). When diastolic pressure in the coronary arteries is abnormally low (as in severe hypotension, partial coronary artery occlusion, or severe aortic stenosis), the ratio of endocardial to epicardial blood flow falls below a value of 1. This ratio indicates that blood flow to the endocardial regions is more severely impaired than that to the epicardial regions of the ventricle. There is also an increase in the gradient of myocardial lactic acid and myocardial adenosine concentrations from epicardium to endocardium. For this reason, the myocardial damage observed in atherosclerotic heart disease (e.g., after coronary occlusion) is greatest in the inner wall of the left ventricle.


Physiology_Levy

Physiology_Levy. Tachycardia and bradycardia have dual effects on coronary blood flow. A change in heart rate mainly alters diastole. In tachycardia, the proportion of time spent in systole, and consequently the period of restricted inflow, increases. However, this mechanical effect is overridden by the dilation of coronary resistance vessels associated with the increased metabolic activity of the more rapidly beating heart. With bradycardia, the opposite occurs: Coronary inflow is less restricted (more time spent in diastole), but so are the metabolic (O2) requirements of the myocardium.


Physiology_Levy

Physiology_Levy. Stimulation of cardiac sympathetic nerves markedly increases coronary blood flow. However, the increase in flow is associated with an increased heart rate and more forceful systole. The stronger contraction and the tachycardia tend to restrict coronary flow. The increase in myocardial metabolic activity, however, tends to dilate coronary resistance vessels. The increase in coronary blood flow evoked by cardiac sympathetic nerve stimulation reflects the sum of these factors. In perfused hearts in which the mechanical effect of extravascular compression is eliminated by cardiac arrest or by ventricular fibrillation, an initial coronary vasoconstriction of the coronary vessels is often observed. After this initial vasoconstriction, the metabolic effect evokes vasodilation (see Fig. 17.32B


Physiology_Levy

Physiology_Levy. Fig. 17.32B Furthermore, when β-adrenergic receptor blockade eliminates the positive chronotropic and inotropic effects, activation of the cardiac sympathetic nerves increases coronary resistance. These observations indicate that the direct action of the sympathetic nerve fibers on the coronary resistance vessels is vasoconstriction. Both α-adrenergic receptors (constrictors) and β2adrenergic receptors (dilators) are present on the coronary vessels. Coronary resistance vessels also participate in the baroreceptor and chemoreceptor reflexes, and the sympathetic constrictor tone of the coronary arterioles can be modulated by such reflexes. Nevertheless, coronary resistance is predominantly under local nonneural control.


Physiology_Levy

Physiology_Levy. Vagus nerve stimulation causes slight dilation of the coronary resistance vessels, and activation of the carotid and aortic chemoreceptors can cause a slight decrease in coronary resistance via the vagus nerves to the heart. Failure of strong vagal stimulation to increase coronary blood flow is not due to lack of muscarinic receptors on the coronary resistance vessels because intracoronary administration of acetylcholine elicits marked vasodilation. In the human heart, acetylcholine caused vasodilation when administered directly into the left anterior descending coronary artery of subjects with no evidence of coronary artery disease. However, acetylcholine caused vasoconstriction in the coronary artery of subjects whose endothelium had been damaged and rendered dysfunctional by atherosclerosis. A striking characteristic of the coronary circulation is the close relationship between the level of myocardial metabolic activity and the magnitude of coronary blood flow (Fig.


Physiology_Levy

Physiology_Levy. A striking characteristic of the coronary circulation is the close relationship between the level of myocardial metabolic activity and the magnitude of coronary blood flow (Fig. 17.33 ). This relationship is also found in a denervated heart and in a completely isolated heart, either in the beating state or in the fibrillating state. Ventricles can fibrillate for many hours when the coronary arteries are perfused with arterial blood from some external source. As already noted, a fibrillating heart uses less O2 than a pumping heart does, and blood flow to the myocardium is reduced accordingly.


Physiology_Levy

Physiology_Levy. The mechanisms that link the cardiac metabolic rate and coronary blood flow remain unsettled. However, it appears that a decrease in the ratio of O2 supply to O2 demand releases vasodilator substances from the myocardial cells into the interstitial fluid, where they relax the coronary resistance vessels. Decreases in arterial blood O2 content or in coronary blood flow and increases in metabolic rate all decrease the O2 supply/demand ratio ( Fig. 17.34 ). As a consequence, substances are released that dilate the arterioles and thereby adjust the O2 supply to the O2 demand. A decrease in O2 demand diminishes the release of vasodilators and enables greater expression of basal tone.


