Physiology_Levy

Physiology_Levy. Fig. 17.40 ). Pericytes regulate blood flow by adjusting vascular diameter, and they secrete angiopoetin, a growth factor that stimulates the expression of occludins in endothelial cells. Occludins are prominently expressed in brain endothelial cells, in contrast to their sparse distribution in nonneural endothelium. The neurovascular unit regulates blood flow and capillary permeability. Thus the neurovascular unit is involved in pathological states, including hypoxia, neurodegenerative diseases, and inflammation, that are characterized by dysfunction of the blood-brain barrier.


Physiology_Levy

Physiology_Levy. The extrinsic innervation of cerebral (pial) vessels consists of components of the autonomic nervous system. Cervical sympathetic nerve fibers that accompany the internal carotid and vertebral arteries into the cranial cavity innervate the cerebral vessels. In comparison to other vascular beds, sympathetic control of the cerebral vessels is weak, and the contractile state of the cerebrovascular smooth muscle depends primarily on local metabolic factors. The density of α1-adrenergic receptors is less than in other vascular beds. Cerebral vessels receive parasympathetic fibers from the facial nerve that produce a slight vasodilation


Physiology_Levy

Physiology_Levy. Controls: rest Sens 1 Sens 2 •Fig. 17.41 Effects of Different Stimuli on Regional Blood Flow in the Contralateral Human Cerebral Cortex. Sens1,low-intensityelectricalstimulationofthehand;Sens2,high-intensity(painful)electricalstimulationofthehand.Otherstimuliareasnoted.(RedrawnfromIngvarDH.Brain Res. 1976;107:181.) on stimulation. The sympathetic nervous system exerts the most prominent effect on cerebral blood flow during pathophysiological conditions.


Physiology_Levy

Physiology_Levy. In general, total cerebral blood flow is relatively constant and is autoregulated. Autoregulation of cerebral blood flow involves interplay among myogenic, metabolic, and neural mechanisms much as described for peripheral vessels (see ). However, regional blood flow in the brain is associated with regional neural activity. For example, movement of one hand results in increased blood flow only in the hand area of the contralateral sensorimotor and premotor cortex. Talking, reading, and other stimuli to the cerebral cortex are also associated with increased blood flow in the appropriate regions of the contralateral cortex ( Fig. 17.41 ). Glucose uptake also corresponds to regional cortical neuronal activity. Thus when the retina is stimulated by light, uptake of glucose is enhanced in the visual cortex.


Physiology_Levy

Physiology_Levy. Fig. 17.41 ). Glucose uptake also corresponds to regional cortical neuronal activity. Thus when the retina is stimulated by light, uptake of glucose is enhanced in the visual cortex. The neurovascular unit plays an integral role in the discrete regulation of blood flow. Production of vasoactive compounds couples increased neuronal activity to greater uptake of oxygen and glucose. Within the neurovascular unit, astrocytes link neurons with the microcirculation (see


Physiology_Levy

Physiology_Levy. Fig. 17.40 ). At one pole, astrocytes surround presynaptic and postsynaptic neurons at synapses. At the other pole, astrocytes converge on vascular smooth muscle and endothelial cells of cerebral vessels. When activated by the neurotransmitter glutamate or acetylcholine, astrocytes produce inositol trisphosphate (IP3), which causes the release of Ca++, which, in turn, activates large conductance potassium (BKCa) channels. The released K+ raises extracellular [K+] to 8 to 15 mEq/L in the space between the astrocyte and arteriolar smooth muscle. The elevated extracellular [K+] causes hyperpolarization of smooth muscle by activating Na+/K+-ATPase and also by increasing the conductance of inward-rectifying K+ channels. The hyperpolarization reduces Ca++ entry into vascular smooth muscle because the membrane potential is shifted away from the threshold. Hence, the parenchymal arteriole dilates, and blood flow increases.


Physiology_Levy

Physiology_Levy. With regard to K+ , stimuli such as hypoxia, electrical stimulation of the brain, and seizures elicit rapid increases in cerebral blood flow, and they are associated with increases in perivascular K+ . The increments in K+ are similar to those that produce pial arteriolar dilation when K+ is applied topically to these vessels. When extracellular K+ exceeds 15 mEq/L, smooth muscle cells depolarize, and Ca++ entry is increased to cause contraction and vasoconstriction. Thus the extracellular [K+] has a dual effect on smooth muscle function that is derived from its actions on Na+/K+-ATPase, K+ conductance, and the K+ concentration gradient.


Physiology_Levy

Physiology_Levy. The cerebral vessels are also regulated by CO2. Increases in arterial blood CO2 tension (PaCO2) elicit marked cerebral vasodilation; for example, inhalation of 7% CO2 increases cerebral blood flow twofold. Conversely, decreases in PaCO2, caused by hyperventilation, diminish cerebral blood flow. CO2 evokes changes in arteriolar resistance by altering perivascular pH. When PaCO2 and the HCO3 − concentration are independently changed, pial vessel diameter and blood flow are inversely related to pH, regardless of the level of PaCO2 or [HCO3 −]. Acidosis initiates a marked vasodilation of brain arterioles. The vasodilation is mediated by a very localized release of Ca++ from the endoplasmic reticulum (Ca++ “sparks”). This local Ca++ signal activates large conductance BKCa channels; the ensuing hyperpolarization stabilizes the vascular smooth muscle cell and opposes vasoconstriction.


Physiology_Levy

Physiology_Levy. Elevationinintracranialpressure,causedbyabraintumor,resultsinanincreaseinsystemicbloodpressure.Thisresponse,calledCushing’s phenomenon, isevokedbyischemicstimulationofvasomotorregionsinthemedulla.Cushing’sphenomenonhelpsmaintaincerebralbloodflowinconditionssuchasexpandingintracranialtumors. Carbon dioxide diffuses into vascular smooth muscle from brain tissue or from the lumen of blood vessels, whereas H+ in blood is prevented from reaching arteriolar smooth muscle by the blood-brain barrier. Hence, cerebral vessels dilate when the [H+] of cerebrospinal fluid is increased, but these vessels dilate only minimally in response to an increase in the [H+] of arterial blood. Chemical regulation of cerebral blood flow by PaCO2 is impaired in humans with endothelial dysfunction (e.g., diabetes, hypertension); the relative roles of H+ and NO in response to changes of PaCO2 are not clear.


Physiology_Levy

Physiology_Levy. Potassium concentration also affects cerebral blood flow. Hypoxia, electrical stimulation of the brain, and seizures elicit rapid increases in cerebral blood flow and in perivascular [K+]. The increases in [K+] are similar in magnitude to those that produce pial arteriolar dilation when K+ is applied topically to these vessels. However, the increase in [K+] is not sustained throughout the period of cerebral stimulation. Thus only the initial increase in cerebral blood flow can be attributed to the release of K+ .


Physiology_Levy

Physiology_Levy. Adenosine also has a major effect on cerebral blood flow. Adenosine levels in the brain increase in response to ischemia, hypoxemia, hypotension, hypocapnia, electrical stimulation of the brain, and induced seizures. Topically applied adenosine is a potent dilator of the pial arterioles. Any intervention that either reduces the O2 supply to the brain or increases the O2 requirements of the brain results in the rapid (within 5 seconds) formation of adenosine in cerebral tissue. Unlike the changes in pH or [K+], the adenosine concentration in the brain increases with initiation of the change in O2 supply, and it remains elevated throughout the period of O2 imbalance. The adenosine that is released into cerebrospinal fluid during cerebral ischemia becomes incorporated into adenine nucleotides in cerebral tissue. These local factors, including pH, K+, and adenosine, act in concert to adjust cerebral blood flow to the metabolic activity of the brain. The cerebral circulation displays


Physiology_Levy

Physiology_Levy. in cerebral tissue. These local factors, including pH, K+, and adenosine, act in concert to adjust cerebral blood flow to the metabolic activity of the brain. The cerebral circulation displays reactive hyperemia


Physiology_Levy

Physiology_Levy. CHAPTER 17 Properties of the Vasculature and excellent autoregulation when arterial blood pressure is between 60 and 160 mm Hg. Mean arterial pressures below 60 mm Hg result in reduced cerebral blood flow and then syncope, whereas mean pressures above 160 mm Hg may lead to increased permeability of the blood-brain barrier and consequently to cerebral edema. Hypercapnia or any other potent vasodilator abolishes autoregulation of cerebral blood flow. Autoregulation of cerebral blood flow is probably mediated by a myogenic mechanism that is modulated by a metabolic component.


Physiology_Levy

Physiology_Levy. The gastrointestinal tract is supplied by the celiac, superior mesenteric, and inferior mesenteric arteries. The superior mesenteric artery carries more than 10% of the cardiac output. Small mesenteric arteries form an extensive vascular network in the submucosa of the gastrointestinal tract. The arterial branches penetrate the longitudinal and circular muscle layers of the tract, and they give rise to thirdand fourth-order arterioles. Some third-order arterioles in the submucosa supply the tips of the villi ( Fig. 17.42 The direction of blood flow in the capillaries and venules in a villus is opposite that in the main arteriole (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 17.42 The direction of blood flow in the capillaries and venules in a villus is opposite that in the main arteriole (see Fig. 17.42 ). This arrangement is a countercurrent exchange system. Effective countercurrent exchange enables diffusion of O2 from arterioles to venules. At low blood flow rates, a substantial portion of the O2 may be shunted from arterioles to venules near the base of the villus. This reduces the O2 supply to the mucosal cells at the tip of the villus. When intestinal blood flow is very low, shunting of O2 is so great that extensive necrosis of the intestinal villi takes place. Neural control of the mesenteric circulation is almost exclusively sympathetic. Increased sympathetic activity, through α1-adrenergic receptors, constricts the mesenteric arterioles and capacitance vessels. These receptors are preeminent in the mesenteric circulation. However, β2-adrenergic receptors are also present, and so the agonist isoproterenol causes vasodilation.


Physiology_Levy

Physiology_Levy. In response to aggressive behavior or to artificial stimulation of the hypothalamic “defense” area, pronounced vasoconstriction occurs in the mesenteric vascular bed. This vasoconstriction shifts blood flow from the less important intestinal circulation to the more crucial skeletal muscles, heart, and brain. Autoregulation of blood flow is not as well developed in the intestinal circulation as in other vascular beds. The principal mechanism responsible for autoregulation is metabolic, although a myogenic mechanism probably also


Physiology_Levy

Physiology_Levy. Simple columnar epithelium with goblet cells •Fig. 17.42 Microcirculation Pattern of the Small Intestine. A, Capillaryplexusesarisefromarteriolesinthevillusandalsointheintestinalcrypt.Bloodleavestheintestinalcryptviavenulesthatentertheportalcirculation.B, Lymphaticvessels(lacteals)originatewithinthevillusandeventuallyformaplexusatthebaseofthevillus.(RedrawnfromKierszenbaumA.Histology and Cell Biology: An Introduction to Pathology. Philadelphia:Mosby;2002.) ). The adenosine concentration in mesenteric venous blood rises fourfold after brief arterial occlusion. It also rises during enhanced metabolic activity of the intestinal mucosa, such as during absorption of food. Adenosine, a potent vasodilator in the mesenteric vascular bed, may be the principal metabolic mediator of autoregulation. However, [K+] and altered plasma osmolality may also contribute to autoregulation.


