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Exam 3 Study GuideChapter 12- MuscleMechanisms of Contraction and Neural Controlability to use chemical energy to produce force & movement is present to a limited extent in most cellsin muscle cells, it has become dominantforce generation and movement by muscle can be used in a variety of ways in the human bodymovement within external environmentregulate internal environmentspeechdrawing a picturetwiddling your thumbstyping these notesMoving blood through vessels, moving liquids through GI tract- all need musculature. Structure of Skeletal MuscleFibrous Connective Tissue fibers within tendon extend around muscle forming an outer sheath—epimysium2 ends of muscleOrigin attachment to immoveable boneInsertion attachment to moveable Outer fascia that compartmentalizes musclesEpimysium– outer later wraps around all muscle fibers/fassicles beneath fasciaCells are packaged into fassicles wrapped in perimysium Within each fassicle there are individual muscle cells= muscle fiber which is wrapped by a delicate endomysium Single muscle cell is made of filaments called actin and myosin. These filaments are grouped together known as a myofibril Multiple myofibrils to form cell wrapped in sarcolemma (plasma membrane of muscle cell) Striated; nuclei are peripherally located. Motor UnitsOne muscle is an individual organ Skeletal muscle (voluntary) somatic nervous system needs to initiate contraction by motor unitMotor Unit—somatic motor neuron and all muscle fibers it innervatesNeuromuscular Junction—a neuron synapses to a skeletal muscle fiber Action potential down axon of motor neuron… opens voltage gated calcium channels at synaptic terminal, intracellular ca levels rise causing vesicles to fuse and release acetylcholine Acetylcholine binds to receptors on the surface of skeletal muscle fiberMotor end plate– area with ligand gated sodium channels ,acetylcholine is ligand, binding opens sodium channelsResting membrane potential changes (positive charge into cell causing depolarization event) Within motor end plate ligand gated channels but outside the region on the plasma membrane of fiber there are voltage gated sodium channels (enough of depolarization to reach threshold an action potential is initiatedEnd plate potential = synaptic potentialGraded contractions—varied number of motor units activated; contractions at different strengths, activate a certain number of motor neurons for the demand; more motor unites needed for more force/greater contractionActivated by rapid, asynchronous contractions for smooth, sustained contractionThey don’t contract at the same timeResilience to fatigue (one motor unit is not excessively used more than the other)Innervation ratio- a motor unit and how many skeletal muscle fibers it innervates to activate5-100The smaller the motor unit– finer control of skeletal muscle contraction (typing on a computer)Gross movements large motor unitsSmaller motor units are activated first by lower levels of excitatory. If we need more force we recruit more motor units (LARGER) There is a lot of variation built into muscleRecruitment– when you recruit more motor units based on the demandMechanisms of ContractionContraction refers to the activation of force-generating sites within muscle fibers cross bridgesCross bridges also referred to myosin heads on the thick filamentsSarcomere is the smallest contractile units A single muscle fiber = single cell Made of myofibrils (run the entire length of muscle and run parallel to each other)Myofibrils made up of myofilamentsMyofilaments = actin and myosinNuclei are peripherally placedSarcolemma- plasma membraneMyofilaments are organized into sarcomere – smallest contractile unitZ line (dark line) – one Z line to the next is one sarcomereThick filaments are STATIONARY made of myosin Held by the M line and do NOT moveThin filaments are made of actin + other things Connected on to Z line then extend toward the centerOnly the thin filaments MOVEArrangement of myofilaments gives sarcomere its dark and light bandsI band = thin filaments (made of two adjacent sarcomere)A band= thick filaments and little thin filaments for overlapH band = JUST thick filamentSliding Filament Theory of Contraction overlapping myofilaments move past each other, propelled by movement of cross-bridges Cross bridges (myosin heads on thick filament) associate with actin on thin filament – move thin filament toward the center (M line or H zone)Sliding Filament Theory of Contraction thin filaments slide over and past/between thick filaments, moving centrally and producing a greater degree of overlap (how sarcomere shorten)ONLY the movement of thin filamentsWhen contraction occurs and cross bridges interact the A band disappears, Z line and I band is reducedH zone is also reduced 018097500A band does not change (it is the length of thick filaments and they don’t move within sarcomere) 30572779687900317563563500Interaction between thin and thick filamentsduring contraction, only a portion of cross-bridges are attached at any given time, thus power strokes are not in synchronyWHY? We have to keep constant tension, if we don’t it will slide back to original presentation; Tug of war to pull something along, don’t have the same pattern Cross-bridge CycleThick filament & myosin heads (2 golf clubs/headed sperm) must be energized! High energy presentation (sticking straight up) Requires ATP4027170106743500ADP and phosphate, cross bridge/myosin head can interact with actin it will bind and phosphate is released causing conformational change and myosin head bends (thin filaments move toward central line) called the POWER STROKEHigh energy to low energy changeADP is release opening a site for another ATP to bindTo release the head from actin the ATP needs to bind Power Stroke due to the release of phosphateRegulation of ContractionRegulation of cross-bridge attachment to actin is function of 2 regulatory molecules associated with the thin filament (serve as a switch for muscle