Physiology_Levy

Physiology_Levy. Numerous metabolites participate in the vasodilation that accompanies increased cardiac work. Accumulation of vasoactive metabolites can also account for the increase in blood flow that results from a brief period of ischemia (i.e., reactive hyperemia; see ). The duration of the enhanced coronary flow after release of the briefly occluded vessel is, within certain limits, proportional to the duration of the period of occlusion. Among the factors implicated in reactive hyperemia are ATP-sensitive potassium (KATP) channels, NO, CO2, H+, K+, hypoxia, H2O2, and adenosine.


Physiology_Levy

Physiology_Levy. Of these agents, the key factors appear to be adenosine, NO, opening of the KATP channels, and H2O2. The contributions of each of these agents and their interaction under basal conditions and during increased myocardial •Fig. 17.33 RelationshipbetweenmyocardialO2consumptionandcoronarybloodflowduringavarietyofinterventionsthatincreaseordecreasethemyocardialmetabolicrate.(FromBerneRM,RubioR:Coronarycirculation.InPageE,ed.Handbook of Physiology: Section 2: The Cardiovascular System: The Heart. Vol1.Bethesda,MD:AmericanPhysiologicalSociety;1979.)18 16 14 12 10 8 6 4 2 20 30 40 50 60 70 80 90 100 110 120 Coronary blood flow (mL/min/100 g) Myocardial oxygen consumption(mL/min/100 g) •Fig. 17.34 ImbalanceintheO2supply–O2demandratioalterscoronarybloodflowbytherateofreleaseofavasodilatormetabolitefromcardiomyocytes.Adecreaseintheratioelicitsanincreaseinvasodilatorrelease,whereasanincreaseintheratiohastheoppositeeffect.


Physiology_Levy

Physiology_Levy. 372 SECTION4Berne & Levy Physiology •Fig. 17.35 Schematic Representation of Factors That Increase (+) or Decrease (−) Coronary Vascular Resistance. Intravascularpressure(arterialbloodpressure)stretchesthevesselwall.KATPchannels,adenosinetriphosphate–sensitivepotassiumchannels;NO,nitricoxide;PCO2,partialpressureofcarbondioxide;PO2,partialpressureofoxygen.˜ Myocardial contractile activity Autonomic control Sympathetic nerves: °-Receptors ˛-Receptors Vagus nerves Oxygen supply Myogenic mechanism ˜ Metabolism ˝ Myocardial PO2 KATP channels H2O2 NO Adenosine – + +± + – – – Other metabolic factors PO2, PCO2, H+, K+ Systolic compression activity are complex. A reduction in oxidative metabolism in vascular smooth muscle reduces ATP synthesis, which in turn opens KATP channels and causes hyperpolarization. This change in potential reduces entry of Ca++ and relaxes coronary vascular smooth muscle to increase flow. A reduction in ATP also opens KATP channels in cardiac muscle and generates an


Physiology_Levy

Physiology_Levy. This change in potential reduces entry of Ca++ and relaxes coronary vascular smooth muscle to increase flow. A reduction in ATP also opens KATP channels in cardiac muscle and generates an outward current that reduces action potential duration and limits Ca++ entry during phase 2 of the action potential. This action may be protective during periods of imbalance between O2 supply and demand. In addition, as cardiac work increases, H2O2 production rises, which activates Kv1.5 channels and thereby causes hyperpolarization of muscle membrane and relaxation of vascular smooth muscle. Moreover, the release of NO and adenosine dilates the arterioles and thereby adjusts the O2 supply to the O2 demand. At low concentrations, adenosine appears to activate endothelial KATP channels and to enhance release of NO. Conversely, at higher concentrations, adenosine acts directly on vascular smooth muscle by activating KATP channels. Decreased O2 demand would sustain the ATP level, as well as reduce the


Physiology_Levy

Physiology_Levy. of NO. Conversely, at higher concentrations, adenosine acts directly on vascular smooth muscle by activating KATP channels. Decreased O2 demand would sustain the ATP level, as well as reduce the amount of vasodilator substances released, and allows greater expression of basal tone. If production of all these agents is inhibited, coronary blood flow is reduced, both at rest and during exercise. Furthermore, contractile dysfunction and signs of myocardial ischemia become evident.