Physiology_Levy

Physiology_Levy. Oxygen consumption by the small intestine is more rigorously controlled than is blood flow. Experiments have shown that O2 uptake of the small intestine remains constant when arterial perfusion pressure is varied between 30 and 125 mm Hg. Food ingestion increases intestinal blood flow. Secretion of certain gastrointestinal hormones contributes to this hyperemia. Gastrin and cholecystokinin augment intestinal blood flow, and they are secreted when food is ingested. Absorption of food also affects intestinal blood flow. Undigested food has no vasoactive influence, whereas several products of digestion are potent vasodilators. Among the various constituents of chyme, the principal mediators of mesenteric hyperemia are glucose and fatty acids.


Physiology_Levy

Physiology_Levy. Normally, blood flow to the liver is approximately 25% of cardiac output. Hepatic blood flow is supplied by two sources: the portal vein (≈75%) and the hepatic artery. Because portal venous blood has already passed through the gastrointestinal capillary bed, much of the O2 of the portal vein blood flow has already been extracted. The hepatic artery delivers the remaining 25% of the blood, which is fully saturated with O2. Hence, approximately three fourths of the O2 used by the liver is derived from hepatic arterial blood. The small branches of the portal vein and hepatic artery give rise to terminal portal venules and hepatic arterioles (


Physiology_Levy

Physiology_Levy. The small branches of the portal vein and hepatic artery give rise to terminal portal venules and hepatic arterioles ( Fig. 17.43 ). These terminal vessels enter the hepatic acinus (the functional unit of the liver) at its center. Blood flows from these terminal vessels into the sinusoid capillaries, which constitute the capillary network of the liver. The sinusoid capillaries radiate toward the periphery of the acinus, where they connect with the terminal hepatic venules. Blood from these terminal venules drains into progressively larger branches of the hepatic veins, which are tributaries of the inferior vena cava.


Physiology_Levy

Physiology_Levy. •Fig. 17.43 Microcirculation of the Hepatic Acinus. Arrows indicatethedirectionofbloodflowfromtheterminalportionsofthehepaticarteryandportalveintothesinusoidcapillaries.Themixtureofarterialandvenousbloodflowsintothecentralveinandthenpassesintothesublobularvein.(RedrawnfromRossMH,PawlingW.Histology:A Text and Atlas: With Correlated Cell and Molecular Biology. Philadelphia:LippincottWilliams&Wilkins;2006.) Periportal space (space of Mall) Capillary Terminal branch of hepatic artery Terminal branch of portal vein Portal canal Arteriosinusoidal branch Lymphatic vessel Bile ductule Inlet venule Hepatic sinusoid Terminal hepatic venule (central vein) Sublobular vein


Physiology_Levy

Physiology_Levy. Mean blood pressure in the portal vein is approximately 10 mm Hg, and mean blood pressure in the hepatic artery is approximately 90 mm Hg. The resistance of the vessels upstream to the hepatic sinusoid capillaries is considerably greater than that of the downstream vessels. Consequently, the pressure in the sinusoid capillaries is only 2 or 3 mm Hg greater than that in the hepatic veins and inferior vena cava. The ratio of presinusoidal to postsinusoidal resistance is much greater in the liver than in almost any other vascular bed. Hence, drugs and other interventions that alter presinusoidal resistance usually affect pressure in the sinusoid capillaries and fluid exchange across the sinusoidal wall only slightly. However, changes in hepatic and central venous pressure are transmitted almost quantitatively to the hepatic sinusoid capillaries, and they profoundly affect the transsinusoidal exchange of fluids. Regulation of Flow


Physiology_Levy

Physiology_Levy. Regulation of Flow Blood flow in the portal venous and hepatic arterial systems varies reciprocally. When blood flow is curtailed in one system, flow increases in the other but does not fully compensate for the decreased flow in the first system. The portal venous system is not autoregulated. As portal Pv and flow are raised, resistance either remains constant or decreases. The hepatic arterial system is autoregulated, however, and adenosine may be involved in this adjustment of blood flow. The liver tends to maintain constant O2 consumption because O2 extraction from hepatic blood is very efficient. As the rate of O2 delivery to the liver varies, the liver compensates by an appropriate change in the fraction of O2 extracted from blood. Such extraction is facilitated by the distance between the presinusoidal vessels at the acinar center and the postsinusoidal vessels at the periphery of the acinus (see


Physiology_Levy

Physiology_Levy. Fig. 17.43 ). The substantial distance between these types of vessels prevents countercurrent exchange of O2, in contrast to the countercurrent exchange that occurs in an intestinal villus. The sympathetic nerves constrict the presinusoidal resistance vessels in the portal venous and hepatic arterial systems. Neural effects on the capacitance vessels are more important, however. The liver contains approximately 15% of the total blood volume of the body. In appropriate conditions, as in response to hemorrhage, approximately half of the hepatic blood volume can be rapidly expelled by constriction of the capacitance vessels (see also ). Hence, the liver is an important blood reservoir in humans.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Fetal circulation differs from the circulation in postnatal infants. Of most importance is that the fetal lungs are functionally inactive, and the fetus depends completely on the placenta for O2 and nutrients. Oxygenated fetal blood from the placenta passes through the umbilical vein to the fetal liver. Approximately half the flow from the placenta passes through the liver, and the remainder bypasses the fetal liver and reaches the inferior vena cava through the ductus venosus (Fig. 17.44 ). Blood from the ductus venosus joins the blood returning from the lower part of the fetal trunk and the extremities in the inferior vena cava. This blood merges with blood from the fetal liver through the hepatic veins.


Physiology_Levy

Physiology_Levy. The streams of blood tend to maintain their characteristics in the inferior vena cava and are divided into two streams of unequal size by the edge of the interatrial septum (crista dividens). The larger stream, which contains mainly blood from the umbilical vein, is shunted from the inferior vena cava to the left atrium through the foramen ovale (see Fig. 17.44 ). The other stream passes into the right atrium, where it merges with blood returning from the upper parts of the fetal body through the superior vena cava and with blood from the myocardium.


Physiology_Levy

Physiology_Levy. Unlike the ventricles in adults, those in a fetus operate essentially in parallel. Only a tenth of right ventricular output passes through the lungs because the pulmonary vascular resistance in the fetus is high. The remainder passes from the fetal pulmonary artery through the ductus arteriosus to the aorta at a point distal to the origins of the arteries to the fetal head and upper extremities. Blood flows from the pulmonary artery to the aorta because pulmonary vascular resistance is high, and the diameter of the ductus arteriosus is as large as that of the descending aorta.


Physiology_Levy

Physiology_Levy. The large volume of blood that passes through the foramen ovale into the fetal left atrium is joined by blood returning from the lungs, and it is pumped out by the left ventricle into the aorta. Most of the blood in the ascending aorta goes to the fetal head, upper thorax, and arms; the remainder joins blood from the ductus arteriosus and supplies the rest of the body. The amount of blood pumped by the left ventricle is approximately half that pumped by the right ventricle. The major fraction of the blood that passes down the descending aorta comes from the ductus arteriosus and right ventricle and flows by way of the two umbilical arteries to the placenta. Oxygen saturation of fetal blood occurs at various loci (see Fig. 17.44 ). Thus the fetal tissues that receive the most highly saturated blood are the liver, heart, and upper parts of the body, including the head.


Physiology_Levy

Physiology_Levy. Fig. 17.44 ). Thus the fetal tissues that receive the most highly saturated blood are the liver, heart, and upper parts of the body, including the head. At the placenta, the chorionic villi dip into the maternal sinuses, and O2, CO2, nutrients, and metabolic waste products are exchanged across the membranes. The barrier to exchange prevents equilibration of O2 between the two circulations at normal rates of blood flow. Therefore, the PO2 of the fetal blood that leaves the placenta is very low. Were it not for the fact that fetal hemoglobin has a greater affinity for O2 than adult hemoglobin does, the fetus would not receive an adequate O2 supply. The fetal oxyhemoglobin dissociation curve is shifted to the left. Therefore, at equal pressures of O2, fetal blood carries significantly more O2 than maternal blood does.


Physiology_Levy

Physiology_Levy. In early gestation, the high glycogen levels that prevail in cardiac myocytes may protect the heart from acute periods of hypoxia. Glycogen levels decrease in late gestation, and they reach adult levels by term. The umbilical vessels have thick muscular walls that react to trauma, tension, sympathomimetic amines, bradykinin, angiotensin, and changes in PO2. In animals in which the umbilical cord is not tied, hemorrhage of the newborn is minimized by constriction of these large umbilical vessels in response to stretching of the umbilical arteries and by an associated increase in PO2 in systemic arteries. Closure of the umbilical vessels increases total peripheral resistance and the arterial blood pressure of the infant. When blood flow through the umbilical vein ceases, the ductus venosus, a thick-walled vessel with a muscular sphincter, closes. The factor that initiates closure of the ductus venosus is unknown.


Physiology_Levy

Physiology_Levy. atupperleftillustratesthedirectionofflowofamajorportionoftheinferiorvenacavalbloodthroughtheforamenovaletotheleftatrium.Arrows indicatethedirectionsofflow.(DatafromDawesGS,etal.J Physiol. 1954;126:563.)


Physiology_Levy

Physiology_Levy. Immediately after birth, the asphyxia caused by constriction or clamping of the umbilical vessels, together with cooling of the body, activates the respiratory center of the newborn infant. As the lungs fill with air, pulmonary vascular resistance decreases to approximately 10% of the value that existed before lung expansion. This change in vascular resistance is not caused by the presence of O2 in the lungs because the change is just as great if the lungs are filled with N2. However, filling the lungs with liquid does not reduce pulmonary vascular resistance.


Physiology_Levy

Physiology_Levy. After birth, left atrial pressure is raised above that in the inferior vena cava and right atrium by (1) the decrease in pulmonary resistance, with the consequent large flow of blood through the lungs to the left atrium; (2) the reduction of flow to the right atrium caused by occlusion of the umbilical vein; and (3) the increased resistance to left ventricular output produced by occlusion of the umbilical arteries. Reversal of the pressure gradient across the atria abruptly closes the valve over the foramen ovale, and the septal leaflets fuse over a period of several days.


Physiology_Levy

Physiology_Levy. The decrease in pulmonary vascular resistance causes the pressure in the pulmonary artery to fall to approximately half its previous level (to ≈35 mm Hg). This change in pressure, coupled with a slight increase in aortic pressure, reverses the flow of blood through the ductus arteriosus. However, within several minutes, the large ductus arteriosus begins to constrict. This constriction produces turbulent flow, which is manifested as a murmur in newborn infants. Constriction of the ductus arteriosus is progressive and usually complete within 1 to 2 days after birth. Closure of the ductus arteriosus appears to be initiated by the high PO2 of the arterial blood passing through it; pulmonary ventilation with O2 closes the ductus, whereas ventilation with air low in O2 opens this shunt vessel. Whether O2 acts directly on the ductus or through the release of a vasoconstrictor substance is not known.


