Physiology_Levy

Physiology_Levy. Exercise such as endurance running can increase the size of the heart as a result of hypertrophy of individual cardiac muscle cells. Concomitant with this enlarged so-called athlete’s heart is improved cardiac performance, as assessed by an increase in stroke volume, increased oxygen consumption, and preserved relaxation. Thus the athlete’s heart represents an example of “physiological hypertrophy,” with beneficial contractile effects. In contrast, if exposed to chronic pressure overload, the heart may undergo either concentric left ventricular hypertrophy or dilated left ventricular hypertrophy, which causes impairment of function. Details regarding the morphological, functional, and mechanistic differences between these various types of hypertrophy can be found elsewhere in this textbook (see Chapter 18).


Physiology_Levy

Physiology_Levy. Concentric hypertrophy is characterized by thickening of the left ventricular wall and represents a compensatory hypertrophy to the increased load. Dilated hypertrophy is characterized by increased ventricular volume (end-diastolic volume). Both concentric/compensatory left ventricular hypertrophy and dilated left ventricular hypertrophy have been shown to exhibit decreased contractile response to β-adrenergic stimulation, which limits the contractile reserve. In dilated left ventricular hypertrophy, normal •Fig. 13.6 Stretchingoftheheartincreasestheforceofcontraction(A). ThisisattributabletobothanincreaseinthemaximalforceofcontractionandanincreaseinthesensitivityofcontractiontoCa++ (B). ItreflectsanintrinsicregulatoryprocessreferredtoastheFrank-Starling law of the heart. (B,RedrawnfromDobeshD,KonhilasJ,deTombeP.Cooperativeactivationincardiacmuscle:impactofsarcomerelength.Am J Physiol Heart Circ Physiol. 2002;282:H1055-H1062.) contractile function, along with the Frank-Starling


Physiology_Levy

Physiology_Levy. J Physiol Heart Circ Physiol. 2002;282:H1055-H1062.) contractile function, along with the Frank-Starling response, may also be impaired.


Physiology_Levy

Physiology_Levy. The cellular and molecular mechanisms underlying the development of cardiac hypertrophy are not clear, although an elevation in intracellular [Ca++] has been implicated. The link or links between cardiac hypertrophy, decreased cardiac performance, and impaired β-adrenergic response during chronic pressure overload are unclear. Decreased cardiac performance has been attributed to dysregulation of intracellular [Ca++]. Alterations in the level, activity, and phosphorylation status of a variety of proteins, including L-type calcium channels, phospholamban, SERCA, and RYR, have all been implicated in the Ca++ dysregulation associated with a failing heart (pathological hypertrophy). A microRNA (miR-222) has been shown to be important for cardiac growth in response to exercise. It also appeared to inhibit maladaptive remodeling of the heart after ischemia/ reperfusion injury.


Physiology_Levy

Physiology_Levy. A microRNA (miR-222) has been shown to be important for cardiac growth in response to exercise. It also appeared to inhibit maladaptive remodeling of the heart after ischemia/ reperfusion injury. Amodestelevationinintracellular[Ca++](asaresultofincreasedcontractileactivity,forexample),hasbeenproposedtoactivateaCa++/calmodulin-dependentproteinphosphatase(calcineurin) thatcandephosphorylatethetranscriptionfactornuclear factor of activated T cells (NFAT), therebyfacilitatingtranslocationofNFATtothenucleusandultimatelypromotingproteinsynthesisandthushypertrophy( Fig.13.7 ).ActivationofCa++/calmodulin-dependentproteinkinasehasalsobeenimplicatedinactivationofthetranscriptionfactormyocyte enhancer factor 2 (MEF2) bypromotingthedissociation(nuclearexport)ofaninhibitorofMEF2(namely,histone deacetylase [HDAC]).


Physiology_Levy


Physiology_Levy

Physiology_Levy. Resultsofstudiessuggestthatdilatedcardiomyopathycanbepreventedinananimalmodelbydownregulatingphospholamban.ThemechanismunderlyingthispreventiveeffectofphospholambandownregulationisthoughttoinvolveanincreaseinCa++ uptakeactivityintheSRbecausephospholambantypicallyinhibitsSERCA.IncreasedactivityofSERCAwouldfacilitaterelaxationoftheheartasaresultofrapidCa++ uptakebytheSR.Inaddition,theforceofcontractionisincreasedbecausemoreCa++ isavailableforrelease.IncreasedCa++ uptakebytheSRmayalsodecreaseactivationoftheCa++-dependentphosphatasesthathavebeenimplicatedinthedevelopmentofcardiachypertrophy. There is evidence that cardiac hypertrophy may not be associated with some functional impairments. Intermittent aortic constrictions, for example, result in decreased β-adrenergic signaling, decreased capillary density, and decreased SERCA2 levels, without evidence of hypertrophy. Activation of PI3K appears to be involved in this response.


Physiology_Levy

Physiology_Levy. 278 SECTION3Berne & Levy Physiology Activity Ca++ Other transducers? Other effectors? Reprogramming Gene Expression Myocyte Hypertrophy/Tissue Remodeling CalcineurinCaMK Other targets? NFAT NFAT GSK3 HDAC CsA Cabin MCIP Agonists MEF2 GATA P •Fig. 13.7 Calcium-dependentactivationofcalcineurinandcalmodulin-dependentproteinkinasehavebeenimplicatedinthedevelopmentofcardiachypertrophyandinvolveactivationofthefollowingtranscriptionfactors:nuclearfactorofactivatedTcells(NFAT),transcriptionfactorbindingtoDNAsequenceGATA(GATA),andmyocyteenhancerfactor2(MEF2).Cabin,calcineurin-bindingprotein/inhibitor;CaMK,Ca++/calmodulin-dependentproteinkinase;CsA,cyclosporine;GSK3,glycogensynthasekinase3;HDAC,histonedeacetylase;MCIP,modulatorycalcineurin-interactingprotein.(RedrawnfromOlsonEN,WilliamsRS.Calcineurinsignalingandmuscleremodeling.Cell. 2000;101:689-692.) 1.


Physiology_Levy

Physiology_Levy. Cardiac muscle is an involuntary, striated muscle. Cardiac muscle cells are relatively small (10 µm × 100 µm) and form an electrical syncytium with tight electrical and mechanical connections between adjacent cardiac muscle cells. Action potentials are initiated in the sinoatrial node and spread quickly throughout the heart to allow synchronous contraction, a feature important for the pumping action of the heart. 2. Contraction of cardiac muscle involves the Ca++dependent interaction of actin and myosin filaments, as in skeletal muscle. However, unlike skeletal muscle, cardiac muscle requires an influx of extracellular Ca++ . Specifically, the influx of Ca++ during an action potential triggers release of Ca++ from the SR, which then promotes actin-myosin interaction and contraction. 3.


Physiology_Levy

Physiology_Levy. 3. Relaxation of cardiac muscle involves reaccumulation of Ca++ by the SR and extrusion of Ca++ from the cell via the 3Na+-Ca++ antiporter and the sarcolemmal Ca++ pump. The Ca++ pump of the SR is associated with numerous proteins (forming a regulosome), including some endogenous micropeptide inhibitors and activators. 4. The force of contraction of cardiac muscle is increased by stretch (Frank-Starling Law of the Heart) and by sympathetic stimulation. Skeletal muscle, in contrast, increases force by recruiting more muscle fibers or by tetany. 5.


Physiology_Levy

Physiology_Levy. 5. Hypertrophy of the heart can occur in response to exercise, chronic pressure overload, or genetic mutations. The cardiac hypertrophy resulting from exercise is typically beneficial, with improved cardiac performance, increased oxygen consumption, and normal relaxation. Chronic pressure overload, on the other hand, can result in cardiac hypertrophy that is initially associated with a decreased β-adrenergic response but may progress to dilated cardiac hypertrophy, characterized by decreased contractile ability. Genetic mutations resulting in cardiac hypertrophy include familial hypertrophic Anderson DM, Anderson KM, Chang CL, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160:595-606. Endoh M. Cardiac Ca2+ signaling and Ca2+ sensitizers. Circ J. 2008;72:1915-1925.


Physiology_Levy

Physiology_Levy. Endoh M. Cardiac Ca2+ signaling and Ca2+ sensitizers. Circ J. 2008;72:1915-1925. Haghighi K, Bidwell P, Kranias EG. Phospholamban interactome in cardiac contractility and survival: a new vision of an old friend. J Mol Cell Cardiol. 2014;77:160-167. Hidalgo C, Granzier H. Tuning the molecular giant titin through phosphorylation: role in health and disease. Trends Cardiovasc Med. 2013;23:165-171. cardiomyopathy, in which a mutation in a single intracellular protein may alter contractile function and promote a hypertrophic response. Researchers have identified a microRNA that appears to contribute to the exercise-induced hypertrophy of the heart and to inhibit maladaptide remodeling after ischemia/reperfusion injury. Kobirumaki-Shimozawa F, Inoue T, Shintani SA, et al. Cardiac thin filament regulation and the Frank–Starling mechanism. J Physiol Sci. 2014;64:221-232. Marks AR. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Invest. 2013;123(1):46-52.


Physiology_Levy

Physiology_Levy. Marks AR. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Invest. 2013;123(1):46-52. Tao L, Bei Y, Zhang H, Xiao J, Li X. Exercise for the heart: signaling pathways. Oncotarget. 2015;6:20773-20784. Williams GS, Boyman L, Lederer WJ. Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol. 2015;78:35-45. Upon completion of this chapter the student should be able to answer the following questions: 1. Describe the organization of smooth muscle in various tissues, and how it meets the demands of each tissue/ organ. 2. Discuss the mechanisms that promote contraction and relaxation of smooth muscle in the vasculature and various organs. 3. Describe the autoregulatory mechanism by which an artery can maintain relatively constant blood flow to a tissue over a broad range of perfusion pressures. 4. Describe the basis and utility of a transition from phasic contraction to tonic contraction. 5.


Physiology_Levy

Physiology_Levy. 4. Describe the basis and utility of a transition from phasic contraction to tonic contraction. 5. Discuss the length-tension curves and force-velocity curves for smooth muscle, and the molecular basis for each of these curves. If the student has already completed on skeletal muscle and cardiac muscle, comparison of all three tissues for each of the learning objectives listed should be possible.


Physiology_Levy

Physiology_Levy. onstriated, or smooth, muscle cells are a major component of hollow organs such as the alimentary canal, airways, vasculature, and urogenital tract. Contraction of smooth muscle serves to alter the dimensions of the organ, which may result in either propelling the contents of the organ (as in peristalsis of the intestine) or increasing the resistance to flow (as in vasoconstriction). The basic mechanism underlying contraction of smooth muscle involves an interaction of myosin with actin (as in striated muscle), although there are some important differences. Specifically, contraction of smooth muscle is thick-filament regulated and requires an alteration in myosin before it can interact with actin, whereas contraction of striated muscle is thin-filament regulated and requires movement of the troponin-tropomyosin complex on the actin filament before myosin can bind to actin. Smooth muscle can contract in response to either electrical or hormonal signals and exhibits the ability to


Physiology_Levy

Physiology_Levy. of the troponin-tropomyosin complex on the actin filament before myosin can bind to actin. Smooth muscle can contract in response to either electrical or hormonal signals and exhibits the ability to remain contracted for extended periods at low levels of energy consumption, which is important for functions such as maintaining vascular tone and hence blood pressure. Thus regulation of contraction of smooth muscle is complex, sometimes involving multiple intracellular signaling cascades. In the present chapter, effort is made to identify mechanisms underlying this diverse regulation of smooth muscle contraction and, when appropriate, compare these regulatory mechanisms with those observed in striated muscle. Alterations in smooth muscle function/ regulation that have been implicated in various pathological conditions are also discussed.


