Physiology_Levy

Physiology_Levy. Potassium is released at the onset of skeletal muscle contraction or with an increase in cardiac muscle activity. Hence, release of K+ could underlie the initial decrease in vascular resistance observed in response to physical exercise or to increased cardiac work. However, release of K+ is not sustained, but arteriolar dilation persists throughout the period of enhanced muscle activity. Furthermore, reoxygenated venous blood obtained from active cardiac and skeletal muscles does not elicit vasodilation when the blood is infused into a test vascular bed. It is unlikely that oxygenation of venous blood alters its K+ or phosphate content or its osmolarity and thereby neutralizes its vasodilator effect. Therefore, some agent other than K+ must mediate the vasodilation associated with metabolic activity of the tissue.


Physiology_Levy

Physiology_Levy. Adenosine, which contributes to the regulation of coronary blood flow, may also participate in control of the resistance vessels in skeletal muscle. In addition, some prostaglandins may be important vasodilator mediators in certain vascular beds. Many prostaglandins have thus been CHAPTER 18 Regulation of the Heart and Vasculature proposed as mediators of metabolic vasodilation, and the relative contribution of each remains to be determined.


Physiology_Levy

Physiology_Levy. CHAPTER 18 Regulation of the Heart and Vasculature proposed as mediators of metabolic vasodilation, and the relative contribution of each remains to be determined. Metabolic control of vascular resistance by the release of a vasodilator substance requires the existence of a basal vessel tone. Tonic activity in vascular smooth muscle is readily demonstrable, but in contrast to tone in skeletal muscle, the tone in vascular smooth muscle is independent of the nervous system. Thus some metabolic factor must be responsible for maintaining this tone. The following factors may be involved: (1) the myogenic response to the stretch imposed by blood pressure, (2) the high partial pressure of oxygen in arterial blood (PaO2), or (3) the presence of Ca++ .


Physiology_Levy

Physiology_Levy. If arterial inflow to a vascular bed is stopped temporarily, blood flow on release of the occlusion immediately exceeds the flow that prevailed before occlusion, and the flow gradually returns to the control level. This increase in blood flow is called reactive hyperemia. This type of event provides evidence for the existence of a local metabolic factor that regulates tissue blood flow. In the experiment shown in Fig. 18.23 , blood flow to the leg was stopped by clamping of the femoral artery for 15, 30, and 60 seconds. Release of the 60-second occlusion resulted in a peak blood flow that was 70% greater than the control flow, and the flow returned to the control level within 110 seconds. Within limits, peak flow and particularly the duration of reactive hyperemia are proportional to the duration of the occlusion (see


Physiology_Levy

Physiology_Levy. Within limits, peak flow and particularly the duration of reactive hyperemia are proportional to the duration of the occlusion (see Fig. 18.23 ). If the extremity is exercised during the occlusion period, reactive hyperemia is increased. These observations and the close relationship between metabolic activity and blood flow in an unoccluded limb are consistent with the notion of a metabolic mechanism in the local regulation of tissue blood flow. •Fig. 18.23 Graphsofreactivehyperemiainthehindlimbofthelegafter15-,30-,and60-secondocclusionofthefemoralartery.(FromBerneRM.Unpublishedobservations.)0 2 4 6 8 10 0 20 40 60 80 100 Time (min) Femoral blood flow(mL/min) 0 20 40 60 80 100 120 Femoral arterial pressure(mm Hg) Coordination of Arterial and Arteriolar Dilation


Physiology_Levy

Physiology_Levy. When the vascular smooth muscle of arterioles relaxes in response to vasodilator metabolites whose release is caused by a decrease in the ratio of O2 supply to O2 demand of the tissue, resistance may diminish concomitantly in the small upstream arteries that feed these arterioles. The result is blood flow greater than that produced by arteriolar dilation alone. There are two possible mechanisms for this coordination of arterial and arteriolar dilation. First, the vasodilation in the microvessels may be propagated, and when dilation is initiated in the arterioles, it can propagate along the vessels from the arterioles back to the small arteries. Second, the metabolite-mediated dilation of the arterioles accelerates blood flow in the feeder arteries. This greater blood flow velocity increases the shear stress on the arterial endothelium, which in turn can induce flow-mediated vasodilation by release of one or more vasodilators (e.g., nitric oxide, prostacyclin, H2O2, epoxyeicosatrienoic


Physiology_Levy

Physiology_Levy. the shear stress on the arterial endothelium, which in turn can induce flow-mediated vasodilation by release of one or more vasodilators (e.g., nitric oxide, prostacyclin, H2O2, epoxyeicosatrienoic acid).


Physiology_Levy

Physiology_Levy. Inthelegs,diseaseofthearterialwallscanleadtoobstructionofthearteriesandsymptoms,aconditioncalledintermittent claudication. Thesymptomsconsistoflegpainwhenthepersonwalksorclimbsstairs,andthepainisrelievedbyrest.Thediseaseiscalledthromboangiitis obliterans, anditappearsmostfrequentlyinmenwhoaresmokers.Withminimalwalking,theresistancevesselsbecomemaximallydilatedbylocalreleaseofmetabolites;whentheO2demandofthemusclesincreaseswithmorerapidwalking,bloodflowcannotincreasesufficientlytomeetthemuscleneedsforO2,andpaincausedbymuscleischemiaresults. Extrinsic Control of Peripheral Blood Flow


Physiology_Levy

Physiology_Levy. Extrinsic Control of Peripheral Blood Flow Several regions in the cerebral medulla influence cardiovascular activity. Stimulation of the dorsal lateral medulla (pressor region) evokes vasoconstriction, cardiac acceleration, and enhanced myocardial contractility. Stimulation of cerebral centers caudal and ventromedial to the pressor region decreases arterial blood pressure. This depressor area exerts its effect by direct inhibition of spinal regions and by inhibition of the medullary pressor region. These areas are not true anatomical centers in which a discrete group of cells is discernible, but they constitute “physiological” centers.


Physiology_Levy

Physiology_Levy. The cerebrospinal vasoconstrictor regions are tonically active. Reflexes or humoral stimuli that enhance this activity increase the frequency of impulses that reach the terminal neural branches to the vessels. A constrictor neurohumor (norepinephrine) is released at the terminals to elicit a constrictive α-adrenergic effect on the resistance vessels. Inhibition of the vasoconstrictor areas diminishes the impulse frequency in the efferent nerve fibers, and vasodilation results. Thus neural regulation of the peripheral circulation is achieved mainly by alteration in the impulse frequency in the sympathetic nerves to the blood vessels. Surgical section of the sympathetic nerves to an extremity abolishes sympathetic vascular tone and thereby increases blood flow to that limb. With time, vascular tone is regained by an increase in basal (intrinsic) tone.


Physiology_Levy

Physiology_Levy. Both the pressor and depressor regions may undergo rhythmic changes in tonic activity that are manifested as oscillations in arterial pressure. Some rhythmic changes (Traube-Hering waves) occur at the frequency of respiration and are caused by a cyclic fluctuation in sympathetic impulses to the resistance vessels. Other fluctuations in sympathetic activity (Mayer waves) occur at a frequency lower than that of respiration.


Physiology_Levy

Physiology_Levy. Vasoconstrictor fibers of the sympathetic nervous system supply the arteries, arterioles, and veins; the neural influence is much less on larger vessels than on arterioles and small arteries. Capacitance vessels (veins) respond more to sympathetic nerve stimulation than do resistance vessels; the capacitance vessels are maximally constricted at a lower stimulation frequency than the are resistance vessels. However, capacitance vessels lack β-adrenergic receptors, and they respond less to vasodilator metabolites. Norepinephrine is the neurotransmitter released at the sympathetic nerve terminals in blood vessel. Factors such as circulating hormones and particularly locally released substances mediate the release of norepinephrine from the nerve terminals. The response of the resistance and capacitance vessels to stimulation of sympathetic fibers is illustrated in Fig.


Physiology_Levy

Physiology_Levy. The response of the resistance and capacitance vessels to stimulation of sympathetic fibers is illustrated in Fig. 18.24 . When arterial pressure is held constant, stimulation of sympathetic fibers reduces blood flow (constriction of resistance vessels) and decreases the blood volume of the tissue (constriction of capacitance vessels). Constriction of the resistance vessels establishes a new equilibrium of the forces responsible for filtration and absorption across the capillary wall (see Eq. 17.20 In addition to active changes (contraction and relaxation of vascular smooth muscle) in vessel caliber, passive changes are also caused by alterations in intraluminal pressure. An increase in intraluminal pressure distends the vessels, and a decrease reduces the caliber of the vessels as a consequence of elastic recoil of the vessel walls.


Physiology_Levy

Physiology_Levy. At basal vascular tone, approximately a third of the blood volume of a tissue can be mobilized when the sympathetic nerves are stimulated at physiological frequencies. Basal tone is very low in capacitance vessels; if these vessels are denervated experimentally, the increases in volume evoked


Physiology_Levy

Physiology_Levy. Change of tissue Arterial pressureBlood flow volume (mL) (mm Hg) •Fig. 18.24 Effect of Sympathetic Nerve Stimulation (2 Hz) on Blood Flow and Tissue Volume of the Lower Limb. Theupward arrow denotesthechangeinslopeofthetissuevolumecurveatthepointatwhichthedecreaseinvolumecausedbyemptyingofcapacitancevesselsceasesandlossofextravascularfluidbecomesevident.Theabruptdecreaseintissuevolumeiscausedbymovementofbloodoutofthecapacitancevesselsandoutofthelowerlimb.Thelate,slow,progressivedeclineinvolume(totherightofthearrow)iscausedbythemovementofextravascularfluidintothecapillariesandhenceawayfromthetissue.Thelossoftissuefluidresultsfromtheloweringofthecapillaryhydrostaticpressuresecondarytoconstrictionoftheresistancevessels.(FromMellanderS.Acta Physiol Scand Suppl. 1960;50[176]:1.) by maximal doses of ACh are small. Therefore, at basal vascular tone, blood volume is close to the maximal blood volume of the tissue. More blood can be mobilized from the capacitance vessels in the skin than from


Physiology_Levy

Physiology_Levy. of ACh are small. Therefore, at basal vascular tone, blood volume is close to the maximal blood volume of the tissue. More blood can be mobilized from the capacitance vessels in the skin than from those in the muscle. This disparity depends in part on the greater sensitivity of the skin vessels to sympathetic stimulation, but it also occurs because basal tone is lower in skin vessels than in muscle vessels. Therefore, in the absence of a neural influence, skin capacitance vessels contain more blood than do muscle capacitance vessels.


Physiology_Levy

Physiology_Levy. Physiological stimuli mobilize blood from capacitance vessels. For example, during physical exercise, activation of sympathetic nerve fibers constricts the peripheral veins and hence augments cardiac filling pressure. In arterial hypo-tension (as occurs in hemorrhage), the capacitance vessels constrict and thereby correct the decreased central venous pressure associated with blood loss. The efferent fibers of the cranial division of the parasympathetic nervous system innervate the blood vessels of the head and some of the viscera, whereas fibers of the sacral division innervate blood vessels of the genitalia, bladder, CHAPTER 18 Regulation of the Heart and Vasculature and large bowel. Skeletal muscle and skin do not receive parasympathetic innervation. The effect of cholinergic fibers on total vascular resistance is small because only a small proportion of the resistance vessels of the body receive parasympathetic fibers.