Physiology_Levy

Physiology_Levy. At birth, the walls of the two ventricles have approximately equal thickness. In addition, the muscle layer of the pulmonary arterioles is thick; this thickness is partly responsible for the high pulmonary vascular resistance of the fetus. After birth, the thickness of the walls of the right ventricle diminishes, as does the muscle layer of the pulmonary arterioles. In contrast, the left ventricular walls become thicker. These changes progress over a period of weeks after birth and reflect the effects of different hemodynamic forces (e.g., vascular resistance) on the two ventricles. Cardiac hypertrophy underlies the increase of heart weight during the normal growth period after birth. The physical demands imposed by the developing cardiovascular system, together with increased levels of soluble factors (e.g., growth hormone, insulin-like growth factor-1), account for physiological hypertrophy by which left ventricular mass more than doubles during the period from birth to early


Physiology_Levy

Physiology_Levy. of soluble factors (e.g., growth hormone, insulin-like growth factor-1), account for physiological hypertrophy by which left ventricular mass more than doubles during the period from birth to early adulthood.


Physiology_Levy

Physiology_Levy. Theductusarteriosusoccasionallyfailstocloseafterbirth.Inthenewborn,thiscongenitalcardiovascularabnormality,calledpatent ductus arteriosus, cansometimesbecorrectedbytheadministrationofnonsteroidalanti-inflammatoryagentssuchasibuprofen.Ifthisdoesnotresultinclosureoftheductusorifthechildisolder,closuremustbeachievedsurgically. 1. The vascular system is composed of two major subdivisions: the systemic circulation and the pulmonary circulation. These subdivisions are in series with each other and are composed of a number of vessel types (e.g., arteries, arterioles, capillaries) that are aligned in series with one another. In general, the vessels of a given type are arranged in parallel with each other. 2. The mean velocity (v) of blood flow in a given type of vessel is directly proportional to the total blood flow being pumped by the heart, and it is inversely proportional to the cross-sectional area of all the parallel vessels of that type. 3.


Physiology_Levy

Physiology_Levy. 3. Poiseuille’s law characterizes blood flow that is steady and laminar in vessels larger than arterioles. However, blood flow is nonnewtonian in very small blood vessels (i.e., Poiseuille’s law is not applicable). 4. Flow tends to become turbulent when (1) flow velocity is high, (2) fluid viscosity is low, (3) fluid density is great, (4) vessel diameter is large, or (5) the wall of the vessel is irregular. 5. Arteries not only conduct blood from the heart to the capillaries but also store some of the ejected blood during each cardiac systole. Hence, blood flow continues through the capillaries during cardiac diastole. Veins return blood to the heart from the capillaries and have a relatively low resistance and high capacitance that enables them to serve as reservoirs for blood. 6.


Physiology_Levy

Physiology_Levy. 6. The aging process diminishes compliance of the arteries, as well as of the veins. The less compliant the arteries are, the more work the heart must do to achieve a given cardiac output. The less compliant the veins are, the poorer is their ability to store blood. 7. Mean arterial pressure varies directly with cardiac output and total peripheral resistance. Arterial pulse pressure varies directly with stroke volume but inversely with arterial compliance. 8. Blood flow through capillaries is regulated chiefly by contraction of arterioles (resistance vessels). The capillary endothelium is the source of NO and PGI2, which relax vascular smooth muscles. 9.


Physiology_Levy

Physiology_Levy. 9. Water and small solutes move between the vascular and interstitial fluid compartments through capillary pores mainly by diffusion but also by filtration and absorption. Molecules larger than approximately 60 kD are essentially confined to the vascular compartment. Lipid-soluble substances, such as CO2 and O2, pass directly through the lipid membranes of the capillary; the rate of transfer is directly proportional to their lipid solubility. Large molecules can move across the capillary wall in vesicles by pinocytosis. The vesicles are formed from the lipid membrane of the capillaries. 10. Capillary filtration and absorption are described by Starling’s equation: Filtration occurs when the algebraic sum of these terms is positive; absorption occurs when it is negative. 11. Fluid and protein that have escaped from blood capillaries enter lymphatic capillaries and are transported via the lymphatic system back to the blood vascular compartment. 12.


Physiology_Levy

Physiology_Levy. Physical factors that influence coronary arterial blood flow are the viscosity of the blood, frictional resistance of the vessel walls, aortic pressure, and extravascular compression of the vessels within the walls of the left ventricle. Left coronary arterial blood flow is restricted during ventricular systole by extravascular compression, and the flow is greatest during diastole, when the intramyocardial vessels are not compressed. Neural regulation of coronary arterial blood flow is much less important than metabolic regulation. Activation of the cardiac sympathetic nerves constricts the coronary resistance vessels. However, the enhanced myocardial metabolism caused by the associated increase in heart rate and contractile force produces vasodilation, which overrides the direct constrictor effect of sympathetic nerve stimulation. Stimulation of the cardiac branches of the vagus nerves causes slight dilation of the coronary arterioles. A striking parallelism exists between metabolic


Physiology_Levy

Physiology_Levy. effect of sympathetic nerve stimulation. Stimulation of the cardiac branches of the vagus nerves causes slight dilation of the coronary arterioles. A striking parallelism exists between metabolic activity of the heart and coronary arterial blood flow. A decrease in O2 supply or an increase in O2 demand apparently releases vasodilators that decrease coronary arterial resistance. Of the known factors (CO2, O2, H+ , K+ , H2O2, adenosine) that can mediate this response, KATP channels, NO, H2O2 and adenosine are the most likely candidates, although CO2, O2, and H+ cannot be ruled out.


Physiology_Levy

Physiology_Levy. 13. Most of the resistance vessels in the skin are under dual control of the sympathetic nervous system and local vasodilator metabolites. The AV anastomoses found in the hands, feet, and face, however, are solely under neural control. The main function of skin blood vessels is to aid in the regulation of body temperature by constricting to conserve heat and by dilating to lose heat. Skin blood vessels dilate directly and reflexively in response to heat, and they constrict directly and reflexively in response to cold. 14. Blood flow in skeletal muscle is regulated centrally by sympathetic nerves and locally by the release of vasodilator metabolites. In persons at rest, neural Camici PG, d’Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and functional assessment. Nat Rev Cardiol. 2015;12:48. Chiu J-J, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev. 2011;91:327.


Physiology_Levy

Physiology_Levy. Chiu J-J, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev. 2011;91:327. Edwards G, Félétou M, Weston AH. Endothelium-derived hyper-polarization factors and associated pathways: a synopsis. Pflügers Arch. 2010;459:863. Kara T, Narkiewicz K, Somers VK. Chemoreflexes—physiology and clinical implications. Acta Physiol Scand. 2003;177:377. regulation of blood flow is paramount, but it yields to metabolic regulation during muscle contractions (as during exercise). 15.


Physiology_Levy

Physiology_Levy. regulation of blood flow is paramount, but it yields to metabolic regulation during muscle contractions (as during exercise). 15. Cerebral blood flow is regulated predominantly by metabolic factors, especially CO2, K+ , and adenosine. The increased regional cerebral activity produced by stimuli such as touch, pain, hand motion, talking, reading, reasoning, and problem solving are associated with enhanced blood flow in the activated area of the contralateral cerebral cortex. The neurovascular unit (microcirculation, pericytes, the extracellular matrix, astrocytes and neurons), a component of the blood-brain barrier, is thought to link brain activity with increased blood flow and oxygenation. 16.


Physiology_Levy

Physiology_Levy. 16. The microcirculation in intestinal villi constitutes a countercurrent exchange system for O2. Because of the presence of this countercurrent exchange system, the villi are in jeopardy in states of low blood flow. The splanchnic resistance and capacitance vessels are very responsive to changes in sympathetic neural activity. 17. The liver receives approximately 25% of cardiac output; approximately three fourths of this output is from the portal vein and approximately a fourth from the hepatic artery. When flow is diminished in either the portal or hepatic system, flow in the other system usually increases, but not proportionately. The liver tends to maintain constant O2 consumption, in part because its mechanism for extracting O2 from blood is so efficient. The liver normally contains approximately 15% of the total blood volume. It serves as an important blood reservoir for the body. 18.


Physiology_Levy

Physiology_Levy. 18. In the fetus, a large percentage of right atrial blood passes through the foramen ovale to the left atrium, and a large percentage of pulmonary arterial blood passes through the ductus arteriosus to the aorta. At birth, the umbilical vessels, ductus venosus, and ductus arteriosus close by contraction of their muscle layers. The reduction in pulmonary vascular resistance caused by lung inflation is the main factor that reverses the pressure gradient between the atria and thereby causes the foramen ovale to close. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046. Ohanyan V, Yin L, Bardakjian R, et al. Requisite role of Kv1.5 channels in coronary metabolic dilation. Circ Res. 2015;117:612. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146:873.


Physiology_Levy

Physiology_Levy. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146:873. Resnick N, Yahav H, Shay-Salit A, et al. Fluid shear stress and the vascular endothelium: for better and for worse. Prog Biophys Mol Biol. 2003;81:177. Upon completion of this chapter, the student should be able to answer the following questions: 1. How do the parasympathetic and sympathetic nervous systems regulate the functions of heart and vasculature? 2. What factors affect the differential sympathetic regulation of resistance and capacitance vessels? 3. How does the baroreceptor-mediated reflex mimic the operation of skeletal muscle proprioceptor reflex? 4. What are the two major mechanisms, intrinsic to heart muscle, that regulate myocardial performance? 5. What are the major hormones that regulate myocardial performance? 6. How is myocardial performance affected by changes in the arterial blood concentrations of O2, CO2, and H+? 7.


Physiology_Levy

Physiology_Levy. 5. What are the major hormones that regulate myocardial performance? 6. How is myocardial performance affected by changes in the arterial blood concentrations of O2, CO2, and H+? 7. What is the myogenic mechanism of vascular smooth muscle, and how does it participate in regulation of tissue blood flow? 8. What are the humoral factors that participate in regulation of blood flow, and what are their actions? Regulation of Heart Rate and Myocardial Performance Cardiac output is defined as the quantity of blood pumped by the heart each minute. Cardiac output may be varied by a change in the heart rate or the volume of blood ejected from either ventricle with each heartbeat; this volume is called the stroke volume. Mathematically, cardiac output (CO) can be expressed as the product of heart rate (HR) and stroke volume (SV): Equation 18.1


Physiology_Levy

Physiology_Levy. Equation 18.1 Thus to understand how cardiac activity is controlled, consider how the heart rate and stroke volume are regulated. Heart rate is regulated by the activity of the autonomic nervous system to modulate the intrinsic cardiac pacemaker. Stroke volume is determined by myocardial performance (which is determined by cardiac cell contractility) and by the hemodynamic loads on the heart. All of these determinants are interdependent, inasmuch as a change in one determinant of cardiac output almost invariably alters another. Nervous Control of the Heart Rate Although certain local factors, such as temperature changes and stretching of tissue, can affect the heart rate, the autonomic nervous system is the principal means by which the heart rate is controlled.