Physiology_Levy

Physiology_Levy. Overview of Smooth Muscle Types of Smooth Muscle


Physiology_Levy

Physiology_Levy. Smooth muscle has been subdivided into two groups: single unit and multiunit. In single-unit smooth muscle the smooth muscle cells are electrically coupled such that electrical stimulation of one cell is followed by stimulation of adjacent smooth muscle cells. This results in a wave of contraction, as in peristalsis. Moreover, this wave of electrical activity, and hence contraction, in single-unit smooth muscle may be initiated by a pacemaker cell (i.e., a smooth muscle cell that exhibits spontaneous depolarization). In contrast, multiunit smooth muscle cells are not electrically coupled, so stimulation of one cell does not necessarily result in activation of adjacent smooth muscle cells. Examples of multiunit smooth muscle include the vas deferens of the male genital tract and the iris of the eye. Smooth muscle, however, is even more diverse, with the single-unit and multiunit classifications representing ends of a spectrum. The terms single-unit and multiunit represent an


Physiology_Levy

Physiology_Levy. the iris of the eye. Smooth muscle, however, is even more diverse, with the single-unit and multiunit classifications representing ends of a spectrum. The terms single-unit and multiunit represent an oversimplification, however; many smooth muscles are modulated by a combination of neural elements with at least some degree of cell-to-cell coupling and locally produced activators or inhibitors that also promote a somewhat coordinated response of smooth muscles.


Physiology_Levy

Physiology_Levy. A second consideration when discussing types of smooth muscle is the activity pattern ( Fig. 14.1 ). In some organs the smooth muscle cells contract rhythmically or intermittently, whereas in other organs the smooth muscle cells are continuously active and maintain a level of “tone.” Smooth muscle exhibiting rhythmic or intermittent activity is termed phasic smooth muscle and includes smooth muscles in the walls of the gastrointestinal (GI) and urogenital tracts. Such phasic smooth muscle corresponds to the single-unit category described earlier because the smooth muscle cells contract in response to action potentials that propagate from cell to cell. Smooth muscle that is continuously active, on the other hand, is termed tonic smooth muscle.


Physiology_Levy

Physiology_Levy. Vascular smooth muscle, respiratory smooth muscle, and some sphincters are continuously active. The continuous partial activation of tonic smooth muscle is not associated with action potentials, although it is proportional to membrane potential. Tonic smooth muscle would thus correspond to the multiunit smooth muscle described earlier. Phasic and tonic contractions of smooth muscle result from interactions of actin and myosin filaments, although as discussed later in this chapter, there is a change in cross-bridge cycling kinetics during tonic contraction, such that the smooth muscle can maintain force at low energy cost.


Physiology_Levy

Physiology_Levy. •Fig. 14.1 Somecontractileactivitypatternsexhibitedbysmoothmuscles.Tonicsmoothmusclesarenormallycontractedandgenerateavariablesteady-stateforce.Examplesaresphincters,bloodvessels,andairways.Phasicsmoothmusclescommonlyexhibitrhythmiccontractions(e.g.,peristalsisintheGItract)butmaycontractintermittentlyduringphysiologicalactivitiesundervoluntarycontrol(e.g.,voidingofurinefromurinarybladder,swallowing). Structure of Smooth Muscle Cells


Physiology_Levy

Physiology_Levy. Fig. 14.2 ). Blood vessels and airways exhibit a simple tubular structure in which the smooth muscle cells are arranged circumferentially, so contraction reduces the diameter of the tube. This contraction increases resistance to the flow of blood or air but has little effect on the length of the organ. Smooth muscle cell organization is more complex in the GI tract. Layers of smooth muscle in both circumferential and longitudinal orientations provide the mechanical action for mixing food and also propelling the luminal contents from the mouth to the anus. Coordination between these layers depends on a complex system of autonomic nerves linked by plexuses. These plexuses cells in the walls of these organs contributes to their ability to reduce internal volume to almost zero during urination are located between the two muscle layers. The smooth muscle in the walls of saccular structures such as the urinary bladder or rectum allows the organ to increase in size with accumulation of urine


Physiology_Levy

Physiology_Levy. are located between the two muscle layers. The smooth muscle in the walls of saccular structures such as the urinary bladder or rectum allows the organ to increase in size with accumulation of urine or feces. The varied arrangement of


Physiology_Levy

Physiology_Levy. Normally partially contracted (tone) Blood vessels, airways Stomach, intestines Esophagus, urinary bladder Phasically active or defecation. Smooth muscle cells in hollow organs occur in a spectrum of forms, depending on their function and mechanical loads. In all hollow organs the smooth muscle is separated from the contents of the organ by other cellular elements, which may be as simple as vascular endothelium or as complex as the mucosa of the digestive tract. The walls of hollow organs also contain large amounts of connective tissue that bear an increasing share of the wall stress as organ volume increases.


Physiology_Levy

Physiology_Levy. The following sections describe the structural components that enable smooth muscle to set or alter hollow organ volume. These components include contractile and regulatory proteins, force-transmitting systems such as the •Fig. 14.2 Scanningelectronmicrographsofsmoothmuscle.A,Musculararteriolewithfusiformsmoothmusclecellsinacircularorientation(bar, 20µm).B,Superimposedimagesofcircular(below) andlongitudinal(above) layersofintestinalsmoothmusclesandwichingneuralcomponentsofthemyentericplexus(asterisk) (bar, 50mm).C,Rectangularsmoothmusclecellswiththinprojectionstoadjacentcellsinasmalltesticularduct(bar, 5µm).(FromMottaPM[ed].Ultrastructure of Smooth Muscle. Norwell,MA:KluwerAcademic;1990.) cytoskeleton, linkages between cells and the extracellular matrix, and membrane systems that transduce extracellular signals into changes in myoplasmic [Ca++].


Physiology_Levy

Physiology_Levy. A variety of specialized contacts exists between smooth muscle cells. Such contacts allow mechanical linkage and communication between cells. In contrast to skeletal muscle cells, which are normally attached at either end to a tendon, smooth (and cardiac) muscle cells are connected to each other. Because smooth muscle cells are anatomically arranged in series, they not only must be mechanically linked but must also be activated simultaneously and to the same degree. This mechanical and functional linkage is crucial to smooth muscle function. If such linkage did Dense bodies c Caveolae Thick filaments Mitochondria Sarcoplasmic reticulum Thick Thin Filaments 0.1 µm0.1 µm C 0.5 mµ not exist, contraction in one region would simply stretch another region without a substantial decrease in radius or increase in pressure. The mechanical connections are provided by attachments to sheaths of connective tissue and by specific junctions between muscle cells.


Physiology_Levy

Physiology_Levy. Several types of junctions are found in smooth muscle. Functional linkage of the cells is provided by gap junctions ( Fig. 14.3A ). Gap junctions form low-resistance pathways between cells (see ). They also allow chemical communication by diffusion of low-molecular-weight compounds. In certain tissues, such as the outer longitudinal layer of smooth muscle in the intestine, large numbers of such junctions exist. Action potentials are readily propagated from cell to cell through such tissues.


Physiology_Levy

Physiology_Levy. B Surface couplings Sarcoplasmic reticulum 0.5 mµ0.2 mµ 0.5 mµ •Fig. 14.3 Junctions,membranes,andmyofilaments,insmoothmuscle.A,TransmissionelectronmicrographofGapjunctionbetweenintestinalsmoothmusclecells.B,Longitudinalviewofapulmonaryarterysmoothmusclecell.Thesarcoplasmicreticulumisstainedwithosmiumferricyanideandappearstoformacontinuousnetworkthroughoutthecellconsistingoftubules,fenestratedsheets(long arrows), andsurfacecouplingsatthecellmembrane(short arrows). C,Transversesectionofabundleofvenoussmoothmusclecellsillustratingtheregularspacingofthickfilaments(long line) andtherelativelylargenumberofsurroundingthin(actin)filaments(inset). Densebodies(arrowheads) aresitesofattachmentforthethinactinfilamentsandequivalenttotheZlinesofstriatedmuscles.Elementsofsarcoplasmicreticulum(short line) occurattheperipheryofthesecells.D,Scanningelectronmicrographoftheinnersurfaceofthesarcolemmaofanintestinalsmoothmusclecell.Longitudinalrowsofcaveolaeprojectintothemyoplasm(small, light-colored


Physiology_Levy

Physiology_Levy. line) occurattheperipheryofthesecells.D,Scanningelectronmicrographoftheinnersurfaceofthesarcolemmaofanintestinalsmoothmusclecell.Longitudinalrowsofcaveolaeprojectintothemyoplasm(small, light-colored spheres), surroundedbydarkerelementsofthetubularsarcoplasmicreticulum.Theattachmentsofthinfilamentstothesarcolemmabetweentherowsofmembraneelementswereremovedduringpreparationofthespecimen.(AandD,FromMottaPM[ed].Ultrastructure of Smooth Muscle. Norwell,MA:KluwerAcademic;1990.BandC,FromSomlyoAP,SomlyoAV.Smoothmusclestructureandfunction.In:FozzardHAetal.[eds].The Heart and Cardiovascular System.2nded.NewYork:RavenPress;1992.) muscle cells. The adherens junction appears as thickened regions of opposing cell membranes that are separated by a small gap (≈60 nm) containing dense granular material. Thin filaments extend into the adherens junction to allow the contractile force generated in one smooth muscle cell to be transmitted to adjacent smooth muscle cells.


Physiology_Levy

Physiology_Levy. Embryonic smooth muscle cells do not fuse, and each differentiated cell has a single centrally located nucleus. Though dwarfed by skeletal muscle cells, smooth muscle cells are nevertheless quite large (typically 40–600 µm long). These cells are 2 to 10 µm in diameter in the region of the nucleus, and most taper toward their ends. Contracting cells become quite distorted as a result of the force exerted on the cell by attachments to other cells or to the extracellular matrix, and cross sections of these cells are often very irregular. Smooth muscle cells lack T tubules, the invaginations of the skeletal muscle sarcolemma that provide electrical links to the sarcoplasmic reticulum (SR). However, the sarcolemma of smooth muscle has longitudinal rows of tiny sac-like inpocketings called caveolae (see


Physiology_Levy

Physiology_Levy. Fig. 14.3B–D ). Caveolae increase the surface-to-volume ratio of the cells and are often closely apposed to the underlying SR. A gap of approximately 15 nm has been observed between the caveolae and the underlying SR, comparable to the gap between the T tubules and terminal SR in skeletal muscle. Moreover, “Ca++ sparks” and a variety of Ca++-handling proteins have been observed in the vicinity of caveolae, thus raising the possibility that the caveolae and the underlying SR may contribute to regulation of intracellular [Ca++] in smooth muscle. The voltage-gated L-type Ca++ channel and the 3Na+-1Ca++ antiporter, for example, are associated with caveolae. The proteins caveolin and cholesterol are both critical for the formation of caveolae, and it is hypothesized that the caveolae reflect a specialized region of the sarcolemma that may also contain various signaling molecules in addition to the Ca++ signaling mentioned earlier.


Physiology_Levy

Physiology_Levy. Smooth muscle also has an intracellular membrane network of SR that serves as an intracellular reservoir for Ca++ (see


Physiology_Levy

Physiology_Levy. Fig. 14.3B–D ). Calcium can be released from the SR into the myoplasm when stimulatory neurotransmitters, hormones, or drugs bind to receptors on the sarcolemma. Importantly, intracellular Ca++ channels in the SR of smooth muscle include the ryanodine receptor (RYR), which is similar to that found in skeletal muscle SR, and the inositol 1,4,5-trisphosphate (InsP3)-gated Ca++ channel. The RYR is typically activated by a rise in intracellular [Ca++] (i.e., Ca++-induced release of Ca++ in response to an influx of Ca++ through the sarcolemma). The InsP3-gated Ca++ channel is activated by InsP3, which is produced when a hormone or hormones bind to various Ca++-mobilizing receptors on the sarcolemma. Intracellular [Ca++] is lowered through the action of an SR Ca++-ATPase (SERCA) and extrusion of Ca++ from the cell via a 3Na+-1Ca++ antiporter and a sarcolemmal Ca++-ATPase. The amount of SR in smooth muscle cells varies from 2% to 6% of cell volume and approximates that of skeletal muscle.