Physiology_Levy

Physiology_Levy. According to the adenosine hypothesis, a reduction in myocardial O2 tension produced by inadequate coronary blood flow, hypoxemia, or increased metabolic activity of the heart leads to release of adenosine from the myocardium. Adenosine enters the interstitial fluid space to reach the coronary resistance vessels and induces vasodilation by activating adenosine receptors. However, it cannot be responsible for the increased coronary flow observed during prolonged enhancement of cardiac metabolic activity because release of adenosine from cardiac muscle is transitory. Factors that alter coronary vascular resistance are illustrated in Fig. 17.35 Effects of Diminished Coronary Blood Flow


Physiology_Levy

Physiology_Levy. Fig. 17.35 Effects of Diminished Coronary Blood Flow Most of the O2 in coronary arterial blood is extracted during one passage through the myocardial capillaries. Thus the supply of O2 to myocardial cells is flow limited; any substantial reduction in coronary blood flow curtails O2 delivery to the myocardium because O2 extraction is nearly maximal even when blood flow is normal.


Physiology_Levy

Physiology_Levy. A reduction in coronary flow that is neither too prolonged nor too severe to induce myocardial necrosis can nonetheless cause substantial (but temporary) dysfunction of the heart. A relatively brief period of severe ischemia followed by reperfusion can result in pronounced mechanical dysfunction (myocardial stunning). However, the heart eventually recovers fully from the dysfunction. The pathophysiological basis for myocardial stunning appears to be intracellular Ca++ overload, initiated during the period of ischemia, combined with the generation of OH− and superoxide free radicals early in the period of reperfusion. These changes impair the responsiveness of myofilaments to Ca++ .


Physiology_Levy

Physiology_Levy. In the normal human heart, there are virtually no functional intercoronary channels. Abrupt occlusion of a coronary artery or one of its branches leads to ischemic necrosis and eventual fibrosis of the areas of myocardium supplied by the occluded vessel. However, if a coronary artery narrows slowly and progressively over a period of days or weeks, collateral vessels develop and may furnish sufficient blood to the ischemic myocardium to prevent or reduce the extent of necrosis. Collateral vessels may develop between branches of occluded and nonoccluded arteries. They originate from preexisting small vessels that undergo proliferative changes of the endothelium and smooth muscle. These changes may occur in response to wall stress and to chemical agents, including vascular endothelial growth factors (VEGFs) released by the ischemic tissue. The VEGFs, of which there are at least five in mammals, are glycoproteins. The VEGFs induce angiogenesis, elicit vasodilation and increase endothelial


Physiology_Levy

Physiology_Levy. factors (VEGFs) released by the ischemic tissue. The VEGFs, of which there are at least five in mammals, are glycoproteins. The VEGFs induce angiogenesis, elicit vasodilation and increase endothelial permeability. By causing vasodilation, VEGFs enable perfusion of more capillaries and increase capillary permeability by opening tight junctions between endothelial cells and by adding fenestrations.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Myocardial hibernation describesthephenomenoninwhichcellularmetabolismisdownregulatedincellswhosefunctionisimpairedbyinadequatedeliveryofO2andnutrients.Myocardialhibernationoccursmainlyinpatientswithcoronaryarterydisease.Thecoronarybloodflowinsuchpatientsisdiminishedpersistentlyandsignificantly,andthemechanicalfunctionoftheheartisimpaired.Ifcoronarybloodflowisrestoredtonormalbybypasssurgeryorangioplasty,mechanicalfunctionreturnstonormal. The O2 and nutrient requirements of the skin are relatively small. Unlike other body tissues, the supply of O2 and nutrients is not the chief factor in the regulation of cutaneous blood flow. The primary function of the cutaneous circulation is to maintain a constant body temperature. Thus the skin undergoes wide fluctuations in blood flow, depending on whether the body needs to lose or conserve heat. Changes in ambient and internal body temperature activate mechanisms responsible for alterations in skin blood flow.