Physiology_Levy

Physiology_Levy. The average resting heart rate is approximately 70 beats per minute in normal adults, and it is significantly faster in children. During sleep, the heart rate decreases by 10 to 20 beats per minute. It may increase during emotional excitement, and during muscular exercise, it may increase to rates well above 150 beats per minute. In well-trained athletes, the usual resting rate is only approximately 50 beats per minute. Both divisions of the autonomic nervous system tonically influence the cardiac pacemaker, which is normally the sinoatrial (SA) node. The sympathetic nervous system enhances automaticity, whereas the parasympathetic nervous system inhibits it. Changes in heart rate usually involve a reciprocal action of these two divisions of the autonomic nervous system. Thus the heart rate ordinarily increases with a combined decrease in parasympathetic activity and increase in sympathetic activity; the heart rate decreases with the opposite changes in autonomic neural activity.


Physiology_Levy

Physiology_Levy. Parasympathetic tone usually predominates in healthy, resting individuals. When a resting individual is given atropine, a muscarinic receptor antagonist that blocks parasympathetic effects, the heart rate generally increases substantially. If a resting individual is given propranolol, a β-adrenergic receptor antagonist that blocks sympathetic effects, the heart rate usually decreases only slightly ( Fig. 18.1 ). When both divisions of the autonomic nervous system are blocked, the heart rate of young adults averages approximately 100 beats per minute. The rate that prevails after complete autonomic blockade is called the intrinsic heart rate.


Physiology_Levy

Physiology_Levy. •Fig. 18.1 Effectsoffourequaldosesofatropine(muscarinicrecep (β-adrenergicreceptorantagonistthatblockssympatheticeffects)ontheheartratesof10healthyyoungmen.Inhalfthetrials,atropine wasgivenfirst(top curve); intheotherhalf,propranololwasgivenfirst(bottom curve). (RedrawnfromKatonaPG,etal.J Appl Physiol. •Fig. 18.2 Changesinheartrateevokedbystimulation(horizontal 1982;52:1652.) bars) ofthevagus(A) andsympatheticnerves(B). (ModifiedfromWarnerHR,CoxA.J Appl Physiol. 1962;17:349.)


Physiology_Levy

Physiology_Levy. The cardiac parasympathetic fibers originate in the medulla oblongata, in cells that lie in the dorsal motor nucleus of the vagus nerve or in the nucleus ambiguus (see ). In humans, centrifugal vagal fibers pass inferiorly through the neck near the common carotid arteries and then through the mediastinum to synapse with postganglionic vagal cells. These cells are located either on the epicardial surface or within the walls of the heart. Most of the vagal ganglion cells are located in epicardial fat pads near the SA and atrioventricular (AV) nodes.


Physiology_Levy

Physiology_Levy. The right and left vagus nerves are distributed to different cardiac structures. The right vagus nerve affects the SA node predominantly; stimulation of this nerve slows SA nodal firing and can even stop the firing for several seconds. The left vagus nerve mainly inhibits AV conduction tissue to produce various degrees of AV block (see ). However, the distribution of the efferent vagal fibers is overlapping in such a way that left vagal stimulation also •Fig. 18.3 Changes in Heart Rate When the Vagus and Cardiac Sympathetic Nerves Are Stimulated Simultaneously. Thesympa depresses the SA node and right vagal stimulation impedes AV conduction. The SA and AV nodes are rich in acetylcholinesterase, an enzyme that rapidly hydrolyzes the neurotransmitter acetylcholine (ACh). The effects of a given vagal stimulus decay very quickly (


Physiology_Levy

Physiology_Levy. The SA and AV nodes are rich in acetylcholinesterase, an enzyme that rapidly hydrolyzes the neurotransmitter acetylcholine (ACh). The effects of a given vagal stimulus decay very quickly ( Fig. 18.2A ) when vagal stimulation is discontinued because ACh is rapidly destroyed. In addition, vagal effects on SA and AV nodal function have a very short latency (≈50 to 100 msec) because the ACh released quickly activates special ACh-regulated potassium (KACh) channels in the cardiac cells. These channels open quickly because the muscarinic receptor is coupled directly to the KACh channel by a guanine nucleotide–binding protein. These two features of the vagus nerves—brief latency and rapid theticnerveswerestimulatedat0,2,and4Hzinthepresenceofvagalnervestimulation(Vag)at0,4,and8Hz.(ModifiedfromLevyMN,ZieskeH.J Appl Physiol. 1969;27:465.) decay of the response—enable them to exert beat-by-beat control of SA and AV nodal function.


Physiology_Levy

Physiology_Levy. Parasympathetic influences usually predominate over sympathetic effects at the SA node, as shown in Fig. 18.3 . When the frequency of sympathetic stimulation increases from 0 to 4 Hz, the heart rate increases by approximately 80 beats per minute in the absence of vagal nerve stimulation (0 Hz). However, when the vagus nerves are stimulated at 8 Hz, increasing the sympathetic stimulation frequency from 0 to 4 Hz has only a negligible influence on heart rate.


Physiology_Levy

Physiology_Levy. The cardiac sympathetic fibers originate in the intermediolateral columns of the upper five or six thoracic segments and the lower one or two cervical segments of the spinal cord (see ). These fibers emerge from the spinal column through the white communicating branches and enter the paravertebral chains of ganglia. The preganglionic and postganglionic neurons synapse mainly in the stellate or middle cervical ganglia, depending on the species. In the mediastinum, postganglionic sympathetic and preganglionic parasympathetic fibers join to form a complicated plexus of mixed efferent nerves to the heart. The postganglionic cardiac sympathetic fibers in this plexus approach the base of the heart along the adventitial surface of the great vessels. From the base of the heart, these fibers are distributed to the various chambers as an extensive epicardial plexus. They then penetrate the myocardium, usually accompanying the coronary vessels.


Physiology_Levy

Physiology_Levy. In contrast to abrupt termination of the response after vagal activity, the effects of sympathetic stimulation decay gradually after stimulation is stopped (see


Physiology_Levy

Physiology_Levy. Fig. 18.2B ). Nerve terminals take up to 70% of the norepinephrine released during sympathetic stimulation; much of the remainder is carried away by the bloodstream. These processes are slow. Furthermore, the facilitatory effects of sympathetic stimulation on the heart attain steady-state values much more slowly than do the inhibitory effects of vagal stimulation. The onset of the cardiac response to sympathetic stimulation begins slowly for two main reasons. First, norepinephrine appears to be released slowly from the sympathetic nerve terminals. Second, the cardiac effects of the neurally released norepinephrine are mediated mainly by a relatively slow second messenger system involving cyclic adenosine monophosphate (cAMP; see ). Hence, sympathetic activity alters the heart rate and AV conduction much more slowly than vagal activity does. Whereas vagal activity can exert beat-by-beat control of cardiac function, sympathetic activity cannot.


Physiology_Levy

Physiology_Levy. Stimulation of various brain regions can have significant effects on cardiac rate, rhythm, and contractility (see ). In the cerebral cortex, centers that regulate cardiac function are located in the anterior half of the brain, principally in the frontal lobe, the orbital cortex, the motor and premotor cortex, the anterior portion of the temporal lobe, the insula, and the cingulate gyrus. Stimulation of the midline, ventral, and medial nuclei of the thalamus elicits tachycardia. Stimulation of the posterior and posterolateral regions of the hypothalamus can also change the heart rate. Stimuli applied to the H2 field of Forel in the posterior hypothalamus evoke various cardiovascular responses, including tachycardia and associated limb movements; these changes resemble those observed during muscular exercise. Undoubtedly, the cortical and hypothalamic centers initiate the cardiac reactions that occur during excitement, anxiety, and other emotional states. The hypothalamic centers also


Physiology_Levy

Physiology_Levy. muscular exercise. Undoubtedly, the cortical and hypothalamic centers initiate the cardiac reactions that occur during excitement, anxiety, and other emotional states. The hypothalamic centers also initiate the cardiac response to alterations in environmental temperature. Experimentally induced temperature changes in the preoptic anterior hypothalamus alter the heart rate and peripheral resistance.


Physiology_Levy

Physiology_Levy. Stimulation of the parahypoglossal area of the medulla reciprocally activates cardiac sympathetic pathways and inhibits cardiac parasympathetic pathways. In certain dorsal regions of the medulla, distinct cardiac accelerator sites (increase the heart rate) and augmentor sites (increase cardiac contractility) have been detected in animals with transected vagus nerves. The accelerator regions are more abundant on the right side, whereas the augmentor sites are more prevalent on the left. A similar distribution also exists in the hypothalamus. Therefore, the sympathetic fibers mainly descend ipsilaterally through the brainstem.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Fig. 18.4 ). Baroreceptors located in the aortic arch and carotid sinuses are responsible for this reflex (see the section ”). The inverse relationship between heart rate and arterial blood pressure is generally most pronounced over an intermediate range of arterial blood pressures. Below this intermediate range, the heart rate maintains a constant, high value; above this pressure range, the heart rate maintains a constant, low value. The effects of changes in carotid sinus pressure on the activity in cardiac autonomic nerves are described in Fig. 18.5 , which shows that over an intermediate range of carotid sinus pressures (100 to 180 mm Hg), reciprocal changes are evoked in efferent vagal and sympathetic neural activity. Below this range of carotid sinus pressure, sympathetic activity is intense, and vagal activity is virtually absent. Conversely, above the intermediate range of carotid sinus pressure, vagal activity is intense and sympathetic activity is minimal.


Physiology_Levy

Physiology_Levy. Bainbridge Reflex, Atrial Receptors, and Atrial Natriuretic Peptide In 1915, Francis A. Bainbridge reported that infusing blood or saline into dogs accelerated their heart rate. This increase did not seem to be tied to arterial blood pressure because the heart rate rose regardless of whether arterial blood pressure did or did not change. However, Bainbridge also noted that the heart rate increased whenever central venous pressure rose sufficiently to distend the right side of the heart. This response is termed the Bainbridge reflex. Bilateral transection of the vagus nerves abolished this response.


Physiology_Levy

Physiology_Levy. Many investigators have confirmed Bainbridge’s observations and have noted that the magnitude and direction of the response depend on the prevailing heart rate. When the heart rate is slow, intravenous infusions of blood or electrolyte solutions usually accelerate the heart. At more rapid heart rates, however, such infusions ordinarily slow the heart. What accounts for these different responses? Increases in blood volume not only evoke Bainbridge reflex but also activate other reflexes (of note, the baroreceptor reflex). These other reflexes tend to elicit opposite changes in heart rate. Therefore, changes in heart rate evoked by an alteration in blood volume are the result of these antagonistic reflex effects ( Fig. 18.6 ). Evidently, the Bainbridge reflex predominates over the baroreceptor reflex when blood volume rises, but the baroreceptor reflex prevails over the Bainbridge reflex when blood volume diminishes.


Physiology_Levy

Physiology_Levy. •Fig. 18.4 Experimentaldatashowingthatheartratedecreasesasarterialpressureisincreased.(AdaptedfromCornishKG,etal.Am J Physiol. 1989;257:r595.)250 200 150 100 50 50 75 100 125 150 Arterial pressure (mm Hg) Heart rate (beats/min) Both atria have receptors that are affected by changes in blood volume and that influence the heart rate. These receptors are located principally in the venoatrial junctions: in the right atrium at its junctions with the venae cavae and in the left atrium at its junctions with the pulmonary veins. Distention of these atrial receptors sends afferent impulses to the brainstem in the vagus nerves. The efferent impulses are carried from the brainstem to the SA node by fibers from both autonomic divisions.