Physiology_Levy

Physiology_Levy. of Ca++ from the cell via a 3Na+-1Ca++ antiporter and a sarcolemmal Ca++-ATPase. The amount of SR in smooth muscle cells varies from 2% to 6% of cell volume and approximates that of skeletal muscle. Chemical signals such as InsP3 or a localized increase in intracellular [Ca++] (e.g., within the gap between the caveolae and SR) functionally link the sarcolemma and the SR.


Physiology_Levy

Physiology_Levy. Smooth muscle cells contain a prominent rough endoplasmic reticulum and Golgi apparatus, which are located centrally at each end of the nucleus. These structures reflect significant protein synthetic and secretory functions. The scattered mitochondria are sufficient for oxidative phosphorylation to generate the increased adenosine triphosphate (ATP) consumed during contraction.


Physiology_Levy

Physiology_Levy. The thick and thin filaments of smooth muscle cells are about 10,000 times longer than their diameter and are tightly packed. Therefore the probability of observing an intact filament by electron microscopy is extremely low. In contrast to skeletal muscle, which contains a transverse alignment of thick and thin filaments that results in striations, the contractile filaments in smooth muscle are not in uniform transverse alignment, and thus smooth muscle has no striations. The lack of striations in smooth muscle does not imply a lack of order. The thick and thin filaments are organized in contractile units that are analogous to sarcomeres.


Physiology_Levy

Physiology_Levy. The thin filaments of smooth muscle have an actin and tropomyosin composition and structure similar to that in skeletal muscle. However, the cellular content of actin and tropomyosin in smooth muscle is about twice that of striated muscle. Smooth muscle lacks troponin and nebulin but contains two proteins not found in striated muscle: caldesmon and calponin. The precise roles of these proteins are unknown, but they do not appear to be fundamental to cross-bridge cycling. It has been suggested that both calponin and caldesmon may regulate the contractility of smooth muscle. (in part by inhibiting actomyosin ATPase activity). Most of the myoplasm is filled with thin filaments that are roughly aligned along the long axis of the cell. The myosin content of smooth muscle is only a fourth that of striated muscle. Small groups of three to five thick filaments are aligned and surrounded by many thin filaments. These groups of thick filaments with interdigitating thin filaments are connected


Physiology_Levy

Physiology_Levy. of striated muscle. Small groups of three to five thick filaments are aligned and surrounded by many thin filaments. These groups of thick filaments with interdigitating thin filaments are connected to dense bodies or areas (


Physiology_Levy

Physiology_Levy. Fig. 14.4 Fig. 14.3A–B ) and represent the equivalent of the sarcomere. The contractile apparatus of adjacent cells is mechanically coupled by the links between membrane-dense areas.


Physiology_Levy

Physiology_Levy. The cytoskeleton in smooth muscle cells serves as an attachment point for the thin filaments and permits transmission of force to the ends of the cell. In contrast to skeletal muscle, the contractile apparatus in smooth muscle is not organized into myofibrils, and Z lines are lacking. The functional equivalents of the Z lines in smooth muscle cells •Fig. 14.4 Apparentorganizationofcell-to-cellcontacts,cytoskeleton,andmyofilamentsinsmoothmusclecells.Smallcontractileelementsfunctionallyequivalenttoasarcomereunderliethesimilaritiesinmechanicsbetweensmoothandskeletalmuscle.Linkagesconsistingofspecializedjunctionsorinterstitialfibrillarmaterialfunctionallycouplethecontractileapparatusofadjacentcells.Densebodies,thefunctionalequivalentofZlinesinstriatedmuscle,areinterconnectedbyintermediatefilaments.Themyofilamentsareorientedlargelyinparallelwiththelongitudinalaxisofthecell,thoughanobliqueorientationhasbeenobservedinsomearteries.


Physiology_Levy

Physiology_Levy. are ellipsoidal dense bodies in the myoplasm and dense areas that form bands along the sarcolemma (see Figs. 14.3A–B 14.4 ). These structures serve as attachment points for the thin filaments and contain α-actinin, a protein also found in the Z lines of striated muscle. Intermediate filaments with diameters between those of thin filaments (7 nm) and thick filaments (15 nm) are prominent in smooth muscle. These filaments link the dense bodies and areas into a cytoskeletal network. The intermediate filaments consist of protein polymers of desmin or vimentin. Control of Smooth Muscle Activity


Physiology_Levy

Physiology_Levy. Control of Smooth Muscle Activity The contractile activity of smooth muscle can be controlled by numerous factors, including hormones, autonomic nerves, pacemaker activity, and a variety of drugs. Like skeletal or cardiac muscle, contraction of smooth muscle is dependent on Ca++ , and the agents just listed induce smooth muscle contraction by increasing intracellular [Ca++]. However, in contrast to skeletal or cardiac muscle, action potentials in smooth muscle are highly variable and not always needed to initiate contraction. Moreover, several agents can increase intracellular [Ca++] and hence contract smooth muscle without changing the membrane potential.


Physiology_Levy

Physiology_Levy. Fig. 14.5 shows various types of action potentials in smooth muscle and the corresponding changes in force. An action potential in smooth muscle can be associated with a slow twitch-like response, and the twitch forces can summate during periods of repetitive action potentials (i.e., similar to tetany in skeletal muscle). Such a pattern of activity is characteristic of single-unit smooth muscle in many viscera.


Physiology_Levy

Physiology_Levy. Periodic oscillations in membrane potential can occur as a result of changes in the activity of Na+,K+-ATPase in the sarcolemma. These oscillations in membrane potential can trigger multiple action potentials in the cell. Alternatively the contractile activity of smooth muscle may not be associated with generation of action potentials or even a change in membrane potential. In many smooth muscles the resting membrane potential is sufficiently depolarized (−60 to −40 mV) that a small decrease in membrane potential can significantly inhibit influx of Ca++ through voltage-gated Ca++ channels in the sarcolemma. By decreasing Ca++ influx, the force developed by smooth muscle decreases. Such a graded response to slight changes in the resting membrane potential is common in multiunit smooth muscles that maintain constant tension (e.g., vascular smooth muscle).


Physiology_Levy

Physiology_Levy. Contraction of smooth muscle in response to an agent that does not produce a change in membrane potential is termed pharmacomechanical coupling and typically reflects the ability of the agent to increase the level of the intracellular second messenger InsP3. Other agents result in a decrease in tension, also without a change in membrane potential. These agents typically increase levels of the intracellular second messengers cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP). The molecular mechanisms by which InsP3, cGMP, cAMP, and Ca++ alter the contractile force of smooth muscle are presented later.


Physiology_Levy

Physiology_Levy. Phosphorylation of a myosin light chain is required for the interaction of myosin with actin, and although Ca++dependent phosphorylation plays a key role in this process, the level of myosin phosphorylation (and hence the degree of contraction) is dependent on the relative activities of both myosin light-chain kinase (MLCK, which promotes phosphorylation) and myosin phosphatase (MP, which promotes dephosphorylation). Several agonists/hormones increase the level of myosin light-chain phosphorylation by simultaneously activating MLCK through an increase in intracellular [Ca++] and inhibiting MP through a signaling cascade involving the monomeric G protein RhoA and its effector Rho kinase (ROK). Moreover, hyperactivity of this RhoA/ROK signaling cascade has been implicated in various pathological conditions such as hypertension and vasospasm (discussed later). Innervation of Smooth Muscle


Physiology_Levy

Physiology_Levy. Neural regulation of smooth muscle contraction depends on the type of innervation and neurotransmitters released, the proximity of the nerves to the muscle cells, and the •Fig. 14.5


Physiology_Levy

Physiology_Levy. depends on the type of innervation and neurotransmitters released, the proximity of the nerves to the muscle cells, and the •Fig. 14.5 Relationshipsbetweenmembranepotential(Em)andgenerationofforce(F)indifferenttypesofsmoothmuscle.A,Actionpotentialsmaybegeneratedandleadtoatwitchorlargersummedmechanicalresponses.Actionpotentialsarecharacteristicofsingle-unitsmoothmuscles(manyviscera).Gapjunctionspermitthespreadofactionpotentialsthroughoutthetissue.B,Rhythmicactivityproducedbyslowwavesthattriggeractionpotentials.Thecontractionsaregenerallyassociatedwithaburstofactionpotentials.Slowoscillationsinmembranepotentialusuallyreflecttheactivityofelectrogenicpumpsinthecellmembrane.C,Toniccontractileactivitymayberelatedtothevalueofthemembranepotentialintheabsenceofactionpotentials.GradedchangesinEmarecommoninmultiunitsmoothmuscles(e.g.,vascular),whereactionpotentialsarenotgeneratedandpropagatedfromcelltocell.D,Pharmacomechanicalcoupling;changesinforceproducedbytheadditionorremoval(arrows)


Physiology_Levy

Physiology_Levy. ofdrugsorhormonesthathavenosignificanteffectonmembranepotential.


Physiology_Levy

Physiology_Levy. type and distribution of the neurotransmitter receptors on the muscle cell membranes ( Fig. 14.6 ). In general, smooth muscle is innervated by the autonomic nervous system. The smooth muscle in arteries is innervated primarily by sympathetic fibers, whereas the smooth muscle in other tissues can have both sympathetic and parasympathetic innervation. In the GI tract, smooth muscle is innervated by nerve plexuses that make up the enteric nervous system. The smooth muscle cells of some tissues (e.g., uterus) have no innervation. The neuromuscular junctions and neuromuscular transmission in smooth muscle are functionally comparable to that of skeletal muscle but structurally less complex. The autonomic nerves that supply smooth muscle have a series of swollen areas, or varicosities, that are spaced at intervals along the axon. These varicosities contain vesicles for the neurotransmitter (see Fig. 14.6).


Physiology_Levy

Physiology_Levy. Fig. 14.6). The postsynaptic membrane of smooth muscle exhibits little specialization when compared with that of skeletal muscle (see ). The synaptic cleft is typically about 80 to 120 nm wide but can be as narrow as 6 to 20 nm or even greater than 120 nm. In synapses in which a wide synaptic cleft is found, release of neurotransmitter can affect multiple smooth muscle cells. There are a large number of neurotransmitters that affect smooth muscle activity. A partial listing is provided in Table 14.1 Regulation of Contraction Contraction of smooth muscle requires phosphorylation of a myosin light chain. Typically this phosphorylation occurs in response to a rise in intracellular [Ca++], either after an action potential or in the presence of a hormone/agonist. As depicted in


Physiology_Levy

Physiology_Levy. Fig. 14.7 , a rise in intracellular [Ca++] in smooth muscle results in the binding of 4 Ca++ ions to the protein calmodulin, and then the Ca++-calmodulin complex activates MLCK, which phosphorylates the regulatory light chain of myosin. This phosphorylation step is critical for the interaction of smooth muscle myosin with actin. In addition to this phosphorylation step in smooth muscle,


Physiology_Levy

Physiology_Levy. Varicosity with neurotransmitter vesicles •Fig. 14.6 Controlsystemsofsmoothmuscle.Inbothmultiunitsmoothmuscle(A)andsingleunitsmoothmuscle(B),neurallyreleasedtransmittersorcirculatingorlocallygeneratedhormonesorsignalingmoleculescaninducecontractionorrelaxationofthesmoothmuscle.Thecombinationofaneurotransmitter,hormone,ordrugwithspecificreceptorsactivatescontractionbyincreasingcellCa++


Physiology_Levy


Physiology_Levy

Physiology_Levy. an ATP molecule is also needed to energize the myosin cross-bridge for the development of force. TheentericnervoussystemcontrolsmanyaspectsofGIfunction,includingmotility.Somechildrenarebornwithoutentericnervesinthedistalportionofthecolon.Theabsenceofnervesiscausedbymutantgenesthatdisruptthesignalsnecessaryfortheembryonicnervestomigratetothecolon.Inthesechildren,normalmotilityofthecolondoesnotoccurandsevereconstipationresults.ThisconditioniscalledHirschsprung’s disease. Itcanbecorrectedbysurgicallyremovingtheportionofthecolonthatdoesnotcontainentericnerves. Contraction of smooth muscle is thus said to be thick-filament regulated, which contrasts with the thin-filament regulation of contraction of striated muscle, where binding of Ca++ to troponin exposes myosin binding sites on the actin thin filament. The thick-filament regulation is attributable to expression of a distinct myosin isoform in smooth muscle.