Physiology_Levy

Physiology_Levy. Regulation of Skin Blood Flow The skin contains essentially two types of resistance vessels: arterioles and arteriovenous anastomoses. AV anastomoses shunt blood from the arterioles to the venules and venous plexuses; hence, they bypass the capillary bed. Such anastomoses are found in the fingertips, palms of the hands, toes, soles of the feet, ears, nose, and lips. AV anastomoses differ morphologically from arterioles; the anastomoses are either short and straight or long coiled vessels, approximately 20 to 40 µm in luminal diameter, and they have thick muscular walls richly supplied with nerve fibers ( Fig. 17.37 ). These vessels are almost exclusively under sympathetic neural control, and they dilate maximally when their nerve


Physiology_Levy

Physiology_Levy. Fig. 17.37 ). These vessels are almost exclusively under sympathetic neural control, and they dilate maximally when their nerve Fig. 17.36 A, Angiogram(withintracoronaryradiopaquedye)ofmarkednarrowingoftheleftanteriordescendingbranchoftheleftcoronaryartery(white arrow). B, Thesamesegmentofthecoronaryartery(black arrow) afterangioplastyandinsertionofadrug-elutingstent.(CourtesyofDr.MichaelAzrin.)


Physiology_Levy

Physiology_Levy. Fig. 17.37 Arteriovenous (AV) Anastomosis in the Ear Injected With Berlin Blue Dye. A,artery;V,vein;arrowpointstoanAVanasto-mosis.ThewallsoftheAVanastomosisinthefingertipsarethickerandmorecellular.(FromPritchardMML,DanielPM.J Anat. 1956;90:309.) supply is interrupted. Conversely, reflex stimulation of the sympathetic fibers to these vessels may constrict them and obliterate the vascular lumen. Although AV anastomoses do not exhibit basal tone, they are highly sensitive to vasoconstrictor agents such as epinephrine and norepinephrine. Furthermore, AV anastomoses are not under metabolic control, and they do not show reactive hyperemia or auto-regulation of blood flow. Thus regulation of blood flow through these anastomotic channels is governed principally by the nervous system in response to reflex activation by temperature receptors or from higher centers of the central nervous system.


Physiology_Levy

Physiology_Levy. Most of the resistance vessels in the skin exhibit some basal tone and are under dual control of the sympathetic nervous system and local regulatory factors. However, neural control predominates. Stimulation of sympathetic nerve fibers Thefingersandtoesofsomeindividualsareverysensitivetocold.Onexposuretocold,thearteriolestothefingersandtoesconstrict.Theconsequentischemiaresultsinlocalizedblanchingoftheskinassociatedwithtingling,numbness,andpain.Theblanchingisfollowedbycyanosis(adarkbluecoloroftheskin)andlaterbyrednessasthearterialspasmsubsides.Thecauseofthiscondition,calledRaynaud’sdisease,isunknown.


Physiology_Levy

Physiology_Levy. induces vasoconstriction, and cutting of the sympathetic nerves induces vasodilation. After chronic denervation of the cutaneous blood vessels, the degree of tone that existed before denervation is gradually regained over a period of several weeks. This restoration of tone is accomplished by an enhancement of basal tone. Denervation of the skin vessels results in enhanced sensitivity to catecholamines in circulation (denervation hypersensitivity). Parasympathetic vasodilator nerve fibers do not innervate cutaneous blood vessels. However, stimulation of the sweat glands, which are innervated by sympathetic cholinergic fibers, dilates the skin resistance vessels. Sweat contains an enzyme that lyses a protein (kallidin) in the tissue fluid to produce bradykinin, a polypeptide with potent vasodilator properties. Bradykinin, formed locally, dilates the arterioles and increases blood flow to the skin.