Physiology_Levy

Physiology_Levy. The cardiac response to these changes in autonomic neural activity is highly selective. Even when the reflex increase in heart rate is large, changes in ventricular contractility are generally negligible. Furthermore, the neurally induced increase in heart rate is not usually accompanied by an increase in sympathetic activity in the peripheral arterioles.


Physiology_Levy

Physiology_Levy. •Fig. 18.5 Experimentaldatashowingthatincreasesincarotidsinuspressureresultindecreasedsympatheticefferentnerve(Symp)activityandincreasedcardiacvagalnerveactivity.(AdaptedfromKollaiM,KoizumiK.Pflügers Arch. 1989;413:365.)100 50 0 60 100 140 180 220 Sinus pressure (mm Hg) Vagal activity (% of max) 100 50 0 Symp. activity (% of max) •Fig. 18.6 Intravenous Infusions of Blood or Electrolyte Solutions Tend to Increase the Heart Rate Through the Bainbridge Reflex and to Decrease the Heart Rate Through the Baroreceptor Reflex. Theactualchangeinheartrateinducedbysuchinfusionsistheresultofthesetwoopposingeffects.Intravenous infusion Increases right atrial pressure Atrial receptors stimulated Bainbridge reflex – + Increases cardiac output Increases arterial pressure Baroreceptor reflex Heart rate


Physiology_Levy

Physiology_Levy. Stimulation of the atrial receptors increases not only the heart rate but also urine volume. Reduced activity in the renal sympathetic nerve fibers may partially account for this diuresis. However, the principal mechanism appears to be a neurally mediated reduction in vasopressin (antidiuretic hormone) secretion by the posterior pituitary gland (see ). Stretch of the atrial walls also releases atrial natriuretic peptide (ANP) from the atria. ANP, a 28–amino acid peptide, exerts potent diuretic and natriuretic effects on the kidneys (see also ) and vasodilator effects on the resistance and capacitance vessels. Thus ANP is an important regulator of blood volume and blood pressure.


Physiology_Levy

Physiology_Levy. Rhythmic variations in heart rate, occurring at the frequency of respiration, are detectable in most individuals and tend to be more pronounced in children. The heart rate typically accelerates during inspiration and decelerates during expiration (Fig. 18.7 *The myocytes of the ventricles secrete a related peptide in response to stretch. This peptide, termed brain natriuretic peptide (BNP) because of its initial discovery in the central nervous system, has actions similar to those of ANP (see •Fig. 18.7 Respiratory Sinus Arrhythmia. Notethattheheartrateincreasesduringinspirationanddecreasesduringexpiration.(ModifiedfromWarnerMR,etal.Am J Physiol. 1986;251:H1134.)50 80 110 140 Expiration Time (sec) Inspiration 3 6 9 12 150 Heart rate(beats/min)


Physiology_Levy

Physiology_Levy. Recordings from cardiac autonomic nerves reveal that neural activity increases in the sympathetic fibers during inspiration and increases in the vagal fibers during expiration. The heart rate response to cessation of vagal stimulation is very quick because, as already noted, ACh released from the vagus nerves is rapidly hydrolyzed by acetylcholinesterase. This short latency enables the heart rate to vary rhythmically at the respiratory frequency. Conversely, the norepinephrine released periodically at the sympathetic endings is removed very slowly. Therefore, the rhythmic variations in sympathetic activity that accompany inspiration do not induce any appreciable oscillatory changes in heart rate. Thus respiratory sinus arrhythmia is brought about almost entirely by changes in vagal activity. In fact, respiratory sinus arrhythmia is exaggerated when vagal tone is enhanced.


Physiology_Levy

Physiology_Levy. Fig. 18.8 ). Stretch receptors in the lungs are stimulated during inspiration, and this action leads to a reflex increase in heart rate. The afferent and efferent limbs of this reflex are located in the vagus nerves. Intrathoracic pressure also decreases during inspiration and thereby increases venous return to the right side of the heart (see ). The consequent stretch of the right atrium elicits the Bainbridge reflex. After the time delay required for the increased venous return to reach the left side of the heart, left ventricular output increases and raises arterial blood pressure. This rise in blood pressure in turn reduces the heart rate through the baroreceptor reflex. Central factors are also responsible for respiratory cardiac arrhythmia. The respiratory center in the medulla directly influences the cardiac autonomic centers (see


Physiology_Levy

Physiology_Levy. Central factors are also responsible for respiratory cardiac arrhythmia. The respiratory center in the medulla directly influences the cardiac autonomic centers (see Fig. 18.8). In heart-lung bypass studies, the chest is opened, the lungs are collapsed, venous return is diverted to a pump-oxygenator, and arterial blood pressure is maintained at a constant level. In such studies, rhythmic movement of the rib cage attests to the activity of the medullary respiratory centers, and is often accompanied by rhythmic changes in heart rate at the respiratory frequency. This respiratory cardiac arrhythmia is almost certainly induced by a direct interaction between the respiratory and cardiac centers in the medulla.


Physiology_Levy

Physiology_Levy. The cardiac response to peripheral chemoreceptor stimulation illustrates the complex interactions that may ensue when one stimulus excites two organ systems simultaneously. Stimulation of carotid chemoreceptors consistently increases ventilatory rate and depth (see ), but ordinarily it changes the heart rate only slightly. The magnitude of the ventilatory response determines whether the heart rate increases or decreases as a result of carotid chemoreceptor stimulation. Mild chemoreceptor-induced stimulation of respiration decreases the heart rate moderately; more pronounced stimulation increases the heart rate only slightly. If the pulmonary response to chemoreceptor stimulation is blocked, the heart rate response may be greatly exaggerated, as described later.


Physiology_Levy

Physiology_Levy. •Fig. 18.9 The Primary Effect of Stimulation of Peripheral Chemoreceptors on the Heart Rate Is to Excite the Cardiac Vagal Center in the Medulla and Thus to Decrease the Heart Rate. Peripheralchemoreceptorstimulationalsoexcitestherespiratorycenterinthemedulla.Thiseffectproduceshypocapniaandincreaseslunginflation,bothofwhichsecondarilyinhibitthemedullaryvagalcenter.Thusthesesecondaryinfluencesattenuatetheprimaryreflexeffectofperipheralchemoreceptorstimulationonheartrate.Medullary vagal center Peripheral chemoreceptors Respiratory activity Primary effect (+) Secondary effects (–) (+) (–) (–) Hypocapnia Increased lung stretch Heart rate •Fig. 18.8 Respiratorysinusarrhythmiaisgeneratedbyadirectinteractionbetweentherespiratoryandcardiaccentersinthemedulla,aswellasbyreflexesthatoriginatefromstretchreceptorsinthelungs,fromstretchreceptorsintherightatrium(theBainbridgereflex),andfrombaroreceptorsinthecarotidsinusesandaorticarch.Cardiac vagal center (medulla) Respiratory center (medulla)


Physiology_Levy

Physiology_Levy. vagal center (medulla) Respiratory center (medulla) Change in intrathoracic pressure Change in venous return Change in arterial pressure Baroreceptor reflex Heart rate Change in lung volume (stretch receptors) Bainbridge reflex


Physiology_Levy

Physiology_Levy. The cardiac response to peripheral chemoreceptor stimulation is the result of primary and secondary reflex mechanisms ( Fig. 18.9). The principal effect of the primary reflex stimulation is to excite the medullary vagal center and thereby decrease the heart rate. The respiratory system mediates secondary reflex effects. The respiratory stimulation by arterial chemoreceptors tends to inhibit the medullary vagal center. This inhibition varies with the level of concomitant stimulation of respiration; small increases in respiration inhibit the vagal center slightly, whereas large increases in ventilation inhibit the vagal center more profoundly. An example of the primary inhibitory influence is shown in


Physiology_Levy

Physiology_Levy. An example of the primary inhibitory influence is shown in Fig. 18.10 . In this example, the lungs are completely collapsed, and blood oxygenation is accomplished with an artificial oxygenator. When the carotid chemoreceptors are stimulated, intense bradycardia and some degree of AV block ensue. Such effects are mediated primarily by efferent vagal fibers. The pulmonary hyperventilation that is ordinarily evoked by carotid chemoreceptor stimulation influences the heart rate secondarily, both by initiating more pronounced pulmonary inflation reflexes and by producing hypocapnia (see Fig. 18.9). Both influences tend to depress the primary cardiac response to chemoreceptor stimulation and thereby accelerate the heart rate. Hence, when pulmonary hyper- ventilation is not prevented, the primary and secondary effects neutralize each other, and carotid chemoreceptor stimulation affects the heart rate only moderately.


Physiology_Levy

Physiology_Levy. Sensory receptors located near the endocardial surfaces of the ventricles initiate reflex effects similar to those elicited •Fig. 18.10 Changes in Heart Rate With Carotid Chemoreceptor Stimulation During Total Heart Bypass. Thelungsremaindeflated,andrespiratorygasexchangeisaccomplishedbyanartificialoxygenator.Thelowertracingrepresentstheoxygensaturationofthebloodperfusingthecarotidchemoreceptors.Thebloodperfusingtheremainderofthebody,includingthemyocardium,isfullysaturatedwithoxygen.(ModifiedfromLevyMN,etal.Circ Res. 1966;18:67.)


Physiology_Levy


Physiology_Levy

Physiology_Levy. by the arterial baroreceptors. Excitation of these endocardial receptors causes the heart rate and peripheral resistance to diminish. Other sensory receptors have been identified in the epicardial regions of the ventricles. Although all these ventricular receptors are excited by various mechanical and chemical stimuli, their exact physiological functions remain unclear. Regulation of Myocardial Performance Intrinsic Regulation of Myocardial Performance


Physiology_Levy

Physiology_Levy. As noted previously, the heart can initiate its own beat in the absence of any nervous or hormonal control. The myocardium can also adapt to changing hemodynamic conditions by means of mechanisms that are intrinsic to cardiac muscle itself. For example, racing greyhounds with •Fig. 18.11 Electrocardiogram of a 30-Year-Old Quadriplegic Man Who Could Not Breathe Spontaneously and Required Tracheal Intubation and Artificial Respiration. Thetwostripsarecontinuous.(ModifiedfromBerkJL,LevyMN.Eur Surg Res. 1977;9:75.) denervated hearts perform almost as well as those with intact innervation. Their maximal running speed decreases by only 5% after complete cardiac denervation. In these dogs, the threefold to fourfold increase in cardiac output during a race is achieved principally by an increase in stroke volume. Normally, the increase in cardiac output with exercise is accompanied by a proportionate increase in heart rate; stroke volume does not change much (see ). This adaptation in the


Physiology_Levy

Physiology_Levy. in stroke volume. Normally, the increase in cardiac output with exercise is accompanied by a proportionate increase in heart rate; stroke volume does not change much (see ). This adaptation in the denervated heart is not achieved entirely by intrinsic mechanisms; circulating catecholamines undoubtedly contribute. For example, if β-adrenergic receptor antagonists are given to greyhounds with denervated hearts, their racing performance is severely impaired.