Physiology_Levy

Physiology_Levy. The myosin cross-bridge cycle in smooth muscle is similar to that in striated muscle in that after attachment to the actin filament, the cross-bridge undergoes a ratchet action in which the thin filament is pulled toward the center of the thick filament and force is generated. ADP and Pi are released from the myosin head at this time, thereby allowing ATP to bind. ATP decreases the affinity of myosin for actin, which allows release of myosin from actin. Energy from the newly bound ATP is then used to produce a conformational change in the myosin head (i.e., recocking the head) so that the cross-bridge is ready for another contraction cycle. The cross-bridge cycle continues as long as the myosin cross-bridge remains phosphorylated. Note that although the four basic steps of the cross-bridge cycle appear to be the same for striated and smooth muscle, the kinetics of cross-bridge cycling is much slower for smooth muscle.


Physiology_Levy

Physiology_Levy. Cross-bridge cycling continues with the hydrolysis of 1 ATP molecule per cycle until myoplasmic [Ca++] falls. With the decrease in [Ca++], MLCK becomes inactive, and the cross-bridges are dephosphorylated by MP (see Fig. 14.7 Fig. 14.4 , the thin filaments in smooth muscle are attached to dense bodies, and the myosin thick filaments appear to reside between two dense bodies and overlap a portion of the thin filaments, much like the overlap of thick and thin filaments in the sarcomere of striated muscle. A bipolar arrangement of myosin molecules within the thick filament is thought to allow the myosin cross-bridges to pull the actin filaments toward the center of the thick filament, thus contracting the smooth muscle and hence developing force.


Physiology_Levy

Physiology_Levy. From a structural standpoint, smooth muscle myosin is similar to striated muscle myosin in that they both contain a pair of heavy chains and two pairs of light chains. Despite this similarity, they represent different gene products and thus have different amino acid sequences. As noted, smooth muscle myosin, unlike skeletal muscle myosin, is unable to interact with the actin thin filament unless the regulatory light chain of myosin is phosphorylated. Moreover, the thin filament in smooth muscle lacks troponin, which plays a •Fig. 14.7


Physiology_Levy

Physiology_Levy. is unable to interact with the actin thin filament unless the regulatory light chain of myosin is phosphorylated. Moreover, the thin filament in smooth muscle lacks troponin, which plays a •Fig. 14.7 RegulationofsmoothmusclemyosininteractionswithactinbyCa++-stimulatedphosphorylation.Intherelaxedstate,cross-bridgesarepresentasahigh-energymyosin-ADP-PicomplexinthepresenceofATP.Attachmenttoactindependsonphosphorylationofthecross-bridgebyaCa++-calmodulin–dependentmyosinlight-chainkinase(MLCK).Phosphorylatedcross-bridgescycleuntiltheyaredephosphorylatedbymyosinphosphatase.Notethatcross-bridgephosphorylationataspecificsiteonamyosinregulatorylightchainrequiresATPinadditiontothatusedineachcyclicinteractionwithactin.


Physiology_Levy

Physiology_Levy. critical role in the thin-filament regulation of contraction in striated muscle (see Although intracellular Ca++ is required for smooth muscle contraction, the sensitivity of contraction to Ca++ is variable. Several hormones/agonists, for example, increase the force of contraction at a given submaximal intracellular [Ca++], thereby resulting in Ca++ sensitization ( Fig. 14.8 ). Ca++ sensitization is depicted as a leftward shift in the Ca++ dependence of smooth muscle contraction (see Fig. 14.8B ) and can occur in response to a decrease in the activity of MP activity at a given intracellular [Ca++]. Likewise an increase in MP activity at a given intracellular [Ca++] promotes a rightward shift in the Ca++ dependence of smooth muscle contraction, resulting in Ca++ desensitization (see Fig. 14.8B ). Reciprocal changes in the activities of MP and MLCK can occur, as shown in


Physiology_Levy

Physiology_Levy. Fig. 14.8B ). Reciprocal changes in the activities of MP and MLCK can occur, as shown in Fig. 14.8A , where stimulation of the ROK signaling cascade by an agonist can simultaneously inhibit MP and stimulate MLCK at a given intracellular [Ca++], thereby increasing the Ca++ sensitivity of contraction (i.e., Ca++ sensitization). Fig. 14.8A ).RhoAactivatesRhokinase(ROK),whichinturninhibitsMPbybothdirectandindirectmechanisms.DirectinhibitionofMPbyactivatedROKinvolvesROKphosphorylationofthemyosin-bindingsubunit(MBS)ofMP.IndirectinhibitionofMPbyactivatedROKinvolvesphosphorylationofCPI-17, anendogenous17-kDaprotein,whichtheninhibitsMP.Hormones/agonistssuchascatecholamines(actingonα1-adrenergicreceptors),vasopressin,endothelin,angiotensin,andmuscarinicagonistsincreasethesensitivityofsmoothmusclecontractiontoCa++ throughactivationofRhoA/ROKsignaling.ROKcanalsobeactivatedbyarachidonicacidandinhibitedbyY-27632,ahighlyspecificinhibitor(see Fig.14.8A ).Thoughnotshownin


Physiology_Levy

Physiology_Levy. Fig.14.8A ).Thoughnotshownin Fig.14.8 ,inactiveRhoAistypicallylocatedinthecytosol,boundtoGDPandaninhibitoryprotein(Rho-GDP dissociation inhibitor [GDI]). BindingofagonisttovariousG-coupledreceptorscanactivateRhoAbystimulatingguanine nucleotide exchange factor (GEF) toyieldRhoA-GTP,whichlocalizestothesarcolemmaandactivatesROK.Conversely,stimulationofMPactivityreducestheCa++ sensitivityofcontractionofsmoothmuscle,therebypromotingrelaxation(andhencevasodilation).


Physiology_Levy

Physiology_Levy. During a phasic contraction, myoplasmic [Ca++], cross-bridge phosphorylation, and force reach a peak and then return to baseline ( Fig. 14.9 ). In contrast, during a tonic contraction, myoplasmic [Ca++] and cross-bridge phosphorylation decline after an initial spike but do not return to baseline levels. During this later phase, force slowly increases and is sustained at a high level (see Fig. 14.9). This sustained force is maintained with only 20% to 30% of the cross-bridges phosphorylated, and thus ATP utilization is reduced. The term latch state refers to this condition of tonic contraction during which force is maintained at low energy expenditure.


Physiology_Levy

Physiology_Levy. P P Ins(1,4,5)P3 Ca++ SR Ca++ CaM MLCK MLC MLC P GEFs Rho Rho-kinase CPI-17 CPI-17 MBS M20 cat MBS Inactive Active Contraction M20 cat MP Y27632 GTP ? AA PLC GqG12/13 •Fig. 14.8 Rho-kinase(ROK)signalinginsmoothmuscle.A,AvarietyofagonistsofG-coupledreceptorssimultaneouslystimulateInsP3productionandactivateRhoA-ROKsignaling.InsP3(Ins[1,4,5]P3)isproducedbyphospholipaseC(PLC)-mediatedhydrolysisofPIP2.InsP3increasesintracellular[Ca++]byopeningInsP3-gatedCa++


Physiology_Levy

Physiology_Levy. The latch state is thought to reflect a slowing of the cross-bridge cycle, so that the myosin heads remain in contact with the actin filament for a longer time, thereby maintaining tension at low energy cost. Note that the intracellular [Ca++] falls to a low level during the tonic phase of contraction, though it is still above the resting/ basal [Ca++]. The mechanism contributing to the ability of smooth muscle to maintain force at a low intracellular [Ca++] during tonic contraction is thought to involve dephosphorylation of the myosin regulatory light chain while the myosin cross-bridge is attached to the actin filament, resulting in slowing of the rate of dissociation of the myosin from the actin, allowing the myosin to spend more time in an attached, force-generating conformation. Relaxation of smooth muscle following tonic contraction occurs when intracellular [Ca++] decreases to a level that prevents a net phosphorylation of the regulatory light chain by MLCK. It has also been


Physiology_Levy

Physiology_Levy. of smooth muscle following tonic contraction occurs when intracellular [Ca++] decreases to a level that prevents a net phosphorylation of the regulatory light chain by MLCK. It has also been proposed that caldesmon may participate in the transition to the latch state.


Physiology_Levy

Physiology_Levy. As already noted, ATP consumption is reduced during the latch state. Under this condition, smooth muscle uses 300fold less ATP than would be required by skeletal muscle to generate the same force. Smooth muscle, like skeletal muscle, requires ATP for ion transport to maintain the resting membrane potential, sequester Ca++ in the SR, and extrude Ca++ from the cell. All these metabolic needs are readily met by oxidative phosphorylation. Fatigue of smooth muscle does not occur unless the cell is deprived of oxygen. However, aerobic glycolysis with lactic acid production normally supports membrane ion pumps even when oxygen is plentiful. Regulation of Myoplasmic Calcium Concentration


Physiology_Levy

Physiology_Levy. Regulation of Myoplasmic Calcium Concentration The mechanisms that couple activation to contraction in smooth muscle involve two Ca++ sources: one involving the sarcolemma and the other involving the SR. The sarcolemma regulates Ca++ influx and efflux from the extracellular Ca++ pool. The SR membranes determine Ca++ movement between the myoplasm and the SR pool. Skeletal muscle contraction does not require extracellular Ca++ (see ). In contrast, extracellular Ca++ is important for smooth muscle contraction. Thus regulation of myoplasmic [Ca++] involves not only the SR but also the sarcolemma ( Fig. 14.10). A number of factors can alter the myoplasmic Na+-K+ pump 2K+ 3 Na+ Ca++ MLCK off CaCM CM ATP Receptor-activated CaCM*MLCK ATP G G Sarcoplasmic reticulum Time IP3 PIP2 3Na Cell Ca++ Neurotransmitter or hormone Neurotransmitter or hormone Ca++ channel Refilling ATP ?


Physiology_Levy

Physiology_Levy. [Ca++] of smooth muscle. This differs from skeletal muscle, in which action potential–induced release of Ca++ from the SR fully activates the contractile apparatus.


Physiology_Levy

Physiology_Levy. The role of smooth muscle SR in regulating myoplasmic [Ca++] is comparable to that of skeletal muscle. Stimulation of the cell opens SR Ca++ channels, and myoplasmic [Ca++] increases rapidly. This release is not linked to voltage sensors, as is the case in skeletal muscle, but to binding of the second messenger InsP3 to receptors in the SR. InsP3 is generated by a stimulus that acts on sarcolemmal receptors that are coupled via a guanine nucleotide–binding protein (G protein) to activate phospholipase C (PLC) (see ). PLC hydrolyzes the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into InsP3 and diacylglycerol. InsP3 then diffuses to the SR and opens the InsP3-gated Ca++ channel, thereby resulting in release of Ca++ from the SR into the myoplasm. This complex process may permit graded release of Ca++ from the SR and also enable many different neurotransmitters and hormones to effect smooth muscle contraction. Calcium is reaccumulated by the SR through the activity of


Physiology_Levy

Physiology_Levy. permit graded release of Ca++ from the SR and also enable many different neurotransmitters and hormones to effect smooth muscle contraction. Calcium is reaccumulated by the SR through the activity of the SERCA, although as indicated later, extrusion of Ca++ from the smooth muscle cell also contributes to the reduction in myoplasmic [Ca++]. Refilling of the SR with Ca++ not only involves reaccumulation of cytosolic Ca++ but also depends on the extracellular [Ca++]. The dependence on extracellular [Ca++] is thought to reflect the operation of a “store-operated” Ca++ channel present in the sarcolemma at points near underlying SR called junctional SR.