Physiology_Levy

Physiology_Levy. Certain skin vessels, particularly those in the head, neck, shoulders, and upper part of the chest, are regulated by higher centers in the brain. Blushing, in response to embarrassment or anger, and blanching, in response to fear or anxiety, are examples of cerebral inhibition and stimulation, respectively, of the sympathetic nerve fibers to the affected cutaneous regions. In contrast to AV anastomoses in the skin, the resistance vessels display autoregulation of blood flow and reactive hyperemia. If the arterial inflow to a limb is stopped briefly by inflation of a blood pressure cuff, the skin becomes bright red below the point of vascular occlusion when the cuff is subsequently deflated. The increased cutaneous blood flow (reactive hyperemia) is also manifested by distention of the superficial veins in the affected extremity. The Role of Temperature in the Regulation of Skin Blood Flow


Physiology_Levy

Physiology_Levy. The primary function of the skin is to maintain a constant internal environment and protect the body from adverse changes. Ambient temperature is one of the most important external variables with which the body must contend. Exposure to cold elicits a generalized cutaneous vasoconstriction that is especially pronounced in the hands and feet. This response is chiefly mediated by the nervous system. Arrest of the circulation to a hand by a pressure cuff plus immersion of that hand in cold water induces vasoconstriction in the skin of the other extremities that are exposed to room temperature. When the circulation to the chilled hand is not occluded, the reflex-generalized vasoconstriction is caused in part by the cooled blood that returns to the general circulation. This returned blood then stimulates the temperature-regulating center in the anterior hypothalamus, which then activates heat preservation centers in the posterior hypothalamus to evoke cutaneous vasoconstriction.


Physiology_Levy

Physiology_Levy. The skin vessels of the cooled hand also respond directly to cold. Moderate cooling or a brief exposure to severe cold (0°C to 15°C) constricts the resistance and capacitance vessels, including the AV anastomoses. Prolonged exposure to severe cold evokes a secondary vasodilator response. Prompt vasoconstriction and severe pain are elicited by immersion of the hand in ice water. However, this response is soon followed by dilation of the skin vessels, with reddening of the immersed part and alleviation of the pain. With continued immersion of the hand, alternating periods of constriction and dilation occur, but the skin temperature rarely drops as much as it did in response to the initial vasoconstriction. Prolonged severe cold, of course, damages tissue. The rosy faces of people exposed to a cold environment are examples of cold-induced vasodilation. However, blood flow through the skin of the face may be greatly reduced despite the flushed appearance. The red color of the slowly


Physiology_Levy

Physiology_Levy. to a cold environment are examples of cold-induced vasodilation. However, blood flow through the skin of the face may be greatly reduced despite the flushed appearance. The red color of the slowly flowing blood is mainly caused by reduced O2 uptake by the cold skin and the cold-induced shift of the oxyhemoglobin dissociation curve to the left (see


Physiology_Levy

Physiology_Levy. Direct application of heat to the skin not only dilates the local resistance and capacitance vessels and the AV anastomoses but also reflexively dilates blood vessels in other parts of the body. The local effect is independent of the vascular nerve supply, whereas the reflex vasodilation is a combined response to stimulation of the anterior hypothalamus by the returning warmed blood and stimulation of cutaneous heat receptors in the heated regions of the skin.


Physiology_Levy

Physiology_Levy. The close proximity of the major arteries and veins allows countercurrent heat exchange between them. Cold blood that flows in veins from a cooled hand toward the heart takes up heat from adjacent arteries; this warms the venous blood and cools the arterial blood. Heat exchange takes place in the opposite direction when the extremity is exposed to heat. Thus heat conservation is enhanced during exposure of extremities to cold environments, and heat conservation is minimized during exposure of the extremities to warm environments. Skin Color: Relationship to Skin Blood Volume, Oxyhemoglobin, and Blood Flow


Physiology_Levy

Physiology_Levy. Skin Color: Relationship to Skin Blood Volume, Oxyhemoglobin, and Blood Flow Skin color is determined mainly by the pigment content. However, the degree of pallor or ruddiness is mainly a function of the amount of blood in the skin, except when the skin is very dark. With little blood in the venous plexus, the skin appears pale, whereas with moderate to large quantities of blood in the venous plexus, the skin displays a color. This color may be red, blue, or some shade between, depending CHAPTER 17 Properties of the Vasculature on the degree of oxygenation of the blood. A combination of vasoconstriction and reduced hemoglobin can impart an ashen gray color to the skin. A combination of venous engorgement and reduced hemoglobin content can impart a dark purple hue.