Physiology_Levy

Physiology_Levy. Theheartispartiallyorcompletelydenervatedinvariousclinicalsituations:(1)asurgicallytransplantedheartistotallydenervated,althoughtheintrinsic,postganglionicparasympatheticfiberspersist;(2)atropineblocksvagaleffectsontheheart,andpropranololblockssympatheticβ-adrenergicinfluences;(3)certaindrugs,suchasreserpine,depletecardiacnorepinephrinestoresandtherebyrestrictorabolishsympatheticcontrol;and(4)inchroniccongestiveheartfailure,cardiacnorepinephrinestoresareoftenseverelydiminished,andanysympatheticinfluencesareattenuated. Two principal intrinsic mechanisms, the Frank-Starling mechanism and rate-induced regulation, enable the myocardium to adapt to changes in hemodynamic conditions. The Frank-Starling mechanism (Frank-Starling law of the heart) is invoked in response to changes in the resting length of myocardial fibers. Rate-induced regulation is evoked by changes in the frequency of the heartbeat. CHAPTER 18 Regulation of the Heart and Vasculature


Physiology_Levy

Physiology_Levy. CHAPTER 18 Regulation of the Heart and Vasculature In the 1910s, the German physiologist Otto Frank and the English physiologist Ernest Starling independently studied the response of isolated hearts to changes in preload and afterload (see Chapter 16). When ventricular filling pressure (preload) is increased, ventricular volume increases progressively, and after several beats, becomes constant and larger. At equilibrium, the volume of blood ejected by the ventricles (stroke volume) with each heartbeat increases to equal the greater quantity of venous return to the right atrium. The increased ventricular volume facilitates ventricular contraction and enables the ventricles to pump a greater stroke volume. This increase in ventricular volume is associated with an increase in length of the individual ventricular cardiac fibers. The increase in fiber length alters cardiac performance mainly by altering the number of myofilament cross-bridges that interact (see Chapter 16).


Physiology_Levy

Physiology_Levy. Chapter 16). More recent evidence indicates that the principal mechanism involves a stretch-induced change in the sensitivity of cardiac myofilaments to Ca++ (see ). There exists an optimal fiber length, however. Excessively high filling pressures that overstretch the myocardial fibers may depress rather than enhance the pumping capacity of the ventricles (see Fig. 16.36 Starling also showed that isolated heart preparations could adapt to changes in the counterforce to the ventricular ejection of blood during systole (i.e., afterload). As the left ventricle contracts, it does not eject blood into the aorta until the ventricle has developed a pressure that just exceeds the prevailing aortic pressure (see


Physiology_Levy

Physiology_Levy. Fig. 16.39 ). The aortic pressure during ventricular ejection essentially constitutes the left ventricular afterload. In Starling’s experiments, arterial pressure was controlled by a hydraulic device in the tubing that led from the ascending aorta to the right atrial blood reservoir. To hold venous return to the right atrium constant, the hydrostatic level of the blood reservoir was maintained. As Starling raised arterial pressure to a new constant level, the left ventricle responded at first to the increased afterload by pumping a diminished stroke volume. Because venous return was held constant, the diminution in stroke volume was accompanied by a rise in ventricular diastolic volume, as well as by an increase in the length of the myocardial fibers. This change in end-diastolic fiber length finally enabled the ventricle to pump a normal stroke volume against the greater peripheral resistance. As mentioned, a change in the number of cross-bridges between the thick and thin filaments


Physiology_Levy

Physiology_Levy. finally enabled the ventricle to pump a normal stroke volume against the greater peripheral resistance. As mentioned, a change in the number of cross-bridges between the thick and thin filaments probably contributes to this adaptation, but the major factor appears to be a stretch-induced change in the sensitivity of the contractile proteins to Ca++ .


Physiology_Levy

Physiology_Levy. Cardiac adaptation to alterations in heart rate also involves changes in ventricular volume. During bradycardia, for example, the increased duration of diastole allows greater ventricular filling. The consequent increase in myocardial fiber length increases stroke volume. Therefore, the reduction in heart rate may be fully compensated by the increase in stroke volume, and cardiac output may therefore remain constant. When cardiac compensation involves ventricular dilation, the effect of the increased size of the ventricle on the generation of intraventricular pressure must be considered. According to Laplace’s relationship (see


Physiology_Levy

Physiology_Levy. Chapter 17), if the ventricle enlarges, the force required by each myocardial fiber to generate a given intraventricular systolic pressure must be appreciably greater than that developed by the fibers in a ventricle of normal size. Thus more energy is required for a dilated heart to perform a given amount of external work than for a normal-sized heart to do so. Hence, computation of afterload on contracting myocardial fibers in the walls of the ventricles must account for ventricular dimensions along with intraventricular (and aortic) pressure.


Physiology_Levy

Physiology_Levy. The relatively rigid pericardium that encloses the heart determines the pressure-volume relationship at high levels of pressure and volume. The pericardium limits heart volume even under normal conditions, when an individual is at rest and the heart rate is slow. In patients with chronic congestive heart failure, the sustained cardiac dilation and hypertrophy may stretch the pericardium considerably. In such patients, the pericardial limitation of cardiac filling is exerted at pressures and volumes entirely different from those in normal individuals.


Physiology_Levy

Physiology_Levy. To assess changes in ventricular performance, the Frank-Starling mechanism is often represented by a family of ventricular function curves. To construct a control ventricular function curve, for example, blood volume is altered over a range of values, and stroke work (i.e., stroke volume × mean arterial pressure) and end-diastolic ventricular pressure are measured at each step. Similar observations are then made during the desired experimental intervention. For example, the ventricular function curve obtained during infusion of norepinephrine lies above and to the left of the control ventricular function curve (


Physiology_Levy

Physiology_Levy. Fig. 18.12). Clearly, for a given level of left ventricular end-diastolic pressure (an index of preload), the left ventricle performs more work during the norepinephrine infusion than during control conditions. Hence, the upward and leftward shift of the ventricular function curve signifies improved ventricular contractility. Conversely, a shift downward and to the right indicates impaired contractility and a tendency toward cardiac failure.


Physiology_Levy

Physiology_Levy. The Frank-Starling mechanism is well suited to match cardiac output to venous return. Any sudden, excessive output by one ventricle soon causes an increase in venous return to the second ventricle. The consequent increase in diastolic fiber length in the second ventricle augments the output of that ventricle to correspond to the output of its mate. In this way, the Frank-Starling mechanism maintains a precise balance between the output of the right and left ventricles. If the two ventricles were not arranged in series in a closed circuit, any small but maintained imbalance in output of the two ventricles would be catastrophic. •Fig. 18.12 Aconstantinfusionofnorepinephrineshiftstheventricu-larfunctioncurveupandtotheleft.Thisshiftsignifiesanenhancementinventricularcontractility.(RedrawnfromSarnoffSJ,etal.Circ Res. 1960;8:1108.)0 5 10 15 20 25 30 35 40 Norepinephrine Control 0 10 20 30 40 50 60 Left ventricular end-diastolic pressure (cm H2O) Left ventricular stroke work (g•m)


Physiology_Levy

Physiology_Levy. The curves that relate cardiac output to mean atrial pressure for the two ventricles do not coincide; the curve for the left ventricle usually lies below that for the right ventricle ( Fig. 18.13). At equal right and left atrial pressures Fig. 18.13 ), right ventricular output exceeds left ventricular output. Hence, venous return to the left ventricle (a function of right ventricular output) exceeds left ventricular output, and left ventricular diastolic volume and pressure rise. According to the Frank-Starling mechanism, left ventricular output therefore increases (from point B toward point C in Fig. 18.13 ). Only when the output of both ventricles is identical (points A and C) is equilibrium reached. Under such conditions, however, left atrial pressure (point C) exceeds right atrial pressure (point A). This is precisely the relationship that ordinarily prevails.


Physiology_Levy

Physiology_Levy. Thefactthatleftatrialpressureexceedsrightatrialpressureaccountsfortheobservationthatinindividualswithcongenitalatrialseptaldefectsinwhichthetwoatriacommunicatewitheachotherviaapatentforamenovale,thedirectionofshuntflowisusuallyfromlefttotherightsideoftheheart. •Fig. 18.13 Relationships Between the Output of the Right and Left Ventricles and Mean Pressure in the Right and Left Atria, Respectively. Atanygivenlevelofcardiacoutput,meanleftatrialpressure(e.g.,pointC)exceedsmeanrightatrialpressure(pointA).Atrial pressure Right Left A C B Cardiac output Force0.632020 •Fig. 18.14 Changesindevelopmentofforce(y-axis)inanisolatedpapillarymuscleastheintervalbetweencontractionsisvariedfrom20secondsto0.63secondandthenbackto20seconds.(RedrawnfromKoch-WeserJ,BlinksJR.Pharmacol Rev. 1963;15:601.)


Physiology_Levy

Physiology_Levy. Myocardial performance is also regulated by changes in the frequency at which the myocardial fibers contract. The effects of changes in contraction frequency on the force developed in an isometrically contracting papillary muscle are shown in Fig. 18.14 . Initially, the cardiac muscle is stimulated to contract once every 20 seconds. When the muscle is suddenly made to contract once every 0.63 seconds, the force developed increases progressively over the next several beats. At the new steady state, the force developed is more than five times greater than the force at the larger contraction interval. A return to the larger interval (20 seconds) has the opposite influence on the development of force.


Physiology_Levy

Physiology_Levy. The rise in the force developed when the contraction interval is decreased is caused by a gradual increase in intracellular [Ca++]. Two mechanisms contribute to the rise in intracellular [Ca++]: an increase in the number of depolarizations per minute and an increase in the inward Ca++ current per depolarization.


Physiology_Levy

Physiology_Levy. In the first mechanism, Ca++ enters the myocardial cell during each action potential plateau (see ). As the interval between beats is diminished, the number of plateaus per minute increases. Although the duration of •Fig. 18.15 Calcium Currents Induced in a Myocyte During the First (Labeled 1) and Seventh (Labeled 7) Depolarizations in a Consecutive Sequence of Depolarizations. Thearrows indicatethehalf-timesofinactivationofthecalciumcurrent,asobtainedfromkineticanalysis.Bytheseventhdepolarization,themaximalinwardrectifyingcalciumcurrenthadincreasedbymorethan50%,andthehalf-timeofinactivationhadincreasedby20msec.(ModifiedfromLeeKS.Proc Natl Acad Sci U S A. 1987;84:3941.) each action potential (and of each plateau) decreases as the interval between beats is reduced, the overriding effect of the increased number of plateaus per minute on the influx of Ca++ prevails, and intracellular [Ca++] increases.