Physiology_Levy

Physiology_Levy. Inhemorrhagicshock,theresistancevesselsconstrictandtherebyassistinthemaintenanceofnormalarterialbloodpressure.Witharterialhypotension,theenhancedarteriolarconstrictionalsoleadstoasmallmobilizationofbloodfromthetissuebyvirtueofrecoilofthepostarteriolarvesselswhenintraluminalpressureisreduced.Furthermore,extravascularfluidismobilizedbecauseofgreaterfluidabsorptionintothecapillariesinresponsetotheloweredcapillaryhydrostaticpressure. Stimulation of the parasympathetic fibers to the salivary glands induces marked vasodilation. A vasodilator polypeptide, bradykinin, formed locally from the action of an enzyme on a plasma protein substrate in the glandular lymphatic vessels, mediates this vasodilation. Bradykinin is formed in other exocrine glands, such as the lacrimal and sweat glands. Its presence in sweat may be partly responsible for the dilation of cutaneous blood vessels.


Physiology_Levy

Physiology_Levy. Epinephrine and norepinephrine exert a powerful effect on peripheral blood vessels. In skeletal muscle, low concentrations of epinephrine dilate resistance vessels (β2-adrenergic effect), but high concentrations produce constriction (α1adrenergic effect), as noted in Table 14.1. In all vascular beds, the primary effect of norepinephrine is vasoconstriction. When stimulated, the adrenal gland can release epinephrine and norepinephrine into the systemic circulation. However, under physiological conditions, the effect of catecholamine release from the adrenal medulla is less important than norepinephrine release from sympathetic nerve endings. Table 14.1 ). Some are released from the endothelium (e.g., nitric oxide, endothelin, thromboxane A2), whereas others are derived from perivascular tissues (e.g., histamine, adenosine, angiotensin II).


Physiology_Levy

Physiology_Levy. Areas of the cerebral medulla that mediate sympathetic and vagal effects are under the influence of neural impulses that originate in the baroreceptors, chemoreceptors, hypothalamus, cerebral cortex, and skin. These areas of the medulla are also affected by changes in the blood concentrations of CO2 and O2. The baroreceptors (or pressoreceptors) are stretch receptors located in the carotid sinuses and in the aortic arch ( Figs. 18.25 18.26 ). The carotid sinuses are the slightly Fig. 18.25 Diagrammaticrepresentationofthecarotidsinusandcarotidbodyandtheirinnervation.(RedrawnfromAdamsWE.The Comparative Morphology of the Carotid Body and Carotid Sinus. Fig. 18.26 Anteriorviewoftheaorticarchshowingtheinnervationoftheaorticbodiesandbaroreceptors.(ModifiedfromNonidezJF.Anat Rec. 1937;69:299.)


Physiology_Levy

Physiology_Levy. Springfield,IL:CharlesCThomas;1958.)Left vagus nerveRight vagus nerve Right inferior cervical ganglion Right stellate ganglion Recurrent branch of right vagus Vagosympathetic fibers Brachiocephalic artery Baroreceptor fibers Cardiac nerves Aorta Right coronary artery Left inferior cervical ganglion Left subclavian ansa Left subclavian artery Recurrent branch of left vagus Aortic bodies Ductus arteriosus Pulmonary artery Left stellate ganglion Vagosympathetic fibers Vagosympathetic fibers widened areas at the origins of the internal carotid arteries. Impulses that arise in the carotid sinus travel up the carotid sinus nerve (nerve of Hering) to the glossopharyngeal nerve (cranial nerve IX) and, via the latter, to the nucleus of the tractus solitarius (NTS) in the medulla. The NTS is the site of the central projections of the chemoreceptors and baroreceptors. Stimulation of the NTS inhibits sympathetic nerve outflow to the peripheral blood vessels (depressor effect), whereas lesions of


Physiology_Levy

Physiology_Levy. of the central projections of the chemoreceptors and baroreceptors. Stimulation of the NTS inhibits sympathetic nerve outflow to the peripheral blood vessels (depressor effect), whereas lesions of the NTS produce vasoconstriction (pressor effect). Impulses that arise in the aortic arch baroreceptors reach the NTS via afferent fibers in the vagus nerves.


Physiology_Levy

Physiology_Levy. Baroreceptor nerve terminals in the walls of the carotid sinus and aortic arch respond to the vascular stretch and deformation induced by changes in arterial blood pressure. The frequency of firing of these nerves is enhanced by an increase in arterial blood pressure and diminished by a reduction in arterial blood pressure. An increase in impulse frequency, as occurs with a rise in arterial pressure, inhibits the cerebral vasoconstrictor regions and results in peripheral vasodilation and lowering of arterial blood pressure. Bradycardia brought about by activation of the cardiac branches of the vagus nerves contributes to this lowering of blood pressure. The carotid sinus baroreceptors are more sensitive than those in the aortic arch. Changes in carotid sinus pressure evoke greater changes in systemic arterial pressure and peripheral resistance than do equivalent changes in aortic arch pressure.


Physiology_Levy

Physiology_Levy. The receptors in the carotid sinus walls respond more to pulsatile pressure than to constant pressure. This is illustrated in Fig. 18.27 , which shows that at normal levels 0 0.5 1.0 1.5 2.0 •Fig. 18.27 Relationshipofphasicaorticbloodpressureinthefiring CHAPTER 18 Regulation of the Heart and Vasculature of mean arterial blood pressure (≈100 mm Hg), a barrage of impulses from a single fiber of the sinus nerve is initiated in early systole by the pressure rise; only a few spikes occur during late systole and early diastole. At lower arterial pressure, these phasic changes are even more evident, but the overall discharge frequency is reduced. The blood pressure threshold for evoking sinus nerve impulses is approxi mately 50 mm Hg; maximal sustained firing is reached at approximately 200 mm Hg. Because the baroreceptors adapt, their response at any mean arterial pressure level is greater to a high pulse pressure than to a low pulse pressure.


Physiology_Levy

Physiology_Levy. The increases in resistance that occur in response to reduced pressure in the carotid sinus vary from one peripheral vascular bed to another. These variations allow blood flow to be redistributed. The resistance changes elicited by altering carotid sinus pressure are greatest in the femoral vessels, less in the renal vessels, and least in the mesenteric and celiac vessels.


Physiology_Levy

Physiology_Levy. In addition, the sensitivity of the carotid sinus reflex can be altered. Local application of norepinephrine or stimulation of sympathetic nerve fibers to the carotid sinuses enhances the sensitivity of its receptors in such a way that a given increase in intrasinus pressure produces a greater depressor response. Baroreceptor sensitivity decreases in hypertension because the carotid sinuses become stiffer as a result of the high intra-arterial pressure. Consequently, a given increase in carotid sinus pressure elicits a smaller decrease in systemic arterial pressure than it does at a normal level of blood pressure. Thus the set point of the baroreceptors is raised in hypertension in such a way that the threshold is increased and the pressure receptors are less sensitive to changes in transmural pressure. As would be expected, denervation of the carotid sinus can produce temporary and, in some instances, prolonged hypertension.


Physiology_Levy

Physiology_Levy. The arterial baroreceptors play a key role in short-term adjustments in blood pressure in response to relatively abrupt changes in blood volume, cardiac output, or peripheral resistance (as in exercise). However, long-term control of blood pressure—over a period of days or weeks—is determined by the fluid balance of the individual: namely, the balance between fluid intake and fluid output. By far, the most important organ in the control of body fluid volume, and hence blood pressure, is the kidney (see also Cardiopulmonary receptors are located in the atria, ventricles, and pulmonary vessels. These baroreceptors are innervated by vagal and sympathetic afferent nerves. Cardiopulmonary reflexes are tonically active and can alter peripheral resistance in response to changes in intracardiac, venous, or pulmonary vascular pressure.


Physiology_Levy

Physiology_Levy. The atria contain two types of cardiopulmonary baroreceptors: those activated by the tension developed during atrial systole (type A receptors) and those activated by ofmeanarterialpressure.stretch of the atria during atrial diastole (type B receptors). Stimulation of these atrial receptors sends impulses up vagal fibers to the vagal center in the medulla. Consequently, sympathetic activity is decreased to the kidney and increased to the sinus node. These changes in sympathetic activity increase renal blood flow, urine flow, and heart rate. Activation of the cardiopulmonary receptors can also initiate a reflex that lowers arterial blood pressure by inhibiting the vasoconstrictor center in the cerebral medulla. Stimulation of the cardiopulmonary receptors inhibits release of angiotensin, aldosterone, and vasopressin (antidiuretic hormone); interruption of the reflex pathway has the opposite effects.


Physiology_Levy

Physiology_Levy. The role that activation of these baroreceptors plays in the regulation of blood volume is apparent in the body’s responses to hemorrhage. The reduction in blood volume (hypovolemia) enhances sympathetic vasoconstriction in the kidney and increases the secretion of renin, angiotensin, aldosterone, and vasopressin (see also ). The renal vasoconstriction (primarily afferent arterioles) reduces glomerular filtration and increases release of renin from the kidney. Renin acts on a plasma substrate to yield angiotensin II, which stimulates aldosterone secretion by the adrenal cortex. The enhanced release of vasopressin decreases renal water excretion, and the release of aldosterone decreases renal NaCl excretion. The kidneys retain salt and water, and hence blood volume increases. Angiotensin II (formed from angiotensin I by angiotensin-converting enzyme) also raises systemic arteriolar tone (see Table 14.1


Physiology_Levy

Physiology_Levy. Table 14.1 Insomeindividuals,thecarotidsinusisabnormallysensitivetoexternalpressure.Hence,tightcollarsorotherformsofexternalpressureovertheregionofthecarotidsinusmayelicitmarkedhypotensionandfainting.Suchhypersensitivityisknownasthecarotid sinus syndrome. Peripheral chemoreceptors consist of small, highly vascular bodies in the region of the aortic arch (aortic bodies; see Fig. 18.26 ) and just medial to the carotid sinuses (carotid bodies; see Fig. 18.25 ). These vascular bodies are sensitive to changes in the PO2, PCO2, and pH of arterial blood. Although they primarily regulate respiration, they also influence the vasomotor regions. A reduction in PaO2 stimulates the chemoreceptors. The increased activity in afferent nerve fibers from the carotid and aortic bodies stimulates the vasoconstrictor regions and thereby increases the tone of resistance and capacitance vessels.


Physiology_Levy

Physiology_Levy. The chemoreceptors are also stimulated by increased arterial blood PCO2 (PaCO2) and by reduced pH. However, the reflex effect is small in comparison to the direct effects of hypercapnia (high PaCO2) and acidosis on the vasomotor regions in the medulla. When hypoxia and hypercapnia occur simultaneously, the effects of the chemoreceptors are greater than the sum of the effects of each of the two stimuli when they act alone. Chemoreceptors are also located in the heart. These cardiac chemoreceptors are activated by ischemia of cardiac muscle, and they transmit the precordial pain (angina pectoris) associated with an inadequate blood supply to the myocardium.