Physiology_Levy

Physiology_Levy. A variety of hormones and neurotransmitters elevate myoplasmic [Ca++] by stimulating InsP3 production. Vascular smooth muscle, for example, is innervated by sympathetic fibers of the autonomic nervous system. These fibers use norepinephrine as a neurotransmitter, which when released binds to α1-adrenergic receptors on vascular smooth muscle cells and results in G protein–dependent activation of PLC. Activation of PLC results in production of InsP3, which activates the InsP3-gated Ca++ channel in the SR, thereby elevating myoplasmic [Ca++] and causing vasoconstriction. Other agents that promote vasoconstriction by activating the InsP3 cascade include angiotensin II and vasopressin. Development of drugs that block production of angiotensin II (e.g., angiotensin-converting enzyme [ACE] inhibitors) provides a means of promoting vasodilation that is important for individuals with hypertension or congestive heart failure. As mentioned previously, a variety of agents can produce contraction


Physiology_Levy

Physiology_Levy. provides a means of promoting vasodilation that is important for individuals with hypertension or congestive heart failure. As mentioned previously, a variety of agents can produce contraction of smooth muscle without altering membrane potential (i.e., pharmacomechanical coupling). Agonist-induced activation of the InsP3 cascade represents an example of pharmacomechanical coupling. Many of the hormones/agonists that activate PLC through G protein– coupled receptors also promote sarcolemmal Ca++ influx and activation of RhoA/ROK. The net effect is a rise in intracellular [Ca++], which activates MLCK, concomitant with a rise in ROK activity, which inhibits MP, both of which act complementarily to increase the level myosin light-chain phosphorylation.


Physiology_Levy

Physiology_Levy. Fig.14.11 ).Specifically,EDHFappearstobeanarachidonicacidmetabolite(e.g.,epoxyeicosatrienoic acid [EET])thatisproducedbyendothelialcellsinresponsetovariousstimuliandthenreleasedtotheunderlyingvascularsmoothmuscle.EEThasbeenshowntoactivateatransient receptor channel (e.g.,TRPV4)inthesarcolemmaofsmoothmusclethatleadstotheinfluxofCa++ ,whichthenopensRYRchannelsintheSRandresultsinCa++ sparks.TheCa++ sparksinturnactivatealarge-conductanceK+ channelinthesarcolemma(BKCa),andthesmoothmusclecellbecomeshyperpolarized.HyperpolarizationinturndecreasesbasalCa++ influxthroughvoltage-gatedCa++ channelsinthesmoothmuscle,therebydecreasingintracellular[Ca++]andhencerelaxingthesmoothmuscle,asdescribedearlier.


Physiology_Levy

Physiology_Levy. In addition to the InsP3 receptor, the SR also contains the Ca++-gated Ca++ channel, also called the RYR, which may be activated during periods of Ca++ influx through the sarcolemma. Short-lived spontaneous opening of the RYR 11,12 EET COOH •Fig. 14.11 Anarachidonicacidmetabolite(11,12-epoxyeicosatrienoicacid[11,12EET])releasedfromendothelialcellscanopenthetransientreceptorchannelTRPV4intheunderlyingsmoothmuscletopermittheinfluxofCa++ ,whichinturninitiatesbriefopeningsoftheSRryanodinereceptor(Ca++ sparks)localizednearthesarcolemma.OpeningofCa++-activatedK+ channelsinthesarcolemmabycalciumsparksresultsinhyperpolarizationofthesmoothmuscleandhencevasodilation.BKCa,largeconductanceCa++-activatedpotassiumchannel.(FromEarleySetal.Circ Res 2005;97:1270-1279.) resulting in localized elevations in myoplasmic [Ca++] occurs in many cells, including smooth muscle. When observed with Ca++-sensitive fluorescent dyes, these spontaneous localized elevations in myoplasmic [Ca++] produce brief light


Physiology_Levy

Physiology_Levy. in myoplasmic [Ca++] occurs in many cells, including smooth muscle. When observed with Ca++-sensitive fluorescent dyes, these spontaneous localized elevations in myoplasmic [Ca++] produce brief light flashes and as a result are named Ca++ sparks. In smooth muscle an increase in cAMP has been associated with an increase in the frequency of Ca++ sparks, particularly in situations in which the SR is in close proximity to the sarcolemma (i.e., junctional SR, perhaps near caveolae). An increase in the frequency of these sparks hyperpolarizes vascular smooth muscle by activation of a large-conductance Ca++-gated K+ channel in the sarcolemma. This hyperpolarization then decreases overall myoplasmic [Ca++], and relaxation occurs.


Physiology_Levy

Physiology_Levy. Calcium is extruded from the smooth muscle cell by the activity of sarcolemmal Ca++-ATPase and by a 3Na+-1Ca++ antiporter (i.e., 3 Na+ ions enter the cell for each Ca++ ion extruded). Extrusion of Ca++ from the cell competes with sequestration of Ca++ in the SR by SERCA and thus reduces the accumulation of Ca++ in the SR. When the [Ca++] in the SR decreases, the SR is thought to initiate Ca++ influx into the cell through a process called store-operated Ca++ entry (SOCE) to facilitate refilling of the SR. Specifically, stromal interaction molecule 1 (STIM1) in the SR is hypothesized to monitor SR [Ca++] and then initiate Ca++ influx through the sarcolemmal channel protein Orai through a protein-protein interaction. Thus the influx of Ca++ during SOCE is thought to occur in the confined space between the caveolae and peripheral SR of smooth muscle. Recent studies raise the possibility that STIM1-Orai–mediated SOCE may also contribute to the rise in intracellular Ca++ transient in smooth


Physiology_Levy

Physiology_Levy. between the caveolae and peripheral SR of smooth muscle. Recent studies raise the possibility that STIM1-Orai–mediated SOCE may also contribute to the rise in intracellular Ca++ transient in smooth muscle following α1-adrenergic receptor stimulation. The Stim1-Orai complex has also been implicated in remodeling of smooth muscle in pathological conditions such as restenosis following balloon angioplasty.


Physiology_Levy

Physiology_Levy. In addition to the stimulatory effects of various agents on sarcolemma Ca++ channels and InsP3 cascades, there are several inhibitory factors that lower myoplasmic [Ca++] and thereby relax smooth muscle. For example, the dihydropyridine class of Ca++ channel blocking drugs decreases the influx of Ca++ through sarcolemmal L-type voltage-gated Ca++ channels and reduces vasomotor tone. Similarly, drugs that open K+ channels in the sarcolemma (e.g., hydralazine) promote relaxation (e.g., vasodilation) by hyperpolarizing the membrane potential, which reduces the influx of Ca++ through voltage-gated Ca++ channels. Conversely, agents that decrease K+ permeability of the sarcolemma may promote vasoconstriction by inducing membrane depolarization, which then increases influx of Ca++ through these same voltage-gated Ca++ channels. Smooth muscle also contains receptor-activated Ca++ channels. Conductance of these receptor-activated Ca++ channels is linked to receptor occupancy.


Physiology_Levy

Physiology_Levy. A variety of drugs and hormones relax smooth muscle by increasing the cellular concentrations of cAMP or cGMP. Nitric oxide (NO) is produced by nerves and vascular endothelial cells and relaxes smooth muscle by increasing cGMP ( Fig. 14.12 ). Acetylcholine released from parasympathetic fibers causes vasodilation in some vascular beds as a result of stimulating the production of NO by vascular endothelial cells. Shear stress and adenosine (e.g., released from exercising muscle) may also promote NO release from vascular endothelial cells. The molecular mechanisms underlying the cGMP-dependent relaxation of vascular smooth muscle are complex and have been reported to involve (1) inhibition of InsP3 production, (2) inhibition of the InsP3 receptor, (3) activation of myosin light-chain phosphatase, and (4) activation of the Ca++-activated K+ channel (BKCa), which promotes hyperpolarization of the cells and thus inhibits Ca++ influx through voltage-gated Ca++ channels.


Physiology_Levy

Physiology_Levy. Similarly, elevation of cAMP in vascular smooth muscle by activation of β-adrenergic receptors or adenosine receptors promotes vasodilation through multiple mechanisms, including (1) decreased affinity of MLCK for Ca++/ calmodulin, (2) decreased cytosolic [Ca++] concentration, and/or (3) increased MP activity. The decreased affinity of MLCK for Ca++/calmodulin following elevation of cAMP involves protein kinase A (PKA)-dependent phosphorylation of MLCK. The ability of PKA to reduce cytosolic [Ca++] is complex and can involve activation of potassium channels (e.g., ATP-dependent potassium channels), resulting in hyperpolarization of the smooth muscle and hence decreased Ca++ influx through voltage-gated Ca++ channels. cAMP has also been shown to increase the frequency of Ca++ sparks in vascular smooth muscle, which as described earlier, hyperpolarizes the membrane potential by activation of Ca++-gated K+ channels, thereby reducing the influx of Ca++ through voltage-gated Ca++ channels.


Physiology_Levy

Physiology_Levy. smooth muscle, which as described earlier, hyperpolarizes the membrane potential by activation of Ca++-gated K+ channels, thereby reducing the influx of Ca++ through voltage-gated Ca++ channels. cAMP can also promote relaxation of smooth muscle by increasing the activity of MP (through either PKA-dependent phosphorylation of a subunit of MP or through inhibition of ROK). Inhibition of ROK can occur through PKA-dependent phosphorylation or through a signaling pathway involving the cAMP-modulated guanine nucleotide exchange factor Epac (exchange protein directly activated by cAMP)


Physiology_Levy

Physiology_Levy. Relaxation of smooth muscle by elevation of cAMP has afforded asthmatics a means of reversing bronchiolar constriction with use of β2-adrenergic agonists. The local vasodilatory effect of adenosine produced in working muscle during periods of intense exercise has also been attributed at least in part to elevated cAMP levels in vascular smooth muscle secondary to adenosine-induced stimulation of purinergic receptors on the sarcolemma of vascular smooth muscle. Adenosine may also activate a sarcolemmal K+ channel to induce membrane hyperpolarization, which as already noted will decrease the influx of Ca++ through voltage-gated Ca++ channels and cause vasodilation. Thus regulation of smooth muscle tone may be under the influence of not only the autonomic nervous system and circulating hormones but also neighboring endothelial cells and skeletal muscle cells via diffusible substances such as NO and adenosine.