Physiology_Levy

Physiology_Levy. In the second mechanism, as the interval between beats is suddenly diminished, the inward rectifying calcium current (iCa) progressively increases with each successive beat until a new steady state is attained at the new basic cycle length. In an isolated ventricular myocyte, influx of Ca++ into the myocyte increases on successive depolarizations ( Fig. 18.15 ). Both the increased magnitude and the slowed inactivation of iCa result in greater Ca++ influx into the myocyte during the later depolarizations than during the first depolarization. This greater Ca++ influx strengthens contraction. Transient changes in the intervals between beats also profoundly affect the strength of contraction. When the left ventricle contracts prematurely (


Physiology_Levy

Physiology_Levy. Transient changes in the intervals between beats also profoundly affect the strength of contraction. When the left ventricle contracts prematurely ( Fig. 18.16 , beat A), the premature contraction (extrasystole) itself is weak, whereas contraction B (postextrasystolic contraction) after the compensatory pause is very strong. In the intact circulatory system, this response depends partly on the Frank-Starling mechanism. Inadequate time for ventricular filling just before the premature beat results in the weak premature contraction. Subsequently, the exaggerated degree of filling associated with the long compensatory pause (see Fig. 18.16 , beat B) contributes to the vigorous postextrasystolic contraction.


Physiology_Levy

Physiology_Levy. Fig. 18.16 , beat B) contributes to the vigorous postextrasystolic contraction. The weakness of the premature beat is directly related to its degree of prematurity: The earlier the premature beat, the weaker its force of contraction. The curve that represents strength of contraction of a premature beat in relation to the coupling interval is called a mechanical restitution curve. Fig. 18.17 shows the restitution curve obtained when the coupling intervals of test beats were isolated in an isolated ventricular muscle preparation. 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 Time (sec) •Fig. 18.16 Inanisovolumicleftventriclepreparation,aprematureventricularsystoliccontraction(beat


Physiology_Levy

Physiology_Levy. 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 Time (sec) •Fig. 18.16 Inanisovolumicleftventriclepreparation,aprematureventricularsystoliccontraction(beat A)istypicallyweak,whereasthepostextrasystoliccontraction(beatB)ischaracteristicallystrong,andtheenhancedcontractilitymaydiminishoverafewcontractions(e.g.,beatC).(FromLevyMN.Unpublishedtracing.) 100 80 60 40 20 0 0 0.2 0.4 0.6 0.8 1.0 Test beat interval (sec) Test beat force (% of max) relatively large amount of Ca++ taken up by it during the time that had elapsed from the end of the last regular beat until the beginning of the postextrasystolic beat. Extrinsic Regulation of Myocardial Performance Although a completely isolated heart can adapt well to changes in preload and afterload, various extrinsic factors also influence the heart in an individual. Often, these extrinsic regulatory mechanisms may overwhelm the intrinsic mechanisms. The extrinsic regulatory factors may be subdivided into nervous and chemical components.


Physiology_Levy

Physiology_Levy. •Fig. 18.17 Force Generated During Premature Contractions in an Isolated Ventricular Muscle Preparation. Themusclewasstimulatedtocontractoncepersecond.Periodically,themusclewasstimulatedprematurely.Thescalealongthex-axisdenotesthetimebetweenthedrivenandtheprematurebeat.Thescalealongthey-axisdenotestheratioofthecontractileforceoftheprematurebeattothatofthedrivenbeat.(ModifiedfromSeedWA,WalkerJM.Cardiovasc Res. 1988;22:303.)


Physiology_Levy

Physiology_Levy. Restitution of the force of contraction depends on the time course of the intracellular circulation of Ca++ in cardiac myocytes during contraction and relaxation. During relaxation, the Ca++ that dissociates from the contractile proteins is taken up by the sarcoplasmic reticulum for subsequent release. However, there is a lag of approximately 500 to 800 msec before this Ca++ is available for release from the sarcoplasmic reticulum in response to the next depolarization. Thus the strength of the premature beat is reduced because the time during the preceding relaxation is insufficient to allow much of the Ca++ taken up by the sarcoplasmic reticulum to become available for release during the premature beat. Conversely, the postextrasystolic beat is considerably stronger than normal because more Ca++ is released from the sarcoplasmic reticulum as a result of the


Physiology_Levy

Physiology_Levy. Sympathetic nervous activity enhances atrial and ventricular contractility. The alterations in ventricular contraction evoked by electrical stimulation of the left stellate ganglion in an isovolumic left ventricle preparation are shown in Fig. 18.18 . Note that the duration of systole is reduced and the rate of ventricular relaxation is increased during the early phases of diastole; both these effects assist ventricular filling. For any given cardiac cycle length, the abbreviated systole allows more time for diastole and hence for ventricular filling. ). Neurally released norepinephrine or circulating catecholamines interact with β-adrenergic receptors on the cardiac cell membranes (


Physiology_Levy

Physiology_Levy. ). Neurally released norepinephrine or circulating catecholamines interact with β-adrenergic receptors on the cardiac cell membranes ( Fig. 18.19 ). This interaction activates adenylate cyclase, which raises intracellular levels of cAMP (see ). Consequently, protein kinases that promote the phosphorylation of various proteins are activated within the myocardial cells. Phosphorylation of phospholamban facilitates reuptake of Ca++ by the sarcoplasmic reticulum, and phosphorylation of troponin I reduces the sensitivity of contractile proteins to Ca++ . These effects facilitate relaxation and reduce end-diastolic pressure (see ). Phosphorylation of specific sarcolemmal proteins also activates calcium channels in the membranes of myocardial cells.


Physiology_Levy

Physiology_Levy. Activation of calcium channels increases the influx of Ca++ during the action potential plateau, and more Ca++ is released from the sarcoplasmic reticulum in response to each cardiac excitation. The contractile strength of the heart is thereby increased. Fig. 18.20 shows the correlation between the contractile force in a thin strip of ventricular muscle and the free [Ca++] (indicated by the aequorin light signal) in the myoplasm as the concentration of isoproterenol (a β-adrenergic agonist) is increased (see also Fig. 13.3


Physiology_Levy

Physiology_Levy. Fig. 13.3 The overall effect of increased cardiac sympathetic activity in intact animals can best be appreciated in terms of 0.1 0.2 0.3 0.4 0.5 0.6 0 0.1 0.2 0.3 0.4 0.5 0.6 Time (sec) •Fig. 18.18 Inanisovolumicleftventriclepreparation,stimulationofcardiacsympatheticnervesevokesasubstantialriseinpeakleftventricularpressureandinthemaximalratesofriseandfallinintraventricularpressure(dP/dt).(FromLevyMN.Unpublishedtracing.) families of ventricular function curves. When the frequency of electrical stimulation applied to the left stellate ganglion increases, the ventricular function curves shift progressively to the left. The changes parallel those produced by infusions of norepinephrine (see


Physiology_Levy

Physiology_Levy. Fig. 18.12 ). Hence, for any given left •Fig. 18.19 Interneuronal and Intracellular Mechanisms Responsible for Interactions Between the Sympathetic and Parasympathetic Systems in the Neural Control of Cardiac Function. AC,adenylatecyclase;ACh,acetycholine;ATP,adenosinetriphosphate;β,β-adrenergicreceptor;βγ,beta/gamma;cAMP,cyclicadenosinemonophosphate;GsandGi,stimulatoryandinhibitoryGproteins;M,muscarinicreceptor;NE,norepinephrine;NPY,neuropeptideY.(ModifiedfromLevyMN.In:KulbertusHE,FranckG,eds.Neurocardiology. Mt.Kisco,NY:Futura;1988.) •Fig. 18.20 Effects of Various Concentrations of Isoproterenol (Iso) on the Aequorin Light Signal (in Nanoamperes) and Contractile Force (in Millinewtons Per Square Millimeter) in a Rat Ventricular Muscle Injected With Aequorin. Theaequorinlightsignalreflectstheinstantaneouschangesinintracel-lular[Ca++].µM,micromolar.(ModifiedfromKuriharaS,KonishiM.Pflügers Arch. 1987;409:427.)0.1 sec Force Aequorin light signal 20 nA 0.2 µM Iso.0.1 µM Iso.0.05 µM


Physiology_Levy

Physiology_Levy. Arch. 1987;409:427.)0.1 sec Force Aequorin light signal 20 nA 0.2 µM Iso.0.1 µM Iso.0.05 µM Iso.Control 5 mN mm2 A B C D ventricular end-diastolic pressure, the ventricle can perform more work as sympathetic nervous activity is increased.


Physiology_Levy

Physiology_Levy. The vagus nerves inhibit the cardiac pacemaker, atrial myocardium, and AV conduction tissue. The vagus nerves also depress the ventricular myocardium, but the effects are less pronounced than in the atria. In pumping heart preparations, the ventricular function curve shifts to the right during vagal stimulation, an indication of reduced contractility. Vagus nerve stimulation suppresses the contractile force in the left ventricle. This is shown in pressure-volume curves obtained at constant ventricular rate ( Fig. 18.21 ). The negative inotropic effect of vagus nerve stimulation, depicted as the reduced slope of the end-systolic pressure-volume relation, is opposed by a muscarinic receptor antagonist and diminished by a β-adrenoceptor antagonist. The results indicate that vagus nerve stimulation reduces contractility in the heart and does so by at least two pathways. Mechanisms for the vagal effects on the ventricular myocardium are shown in


Physiology_Levy

Physiology_Levy. Mechanisms for the vagal effects on the ventricular myocardium are shown in Fig. 18.19 . ACh released by the vagal nerves interact with muscarinic receptors on the cardiac ventricular cell membrane to inhibit adenylate cyclase and the cAMP/protein kinase A cascade. This direct inhibition diminishes the Ca++ conductance of the cell membrane, reduces phosphorylation of the calcium channel, and hence decreases myocardial contractility. The ACh released from vagal nerves can also inhibit norepinephrine release by activating muscarinic receptors on neighboring sympathetic nerves, a mechanism of indirect inhibition. Thus vagal activity can decrease ventricular contractility partly by antagonizing any stimulatory effects that concomitant sympathetic activity may be exerting on ventricular contractility. Similarly, sympathetic nerves release norepinephrine and certain neuropeptides, including neuropeptide Y, which inhibits the release of ACh from neighboring vagal fibers (see Fig. 18.19


Physiology_Levy

Physiology_Levy. Fig. 18.19 The adrenal medulla is essentially a component of the auto ). The principal hormone secreted by the adrenal medulla is epinephrine; some norepinephrine is also released. The rate of secretion of these catecholamines by the adrenal medulla is regulated by mechanisms that control the activity of the sympathetic nervous system. Concentrations of catecholamines in blood thus rise under the same conditions that activate the sympathetic nervous system. However, the cardiovascular effects of circulating catecholamines are probably minimal under normal conditions. Moreover, the pronounced changes in myocardial contractility with exercise, for example, are mediated mainly by the norepinephrine released from cardiac sympathetic nerve fibers rather than by the catecholamines released from the adrenal medulla.


Physiology_Levy

Physiology_Levy. How adrenocortical steroids influence myocardial contractility is controversial. Cardiac muscle taken from adrenalectomized animals and placed in a tissue bath is more likely to fatigue in response to stimulation than is cardiac muscle obtained from normal animals. In some species, however, adrenocortical hormones enhance contractility. In addition, the glucocorticoid hydrocortisone potentiates the cardiotonic effects of catecholamines. This potentiation is mediated in part by the ability of adrenocortical steroids to inhibit the extraneuronal catecholamine uptake mechanisms.