Physiology_Levy

Physiology_Levy. Optimal function of the cardiovascular reflexes requires integrity of the pontine and hypothalamic structures. Furthermore, these structures are responsible for behavioral and emotional control of the cardiovascular system (see also ). Stimulation of the anterior hypothalamus produces both a fall in blood pressure and bradycardia, whereas stimulation of the posterolateral region of the hypothalamus increases both blood pressure and the heart rate. The hypothalamus also contains a temperature-regulating center that affects blood vessels in the skin. Stimulation by the application of cold to the skin or by cooling of the blood perfusing the hypothalamus results in constriction of the skin vessels and heat conservation, whereas warm stimuli to the skin result in cutaneous vasodilation and enhanced heat loss.


Physiology_Levy

Physiology_Levy. The cerebral cortex also affects blood flow distribution in the body. Stimulation of the motor and premotor areas affects blood pressure; usually, a pressor response occurs. However, vasodilation and depressor responses may be evoked, as in blushing or fainting, in response to an emotional stimulus. Painful stimuli can elicit either pressor or depressor responses, depending on the magnitude and location of the stimulus. Distention of the viscera often evokes a depressor response, whereas painful stimuli to the body surface generally evoke a pressor response.


Physiology_Levy

Physiology_Levy. Inflation of the lungs initiates a reflex that induces systemic vasodilation and a decrease in arterial blood pressure. Conversely, collapse of the lungs evokes systemic vasoconstriction. Afferent fibers that mediate this reflex are in the vagus nerves and possibly also in the sympathetic nerves. Stimulation of these fibers by stretch of the lungs inhibits the vasomotor areas. The magnitude of the depressor response to lung inflation is directly related to the degree of inflation and to the existing level of vasoconstrictor tone (see also


Physiology_Levy

Physiology_Levy. Increases in PCO2 stimulate chemosensitive regions of the medulla (the central chemoreceptors), and they elicit vasoconstriction and increased peripheral resistance. A reduction in PCO2 to subnormal levels (in response to hyperventilation) decreases tonic activity in these areas in the medulla and thereby decreases peripheral resistance. The chemosensitive regions are also affected by changes in pH. Lowering of blood pH stimulates these cerebral areas, and a rise in blood pH inhibits them. These effects of changes in PCO2 and blood pH may operate through changes in cerebrospinal fluid pH, as may also the respiratory center.


Physiology_Levy

Physiology_Levy. PaO2 has little direct effect on the medullary vasomotor region. The primary effect of hypoxia is mediated by reflexes via the carotid and aortic chemoreceptors. A moderate reduction in PaO2 stimulates the vasomotor region, but a severe reduction depresses vasomotor activity in the same manner by which other areas of the brain are depressed by very low O2 tension. Balance Between Extrinsic and Intrinsic Factors in Regulation of Peripheral Blood Flow Dual control of peripheral vessels by intrinsic and extrinsic mechanisms evokes a number of important vascular adjustments. Such regulatory mechanisms enable the body to direct blood flow to areas where it is most needed and away from areas that have fewer requirements. In some tissues, the effects of the extrinsic and intrinsic mechanisms are fixed; in other tissues, the ratio is changeable and depends on the state of activity of that tissue.


Physiology_Levy

Physiology_Levy. Cerebralischemia,whichmayoccurbecauseofexcessivepressureexertedbyanexpandingintracranialtumor,resultsinamarkedincreaseinperipheralvasoconstriction.ThestimulationisprobablycausedbylocalaccumulationofCO2andareductioninO2andpossiblybyexcitationofintracranialbaroreceptors.Withprolonged,severeischemia,centraldepressioneventuallysupervenes,andbloodpressurefalls. CHAPTER 18 Regulation of the Heart and Vasculature In the brain and heart, which are vital structures with limited tolerance for a reduced blood supply, intrinsic flow-regulating mechanisms are dominant. For instance, massive discharge of the vasoconstrictor region via the sympathetic nerves, which might occur in severe, acute hemorrhage, has negligible effects on the cerebral and cardiac resistance vessels, whereas the cutaneous, renal, and splanchnic blood vessels become greatly constricted.


Physiology_Levy

Physiology_Levy. In the skin, extrinsic vascular control is dominant. The cutaneous vessels not only participate strongly in a general vasoconstrictor discharge but also respond selectively via hypothalamic pathways to subserve the functions of heat loss and heat conservation required for regulation of body temperature. However, intrinsic control can be elicited by local temperature changes that modify or override the central influence on resistance and capacitance vessels (see also


Physiology_Levy

Physiology_Levy. In skeletal muscle, the extrinsic and intrinsic mechanisms interact. In resting skeletal muscle, neural control (vasoconstrictor tone) is dominant, as can be demonstrated by the large increase in blood flow that occurs immediately after section of the sympathetic nerves to the tissue. After the onset of exercise, the intrinsic flow-regulating mechanism assumes control, and vasodilation occurs in the active muscles because of the local increase in metabolites. Vasoconstriction occurs in the inactive tissues as a manifestation of the general sympathetic discharge. However, constrictor impulses that reach the resistance vessels of the active muscles are overridden by the local metabolic effect. Operation of this dual control mechanism thus increases blood flow where it is required and shunts it away from relatively inactive areas (see also Chapter 17).


Physiology_Levy

Physiology_Levy. Chapter 17). Similar effects may be achieved in response to an increase in PCO2. Normally, the hyperventilation associated with exercise keeps PCO2 at normal levels. However, if PCO2 is increased, generalized vasoconstriction would occur because CO2 stimulates the medullary vasoconstrictor region. In active muscles, where [CO2] would be highest, the smooth muscle of the arterioles would relax in response to the local PCO2. Factors that affect and are affected by the vasomotor region are summarized in Fig. 18.28 408 SECTION4Berne & Levy Physiology •Fig. 18.28 Schematic Diagram Illustrating Neural Input and Output of the Vasomotor Region (VR). Arrows indicatedirectionofneuralinputandoutput.IX,glossopharyngealnerve;↑PCO2,increasedpartialpressureofcarbondioxide;↓PCO2,increasedPCO2;↑PO2,increasedpartialpressureofoxygen;↓PO2,increasedPO2;SA,sinoatrial;X,vagusnerve.Aortic bodies SA node Sympathetic chain V R Carotid body X X IX ˜ PCO2 ° PO2 ˜ PCO2 ° PO2 ˜ PCO2 ° PO2 1.


Physiology_Levy

Physiology_Levy. Cardiac function is regulated by a number of intrinsic and extrinsic mechanisms. The principal intrinsic mechanisms that regulate myocardial contraction are the Frank-Starling mechanism and rate-induced regulation. 2. The heart rate is regulated mainly by the autonomic nervous system. Sympathetic nervous activity increases the heart rate, whereas parasympathetic (vagal) activity decreases the heart rate. When both systems are active, the vagal effects usually dominate. The autonomic nervous system regulates myocardial performance mainly by varying the Ca++ conductance of the cell membrane via the adenylate cyclase system. 3. The reflexes that regulate the heart rate are the baroreceptor, chemoreceptor, pulmonary inflation, atrial receptor (Bainbridge), and ventricular receptor reflexes. 4.


Physiology_Levy

Physiology_Levy. 3. The reflexes that regulate the heart rate are the baroreceptor, chemoreceptor, pulmonary inflation, atrial receptor (Bainbridge), and ventricular receptor reflexes. 4. Certain hormones—such as epinephrine, adrenocortical steroids, thyroid hormones, insulin, glucagon, and anterior pituitary hormones—regulate myocardial performance. Changes in the arterial blood concentrations of O2, CO2, and H+ alter cardiac function directly and, through the chemoreceptors, indirectly.


Physiology_Levy

Physiology_Levy. 5. The arterioles (resistance vessels) regulate blood flow mainly through their downstream capillaries. Smooth muscle, which makes up most of the walls of arterioles, contracts and relaxes in response to neural and humoral stimuli. Neural regulation of blood flow is almost completely accomplished by the sympathetic nervous system. Sympathetic nerves to blood vessels are tonically active; inhibition of the vasoconstrictor center in the medulla reduces peripheral vascular resistance. Stimulation of the sympathetic nerves constricts the resistance and capacitance (veins) vessels. Parasympathetic fibers innervate the head, viscera, and genitalia; they do not innervate the skin and muscle. 6.


Physiology_Levy

Physiology_Levy. 6. Autoregulation of blood flow occurs in most tissues. This process is characterized by a constant blood flow in the presence of a change in perfusion pressure. Autoregulation is mediated by a myogenic mechanism whereby an increase in transmural pressure elicits a contraction of vascular smooth muscle and a decrease in transmural pressure elicits a relaxation. 7. The striking parallelism between tissue blood flow and tissue O2 consumption indicates that blood flow is regulated largely by a metabolic mechanism. A decrease in the ratio of O2 supply to O2 demand of a tissue releases vasodilator metabolites that dilate arterioles and thereby enhance the O2 supply. 8.


Physiology_Levy

Physiology_Levy. 8. The baroreceptors in the internal carotid arteries and aorta are tonically active and regulate blood pressure on a moment-to-moment basis. An increase in arterial pressure stretches these receptors to initiate a reflex that inhibits the medullary vasoconstrictor center and induces vasodilation. Conversely, a decrease in arterial pressure disinhibits the vasoconstrictor center and induces vasoconstriction. The baroreceptors in the internal carotid arteries Fukuda K, Kanazawa H, Aizawa Y, et al. Cardiac innervation and sudden cardiac death. Circ Res. 2015;116:2005. Iancu RV, Jones SW, Harvey RD. Compartmentation of cAMP signaling in cardiac myocytes. Biophys J. 2007;92:3317. Liu Y, Bubolz AH, Mendoza S, et al. H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles. Circ Res. 2011;108:566. predominate over those in the aorta, and they respond more vigorously to changes in pressure (stretch) than to elevated or reduced nonpulsatile pressure.


Physiology_Levy

Physiology_Levy. predominate over those in the aorta, and they respond more vigorously to changes in pressure (stretch) than to elevated or reduced nonpulsatile pressure. 9. Peripheral chemoreceptors (carotid and aortic bodies) and central chemoreceptors in the medulla oblongata are stimulated by a decrease in blood PaO2 and by an increase in blood PCO2. Stimulation of these chemoreceptors increases the rate and depth of respiration, but it also produces peripheral vasoconstriction. Cardiopulmonary baroreceptors are also present in the cardiac chambers and large pulmonary vessels. They have less influence on blood pressure but do participate in regulation of blood volume. 10.


Physiology_Levy

Physiology_Levy. 10. Peripheral resistance and hence blood pressure are affected by stimuli that arise in the skin, viscera, lungs, and brain. The combined effect of neural and local metabolic factors distributes blood to active tissues and diverts it from inactive tissues. In vital structures, such as in the heart and brain and in contracting skeletal muscle, the metabolic factors predominate. Llewellyn-Smith IJ, Verberne AJM, eds. Central Regulation of Autonomic Functions. New York: Oxford University Press; 2011. Timmers HJ, Wieling W, Karemaker JM, et al. Cardiovascular responses to stress after carotid baroreceptor denervation in humans. Ann N Y Acad Sci. 2004;1018:515. Zhang P, Mende U. Regulators of G-protein signaling in the heart and their potential as therapeutic targets. Circ Res. 2011;109: 320. Upon completion of this chapter, the student should be able to answer the following questions: 1.