Physiology_Levy

Physiology_Levy. Cat.Cat.Ca2˜Ca2˜IP3RICa2˜Ca2˜K˜CaV1.2BKCaCaMMLCK PDE5 RGS2 MYPT1 MLCP GMP pGC cGMP Hyper-polarization NucleuscGMP-A/B cGMP-A/B LZ LZ ˜˜˜°PKG1 NO sGC GTPGPCR IRAG ER Actin/myosin °˛G˜q IP3 PLC°12354 •Fig. 14.12 Signalingmechanismsbywhichnitricoxide(NO)andnitroprusside(NP)promoterelaxationofvascularsmoothmuscle.Nitricoxidestimulatessolubleguanylcyclase(sGC)inthevascularsmoothmusclecell,resultinginproductionofcGMP,activationofproteinkinaseG(PKG1),whichinturnphosphorylatesvarioussubstratesthat(1)inhibitInP3production,(2)inhibitInsP3-inducedCa++ release, (3)activatemyosinlight-chainphosphatase,(4)activatethelargeconductanceCa++-activatedK+ channel(BKCa),whichhyperpolarizesthecellandthusinhibitsthevoltage-gatedCa++


Physiology_Levy


Physiology_Levy

Physiology_Levy. Blood flow to tissues such as the brain is maintained at a relatively constant flow over a wide range of blood pressures through a process called autoregulation. The mechanism underlying autoregulation of blood flow involves the myogenic response, wherein an increase in distending pressure in an artery results in vasoconstriction, whereas a decrease in transmural pressure results in a vasodilation (over a given range of pressures). As shown in Fig. 14.13 , distention of the resistance artery resulted in an immediate elevation of intracellular [Ca++], followed by vasoconstriction in an effort to maintain relatively constant flow. The mechanism underlying this elevation of intracellular [Ca++] and subsequent vasoconstriction is complex. The rise in intracellular [Ca++] in response to stretch been reported to involve stretch-activated channels, InsP3-signaling, and voltage-gated Ca++ channels. During development and growth, the number of smooth muscle cells increases (


Physiology_Levy

Physiology_Levy. During development and growth, the number of smooth muscle cells increases ( Fig. 14.14 ). Smooth muscle tissue mass also increases if an organ is subjected to a sustained increase in mechanical work. This increase in mass is called compensatory hypertrophy. A striking example occurs with arterial smooth muscle cells (i.e., in the tunica media of the artery) in hypertensive patients. The increased mechanical load on the muscle cells appears to be the common factor that induces this hypertrophy. Chromosomal replication can result in significant numbers of polyploid muscle cells. The polyploid cells contain multiple sets of the normal number of chromosomes. They synthesize more contractile proteins and thus increase the size of the cell (see Fig. 14.14


Physiology_Levy

Physiology_Levy. Fig. 14.14 The myometrium, which is the smooth muscle component of the uterus, undergoes hypertrophy as parturition (birth) approaches. Hormones play an important role in this response. The smooth muscle is quiescent during pregnancy when the hormone progesterone predominates, and few gap junctions that electrically couple the smooth muscle cells are present. At term, under the dominant influence of estrogen, the myometrium undergoes marked hypertrophy. Large numbers of gap junctions form just before birth and convert the myometrium to a single-unit tissue to coordinate contraction during parturition.


Physiology_Levy

Physiology_Levy. The growth and development of tissues that contain smooth muscle are associated with increases in the connective tissue 1.4 1.2 1.0 0.8 0.6 0.0 •Fig. 14.14 Smoothmusclecellscarryoutmanyactivities.A,Theyretainthecapacitytodivideduringnormalgrowthorincertainpatho logicalresponsessuchasformationofatheroscleroticplaque.B,Cellsmayalsohypertrophyinresponsetoincreasedloads.Chromosomalreplicationnotfollowedbycelldivisionyieldscellswithagreatercontentofcontractileproteins.C,Smoothmusclecellsalsosynthesizeandsecretetheconstituentsoftheextracellularmatrix.


Physiology_Levy

Physiology_Levy. Althoughsmoothmuscleisinvolvedinphysiologicaladjustmentstoexercise,sustainedchangesinthe mechanicalloadingthatinducecellularadaptationsareusuallytheresultofapathologicalcondition(e.g.,hypertension).Afairlycommonexampleinmenisurinary bladder hypertrophy causedbybenignorcancerous enlargementoftheprostategland,whichobstructsthebladderoutlet.Theclinicalresultisdifficultyurinating, •Fig. 14.13 Myogenicresponseinvascularsmoothmuscleisanautoregulatoryresponsetomaintainconstantflowtoatissue.Anincreaseintransmuralpressure(TMP; top panel) elevatesintracellular[Ca++](middle panel), resultinginavasoconstriction(bottom panel). Notethattheincreaseintransmuralpressureinitiallystretchestheskeletalmuscleresistanceartery(bottom panel), butthisisquicklyfollowedbyvasoconstriction.(FromSchubertRetal.Cardiovasc Res 2008;77:8-18.) matrix. Smooth muscle cells can synthesize and secrete the materials that make up this matrix, including collagen, elastin, and proteoglycans (see


Physiology_Levy

Physiology_Levy. Fig. 14.14 ). The synthetic and secretory capacities are evident when smooth muscle cells are isolated and placed in tissue culture. The cells rapidly distentionofthebladder,andimpairedemptying.Inthissituationtheabilityofthebladdersmoothmuscletocontractanddevelopstressisdiminished.Thereasonsforthisremainunexplained,butphenotypicmodulationofthesmoothmusclecellswithalteredcontractileproteinisoformexpressionandgrossanatomicdistortionofthebladderwalloccurs.NeuromuscularchangesalsoaffectmyoplasmicCa++ mobilizationandcross-bridgephosphorylation.Fortunately,normalstructureandfunctionareusuallyrestoredaftertheobstructionisalleviated.


Physiology_Levy

Physiology_Levy. lose thick myosin filaments and much of the thin-filament lattice, and there is expansion of the rough endoplasmic reticulum and Golgi apparatus. The phenotypically altered cells multiply and lay down connective tissue. This process is reversible, and some degree of redifferentiation with the formation of thick filaments occurs after cell replication ceases. Determinants of the smooth muscle cell phenotype are largely unknown, but hormones and growth factors in blood, as well as mechanical loads on cells, have been implicated in the control of phenotypic modulation.


Physiology_Levy

Atherosclerosis

Physiology_Levy. Atherosclerosis


Physiology_Levy

Physiology_Levy. Biophysical Properties of Smooth Muscle Smooth muscle contains large amounts of connective tissue composed of extensible elastin fibrils and inextensible collagen fibrils. Because this extracellular matrix can withstand high distending forces or loads, it is responsible for the passive length-tension curve measured in relaxed tissues. This ability of the matrix also limits organ volume. When lengths are normalized to the optimal length for development of force (i.e., L0), the length-tension curves for smooth and skeletal muscle are very similar (


Physiology_Levy

Physiology_Levy. Fig. 14.15 ). However, the length-tension curves of striated and smooth muscle differ quantitatively. For example, smooth muscle cells shorten more than skeletal muscle cells do. In addition, smooth muscle is characteristically only partially activated, and the peak isometric force attained varies with the stimulus. In skeletal muscle the stimulus (i.e., action potential) always produces a full twitch contraction. Smooth muscle can generate active force comparable to that of skeletal muscle, even though smooth muscle contains only about a fourth as much myosin. This does not imply that the cross-bridges in smooth muscle have greater force-generating capacity. Instead, active cross-bridges in smooth muscle are much more likely to be in 2.4 2.0 1.6 1.2 0.8 0.4 0.6 0.8 1.0 1.2 Po = 2.22 ± 0.17 × 106 dynes/cm2 N = 11 •Fig. 14.15


Physiology_Levy

Physiology_Levy. force-generating capacity. Instead, active cross-bridges in smooth muscle are much more likely to be in 2.4 2.0 1.6 1.2 0.8 0.4 0.6 0.8 1.0 1.2 Po = 2.22 ± 0.17 × 106 dynes/cm2 N = 11 •Fig. 14.15 Lengthdependenceofcontractionofsmoothmuscleshowsabell-shapedresponsesimilartothatseeninskeletalmuscle.Thesmoothmusclestripswereobtainedfromhogcarotidartery.Contractionwasinducedbypotassiumdepolarization.Optimalmusclelength(Lo)wasgraphicallydeterminedasthelengthatwhichmaximaltension(Po)wasdeveloped.Redcircles,passivetension;bluecircles,activetension,triangles,totaltension;(FromHerlihyJT,MurphyRA.Circ. Res. 1973;33:275-283.) the attached force-generating configuration because of their slow cycling kinetics.


Physiology_Levy

Physiology_Levy. Smooth and striated muscles both exhibit a hyperbolic dependence of shortening velocity on load. However, contraction velocities are far slower in smooth muscle than in striated muscle. One factor that underlies these slow velocities is that the myosin isoform in smooth muscle cells has low ATPase activity. Skeletal muscle cells have a force-velocity curve in which shortening velocities are determined only by load and the myosin isoform (see ). In contrast, both force and shortening velocity, which reflect the number of cycling cross-bridges and their cycling rates, vary in smooth muscle. When activation of smooth muscle is altered, for example, by different frequencies of nerve stimulation or changing hormone concentrations, a “family” of velocity-stress curves can be derived ( Fig. 14.16 ). This implies that both cross-bridge cycling rates and the number of active cross-bridges in smooth muscle are regulated in some way, Vo(% of max) Velocity (% of max)


Physiology_Levy

Physiology_Levy. Fig. 14.16 ). This implies that both cross-bridge cycling rates and the number of active cross-bridges in smooth muscle are regulated in some way, Vo(% of max) Velocity (% of max) Stress (% of max) •Fig. 14.16 A,Force-velocitycurvesforfastandslowhumanskeletalmusclecellsandsmoothmuscle.B,Smoothmuscleshavevariableforce-velocityrelationshipsthataredeterminedbythelevelofCa++-stimulatedcross-bridgephosphorylation.C,Maximalshorteningvelocitieswithnoload(Vo,whichrepresentstheinterceptsontheordinateinB)aredirectlydependentoncross-bridgephosphorylationbyMLCK.D,Activeforce/stress(abscissainterceptsinB)risesrapidlywithphosphorylation;nearmaximalstress,itmaybegeneratedwithonly20%to30%ofthecross-bridgesinthephosphorylatedstate.


Physiology_Levy

Physiology_Levy. which is in marked contrast to striated muscle. This difference is conferred by a regulatory system that depends on phosphorylation of cross-bridges, which in turn depends on myoplasmic [Ca++]. Because myosin light-chain phosphorylation is required for actin-myosin interaction in smooth muscle, a dependence of maximal force on the degree of myosin phosphorylation is expected (i.e., phosphorylation of more myosin molecules results in more actin-myosin interactions and hence more force generated). The variation in maximal shortening velocity as a function of the degree of myosin phosphorylation may reflect dephosphorylation of the myosin light chain while the myosin is still attached to the actin, thus slowing the rate of detachment (i.e., latch state) at low levels of phosphorylation. At higher levels of phosphorylation, the likelihood of latch states would be reduced and the myosin cross-bridges would be released more quickly from actin, thereby yielding a higher shortening velocity


Physiology_Levy

Physiology_Levy. higher levels of phosphorylation, the likelihood of latch states would be reduced and the myosin cross-bridges would be released more quickly from actin, thereby yielding a higher shortening velocity at all loads (see


Physiology_Levy

Physiology_Levy. Fig. 14.16B 1. Smooth muscle cells are linked by a variety of junctions that serve both mechanical and communication roles. These linkages are essential in cells that must contract uniformly. 2.


Physiology_Levy

Physiology_Levy. The sarcolemma plays an important role in Ca++ exchange between extracellular fluid and myoplasm. The sarcolemma of smooth muscle contains numerous caveolae that contribute to regulation of intracellular [Ca++] and also appear to serve as a scaffold for signaling molecules. The sarcoplasmic reticulum (SR) contains an intracellular Ca++ pool that can be mobilized to transiently increase myoplasmic [Ca++]. Myoplasmic [Ca++] is dependent on extracellular Ca++ . Transporters in the sarcolemma that regulate myoplasmic [Ca++] include receptor-mediated Ca++ channels, voltage-gated Ca++ channels, Ca++-ATPase, and the 3Na+1Ca++ antiporter. The SR also regulates myoplasmic [Ca++]. The Ca++ channels in the SR open in response to a chemical. Neurotransmitters or hormones that act via receptors in the sarcolemma can activate phospholipase C (PLC), followed by generation of the second messenger inositol 1,4-triphosphate (InsP3). InsP3 then activates InsP3-gated Ca++ channels on the SR. Many


Physiology_Levy

Physiology_Levy. in the sarcolemma can activate phospholipase C (PLC), followed by generation of the second messenger inositol 1,4-triphosphate (InsP3). InsP3 then activates InsP3-gated Ca++ channels on the SR. Many agonists that activate PLC through G protein–coupled receptors also activate the RhoA/Rho kinase (ROK) signaling cascade, thereby increasing the sensitivity of smooth muscle contraction to Ca++ . Smooth muscle SR also contains Ca++-gated Ca++ channels (ryanodine receptor [RYR]). Ca++ reaccumulates in the SR via SERCA (sarcoplasmic endoplasmic reticulum Ca++ ATPase).