Physiology_Levy

Physiology_Levy. •Fig. 18.21 Vagus Nerve Stimulation Reduces Ventricular Con tractility. Pressure-volumecurvesobtainedatconstantventricular ratebeforeopenheartsurgeryinhuman.A, Controlpressure-volumecurveswerecalculatedduringocclusionoftheinferiorvenacava.Theend-systolicpressure-volumerelation,definedbytheslopeofthestraight line, measuredapproximately4mmHg/mL.B, Duringstimulationoftheleftvagusnerve,theslopeoftheend-systolicpressure-volumerelationdecreasedtoapproximately3mmHg/mL,anindicationthatcontractilityhaddecreased.LV,leftventricular.(RedrawnfromLewisME,Al-KhalidiAH,BonserRS,etal.Vagusnervestimulationdecreasesleftventricularcontractilityinvivointhehumanandpigheart.J Physiol. 2001;534:547.)


Physiology_Levy

Physiology_Levy. Thyroid hormones enhance myocardial contractility. Rates of ATP hydrolysis and Ca++ uptake by the sarcoplasmic reticulum are increased in hyperthyroidism; the opposite effects occur in hypothyroidism. Thyroid hormones increase cardiac protein synthesis, and this response leads to cardiac hypertrophy. These hormones also affect the composition of myosin isoenzymes in cardiac muscle. By increasing isoenzymes with the greatest ATPase activity, thyroid hormones enhance myocardial contractility. Cardiovascularproblemsarecommoninpatientswithadrenocorticalinsufficiency(Addison’sdisease).Bloodvolume The cardiovascular changes in thyroid dysfunction also depend on indirect mechanisms. Thyroid hyperactivity tendstofall,whichmayleadtoseverehypotensionandcardiovascularcollapse,theso-calledaddisoniancrisis(see


Physiology_Levy


Physiology_Levy

Physiology_Levy. Cardiacactivityisdepressedinpatientswithinadequatethyroidfunction(hypothyroidism).Theconverseistrueinpatientswithoveractivethyroidglands(hyperthyroidism).Characteristically,patientswithhyperthyroidismexhibittachycardia,highcardiacoutput,andarrhythmiassuchasatrialfibrillation.Insuchpatients,sympatheticneuralactivitymaybeincreased,orthesensitivityofthehearttosuchactivitymaybeenhanced.Studieshaveshownthatthyroidhormoneincreasesthedensityofβ-adrenergicreceptorsincardiactissue(seealso ).Inexperimentalanimals,thecardiovascularmanifestationsofhyperthyroidismmaybesimulatedbytheadministrationofexcessthyroxine. increases the body’s metabolic rate, which in turn results in arteriolar vasodilation. The consequent reduction in total peripheral resistance increases cardiac output, as explained in Insulin has a positive inotropic effect on the heart. The effect of insulin is evident even when hypoglycemia is prevented by glucose infusions and when β-adrenergic receptors are


Physiology_Levy

Physiology_Levy. Insulin has a positive inotropic effect on the heart. The effect of insulin is evident even when hypoglycemia is prevented by glucose infusions and when β-adrenergic receptors are CHAPTER 18 Regulation of the Heart and Vasculature blocked. Indeed, the positive inotropic effect of insulin is potentiated by β-adrenergic receptor antagonists. The enhanced contractility cannot be explained satisfactorily by the concomitant augmentation of glucose transport into myocardial cells.


Physiology_Levy

Physiology_Levy. Glucagon has potent positive inotropic and chronotropic effects on the heart. This endogenous hormone is probably not important in normal regulation of the cardiovascular system, but it has been used clinically to enhance cardiac performance. The effects of glucagon on the heart and certain metabolic effects are similar to those of catecholamines. Both glucagon and catecholamines activate adenylate cyclase to increase myocardial levels of cAMP. The catecholamines activate adenylate cyclase by interacting with β-adrenergic receptors, but glucagon activates this enzyme by a different mechanism. Nevertheless, the rise in cAMP increases influx of Ca++ through calcium channels in the sarcolemma and facilitates release and reuptake of Ca++ by the sarcoplasmic reticulum, just as catecholamines do.


Physiology_Levy

Physiology_Levy. The cardiovascular derangements in hypopituitarism are related principally to the associated deficiencies in adrenocortical and thyroid function. Growth hormone affects the myocardium, at least in combination with thyroxine. In hypophysectomized animals, growth hormone alone has little effect on the depressed heart, whereas thyroxine by itself restores adequate cardiac performance under basal conditions. However, when blood volume or peripheral resistance is increased, thyroxine alone does not restore adequate cardiac function, but the combination of growth hormone and thyroxine reestablishes normal cardiac performance. In certain animal models of heart failure, administration of growth hormone alone increases cardiac output and myocardial contractility.


Physiology_Levy

Physiology_Levy. Changes in cardiac performance as a result of stimulation of central and peripheral chemoreceptors have been described previously in this chapter. These effects usually predominate. However, O2 and CO2 do have direct effects on the myocardium. Hypoxia has a biphasic effect on myocardial performance. Mild hypoxia stimulates performance, but more severe hypoxia depresses performance because oxidative metabolism is limited. An increase in partial pressure of carbon dioxide (PCO2)— which results in a decrease in pH—has a direct depressant effect on the heart. This effect is mediated by changes in intracellular pH. A reduction in intracellular pH, induced by an increase in PCO2, diminishes the amount of Ca++ released from the sarcoplasmic reticulum in response to excitation. The diminished pH also decreases the sensitivity of the myofilaments to Ca++ . Increases in intracellular pH have the opposite effect; that is, they enhance sensitivity to Ca++ .


Physiology_Levy

Physiology_Levy. Regulation of the Peripheral Circulation The peripheral circulation is essentially under dual control: centrally through the nervous system and locally by conditions in tissues surrounding the blood vessels. Nervous and humoral regulation of vascular smooth muscle is described in Fig. 14.7 Table 14.1 ), in which transmitters, hormones and their receptors are discussed. Aspects of local control are discussed in , in which the relative importance of these two control mechanisms is shown to vary in different tissues. The arterioles are involved in regulating the rate of blood flow throughout the body. These vessels offer the greatest resistance to the flow of blood pumped to the tissues by the heart, and thus these vessels are important in the maintenance of arterial blood pressure. The arteriole walls are composed in large part of smooth muscle fibers that allow the diameter of the vessel lumen to vary (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 15.2 ). When this smooth muscle contracts strongly, the endothelial lining folds inward and completely obliterates the vessel lumen. When the smooth muscle is completely relaxed, the vessel lumen is maximally dilated. Some resistance vessels are closed at any given time. In addition, the smooth muscle in these vessels is partially contracted (which accounts for the tone of these vessels). If all the resistance vessels in the body dilated simultaneously, arterial blood pressure would fall precipitously. Vascular smooth muscle controls total peripheral resistance, arterial and venous tone, and the distribution of blood flow throughout the body. The properties of vascular smooth muscle are discussed in . In the following sections, intrinsic and extrinsic control of vascular smooth muscle tone, and thus perfusion of peripheral tissues, is reviewed. Intrinsic or Local Control of Peripheral Blood Flow


Physiology_Levy

Physiology_Levy. Intrinsic or Local Control of Peripheral Blood Flow In certain tissues, blood flow is adjusted to the existing metabolic activity of the tissue. Furthermore, when tissue metabolism is steady, changes in perfusion pressure (arterial blood pressure) evoke changes in vascular resistance that tend to maintain a constant blood flow. This myogenic mechanism, which is illustrated graphically in Fig. 18.22 , is commonly referred to as autoregulation of blood flow. When pressure is abruptly increased or decreased from a control pressure of 100 mm Hg, flow increases or decreases, respectively. However, even with pressure maintained at its new level, blood flow returns toward the control level within 30 to 60 seconds.


Physiology_Levy

Physiology_Levy. •Fig. 18.22 Pressure-flowrelationshipinthevascularbedoftheskeletalmuscle.Filled (red) circles representtheflowratesobtainedimmediatelyafterabruptchangesinperfusionpressurefromthecontrollevel(thepointwherelinescross).Open (blue) circles representthesteady-stateflowratesobtainedatthenewperfusionpressure.(RedrawnfromJonesRD,BerneRM.Circ Res. 1964;14:126.)0 20 40 60 10080 120 140 160 180 0 2 4 6 8 10 12 Perfusion pressure (mm Hg) Muscle blood flow (mL/min/100 g)


Physiology_Levy

Physiology_Levy. Over the pressure range of 20 to 120 mm Hg, the steady-state flow is relatively constant. Calculation of hydraulic resistance (pressure/flow) across the vascular bed during steady-state conditions shows that the resistance vessels constrict with an elevation in perfusion pressure but dilate with a reduction in perfusion pressure. This response to perfusion pressure is independent of the endothelium because it is identical in intact vessels and in vessels that have been stripped of their endothelium. According to the myogenic mechanism, vascular smooth muscle contracts in response to an increase in the pressure difference across the wall of a blood vessel (transmural pressure), and it relaxes in response to a decrease in transmural pressure. The signaling mechanisms that allow distention of a vessel to elicit contraction are unknown. However, because stretch of vascular smooth muscle has been shown to raise intracellular [Ca++], an increase in transmural pressure is believed to


Physiology_Levy

Physiology_Levy. of a vessel to elicit contraction are unknown. However, because stretch of vascular smooth muscle has been shown to raise intracellular [Ca++], an increase in transmural pressure is believed to activate membrane calcium channels.


Physiology_Levy

Physiology_Levy. In normal subjects, blood pressure is maintained at a fairly constant level via the baroreceptor reflex. Hence, the myogenic mechanism may play little role in regulating blood flow to tissues under normal conditions. However, when a person changes from a lying to a standing position, transmural pressure rises in the lower extremities, and the precapillary vessels constrict in response to this imposed stretch. , the endothelium lining the vasculature produces a number of substances that can relax (e.g., nitric oxide) or contract (e.g., angiotensin II and endothelin) vascular smooth muscle. Thus the endothelium plays an important role in regulating blood flow to specific vascular beds.


Physiology_Levy

Physiology_Levy. The metabolic activity of a tissue governs blood flow in that tissue. Any intervention that results in inadequate O2 supply prompts the formation of vasodilator metabolites that are released from the tissue and act locally to dilate the resistance vessels. When the metabolic rate of the tissue increases, or when O2 delivery to the tissue decreases, more vasodilator substances are released (see Chapter 17).


Physiology_Levy

Physiology_Levy. Chapter 17). Potassium, inorganic phosphate ions, and interstitial fluid osmolarity induce vasodilation. During skeletal muscle contraction, both (1) K+ and phosphate are released and (2) osmolarity is increased. Therefore, these factors may contribute to active hyperemia (increase in blood flow caused by enhanced tissue activity). However, significant increases in the phosphate concentration and in osmolarity are not always observed during muscle contraction, and they may increase blood flow only transiently. Therefore, they probably do not mediate the vasodilation observed during muscular activity.