Physiology_Levy

Physiology_Levy. Upon completion of this chapter, the student should be able to answer the following questions: 1. What are the four major factors that determine cardiac output? Which two of these factors are said to be “coupling factors,” and what is the reason for that description? 2. What is a cardiac function curve, and how is it related to the Frank-Starling mechanism? 3. What is a vascular function curve, and how is it affected by changes in total peripheral resistance, blood volume, and venous tone? 4. Why does the operating point of the cardiovascular system occur at the intersection of the vascular and cardiac function curves? 5. How does evaluation of the cardiac function curve and the vascular function curve enable clinicians to determine the effect of changes in blood volume, vascular tone, and contractility on cardiac output? 6.


Physiology_Levy

Physiology_Levy. 6. What mechanisms in the central nervous system, heart, and systemic vasculature allow cardiac output to increase to the necessary levels during vigorous exercise? 7. What are the cardiovascular consequences of hemorrhage, and what are the compensatory mechanisms that tend to restore arterial pressure and cardiac output? Regulation of Cardiac Output and Blood Pressure Four factors control cardiac output: heart rate, myocardial contractility, preload, and afterload (


Physiology_Levy

Physiology_Levy. Regulation of Cardiac Output and Blood Pressure Four factors control cardiac output: heart rate, myocardial contractility, preload, and afterload ( Fig. 19.1). Heart rate and myocardial contractility are strictly cardiac factors, although they are controlled by various neural and humoral mechanisms. Preload and afterload are factors that are mutually dependent on function of the heart and the vasculature and are important determinants of cardiac output. Preload and afterload are themselves determined by cardiac output and by certain vascular characteristics. Preload and afterload are called coupling factors because they constitute a functional coupling between the heart and blood vessels. To understand regulation of cardiac output, the nature of the coupling between the heart and the vascular system must be appreciated.


Physiology_Levy

Physiology_Levy. In this chapter, two kinds of graphed curves are used to analyze interactions between the cardiac and vascular components of the circulatory system. The first curve, the cardiac function curve, is an expression of the well-known Frank-Starling relationship, and it illustrates the dependence of cardiac output on preload (i.e., central venous or right atrial pressure). The cardiac function curve is a characteristic of the heart itself and is usually studied in hearts completely isolated from the rest of the circulation. This curve has already been discussed in detail in . Later in this chapter, this curve is discussed in association with the other characteristic curve, the vascular function curve, to analyze interactions between the heart and the vasculature. The vascular function curve defines the dependence of central venous pressure on cardiac output. This relationship depends only on several vascular system characteristics, including peripheral vascular resistance, arterial and


Physiology_Levy

Physiology_Levy. defines the dependence of central venous pressure on cardiac output. This relationship depends only on several vascular system characteristics, including peripheral vascular resistance, arterial and venous compliance, and blood volume. The vascular function curve is entirely independent of the characteristics of the heart. Because of this independence, it can be derived experimentally even if a mechanical pump replaces the heart.


Physiology_Levy

Physiology_Levy. The vascular function curve defines the changes in central venous pressure (Pv) that are caused by changes in cardiac output. In this curve, Pv is the dependent variable (or response), and cardiac output is the independent variable (or stimulus). These variables are opposite those of the cardiac function curve, in which Pv (or preload) is the independent variable and cardiac output is the dependent variable. The simplified model of the circulation shown in Fig. 19.2 helps explain how cardiac output determines the level of Pv. In this model, all essential components of the cardiovascular system have been lumped into four basic elements. The right and left sides of the heart, as well as the pulmonary vascular bed, constitute a pump-oxygenator, much like an artificial heart-lung machine used to perfuse •Fig. 19.1 Thefourfactors(inblue squares)thatdeterminecardiacoutput.


Physiology_Levy

Physiology_Levy. the body during open heart surgery. The high-resistance microcirculation is designated the peripheral resistance. Finally, the compliance of the system is subdivided into arterial compliance (Ca) and venous compliance (Cv). As defined in , the compliance (C) of a blood vessel is the change in volume (ΔV) that is accommodated in that vessel per unit change in transmural pressure (ΔP); that is, Equation 19.1 Venous compliance is approximately 20 times greater than arterial compliance. In the example in Fig. 19.2, the ratio of Cv to Ca is set at 19:1 to simplify calculations. To show how a change in cardiac output causes an inverse change in Pv, the hypothetical model has certain characteristics that mimic those of an average adult (see


Physiology_Levy

Physiology_Levy. To show how a change in cardiac output causes an inverse change in Pv, the hypothetical model has certain characteristics that mimic those of an average adult (see Fig. 19.2A ). The flow generated by the heart (i.e., cardiac output; Qh) is 5 L/minute; mean arterial pressure (Pa) is 102 mm Hg; and Pv is 2 mm Hg. Peripheral resistance (R) is the ratio of the arteriovenous pressure difference (Pa − Pv) to flow (Qr) through the resistance vessels; this ratio is equal to 20 mm Hg/L/minute. An arteriovenous pressure difference of 100 mm Hg is sufficient to force a flow rate (Qr) of 5 L/minute through a peripheral resistance of 20 mm Hg/L/minute (see Fig.


Physiology_Levy

Physiology_Levy. An arteriovenous pressure difference of 100 mm Hg is sufficient to force a flow rate (Qr) of 5 L/minute through a peripheral resistance of 20 mm Hg/L/minute (see Fig. 19.2A ). Under equilibrium conditions, this flow rate (Qr) is precisely equal to the flow rate (Qh) pumped by the heart. From heartbeat to heartbeat, the volume of blood in the arteries (Va) and the volume of blood in the veins (Vv) remain constant because the volume of blood transferred from the veins to the arteries by the heart is equal to the volume of blood that flows from the arteries through the resistance vessels and into the veins. *Thus if it were necessary to add x mL of blood to the arterial system to produce a 1–mm Hg increase in arterial pressure, 19x mL of blood would need to be added to the venous system to raise venous pressure by the same amount. Effects of Cardiac Arrest on Arterial and Venous Pressure


Physiology_Levy

Physiology_Levy. Effects of Cardiac Arrest on Arterial and Venous Pressure Fig. 19.2B depicts the circulation at the very beginning of an episode of cardiac arrest; that is, Qh = 0. In the instant immediately after arrest of the heart, the volume of blood in the arteries (Va) and veins (Vv) has not had time to change appreciably. Because arterial pressure and venous pressure depend on Va and Vv, respectively, these pressures are identical to the respective pressures in


Physiology_Levy

Physiology_Levy. Fig. 19.2A (i.e., Pa = 102 and Pv = 2). This arteriovenous pressure gradient of 100 mm Hg forces a flow rate (Qr) of 5 L/minute through the peripheral resistance of 20 mm Hg/L/minute. Thus although cardiac output (Qh) at that point is 0 L/ minute, the rate of flow through the microcirculation (Qt) is 5 L/minute because the potential energy stored in the arteries by the preceding pumping action of the heart causes blood to be transferred from arteries to veins. This transfer occurs initially at the control (steady-state) rate, even though the heart can no longer transfer blood from the veins to the arteries.


Physiology_Levy

Physiology_Levy. As cardiac arrest continues, blood flow through the resistance vessels causes the blood volume in the arteries to decrease progressively and the blood volume in the veins to increase progressively at the same absolute rate. Because the arteries and veins are elastic structures, arterial pressure falls gradually, and the venous pressure rises gradually. This process continues until arterial and venous pressures become equal (see Fig. 19.2C ). Once this condition is reached, the rate of flow (Qr) from the arteries to the veins through the resistance vessels is 0 L/minute, as is Qh. When the effects of cardiac arrest reach this equilibrium state (see


Physiology_Levy

Physiology_Levy. When the effects of cardiac arrest reach this equilibrium state (see Fig. 19.2C ), the pressure attained in the arteries and veins depends on the relative compliance of these vessels. If arterial compliance (Ca) and venous compliance (Cv) are equal, the decline in Pa is equal to the rise in Pv because the decrease in arterial volume would be equal to the increase in venous volume (according to the principle of conservation of mass). Both Pa and Pv would attain the average of their combined values in Fig. 19.2A ; that is, Pa = Pv = (102 + 2)/2 = 52 mm Hg. However, Ca and Cv in a living person are not equal. Veins are much more compliant than arteries; the compliance ratio (Cv/Ca) is approximately 19, the ratio assumed for the model in


Physiology_Levy

Physiology_Levy. Fig. 19.2 . When the effects of cardiac arrest reach equilibrium in an intact subject, the pressure in the arteries and veins is much lower than the average value of 52 mm Hg that occurs when Ca and Cv are equal. Hence, transfer of blood from arteries to veins at equilibrium induces a fall in arterial pressure 19 times greater than the concomitant rise in venous pressure. As Fig. 19.2C shows, Pv would increase by 5 mm Hg (to 7 mm Hg), whereas Pa would fall by 95 (i.e., 19 × 5) mm Hg (to 7 mm Hg). This equilibrium pressure, which prevails in the absence of flow, is referred to as either mean circulatory pressure or static pressure. The pressure in the static system reflects the total blood volume in the system and the overall compliance of the system. •Fig. 19.2 A toD, Simplifiedmodelofthecardiovascularsystem,consistingofapump,arterialcompliance(Ca),peripheralresistance,andvenouscompliance(Cv).


Physiology_Levy

Physiology_Levy. •Fig. 19.2 A toD, Simplifiedmodelofthecardiovascularsystem,consistingofapump,arterialcompliance(Ca),peripheralresistance,andvenouscompliance(Cv). The example of cardiac arrest aids in the understanding of the vascular function curve. The clinician can now begin to assemble a vascular function curve ( Fig. 19.3 ). The independent variable (plotted along the x-axis) is cardiac output, and the dependent variable (plotted along the y-axis) is Pv. Two important points on this curve can be derived from the example in Fig. 19.2 . One point (A in Fig. 19.3 ) represents the control state; that is, when cardiac output is 5 L/minute, Pv is 2 mm Hg. When the heart is arrested (cardiac output = 0), Pv becomes 7 mm Hg at equilibrium (see Fig. 19.2C ); this pressure is the mean circulatory pressure.