Physiology_Levy

Physiology_Levy. 3. Smooth muscles contain contractile units that consist of small groups of thick myosin filaments that interdigitate with large numbers of thin filaments attached to Z-line equivalents termed dense bodies or membrane-dense areas. No striations are evident. Contraction is caused by a sliding filament–crossbridge mechanism. 4. Contraction of smooth muscle is dependent on both release of Ca++ from the SR and entry of Ca++ across the sarcolemma. Smooth muscle lacks troponin. Phosphorylation of cross-bridges by a Ca++-dependent myosin light chain kinase (MLCK) is necessary for attachment to the thin filament. Dephosphorylation of an attached cross-bridge by myosin phosphatase (MP) slows its cycling rates. Higher myoplasmic [Ca++] increases the ratio of MLCK to MP activity, with the result that more of the cross-bridges remain phosphorylated throughout a cycle. This increases shortening velocities. 5.


Physiology_Levy

Physiology_Levy. 5. Smooth muscle activity is controlled by nerves (principally autonomic), circulating hormones, locally generated signaling substances, junctions with other smooth muscle cells, and even junctions with other non–smooth muscle cells. A variety of hormones/ agonists increase the sensitivity of smooth muscle contraction to Ca++ by reducing the activity of MP and reciprocally increasing the activity of MLCK at a given intracellular [Ca++]. Activation of the RhoA/ROK signaling cascade contributes to this inhibition of MP and stimulation of MLCK, and hence to the increase in sensitivity of smooth muscle contraction to Ca++ . Smooth muscle also has an intrinsic ability to respond to stretch, which is important for autoregulation of blood flow to various tissues. 6.


Physiology_Levy

Physiology_Levy. 6. The response to sustained or tonic stimulation is a rapid contraction followed by sustained maintenance of force with reduced cross-bridge cycling rates and ATP consumption. This behavior, called the latch state, is advantageous for muscles that may need to withstand continuous external force, such as blood vessels, which must be able to withstand blood pressure. During the latch state, ATP is consumed at less than 1/300 the rate needed to maintain the same force in skeletal muscle. 7.


Physiology_Levy

Physiology_Levy. 7. The length-tension relationships, hyperbolic velocity-load relationships, power output curves, and ability to resist imposed loads are comparable to those of skeletal muscle. Shortening velocities and ATP consumption rates are very low in smooth muscle, in keeping with expression of a myosin isoform with low activity. Smooth muscles also have the unusual ability to alter velocity-stress relationships, which reflects regulation of both the number of active cross-bridges (determining force) and their average cycling rates for a given load (determining velocity). Burnstock G, Ralevic V. Purinergic signaling and blood vessels in health and disease. Pharmacol Rev. 2014;66:102-192. Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev. 2015;95:549-601. Longden TA, et al. Ion channel networks in the control of cerebral blood flow. J Cereb Blood Flow Metab. 2016;36:492-512.


Physiology_Levy

Physiology_Levy. Longden TA, et al. Ion channel networks in the control of cerebral blood flow. J Cereb Blood Flow Metab. 2016;36:492-512. Momotani K, Somlyo AV. p63RhoGEF: a new switch for G q-mediated activation of smooth muscle. Trends Cardiovasc Med. 2012;22:122-127. Roberts OL, Dart C. cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP). Biochem Soc Trans. 2014;42:89-97. 8. Smooth muscle is also a synthetic and secretory cell with a major role in formation of the extensive extracellular matrix that surrounds and links the cells. Cellular hypertrophy occurs in response to physiological needs, and smooth muscle cells retain the potential to divide. Schlossmann J, Desch M. IRAG and novel PKG targeting in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2011;301: H672-H682. Shimokawa H, et al. RhoA/Rho-Kinase in the Cardiovascular System. Circ Res. 2016;118:352-366.


Physiology_Levy

Physiology_Levy. Shimokawa H, et al. RhoA/Rho-Kinase in the Cardiovascular System. Circ Res. 2016;118:352-366. Somlyo AP, Somlyo AV. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev. 2003;83:1325-1358. Spinelli AM, Trebak M. ORAI channel-mediated Ca2+ signals in vascular and airway smooth muscle. Am J Physiol Cell Physiol. 2016;310:C402-C413. Tinker A, et al. The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system. Br J Pharmacol. 2014;171:12-23. SECTION 4The Cardiovascular System ACHILLES J. PAPPANO AND WITHROW GIL WIER Overview of Circulation Regulation of the Heart and Vasculature Chapter 16 Elements of Cardiac Function Chapter 19 Integrated Control of the Chapter 17 Cardiovascular System Properties of the Vasculature Upon completion of this chapter, the student should be able to answer the following questions: 1.


Physiology_Levy

Physiology_Levy. Upon completion of this chapter, the student should be able to answer the following questions: 1. How does the arrangement of heart and vessels enable unidirectional flow of well-oxygenated blood to the body? 2. What is the advantage of the reciprocal relation between blood flow velocity and vascular cross-sectional area? 3. How do the differing compositions (smooth muscle, fibrous and elastic tissue) of blood vessels contribute to their respective functions?


Physiology_Levy

Physiology_Levy. he circulatory system transports and distributes essential substances to tissues and removes metabolic byproducts. This system also participates in homeostatic mechanisms such as regulation of body temperature, maintenance of fluid balance, and adjustment of O2 and nutrient supply in various physiological states. The cardiovascular system, which accomplishes these tasks, is composed of a pump (the heart), a series of distributing and collecting tubes (blood vessels), and an extensive system of thin vessels (capillaries) that enable rapid exchange between the tissues and vascular channels. Blood vessels throughout the body are filled with a heterogeneous fluid (blood) that is essential for the transport processes performed by the heart and blood vessels. This chapter is a general, functional overview of the heart and blood vessels, whose functions are analyzed in much greater detail in subsequent chapters. The Heart


Physiology_Levy

Physiology_Levy. The Heart The heart consists of two pumps in series: one pump propels blood through the lungs for exchange of O2 and CO2 (the pulmonary circulation) and the other pump propels blood to all other tissues of the body (the systemic circulation). Flow of blood through the heart is in one direction (unidirectional). Unidirectional flow through the heart is achieved by the appropriate arrangement of flap valves. Although cardiac output is intermittent, continuous flow to body tissues (periphery) occurs by distention of the aorta and its branches during ventricular contraction (systole) and by elastic recoil of the walls of the large arteries with forward propulsion of the blood during ventricular relaxation (diastole). The Cardiovascular Circuit


Physiology_Levy

Physiology_Levy. The Cardiovascular Circuit In the normal intact circulation, the total volume of blood is constant, and an increase in the volume of blood in one area must be accompanied by a decrease in another. However, the distribution of blood circulating to the different regions of the body is determined by the output of the left ventricle and by the contractile state of the resistance vessels (arterioles) of these regions. The circulatory system is composed of conduits arranged in series and in parallel ( Fig. 15.1 ). This arrangement, which is discussed in subsequent chapters, has important implications in terms of resistance, flow, and pressure in blood vessels.


Physiology_Levy

Physiology_Levy. Fig. 15.1 ). This arrangement, which is discussed in subsequent chapters, has important implications in terms of resistance, flow, and pressure in blood vessels. Blood entering the right ventricle via the right atrium is pumped through the pulmonary arterial system at a mean pressure about one seventh that in the systemic arteries. The blood then passes through the lung capillaries, in which CO2 in the blood is released and O2 is taken up. The O2-rich blood returns via the pulmonary veins to the left atrium, where it is pumped from the ventricle to the periphery, which thus completes the cycle. Blood moves rapidly through the aorta and its arterial branches. As these branches approach the periphery, the branches narrow, and their walls become thinner. They also change histologically. The aorta is a predominantly elastic structure, but the peripheral arteries become more muscular until, at the arterioles, the muscular layer predominates ( Fig. 15.2


Physiology_Levy

Physiology_Levy. Fig. 15.2 In the large arteries, frictional resistance is relatively small, and pressures are only slightly less than those in the aorta. The small arteries, on the other hand, offer moderate resistance to blood flow. This resistance reaches a maximal level in the arterioles, which are sometimes referred to as the “stopcocks” of the vascular system. Hence, the pressure drop is greatest across the terminal segment of the small arteries and the arterioles ( Fig. 15.3 ). Adjustment in the degree of contraction of the circular muscle of these small vessels allows regulation of tissue blood flow and aids in the control of arterial blood pressure. In addition to the reduction in pressure along the arterioles, there is a change from pulsatile to steady blood flow (see


Physiology_Levy

Physiology_Levy. Fig. 15.3 ). Pulsatile arterial blood flow, caused by the intermittent ejection of blood from the heart, is damped • Fig. 15.3 Phasic Pressure, Velocity of Flow, and Cross-Sectional • Fig. 15.1 Schematic Diagram of the Parallel and Series Arrange-Area of the Systemic Circulation. The important features are the major ment of the Vessels That Constitute the Circulatory System. The pressure drop across the small arteries and arterioles, the inverse capillary beds are represented by thin lines connecting the arteries relationship between blood flow velocity and cross-sectional area, and (on the right) with the veins (on the left). The crescent-shaped thicken-the maximal cross-sectional area and minimal flow rate in the capilings proximal to the capillary beds represent the arterioles (resistance laries. (From Levick JR. An Introduction to Cardiovascular Physiology. vessels). (Redrawn from Green HD. In: Glasser O [ed]. Medical


Physiology_Levy

Physiology_Levy. Introduction to Cardiovascular Physiology. vessels). (Redrawn from Green HD. In: Glasser O [ed]. Medical Physics. 5th ed. London: Hodder Arnold; 2010.)Vol 1. Chicago: Year Book; 1944.) • Fig. 15.2 Internal Diameter, Wall Thickness, and Relative Amounts of the Principal Components of the Vessel Walls of the Various Blood Vessels That Constitute the Circulatory System. Cross-sections of the vessels are not drawn to scale because of the huge range in size from aorta and venae cavae to capillary. (Redrawn from Burton AC. Relation of structure to function of the tissues of the wall of blood vessels. Physiol Rev. 1954;34:619.) at the capillary level by a combination of two factors: distensibility of the large arteries and frictional resistance in the small arteries and arterioles.