Physiology_Levy

Physiology_Levy. Skin color provides little information about the rate of cutaneous blood flow. Rapid blood flow may be accompanied by skin pallor when the AV anastomoses are open, and slow blood flow may be associated with skin ruddiness when the skin is exposed to cold. The rate of blood flow in skeletal muscle varies directly with the contractile activity of the tissue and the type of muscle. Blood flow and capillary density are greater in red muscle (slow-twitch muscle with high oxidative capacity) than in white muscle (fast-twitch muscle with low oxidative capacity). In resting muscle, the precapillary arterioles contract and relax intermittently. Thus at any given moment, most of the capillary bed is not perfused, and total blood flow through quiescent skeletal muscle is low (1.4 to 4.5 mL/ minute/100 g). During exercise, the resistance vessels relax, and muscle blood flow may increase to 15 to 20 times the resting level, depending on the intensity of the exercise.


Physiology_Levy

Physiology_Levy. Regulation of Skeletal Muscle Blood Flow Neural and local factors regulate muscle circulation. Physical factors such as Pa, tissue pressure, and blood viscosity influence muscle blood flow. However, another physical factor, the squeezing effect of the active skeletal muscle, affects blood flow in the vessels. With intermittent contractions, inflow is restricted, and as previously described, venous outflow is enhanced. The venous valves prevent backward flow of blood between contractions and thereby aid in the forward propulsion of blood. With strong sustained contractions, as occur during exercise, the vascular bed can be compressed to the point at which blood flow actually ceases temporarily.


Physiology_Levy

Physiology_Levy. The resistance vessels of muscle possess a high degree of basal tone; they also display tone in response to continuous low-frequency activity in the sympathetic vasoconstrictor nerve fibers. The basal firing frequency of sympathetic vasoconstrictor fibers is only approximately 1 to 2 per second, and maximal vasoconstriction occurs at frequencies of approximately 10 per second. Vasoconstriction evoked by sympathetic nerve activity is caused by the local release of norepinephrine. Intra-arterially injected norepinephrine elicits only vasoconstriction (α1adrenergic receptor). In contrast, low doses of epinephrine produce vasodilation (β2-adrenergic receptor), whereas large doses cause vasoconstriction. Baroreceptor reflexes greatly influence the tonic activity of the sympathetic nerves. An increase in carotid sinus pressure causes the muscle vascular bed to dilate, whereas a decrease in carotid sinus pressure elicits vasoconstriction (


Physiology_Levy

Physiology_Levy. Fig. 17.38 ). When sympathetic constrictor tone is high, the decrease in blood flow evoked by common carotid artery occlusion is small, but the increase in flow after the release of occlusion is large. The vasodilation produced by baroreceptor stimulation is caused by inhibition of sympathetic vasoconstrictor activity. The resistance vessels in skeletal muscle contribute significantly to maintenance of arterial blood pressure because skeletal muscle constitutes a large fraction of the body’s mass, and the muscle vasculature thus constitutes the largest vascular bed. Participation of the skeletal muscle vessels in vascular reflexes is important in maintaining normal arterial blood pressure. A comparison of the sympathetic neural effects on the blood vessels of muscle and skin is summarized in Fig. 17.39. Note that the lower the basal tone of the skin vessels, the greater their constrictor response; also note the absence of active cutaneous vasodilation.


Physiology_Levy

Physiology_Levy. Fig. 17.39. Note that the lower the basal tone of the skin vessels, the greater their constrictor response; also note the absence of active cutaneous vasodilation. In active skeletal muscle, blood flow is regulated by meta- bolic factors. In resting muscle, neural factors predominate, Fig. 17.39 ). Cutting of the sympathetic nerves to muscle abolishes the neural component of vascular tone, and it unmasks the intrinsic basal tone of the blood vessels. The neural and local mechanisms that regulate blood flow oppose each other, and during muscle contraction, the local vasodilator mechanism supervenes. However, during exercise, strong sympathetic nerve stimulation slightly attenuates the vasodilation induced by locally released metabolites.


Physiology_Levy

Physiology_Levy. •Fig. 17.38 Evidence of Participation of the Muscle Vascular Bed in Vasoconstriction and Vasodilation Mediated by the Carotid Sinus Baroreceptors After Occlusion and Release of the Common Carotid Artery. Inthispreparation,thesciaticandfemoralnervesconstitutedtheonlydirectinnervationofthehindlegmusclemass.Themusclewasperfusedwithbloodataconstantpressure.(RedrawnfromJonesRD,BerneRM.Am J Physiol. 1963;204:461.)