Physiology_Levy

Physiology_Levy. Fig. 19.2C ); this pressure is the mean circulatory pressure. The inverse relationship between Pv and cardiac output simply means that when cardiac output is suddenly decreased, the rate at which blood flows from arteries to veins through the capillaries is temporarily greater than the rate at which the heart pumps blood from the veins back •Fig. 19.3 Changes in Central Venous Pressure Produced by Changes in Cardiac Output. Themeancirculatory(orstatic)pressure(Pmc)istheequilibriumpressurethroughoutthecardiovascularsystemwhencardiacoutputis0.PointsBandArepresentthevaluesofvenouspressureatcardiacoutputsof1and5L/minute,respectively. into the arteries. During that transient period, a net volume of blood is transferred from arteries to veins; hence, Pa falls and Pv rises. Now suppose that cardiac output suddenly increases. This example illustrates how a third point (B in


Physiology_Levy

Physiology_Levy. Now suppose that cardiac output suddenly increases. This example illustrates how a third point (B in Fig. 19.3 ) on the vascular function curve is derived. Consider that the arrested heart is suddenly restarted and immediately begins pumping blood from the veins into the arteries at a rate of 1 L/minute (see


Physiology_Levy

Physiology_Levy. Fig. 19.2D ). When the heart first begins to beat, the arteriovenous pressure gradient is 0, and no blood is transferred from the arteries through the capillaries and into the veins. Thus when beating resumes, blood is depleted from the veins at the rate of 1 L/minute, and arterial blood volume is replenished from venous blood volume at that same absolute rate. Hence, Pv begins to fall and Pa begins to rise. Because of the difference in arterial and venous compliance, Pa rises at a rate 19 times faster than the rate at which Pv falls. The resultant arteriovenous pressure gradient causes blood to flow through the peripheral resistance vessels. If the heart maintains a constant output of 1 L/minute, Pa continues to rise and Pv continues to fall until the pressure gradient becomes 20 mm Hg. This gradient forces a rate of flow of 1 L/minute through a peripheral resistance of 20 mm Hg/L/minute. This gradient is achieved by a 19–mm Hg rise (to 26 mm Hg) in Pa and a 1–mm Hg fall (to 6 mm Hg)


Physiology_Levy

Physiology_Levy. gradient forces a rate of flow of 1 L/minute through a peripheral resistance of 20 mm Hg/L/minute. This gradient is achieved by a 19–mm Hg rise (to 26 mm Hg) in Pa and a 1–mm Hg fall (to 6 mm Hg) in Pv. This equilibrium value of Pv (6 mm Hg) for a cardiac output of 1 L/minute also appears on the vascular function curve of


Physiology_Levy

Physiology_Levy. Fig. 19.3 (point B). The 1–mm Hg reduction in Pv reflects a net transfer of blood from the veins to the arteries of the circuit. The reduction in Pv that can be evoked by a sudden increase in cardiac output is limited. At some critical maximal value of cardiac output, sufficient fluid is transferred from the veins to the arteries of the circuit for Pv to fall below ambient pressure. In a system of very distensible vessels, such as the venous system, the greater external pressure causes the vessels to collapse (see ). This •Fig. 19.4 Effectsofincreasedbloodvolume(transfusion curve) anddecreasedbloodvolume(hemorrhage curve) onthevascularfunctioncurve.Similarshiftsinthevascularfunctioncurvecanbeproducedbyincreasesanddecreases,respectively,invenomotortone. venous collapse impedes venous return to the heart. Hence, it limits the maximal value of cardiac output to 7 L/minute in this example (see Fig. 19.3 ), regardless of the capabilities of the pump.


Physiology_Levy

Physiology_Levy. venous collapse impedes venous return to the heart. Hence, it limits the maximal value of cardiac output to 7 L/minute in this example (see Fig. 19.3 ), regardless of the capabilities of the pump. Factors That Influence the Vascular Function Curve Dependence of Venous Pressure on Cardiac Output According to experimental and clinical observations, changes in cardiac output do indeed evoke the alterations in Pa and Pv that have been predicted by the simplified model in Fig. 19.2 The vascular function curve is affected by variations in total blood volume. During circulatory standstill (zero cardiac output), mean circulatory pressure depends only on total vascular compliance and blood volume. For a given vascular compliance, mean circulatory pressure is increased when blood volume is expanded (hypervolemia) and is decreased when blood volume is diminished (hypovolemia). This relationship is illustrated by the y-axis intercepts in Fig.


Physiology_Levy

Physiology_Levy. Fig. 19.4 , in which mean circulatory pressure is 5 mm Hg after hemorrhage and 9 mm Hg after transfusion, in comparison with a value of 7 mm Hg at normal blood volume (normovolemia or euvolemia). The effects of changes in venomotor tone on the vascular function curve closely resemble those of changes in blood volume. In Fig. 19.4 , for example, the transfusion curve could also represent increased venomotor tone, whereas the hemorrhage curve could represent decreased tone. During Cardiacoutputmaydecreaseabruptlywhenamajorcoronaryarterysuddenlybecomesoccluded.Theacute heart failure thatoccursasaresultofmyocardial infarction (deathofmyocardialtissue)isusuallyaccompaniedbyafallinarterialbloodpressureandariseinPv.In


Physiology_Levy

Physiology_Levy. Fig.19.4 itisalsoapparentthatthecardiacoutputatwhichPv= 0variesdirectlywithbloodvolume.Therefore,themaximalvalueofcardiacoutputbecomesprogressivelymorelimitedasthetotalbloodvolumeisreduced.However,thePvatwhichtheveinscollapse(illustratedbythesharpchangeinslopeofthevascularfunctioncurve)isnotsignificantlyalteredbychangesinbloodvolume.Thispressuredependsonlyontheambientpressuresurroundingthecentralveins.Ambientpressureisthepleuralpressureinthethorax(see circulatory standstill, for a given blood volume, the pressure within the vascular system rises as smooth muscle tension exerted within the vascular walls increases (these contractile changes in arteriolar and venous smooth muscle are under nervous and humoral control). The fraction of the blood volume located within the arterioles is very small, whereas the blood volume in the veins is large percentage of total blood volume (see


Physiology_Levy

Physiology_Levy. Table 15.1 ). Thus changes in peripheral resistance (arteriolar tone) have no significant effect on mean circulatory pressure, but changes in venous tone can alter mean circulatory pressure appreciably. Hence, mean circulatory pressure rises with increased venomotor tone and falls with diminished venomotor tone. In experiments, the mean circulatory pressure attained approximately 1 minute after abrupt circulatory standstill is usually substantially above 7 mm Hg, even when blood volume is normal. The elevation to this pressure level is attributable to the generalized venoconstriction that is caused by cerebral ischemia, activation of chemoreceptors, and reduced excitation of baroreceptors. If resuscitation fails, this reflex response subsides as central nervous activity ceases, and mean circulatory pressure then usually falls to a value close to 7 mm Hg.


Physiology_Levy

Physiology_Levy. Venoconstriction is considerably greater in certain regions of the body than in others. In effect, vascular beds that undergo significant venoconstriction constitute blood reservoirs. The skin’s vascular bed is one of the major blood reservoirs in humans. Blood loss evokes profound subcutaneous venoconstriction, which gives rise to the characteristically pale appearance of the skin in response to hemorrhage. Diversion of blood away from the skin frees several hundred milliliters of blood that can be perfused through more vital regions of the body. The vascular beds of the liver, lungs, and spleen are also important blood reservoirs. In humans, however, the volume changes in the spleen are considerably less extensive (see also the sections “ •Fig. 19.5 Effectsofarteriolardilationandconstrictiononthevascularfunctioncurve. The changes in the vascular function curve induced by alterations in arteriolar tone are depicted in


Physiology_Levy

Physiology_Levy. The changes in the vascular function curve induced by alterations in arteriolar tone are depicted in Fig. 19.5 . The amount of blood in the arterioles is small; these vessels contain only approximately 3% of total blood volume (see ). Changes in the contractile state of arterioles do not significantly alter mean circulatory pressure. Thus vascular function curves that represent different peripheral resistances converge at a common point on the y-axis (see Fig. 19.5


Physiology_Levy

Physiology_Levy. Fig. 19.5 Pv varies inversely with total peripheral resistance (TPR) when all other factors remain constant. Physiologically, the relationship between Pv and TPR can be explained as follows: if cardiac output is held constant, a sudden increase in TPR causes a progressively greater volume of blood to be retained in the arterial system. Blood volume in the arterial system continues to increase until Pa rises sufficiently to force a flow of blood equal to cardiac output through the resistance vessels. If total blood volume does not change, this increase in arterial blood volume is accompanied by an equivalent decrease in venous blood volume. Hence, an increase in TPR diminishes Pv proportionately. This relationship between TPR and Pv, together with the inability of peripheral resistance to affect mean circulatory pressure, accounts for the clockwise rotation of the vascular function curves in response to increased arteriolar constriction (see


Physiology_Levy

Physiology_Levy. Fig. 19.5 ). Similarly, arteriolar dilation produces a counterclockwise rotation from the same vertical axis intercept. A higher maximal level of cardiac output is attainable when the arterioles are dilated than when they are constricted (see Fig. 19.5). Cardiac output and venous return are tightly linked. Except for small, transient disparities, the heart cannot pump any more blood than is delivered to it through the venous system. Similarly, because the circulatory system is a closed circuit, venous return to the heart must equal cardiac output over any appreciable time interval. The flow around the entire closed circuit depends on the capability of the pump, the characteristics of the circuit, and the total fluid volume of the system.


Physiology_Levy

Physiology_Levy. Thus cardiac output and venous return are simply two terms for the flow around this closed circuit. Cardiac output is the volume of blood being pumped by the heart per unit time. Venous return is the volume of blood returning to the heart per unit time. At equilibrium, these two volumes are equal. In the following section, certain techniques of circuit analysis are discussed to provide some insight into the control of flow around the circuit. Relating the Cardiac Function Curve to the Vascular Function Curve Coupling Between the Heart and the Vasculature


Physiology_Levy

Physiology_Levy. Relating the Cardiac Function Curve to the Vascular Function Curve Coupling Between the Heart and the Vasculature In accordance with the Frank-Starling law of the heart, cardiac output depends closely on right atrial (or central venous) pressure. Furthermore, right atrial pressure is approximately equal to right ventricular end-diastolic pressure because the normal tricuspid valve acts as a low-resistance junction between the right atrium and ventricle. Graphs of cardiac output as a function of Pv are called cardiac function curves; extrinsic regulatory influences may be expressed as shifts in such curves. A typical cardiac function curve is plotted on the same coordinates as those for a normal vascular function curve in


Physiology_Levy

Physiology_Levy. A typical cardiac function curve is plotted on the same coordinates as those for a normal vascular function curve in Fig. 19.6 . The cardiac function curve is plotted according to the usual convention; that is, the independent variable (Pv) is plotted along the x-axis, and the dependent variable (cardiac output) is plotted along the y-axis. In accordance with the Frank-Starling mechanism, the cardiac function curve reveals that a rise in Pv increases cardiac output. Conversely, the vascular function curve characterizes an inverse relationship between cardiac output and Pv; that is, a rise in cardiac output diminishes Pv. Pv is the dependent variable (or response) and cardiac output is the independent variable (or stimulus) for the vascular function curve. Therefore, to plot a vascular function curve in the conventional manner, Pv should be scaled along the y-axis and cardiac output along the x-axis.


Physiology_Levy

Physiology_Levy. To plot the cardiac and vascular function curves on the same set of axes requires a modification of the plotting convention for one of these curves. The convention for the vascular function curve is violated arbitrarily in this chapter. Note that the vascular function curve in Fig. 19.6 is intended to reflect how Pv (scaled along the x-axis) varies in response to a change in cardiac output (scaled along the y-axis). When the cardiovascular system is represented by a given pair of cardiac and vascular function curves, the intersection of these two curves defines the equilibrium point of that system. The coordinates of this equilibrium point represent •Fig. 19.6 Typical Vascular and Cardiac Function Curves Plotted on the Same Coordinate Axes. Toplotbothcurvesonthesamegraph,thex-axisandy-axisforthevascularfunctioncurveshadtobeswitched;comparetheassignmentofaxeswiththosein Figs. 19.3,19.4,and19.5.