Physiology_Levy

Physiology_Levy. Many capillaries arise from each arteriole. The total cross-sectional area of the capillary bed is very large despite the fact that the cross-sectional area of each capillary is less than that of each arteriole. As a result, blood flow velocity becomes quite slow in the capillaries (see Fig. 15.3 ), which is analogous to the decrease in velocity of flow in the wide regions of a river. Conditions in the capillaries are ideal for the exchange of diffusible substances between blood and tissue because capillaries consist of short tubes with walls that are only one cell thick and in which flow velocity is low. On its return to the heart from the capillaries, blood passes through venules and then through veins of increasing size. Pressure within these vessels progressively decreases until the blood reaches the right atrium (see Fig. 15.3 ). Near the heart, the number of veins decreases, the thickness and composition of the vein walls change (see


Physiology_Levy

Physiology_Levy. Fig. 15.3 ). Near the heart, the number of veins decreases, the thickness and composition of the vein walls change (see Fig. 15.2), the total cross-sectional area of the venous channels diminishes, and the velocity of blood flow increases (see Fig. 15.3 ). The velocity of blood flow and the cross-sectional area at each level of the vasculature are essentially mirror images (see Fig. 15.3


Physiology_Levy

Physiology_Levy. Fig. 15.3 ). The velocity of blood flow and the cross-sectional area at each level of the vasculature are essentially mirror images (see Fig. 15.3 Table 15.1 ) indicate that between the aorta and the capillaries, the total cross-sectional area increases about 500-fold. The volume of blood in the systemic vascular system is greatest in the veins and venules (64%). Only 6% of total blood volume exists in the capillaries, and 14% of total blood volume is found in the aorta, arteries, and arterioles. In contrast, blood volume in the pulmonary vascular bed is about equally divided among the arterial, capillary, and venous vessels. The cross-sectional area of the venae cavae is larger than that of the aorta. Therefore, the velocity of flow is slower in the venae cavae than in the aorta (see Fig. 15.3 Aortaandlargearteries3006.0Smallarteries4008.0Capillaries3006.0Smallveins230046.0Largeveins90018.0Total420084.0


Physiology_Levy

Physiology_Levy. Fig. 15.3 Aortaandlargearteries3006.0Smallarteries4008.0Capillaries3006.0Smallveins230046.0Largeveins90018.0Total420084.0 Arteries1302.6Capillaries1102.2Veins2004.0Total4408.8Heart (End-Diastole) 3607.2 DatafromBoronWF,BoulpaepEL.Medical Physiology. 2nded.Philadelphia:ElsevierSaunders;2009.*Valuesrefertoa70-kgwoman. Inapatientwithhyperthyroidism(Graves’ disease), basalmetabolismiselevatedandoftenassociatedwitharteriolarvasodilation.Thisreductioninarteriolarresistancediminishesthedampingeffectonpulsatilearterialpressureandismanifestedaspulsatileflowinthecapillaries,asobservedinthefingernailbedsofpatientswiththisailment. Upon completion of this chapter, the student should be able to answer the following questions: 1. How does the action potential contribute to excitability and contraction in heart muscle? 2. What is automaticity, and how does it differ from excitability? How do derangements of these properties contribute to arrhythmias? 3.


Physiology_Levy

Physiology_Levy. 2. What is automaticity, and how does it differ from excitability? How do derangements of these properties contribute to arrhythmias? 3. What is the structural basis of the electrocardiogram? 4. How are the concepts of preload and afterload, developed for skeletal muscle, applied to the contraction of the heart? 5. What is the role of Ca++ in excitation-contraction coupling? 6. What changes occur in atrial and ventricular pressures and volumes during a cardiac cycle, and what is their temporal relation to the electrocardiogram? 7. How does the relation between end-diastolic volume and left ventricular developed pressure define the Frank-Starling law of the heart and regulate the force of cardiac contraction? 8. What is the pressure-volume loop of the left ventricle, and how does it define changes in left ventricular function? 9. How is cardiac metabolism linked to O2 consumption, and how are these processes affected by changes in cardiac work?


Physiology_Levy

Physiology_Levy. 9. How is cardiac metabolism linked to O2 consumption, and how are these processes affected by changes in cardiac work? Electrical Properties of the Heart The cells of the heart, like neurons, are excitable and generate action potentials. These action potentials initiate contraction and thus determine the heart rate. Disorders in electrical activity can induce serious and sometimes lethal disturbances in cardiac rhythm. In this section, the electrical properties of cardiac cells are described. In addition, how these electrical properties account for the electrocardiogram (ECG) is considered. The initiation of contraction as a result of the electrical properties of cardiac cells is considered in a later section. The Cardiac Action Potential


Physiology_Levy

Physiology_Levy. Fig. 16.1 illustrates action potentials found in different cardiac cells. Two main types of action potentials occur in the heart and are depicted. One type, the fast response, occurs in normal atrial and ventricular myocytes and in the specialized conducting fibers (Purkinje fibers of the heart) and is divided into five phases. The rapid upstroke of the action potential is designated phase 0. The upstroke is followed by a brief period of partial, early repolarization (phase 1) and then by a plateau (phase 2) that persists for approximately 0.1 to 0.2 second. The membrane then repolarizes (phase 3) until the resting state of polarization (phase 4) is again attained. Final repolarization (phase 3) develops more slowly than depolarization (phase 0). The other type of action potential, the slow response, occurs in the sinoatrial (SA) node, which is the natural pacemaker region of the heart, and in the atrioventricular (AV) node, which is the specialized tissue that conducts the cardiac


Physiology_Levy

Physiology_Levy. slow response, occurs in the sinoatrial (SA) node, which is the natural pacemaker region of the heart, and in the atrioventricular (AV) node, which is the specialized tissue that conducts the cardiac impulse from the atria to the ventricles. The slow-response cells lack the early repolarization phase (phase 1).


Physiology_Levy

Physiology_Levy. Other differences between the electrical properties of the fast-response and slow-response cells include the following: The resting membrane potential (phase 4) of the fast-response cells is considerably more negative than that of the slow-response cells. Moreover, the slope of the upstroke (phase 0), the amplitude of the action potential, and the overshoot (membrane voltage positive to 0 mV) are greater in the fast-response cells than in the slow-response cells. The action potential amplitude and the steepness of the upstroke are important determinants of propagation velocity along the myocardial fibers. In slow-response cardiac tissue, the action potential is propagated more slowly and conduction is more likely to be blocked than in fast-response cardiac tissue. Slow conduction and a tendency toward conduction block increase the likelihood of some rhythm disturbances (see the section “


Physiology_Levy

Physiology_Levy. The action potential initiates contraction of the myocyte. The relationship between the action potential and contraction of a cardiac myocyte is shown in Fig. 16.2 . Rapid depolarization (phase 0) precedes cell shortening, and completion of repolarization occurs just before peak shortening. Relaxation of the muscle takes place mainly during phase 4 of the action potential. The duration of contraction usually parallels the duration of the action potential. The various phases of the cardiac action potential are associated with changes in cell membrane permeability, mainly by Na+, K+, and Ca++ ions. Changes in cell membrane permeability alter the rate of movement of these ions across the membrane and thereby change the membrane voltage (Vm). These changes in permeability are accomplished by the opening and closing of ion channels that are specific for individual ions (see


Physiology_Levy

Physiology_Levy. As with all other cells in the body, the concentration of K+ inside a cardiac muscle cell (intracellular [K+]) exceeds the concentration outside the cell (extracellular [K+]). The concentration gradient is reversed for Na+ and Ca++ . Estimates of the extracellular and intracellular concentrations of Na+, K+, and Ca++ and the Nernst equilibrium potentials (see Eq. 1.5b ) for these ions are compiled in Table 16.1 The resting cell membrane has a relatively high permeability for K+; permeability for Na+ and Ca++ is much less. Because of the existing chemical gradient for K+ and Vm, K+ tends to diffuse from the inside to the outside of the cell. 3 Any diffusion of K+ that occurs at the resting membrane potential (i.e., during phase 4) takes place mainly through 4 specific potassium channels. Several types of potassium channels exist in cardiac cell membranes. Opening and –120


Physiology_Levy

Physiology_Levy. ERP RRP closing of some of these channels are regulated by Vm, whereas others are controlled by a chemical signal (e.g., the extracellular acetylcholine concentration). The specific 4 is a voltage-regulated channel that conducts the inward rectifying K+ current (iK1), which is discussed in more detail later. For now, it is necessary only to know how this current is established.


Physiology_Levy

Physiology_Levy. The dependence of Vm on conductance and the intracellular and extracellular concentrations of K+, Na+, and other ions are described by the chord conductance equation •Fig. 16.2 Temporalrelationshipbetweenthechangesintrans-membranepotential(top trace) andcellshortening(bottom trace) inasingleventricularmyocyte.Thevalueof0mVmembranepotentialisindicatedby“0.”(FromPappanoA.unpublishedrecord,1995.)0 50 mV 400 msec 7˜m •Fig. 16.1 Action Potentials of Cardiac Fibers. A, Fast-responsecardiacfibers.B, Slow-responsecardiacfibers.Thephasesoftheactionpotentialsarelabeled(seetextfordetails),asaretheeffectiverefractoryperiod(ERP)andtherelativerefractoryperiod(RRP).Notethatincomparisonwithfast-responsefibers,therestingpotential ofslowfibersislessnegative,theupstroke(phase0)oftheactionpotentialislesssteep,theamplitudeoftheactionpotentialissmaller,phase1isabsent,andtheRRPextendswellintophase4afterthefibershavefullyrepolarized.


Physiology_Levy

Physiology_Levy. Eq. 2.7 ). In a resting cardiac cell, K+ conductance (gK) is approximately 100 times greater than Na+ conductance (gNa). Therefore, Vm is similar to the Nernst equilibrium potential for K+ . As a result, alterations in extracellular [K+] can significantly change Vm: Hypokalemia causes hyperpolarization, and hyperkalemia causes depolarization. In contrast, because gNa is so small in the resting cell, changes in extracellular [Na+] do not significantly affect Vm. Fastresponsesofcardiacmusclemaychangetoslowresponsesincertainpathologicalconditions.Forexample,incoronaryarterydisease,aregionofcardiacmusclemaybedeprivedofitsnormalbloodsupply.Asaresult,[K+]intheinterstitialfluidthatsurroundstheaffectedmusclecellsrisesbecauseK+ islostfromtheinadequatelyperfused(orischemic)cells.Theactionpotentialsinsomeofthesecellsmaythenbeconvertedfromfasttoslowresponses.Conversionfromafasttoaslowresponseasaresultofincreasinginterstitial[K+]isillustratedlaterin Fig.16.13 Genesis of the Upstroke (Phase 0)


Physiology_Levy

Physiology_Levy. Fig.16.13 Genesis of the Upstroke (Phase 0) Any stimulus that abruptly depolarizes Vm to a critical value (the threshold) elicits an action potential. The characteristics of fast-response action potentials are shown in Fig. 16.1A. The rapid depolarization (phase 0) is related almost exclusively to the influx of Na+ into the myocyte as a result of a sudden increase in gNa. The action potential amplitude (the membrane potential change during phase 0) is dependent on extracellular [Na+]. When extracellular [Na+] is decreased, the amplitude of the action potential decreases, and when it is reduced from its normal value of approximately 140 mEq/L to approximately 20 mEq/L, the cell is no longer excitable.


Physiology_Levy

Physiology_Levy. When the resting membrane potential, Vm, is suddenly depolarized from −90 mV to the threshold level of approximately −65 mV, the cell membrane properties change dramatically. Na+ enters the myocyte through specific fast voltage-activated sodium channels that exist in the membrane (see Fig. 5.7). These channels can be blocked by the puffer fish toxin tetrodotoxin. In addition, many drugs used to treat certain cardiac rhythm disturbances (cardiac arrhythmias) act by blocking these fast sodium channels.


Physiology_Levy

Physiology_Levy. The sodium channels open very rapidly, or activate (in ≈0.1 msec), thereby resulting in an abrupt increase in gNa. However, once open, the sodium channels inactivate (time course ≅ 1 to 2 msec), and gNa rapidly decreases (Fig. 16.3 ). The sodium channels remain in the inactivated state until the membrane begins to repolarize. With repolarization, the channel transitions to the closed state, from which it can then be reopened by another depolarization of Vm to the threshold. These properties of the sodium channel are the basis of the refractory period of the action potential. When the sodium channels are in the inactivated state, they cannot be reopened, and another action potential cannot be generated. During this period, the cell is said to be in the effective refractory period. This prevents a sustained, tetanic contraction of cardiac muscle, which would retard ventricular relaxation and therefore interfere with the normal intermittent pumping action of the heart. As the cell