Physiology_Levy

Physiology_Levy. Blood reaches the brain through the internal carotid and vertebral arteries. The vertebral arteries join to form the basilar artery, which, in conjunction with branches of the •Fig. 17.39 Basaltoneandtherangeofresponseofresistancevesselsinmuscle(dashed lines) andskin(shaded areas) tostimulationandsectionofsympatheticnerves.Peripheralresistanceisplottedonalogarithmicscale.(RedrawnfromCelanderO,FolkowB.Acta Physiol Scand. 1953;29:241.) internal carotid arteries, forms the circle of Willis. Arteries on the brain surface differ from those that penetrate the brain parenchyma. Pial arteries and arterioles have an extrinsic innervation (e.g., via superior cervical ganglion, sphenopalatine nerves, trigeminal nerve); parenchymal arterioles have an intrinsic innervation (via cerebral neurons). Pial arteries have more smooth muscle cells than do parenchymal arterioles. Also, pial arteries and arterioles have collateral branches, whereas parenchymal arterioles do not. Therefore, parenchymal


Physiology_Levy

Physiology_Levy. Pial arteries have more smooth muscle cells than do parenchymal arterioles. Also, pial arteries and arterioles have collateral branches, whereas parenchymal arterioles do not. Therefore, parenchymal arterioles regulate blood flow to discrete cortical regions, and their occlusion can reduce blood flow significantly.


Physiology_Levy

Physiology_Levy. The cerebral circulation is unique because it lies within a rigid structure, the cranium. Any increase in arterial inflow must be associated with a comparable increase in venous outflow because the intracranial contents cannot be compressed. The volume of blood and extravascular fluid can vary considerably in most body tissues. In the brain, however, the volume of blood and extravascular fluid is relatively constant; a change in one of these fluid volumes must be accompanied by a reciprocal change in the other. The rate of cerebral blood flow is maintained within a narrow range; in humans, it averages 55 mL/minute/100 g of brain tissue. Regulation of Cerebral Blood Flow


Physiology_Levy

Physiology_Levy. Regulation of Cerebral Blood Flow At rest, the brain consumes 20% of total body oxygen and 25% of total body glucose. Of all body tissues, the brain is the least tolerant of ischemia. Interruption of cerebral blood flow for as little as 5 seconds results in loss of consciousness. Ischemia that lasts just a few minutes may cause irreversible tissue damage. Fortunately, regulation of the cerebral circulation is primarily under the direction of the brain itself. Local regulatory mechanisms and reflexes that originate in the brain tend to maintain a relatively constant cerebral circulation in the presence of such adverse effects as sympathetic vasomotor nerve activity, circulating humoral vasoactive agents, and changes in arterial blood pressure. Under certain conditions, the brain also regulates its blood flow by initiating changes in systemic blood pressure.


Physiology_Levy

Physiology_Levy. Changes in cerebral blood flow are associated with “functional recruitment” of capillaries. Thus the rate of flow through each capillary is adjusted to meet the needs of the organ. In “capillary recruitment,” in contrast, more capillaries are open to accommodate greater blood flow. The brain has several protective mechanisms that regulate blood flow. These mechanisms include the blood-brain barrier, extrinsic regulation of central cardiovascular centers, intrinsic control (autoregulation) of circulation, and functional hyperemia, in which blood flow increases to a brain region that is active. The blood-brain barrier regulates ion and nutrient transport between the blood and the brain and also limits the entry of harmful substances from the blood into the brain. The •Fig. 17.40 Diagram of a Neurovascular Unit With an Astrocyte Linking a Neuron to an Arteriole of the Brain Microcirculation.


Physiology_Levy

Physiology_Levy. Arteriolartoneismodulatedbyvascularsmoothmuscleandbytheactionofpericytes.Theendothelialcellrestrictsdiffusionofsubstancesbyvirtueoftightjunctions.Theneurovascularunitisacomponentoftheblood-brainbarrierandalsoservesasaregulatorofbloodflowduringneuronalactivity. blood-brain barrier includes tight junction proteins (junctional adhesion molecule-1, occludins, claudins), which are connected to the endothelial cell cytoskeleton to form a barrier that opposes paracellular movement of substances from blood to brain. In addition, the blood-brain barrier includes the neurovascular unit (microcirculation, pericytes, the extracellular matrix, astrocytes, and neurons; Fig.