Physiology_Levy

Physiology_Levy. Figs. 19.3,19.4,and19.5. Thecoordinatesoftheequilibriumpoint,attheintersectionofthecardiacandvascularfunctioncurves,representthestablevaluesofcardiacoutputandcentralvenouspressureatwhichthesystemtendstooperate.Anyperturbation(e.g.,asuddenincreaseinvenouspressuretopointA)institutesasequenceofchangesincardiacoutputandvenouspressurethatrestorethesevariablestotheirequilibriumvalues. the values of cardiac output and Pv at which the system tends to operate. Only transient deviations from such values of cardiac output and Pv are possible, as long as the given cardiac and vascular function curves characterize the system accurately. The tendency to operate about this equilibrium point may best be illustrated by the response to a sudden change. Consider the changes caused by a sudden rise in Pv from the equilibrium point to point A in


Physiology_Levy

Physiology_Levy. Fig. 19.6 . This change in Pv might be caused by the rapid injection, during ventricular diastole, of a given volume of blood on the venous vessels of the circuit and simultaneous withdrawal of an equal volume from the arterial vessels of the circuit. Thus although Pv rises, total blood volume remains constant. As defined by the cardiac function curve, this elevated Pv would increase cardiac output (from point A to point B in


Physiology_Levy

Physiology_Levy. Fig. 19.6 ) during the next ventricular systole. The increased cardiac output would then cause the transfer of a net quantity of blood from the veins to the arteries of the circuit, with a consequent reduction in Pv. In one heartbeat, the reduction in Pv would be small (from point B to point C) because the heart would transfer only a fraction of the total venous blood volume to the arteries. As a result of this reduction in Pv, cardiac output during the very next beat diminishes (from point C to point D) by an amount dictated by the cardiac function curve. Because point C is still above the intersection point, the heart pumps blood from the veins to the arteries at a rate greater than that at which blood flows across the peripheral resistance from arteries to veins. Hence, Pv continues to fall. This process continues in diminishing steps until the point of •Fig. 19.7


Physiology_Levy

Physiology_Levy. greater than that at which blood flows across the peripheral resistance from arteries to veins. Hence, Pv continues to fall. This process continues in diminishing steps until the point of •Fig. 19.7 Enhancementofmyocardialcontractility,asbystimulationofcardiacsympatheticnerves,causestheequilibriumvaluesofcardiacoutputandcentralvenouspressure(Pv)toshiftfromtheintersection(pointA)ofthecontrolvascularandcardiacfunctioncurves(continuous curve) totheintersection(pointD)ofthesamevascularfunctioncurvewiththecardiacfunctioncurve(dashed curve) thatrepresentstheresponsetosympatheticstimulation.


Physiology_Levy

Physiology_Levy. intersection is reached. Only one specific combination of cardiac output and venous pressure—the equilibrium point, denoted by the coordinates of the point at which the curves intersect—satisfies the requirements of the cardiac and vascular function curves simultaneously. At the equilibrium point, cardiac output equals venous return, and the system is stable. Combinations of cardiac and vascular function curves also help explain the effects of alterations in ventricular contractility on cardiac output and Pv. In Fig. 19.7, the lower cardiac function curve represents the control state, whereas the upper curve reflects the influence of increased myocardial contractility. This pair of curves is analogous to the ventricular function curves shown in Fig. 18.12. The enhanced ventricular contractility represented by the upper curve in


Physiology_Levy

Physiology_Levy. Fig. 18.12. The enhanced ventricular contractility represented by the upper curve in Fig. 19.7 can be produced by electrical stimulation of the cardiac sympathetic nerves. When the effects of such neural stimulation are restricted to the heart, the vascular function curve is unaffected. Therefore, only one vascular function curve is needed for this hypothetical intervention (see Fig. 19.7 During the control state of the model, the equilibrium values for cardiac output and Pv are designated by point A in


Physiology_Levy

Physiology_Levy. Fig. 19.7 During the control state of the model, the equilibrium values for cardiac output and Pv are designated by point A in Fig. 19.7 . Cardiac sympathetic nerve stimulation abruptly raises cardiac output to point B because of the enhanced myocardial contractility. However, this high cardiac output causes an increase in the net transfer of blood from the veins to the arteries of the circuit, and as a consequence, Pv subsequently begins to fall (to point C). The reduction in Pv then leads to a small decrease in cardiac output. However, cardiac output is still sufficiently high to effect •Fig. 19.8 Duringelectricalstimulationofthecardiacsympatheticnervefibers,aorticbloodflow(cardiacoutput)increased,whereaspressuresintheleftatrium(PLA)andrightatrium(PRA)diminished.Thesedataconformtotheconclusionsderivedfrom


Physiology_Levy

Physiology_Levy. Fig.19.7 ,inwhichtheequilibriumvaluesofcardiacoutputandvenouspressureareobservedtoshiftfrompointAtopointD(i.e.,cardiacoutputincreased,butcentralvenouspressuredecreased)duringcardiacsympatheticnervestimulation.(RedrawnfromSarnoffSJ,etal.Circ Res. 1960;8:1108.) the net transfer of blood from the veins to the arteries of the circuit. Thus both Pv and cardiac output continue to fall gradually until a new equilibrium point (point D) is reached. This equilibrium point is located at the intersection of the vascular function curve and the new cardiac function curve. In Fig. 19.7 , point D lies above and to the left of the control equilibrium point (point A) and indicates that sympathetic stimulation can evoke greater cardiac output despite the lower level of Pv. The biological response to enhancement of myocardial contractility is mimicked by the hypothetical change predicted by the model in this chapter. As depicted in


Physiology_Levy

Physiology_Levy. The biological response to enhancement of myocardial contractility is mimicked by the hypothetical change predicted by the model in this chapter. As depicted in Fig. 19.8 , sympathetic nerves innervating the heart are stimulated during the time denoted by the double-headed arrow. During neural stimulation, cardiac output (aortic flow) rises quickly to a peak value and then falls gradually to a steady-state value significantly higher than the control level. The increase in aortic flow is accompanied by reductions in right and left atrial pressures. Changes in blood volume do not directly affect myocardial contractility, but they do influence the vascular function curve in the manner shown in Fig. 19.4 . Thus to understand how changes in blood volume affect cardiac output and Pv, the appropriate cardiac function curve is plotted along with the vascular function curves that represent the control and experimental states (


Physiology_Levy

Physiology_Levy. Fig. 19.9 ). When blood volume is increased by a blood transfusion, the equilibrium point (point B in Fig. 19.9 ), which denotes the values of cardiac output and Pv after transfusion, lies above and to the right of the control equilibrium point (point A). Thus transfusion increases both cardiac output and Pv. Hemorrhage causes the opposite effect. Mechanistically, the change in ventricular filling pressure (Pv) evoked by a given change in blood volume alters cardiac output by changing the sensitivity of the contractile proteins to the prevailing concentration of intracellular Ca++ (see ). For reasons explained earlier, pure increases or decreases in venomotor tone elicit responses that are like those evoked by increases or decreases, respectively, in total blood volume.


Physiology_Levy

Physiology_Levy. •Fig. 19.9 Afterabloodtransfusion,thevascularfunctioncurveisshiftedtotheright.Therefore,bothcardiacoutputandvenouspressureareincreased,asdenotedbytranslocationoftheequilibriumpointfrompointAtopointB.–2 A B 1086420 0 2 4 6 8 10 Central venous pressure (mm Hg) Transfusion ControlCardiac output (L/min) Analysis of the effects of changes in peripheral resistance on cardiac output and Pv is complex because both the cardiac and vascular function curves shift. When peripheral resistance increases ( Fig. 19.11 ), the vascular function curve is rotated counterclockwise, but it converges on the same Pv axis intercept as the control curve does. Note that vasoconstriction causes a counterclockwise rotation of the vascular function curve in Fig. 19.11 Fig. 19.5 . The direction of rotation differs because the axes for the vascular function curves were switched in these two figures, as explained earlier. The cardiac function curve in


Physiology_Levy

Physiology_Levy. Fig. 19.11 Fig. 19.5 . The direction of rotation differs because the axes for the vascular function curves were switched in these two figures, as explained earlier. The cardiac function curve in Fig. 19.11 is also shifted downward because at any given Pv, the heart is able to pump less blood against the greater cardiac afterload imposed by the increased peripheral resistance. Because both curves in Fig. 19.11 are displaced downward, the new equilibrium point (point B) is below the control point (point A); that is, an increase in peripheral resistance diminishes cardiac output.


Physiology_Levy

Physiology_Levy. Fig. 19.11 are displaced downward, the new equilibrium point (point B) is below the control point (point A); that is, an increase in peripheral resistance diminishes cardiac output. Whether point B falls directly below point A or lies slightly to the right or left of it depends on the magnitude of the shift in each curve. For example, if a given increase •Fig. 19.10 Moderateorsevereheartfailureshiftsthecardiacfunctioncurvesdownwardandtotheright.Beforechangesinbloodvolume,cardiacoutputdecreasesandcentralvenouspressurerises(fromcontrolequilibriumpointAtopointBorpointC).Aftertheincreaseinbloodvolumethatusuallyoccursinheartfailure,thevascularfunctioncurveisshiftedtotheright.Hence,centralvenouspressuremaybeelevatedwithnoreductionincardiacoutput(pointD)or,insevereheartfailure,withsomereductionincardiacoutput(pointE).


Physiology_Levy


Physiology_Levy

Physiology_Levy. Fig.19.10. Hence,withmoderatedegreesofheartfailure,Pviselevated,butcardiacoutputmaybenormal(pointD).Withmoreseveredegreesofheartfailure,Pvisstillelevated,butcardiacoutputissubnormal(pointE). in peripheral resistance shifts the vascular function curve more than it does the cardiac function curve, equilibrium point B is below and to the left of point A; that is, both cardiac output and Pv diminish. Conversely, if the cardiac function curve is displaced more than the vascular function •Fig. 19.11 Anincreaseinperipheralresistanceshiftsthecardiacandvascularfunctioncurvesdownward.Atequilibrium,cardiacoutputisless(pointB)whenperipheralresistanceishighthanwhenperipheralresistanceisnormal(pointA).


Physiology_Levy

Physiology_Levy. •Fig. 19.12 Simplifiedmodelofthecardiovascularsystemthatconsistsoftheleftventricle(LV)andrightventricle(RV),systemicvascularresistance(Rs)andpulmonaryvascularresistance(Rp),systemicarterialandvenouscompliance,andpulmonaryarterialandvenouscompliance.PsaandPsvarethepressuresinthesystemicarteriesandveins,respectively;PpaandPpvarethepressuresinthepulmonaryarteriesandveins,respectively. curve, point B falls below and to the right of point A; that is, cardiac output decreases, but Pv rises. A More Complete Theoretical Model: The Two-Pump System


Physiology_Levy

Physiology_Levy. curve, point B falls below and to the right of point A; that is, cardiac output decreases, but Pv rises. A More Complete Theoretical Model: The Two-Pump System The preceding discussion shows that the interrelationships between cardiac output and Pv are complex, even in an oversimplified circulation model that includes only one pump and just the systemic circulation. In reality, the cardiovascular system includes the systemic and pulmonary circulations and two pumps: the left and right ventricles. Thus the interrelationships among ventricular output, arterial pressure, and atrial pressure are much more complex.


Physiology_Levy

Physiology_Levy. Fig. 19.12 depicts a more complete (but still oversimplified) cardiovascular system model that has two pumps in series (the left and right ventricles) and two vascular beds in series (the systemic and pulmonary vasculature). The series arrangement requires that the flow pumped by the two ventricles be virtually equal to each other over any substantial period; otherwise, all the blood would ultimately accumulate in one or the other of the vascular systems. Because the cardiac function curves for the two ventricles differ substantially, the filling (atrial) pressures for the two ventricles must differ appropriately to ensure equal stroke volumes (see Fig. 18.13


Physiology_Levy

Physiology_Levy. Two basic principles to remember about ventricular function are that (1) the left ventricle pumps blood through the systemic vasculature, and (2) the right ventricle pumps blood through the pulmonary vasculature. However, these principles do not necessarily imply that both ventricles are essential to perfuse the systemic and pulmonary vascular beds adequately. To better understand the relationships between the two ventricles and the two vascular beds, the right ventricular function is examined in more detail as follows. In the circulatory system model shown in


Physiology_Levy

Physiology_Levy. In the circulatory system model shown in Fig. 19.12, consider the hemodynamic consequences that would occur if the right ventricle suddenly ceased its pump function but instead served merely as a passive, low-resistance conduit between the systemic veins and the pulmonary arteries. Under these conditions, the only functional pump would be the left ventricle, which would then be required to pump blood through both the systemic and pulmonary resistances (for the purposes of this discussion, consider the resistance to the flow of blood through the inactive right ventricle to be negligible).


Physiology_Levy

Physiology_Levy. Normally, pulmonary vascular resistance is approximately 10% as great as systemic vascular resistance. Because the two resistances are in series with one another, total resistance would be 10% greater than systemic resistance alone (see ). In a normal cardiovascular system, a 10% (and hence left ventricular afterload) by approximately 10%. This increase would not drastically affect left ventricular function. Under certain conditions, however, this increase in Pa could significantly alter the function of the cardiovascular system. If the 10% increase in total resistance is achieved by adding a small degree of resistance (i.e., pulmonary vascular resistance) to that of the much larger systemic resistance, and if the pulmonary vascular resistance is separated from the systemic resistance by a large degree of compliance (the combined systemic venous and pulmonary arterial compliance), the 10% increase in total resistance could drastically impair operation of the cardiovascular system.


Physiology_Levy

Physiology_Levy. The simulated effects of inactivating the pumping action of the right ventricle in a hydraulic analogue of the circula tory system are shown in Fig. 19.13 . In the model, the right and left ventricles generate cardiac outputs that vary directly with their respective filling pressures. Under control conditions (when the right ventricle is functioning normally), the outputs of the left and right ventricles are equal (5 L/ minute). The right ventricular pumping action causes the pressure in the pulmonary artery (not shown) to exceed the pressure in the pulmonary veins (Ppv) by an amount that forces fluid through the pulmonary vascular resistance at a rate of 5 L/minute. When the right ventricle ceases pumping (arrow 1 in


Physiology_Levy

Physiology_Levy. Fig. 19.13 ), the systemic venous and pulmonary arterial systems, along with the right ventricle itself, become a common passive conduit with a large compliance. When the right ventricle ceases to transfer blood actively from the systemic veins to the pulmonary arteries, pulmonary arterial pressure (Ppa) decreases rapidly (not shown) and systemic venous pressure (Psv) rises rapidly to a common value (≈5 mm Hg). At this low pressure, however, fluid flows from the pulmonary arteries to the pulmonary veins at a greatly reduced rate.


Physiology_Levy

Physiology_Levy. At the start of right ventricular arrest, the left ventricle is pumping fluid from the pulmonary veins to the systemic arteries at the control rate of 5 L/minute, which greatly exceeds the rate at which blood returns to the pulmonary veins once the right ventricle ceases to operate. Hence, pulmonary venous pressure (Ppv) drops sharply. Because pulmonary venous pressure is the preload for the left ventricle, left ventricular (cardiac) output drops abruptly as well and attains a steady-state value of approximately 2.5 L/minute. This effect in turn leads to a rapid reduction in systemic arterial pressure (Psa). In short, stoppage of right ventricular pumping markedly curtails cardiac output, systemic arterial pressure, and pulmonary venous •Fig. 19.13 Changesincardiacoutput,systemicarterialpressure(Psa),systemicvenouspressure(Psv),andpulmonaryvenouspressure(Ppv)evokedbysimulatedrightventricular(RV)failureandbysimulatedinfusionoffluidinthecirculatorymodelshownin


Physiology_Levy

Physiology_Levy. Fig.19.12 .Atarrow 1, thepumpingactionoftherightventriclewasdiscontinued(simulatedRVfailure),andtherightventricleservedonlyasalow-resistanceconduit.Atarrow 2, thefluidvolumeinthesystemwasexpanded,andtherightventriclecontinuedtoserveonlyasaconduit.(ModifiedfromFureySA,etal.Am Heart J. 1984;107:404.) Fig. 19.13). Most of the hemodynamic problems induced by inactivation of the right ventricle can be reversed by an increase in the fluid (blood) volume of the system (arrow 2 in Fig.


Physiology_Levy

Physiology_Levy. Fig. 19.13). Most of the hemodynamic problems induced by inactivation of the right ventricle can be reversed by an increase in the fluid (blood) volume of the system (arrow 2 in Fig. 19.13). If fluid is added until pulmonary venous pressure (left ventricular preload) is raised to its control value, cardiac output and systemic arterial pressure are restored almost to normal, but systemic venous pressure is abnormally elevated. If left ventricular function is normal, adding a normal left ventricular preload evokes normal left ventricular output. The 10% increase in peripheral resistance caused by adding the pulmonary vascular resistance to that of the systemic vascular resistance does not impose a serious burden on left ventricular pumping capacity.


Physiology_Levy

Physiology_Levy. When the right ventricle is inoperative, however, pulmonary blood flow is not normal unless the usual pulmonary arteriovenous pressure gradient (≈10 to 15 mm Hg) prevails. Hence, systemic venous pressure (Psv) must exceed pulmonary venous pressure (Ppv) by this amount.


Physiology_Levy

Physiology_Levy. Maintenance of high systemic venous pressure may lead to the accumulation of tissue fluid (edema) in dependent regions of the body, a characteristic finding in patients with right ventricular heart failure. With this information, the principal function of the right ventricle may be characterized as as follows. From the viewpoint of providing sufficient flow of blood to all tissues in the body, the left ventricle alone can carry out this function. Operation of the two ventricles in series is not essential to provide adequate blood flow to the tissues. The crucial function of the right ventricle is to prevent the rise in systemic venous (and pulmonary arterial) pressure that would be required to force the normal cardiac output through the pulmonary vascular resistance. A normal right ventricle, by preventing an abnormal rise in systemic venous pressure, prevents the development of extensive edema in dependent regions of the body.


Physiology_Levy

Physiology_Levy. Clinically,right ventricular heart failure maybecausedbyocclusivediseasepredominantlyofthecoronaryvesselstotherightventricle.Thesevesselsareaffectedmuchlesscommonlythanthevesselstotheleftventricle.Themajorhemodynamiceffectsofacuteright-sidedheartfailurearepronouncedreductionsincardiacoutputandarterialbloodpressure,andtheprincipaltreatmentisinfusionofbloodorplasma.Bypassoftherightventricle(byanastomosisoftherightatriumtothepulmonaryartery)maybeperformedsurgicallyinpatientswithcertaincongenital cardiac defects, suchasseverenarrowingofthetricuspidvalveormaldevelopmentoftherightventricle.Theeffectsofacuteright-sidedheartfailureorrightventricularbypassaredirectionallysimilartothosepredictedpreviouslyfromanalysisofthemodelshownin Fig.19.13 Role of the Heart Rate in Control of Cardiac Output


Physiology_Levy

Physiology_Levy. Fig.19.13 Role of the Heart Rate in Control of Cardiac Output Cardiac output is the product of stroke volume and heart rate. Analysis of the control of cardiac output has thus far been restricted to the control of stroke volume, and the role of heart rate has not been considered. Analysis of the effect of a change in heart rate on cardiac output is complex because a change in heart rate alters the other three factors (preload, afterload, and myocardial contractility) that determine stroke volume (see Fig. 19.1 ). An increase in heart rate, for example, shortens the duration of diastole. Hence, ventricular filling is diminished; that is, preload is reduced. If an increase in heart rate altered cardiac output, arterial pressure would change; that is, afterload would be altered. A rise in heart rate would increase the net influx of Ca++ per minute into myocardial cells (see also ), and this influx would enhance myocardial contractility.


Physiology_Levy

Physiology_Levy. The effects of changes in heart rate on cardiac output have been studied extensively, and the results are similar to those shown in Fig. 19.14 . As atrial pacing frequency is •Fig. 19.14 Changesinstrokevolume(A) andcardiacoutput (B) inducedbychangesintherateofatrialpacing.(RedrawnfromKumadaM,etal.Jpn J Physiol. 1967;17:538.) gradually increased, stroke volume progressively diminishes (see Fig. 19.14A ). The decrease in stroke volume is caused by the reduced time for ventricular filling. The change in stroke volume is not inversely proportional to the change in heart rate because the direction of the change in cardiac output (Qh) is markedly influenced by the actual heart rate (see Fig. 19.14B ). For example, as pacing frequency is increased from 50 to 100 beats/minute, the increase in heart rate augments Qh. Because Qh = SV × HR, the decrease in stroke volume (SV) over this frequency range must be proportionately less than the increase in heart rate (HR).


Physiology_Levy

Physiology_Levy. Over the frequency range from approximately 100 to 200 beats/minute, however, cardiac output is not affected significantly by changes in pacing frequency (see Fig. 19.14B ). Hence, as pacing frequency is increased, the decrease in stroke volume must be approximately equal to the increase in heart rate. In addition, generalized vascular autoregulation tends to keep tissue blood flow constant (see also ). This adaptation leads to changes in preload and afterload that also keep cardiac output nearly constant. Moreover, at excessively high pacing frequencies (above 200 beats/minute; see


Physiology_Levy

Physiology_Levy. Moreover, at excessively high pacing frequencies (above 200 beats/minute; see Fig. 19.14 ), further increases in heart rate decrease cardiac output. Therefore, the induced decrease in stroke volume must have exceeded the increase in heart rate at this high range of pacing frequencies. At such high pacing frequencies, the ventricular filling time is so severely restricted that compensation is inadequate, and cardiac output decreases sharply. Although the relationship of cardiac output to heart rate is characteristically that of an inverted U in the general population, the relationship varies quantitatively among subjects and among physiological states.


Physiology_Levy

Physiology_Levy. Strong correlations between heart rate and cardiac output must be interpreted cautiously. In people who are exercising, for example, cardiac output and heart rate usually increase proportionately, and stroke volume may remain constant or increase only slightly (see the later section ”). It is tempting to conclude that the increase in cardiac output during exercise must be caused solely by the observed increase in heart rate. However,


Physiology_Levy

Physiology_Levy. Fig. 19.14 shows that over a wide range of heart rates, a change in heart rate may have little influence on cardiac output. The principal increase in cardiac output during exercise must therefore be attributed to other factors. Such ancillary factors include the pronounced reduction in peripheral vascular resistance because of the vasodilation in the active skeletal muscles and the increased contractility of cardiac muscle associated with the generalized increase in sympathetic neural activity. Nevertheless, the increase in heart rate is still an important factor. Abundant data show that if the heart rate cannot increase normally during exercise, the augmentation in cardiac output and the capacity for exercise are severely limited. Because stroke volume changes only slightly during exercise, the increase in heart rate may play an important permissive role in augmenting cardiac output during physical exercise.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Ancillary Factors That Affect the Venous System and Cardiac Output In earlier sections of this chapter, the descriptions of the interrelationships between Pv and cardiac output were simplified by restricting the discussion to the effects evoked by individual variables. However, because the cardiovascular system is regulated by so many feedback control loops, its responses are rarely simple. A change in blood volume, for example, not only affects cardiac output directly through the Frank-Starling mechanism but also triggers reflexes that alter other aspects of cardiac function (such as the heart rate, atrioventricular conduction, and myocardial contractility) and other characteristics of the vascular system (such as peripheral resistance and venomotor tone). Several other factors, especially gravity (see ) and respiration, also regulate cardiac output. Circulatory Effects of Respiratory Activity


Physiology_Levy

Physiology_Levy. Circulatory Effects of Respiratory Activity The normal, periodic activity of the respiratory muscles causes rhythmic variations in vena caval flow (Fig. 19.15 ). During respiration, the reduction in intrathoracic pressure is transmitted to the lumens of the thoracic blood vessels. The reduction in Pv during inspiration increases the pressure gradient between extrathoracic and intrathoracic veins. The consequent acceleration in venous return to the right atrium is shown in Fig. 19.15 as an increase in superior vena caval blood flow from 5.2 mL/sec during expiration to 11 mL/ sec during inspiration.


Physiology_Levy

Physiology_Levy. Fig. 19.15 as an increase in superior vena caval blood flow from 5.2 mL/sec during expiration to 11 mL/ sec during inspiration. The exaggerated reduction in intrathoracic pressure achieved by a strong inspiratory effort against a closed glottis (called Müller’s maneuver) does not increase venous return proportionately. The extrathoracic veins collapse near their entry into the chest when their internal pressures fall below the ambient level. As the veins collapse, flow into the chest momentarily stops. The cessation of flow causes pressure upstream to rise, which forces the collapsed segment to reopen.


Physiology_Levy

Physiology_Levy. During normal expiration, flow into the central veins decelerates. However, the mean rate of venous return during normal respiration exceeds the flow during a brief period of apnea (cessation of respiration). Hence, normal inspiration apparently facilitates venous return more than normal expiration impedes it. In part, venous return is facilitated by the valves in the veins of the extremities. These valves prevent any reversal of flow during expiration. Thus the respiratory muscles and venous valves constitute an auxiliary pump for venous return. •Fig. 19.15 Duringanormalinspiration,intrathoracicpressure,rightatrialpressure(RAP),andjugularvenous(JVP)pressuredecrease,andflowinthesuperiorvenacava(SVCF)increases(from5.2to11mL/sec).AllpressuresaregiveninmmH2O.Femoralarterialpressure(notshown)didnotchangesubstantiallyduringthenormalinspiration.Jugular vein 50 5.2 mL/sec 11 mL/sec SVCF JVP RAP 0 Atrial 0 –100


Physiology_Levy

Physiology_Levy. Sustained expiratory efforts increase intrathoracic pressure and thus impede venous return. Straining against a closed glottis (Valsalva’s maneuver) regularly occurs during coughing, defecation, and heavy lifting. Intrathoracic pressures in excess of 100 mm Hg have been recorded in trumpet players, and pressures higher than 400 mm Hg have been observed during paroxysms of coughing. Such increases in pressure are transmitted directly to the lumens of the intrathoracic arteries. After coughing stops, arterial blood pressure may fall precipitously because of the preceding impediment to venous return. Interplay of Central and Peripheral Factors in Control of the Circulation


Physiology_Levy

Physiology_Levy. Interplay of Central and Peripheral Factors in Control of the Circulation The primary function of the circulatory system is to deliver the nutrients needed for tissue metabolism and growth and to remove the products of metabolism. The contributions of the components of the cardiovascular system to maintain adequate tissue perfusion under different physiological conditions were discussed previously. In this section, the interrelationships among the various components of the circulatory system are explored. The autonomic nervous system and the baroreceptors and chemoreceptors play key roles in regulating the cardiovascular system. Control of fluid balance by the kidneys, with maintenance of a constant blood volume, is also very important.


Physiology_Levy

Physiology_Levy. In any well-regulated system, one way to evaluate the extent and sensitivity of its regulatory mechanisms is to disturb the system and to observe how it restores the preexisting steady state. Two such disturbances, physical exercise and hemorrhage, are discussed in the following sections to illustrate operation of the various regulatory factors.


Physiology_Levy

Physiology_Levy. The cardiovascular adjustments that occur during exercise consist of a combination of neural and local (chemical) factors. Neural factors include (1) central command, (2) reflexes that originate in the contracting muscle, and (3) the baroreceptor reflex. Central command is the cerebrocortical activation of the sympathetic nervous system that produces cardiac acceleration, increased myocardial contractile force, and peripheral vasoconstriction. Reflexes are activated intramuscularly by stimulation of mechanoreceptors (by stretch, tension) and chemoreceptors (by metabolic products) in response to muscle contraction. Impulses from these receptors travel centrally via small myelinated (group III) and unmyelinated (group IV) afferent nerve fibers. Group IV unmyelinated fibers may represent the muscle chemoreceptors, inasmuch as no morphological chemoreceptor has been identified. The central connections of this reflex are unknown, but the efferent limb consists of sympathetic nerve fibers


Physiology_Levy

Physiology_Levy. muscle chemoreceptors, inasmuch as no morphological chemoreceptor has been identified. The central connections of this reflex are unknown, but the efferent limb consists of sympathetic nerve fibers to the heart and peripheral blood vessels. The baroreceptor reflex is described in , and local factors that influence skeletal muscle blood flow (metabolic vasodilators) are described in . Vascular chemoreceptors are important in regulation of the cardiovascular system during exercise. Evidence for this assertion comes from the observations that the PaCO2, the PaO2, and the pH of arterial blood remain normal during exercise.


Physiology_Levy

Physiology_Levy. Mild to Moderate Exercise In humans or trained animals, anticipation of physical activity inhibits vagal nerve impulses to the heart and increases sympathetic discharge. The result is an increase in heart rate and myocardial contractility. The tachycardia and enhanced contractility increase cardiac output. When cardiac stimulation occurs, the sympathetic nervous system also changes vascular resistance in the periphery. Sympathetic nervous system–mediated vasoconstriction increases vascular resistance and thereby diverts blood away from the skin, kidneys, splanchnic regions, and inactive Cardiac output (L/min) 22 18 14 10 6 2 0.25 1 2 3 4 O2 uptake (L/min) Skin Heart and brain Viscera Muscle Maximum Vo2 .


Physiology_Levy

Physiology_Levy. Cardiac output (L/min) 22 18 14 10 6 2 0.25 1 2 3 4 O2 uptake (L/min) Skin Heart and brain Viscera Muscle Maximum Vo2 . •Fig. 19.16 ApproximatedistributionofcardiacoutputatrestandatdifferentlevelsofexerciseuptothemaximalO2consumption(V˜O2)in 0 0 5 10 15 800 1600 0.006 0.010 0.014 60 100 140 180 5 10 15 90 100 110 60 100 140 180 Mean Systolic pressure Diastolic pressure anormalyoungman.(RedrawnfromRuchHP,PattonTC.Physiology and Biophysics. 12thed.Philadelphia:Saunders;1974.) Fig. 19.16 ). This increase in vascular resistance persists throughout the period of exercise.


Physiology_Levy

Physiology_Levy. Fig. 19.16 ). This increase in vascular resistance persists throughout the period of exercise. Cardiac output and blood flow to active muscles increase as the intensity of exercise increases. Blood flow to the myocardium increases, whereas flow to the brain is unchanged. Blood flow in the skin initially decreases during exercise, then increases as body temperature rises with increments in the duration and intensity of exercise, and finally decreases when the skin vessels constrict as total body O2 consumption nears its maximal value (see Fig. 19.16


Physiology_Levy

Physiology_Levy. The major circulatory adjustment to prolonged exercise occurs in the vasculature of the active muscles. Local formation of vasoactive metabolites causes marked dilation of the resistance vessels. This dilation progresses with increases in the intensity of exercise. Potassium is one of the vasodilator substances released by the contracting muscle, and this ion may be partly responsible for the initial decrease in vascular resistance in the active muscles. Other contributing factors may be the release of adenosine and a decrease in tissue pH during sustained exercise. The local accumulation of metabolites causes the terminal arterioles to relax, and blood flow through the muscle may increase 15to 20-fold above the resting level. This metabolic vasodilation of the precapillary vessels in active muscles occurs very soon after the onset of exercise. The decrease in TPR enables the heart to pump more blood at a lesser load, and it pumps more efficiently than if TPR were unchanged (see •Fig.


Physiology_Levy

Physiology_Levy. muscles occurs very soon after the onset of exercise. The decrease in TPR enables the heart to pump more blood at a lesser load, and it pumps more efficiently than if TPR were unchanged (see •Fig. 19.17 Effectsofdifferentlevelsofexercise(i.e.,work)onseveralcardiovascularvariables.(DatafromCarlstenA,GrimbyG.The Circulatory Response to Muscular Exercise in Man. Springfield,


Physiology_Levy

Physiology_Levy. IL:CharlesCThomas;1966.) Marked changes in the capillary circulation also occur during exercise. At rest, only a small percentage of the capillaries are perfused, whereas in actively contracting muscle, all or nearly all of the capillaries contain flowing blood (capillary recruitment). The surface area available for exchange of gases, water, and solutes is increased many times. Furthermore, hydrostatic pressure in the capillaries is increased because of relaxation of the resistance vessels. Hence, water and solutes move into the muscle tissue. Tissue pressure rises and remains elevated during exercise as fluid continues to move out of the capillaries; this tissue fluid is carried away by the lymphatic vessels. Lymph flow is increased as a result of the rise in capillary hydrostatic pressure and the massaging effect of the contracting muscles on the valve-containing lymphatic vessels (see


Physiology_Levy

Physiology_Levy. Contracting muscle avidly extracts O2 from the perfusing blood and thereby increases the arteriovenous O2 difference (


Physiology_Levy

Physiology_Levy. Fig. 19.17 ). This release of O2 from blood is facilitated by the shift in the oxyhemoglobin dissociation curve during exercise. During exercise, the high concentration of CO2 and the formation of lactic acid cause a reduction in tissue pH. This decrease in pH, in addition to the increase in temperature in the contracting muscle, shifts the oxyhemoglobin dissociation curve to the right (see ). Therefore, at any given PO2, less O2 is held by the hemoglobin in the red blood cells, and consequently more O2 is available for the tissues. Oxygen consumption may increase as much as 60-fold, with only a 15-fold increase in muscle blood flow. Muscle myoglobin may serve as a limited O2 store during exercise, and it can release the attached O2 at very low partial pressures. However, myoglobin can also facilitate O2 transport from capillaries to mitochondria by serving as an O2 carrier.