contraction/relaxation)Tropomyosin—lies within groove between G-actin monomers, covers binding site for myosin G actin—individual actin moleculesF actin—G actin bound together looks like pearls on a stringTroponin—3 protein complexTnT—binds to tropomyosinTnI- inhibitory portinTnC—binds to calcium Calcium is the regulatorRole of Ca in Muscle ContractionCa is tightly regulated, observe regulation by 2 intracellular proteins, calsequestrin within sarcoplasmic reticulum (storage site for Ca) as well as calmodulin within sarcoplasm Ca interacts with troponin (our GO signal) very tightly regulatedIn a relaxed state tropomyosin cover actin binding sites, when calcium is present it binds to TnC on troponin, troponin changes shape and drags tropomyosin with it– exposing binding sites on actin When myosin binding sites on actin, the high energy stage kicks off phosphate and cross bridge cycle continues as long as calcium is bound to troponin we need a certain level of Ca for contraction to begin Ca activates glycogen breakdown to produced glucose and enhances ATP synthesis. 103695543688000389953538290500If we have phosphate available forms a complex with Ca – make bone hard! Hardening within the Cell BAD (we want it stored or bound to troponin NOT stored)Anatomical Muscle ReviewA muscle is an organSarcoplasmic reticulum (blue) where calcium is storedTerminal cisternae (enlargments) lateral sacTtubules (transverse Ttubules) connect up to sarcolemma – PM of muscle cellConnection between T-tubule and terminal cisternae of SRAction potential flows on sarcolemma and hits Ttubule and bring the signal deep into the cell (moves signal from the surface) In sarcolemma next to motor end plate– voltage gated channels help action potential ***Excitation-Contraction CouplingMuscle contraction begins when sufficient intracellular Ca levels are reached (a certain number of troponin molecules need to be activated As action potential runs across sarcolemma runs down Ttubules and open DHP (dihydropyrodine) receptor – voltage gated calcium channel DHP receptor is molecularly linked to ryanodine (calcium release channel)The ryanodine receptor opens! Ca flows out (10x size of normal receptor)Calcium flows out of SR channelCalcium-induced calcium release channels flood the sarcoplasm with calcium. Calcium is going to bind to troponin then move tropomyosin causing contractionInitiate contraction of voluntary muscle begins with activation of somatic motor neuron—NMJ—open voltage gated calcium channels in axon terminal— synaptic vesicles release acetylcholine– acetylcholine bind to ligand gated sodium channels on motor end plate– initiate end plate potential– enough depolarization activated voltage gates sodium on plasma membrane- flow along plasma membrane – hit a Ttubule- go down open DHP receptor (molecularly linked to ryanodine receptors) open up calcium channels– DHP and ryanodine connection (ELECTROMECHANICAL RELEASE MECHANISM)DHP changes shape (open) it pulls ryanodine allowing Ca to flow out Sarcoplasmic Reticulum Localized event 36131500As Ca increase, we open ca-induced ca channels until we get high enough intracellular ca to cause contractionCa binds to troponin and troponin moves tryopomyosin Ca-ATPase (SERCA pumps) pump is a continuous pump – ion pump that continuous pump Ca from sarcomplasm to SR When AP stops this process stops Calcium channels shutAs calcium ion decrease in concentration Pulling ca off troponin and actin and myosin can not longer interact with each other Don’t care concentration always pump Ca into the SRATP is not only needed for contraction but also for relaxation Need to allow for the heads to detachNeeded for the Ca-ATPase pump to runRelaxation = produced by active Ca transport out of sarcoplasm into SRMechanism of Skeletal Muscle SkM contractions typically produce bone movement at joints, which act as levers to move load against which the muscle tension is exertedtension is the force exerted on an object-the load-by the contracting muscleload & tension are opposing forcesload > tensionno movementisometric contraction (constant length): muscle is generating tension but it is not movingtension > loadmovementisotonic contraction (constant tension): tension is greater than load and we get movementconcentric—muscle shortens, tensions is generated by sarcomere shortening and moving loadeccentric** (lengthening)—muscles never lengthen but length compared to shortening via concentric greater control of movementSeries-elastic component—during contraction, noncontractile parts of muscle and connective tissue of tendon also being pulled have elasticity when distending force released, then spring back to resting lengthsMuscle contraction pulls on CT wrappings tendon boneAdditional elasticity due to the pulling of other partsWhen everything relaxes tendon helps us reset our muscle to original length Absorb some of the tension as muscle contractsMuscle Twitch3 periods within muscle twitch- latent period (no tension), contraction period (sharp increase in tension) & relaxation period (gradual decrease in tension)Latent period– excitation contraction coupling, AP of motor neuron connecting AP sarcolemma--- flow down Ttubules to released calciumContraction period-- Ca ATPase pumps running Relaxation period-- Relaxation sucks up all calcium and muscle returns to original length (majority of time spent here)mechanical response of a muscle to a single AP/electrical stimulusmuscle contractions are graded responses (there isn’t just one level- many different levels)in general, muscle contraction can be graded in 2 ways:changing the strength of stimulusthreshold stimulusWeakest stimulus at which motor unit is stimulated to contractmaximal stimulusStrongest stimulus to recruit all motor unit to contractWe can increase voltage stimulus but the muscle contraction doesn’t go any higherchanging frequency of stimulationProportion of nerve fibers excited (how many motor units are being activated) Smaller motor units activated firstIncrease stimulus until threshold stimulus (weakest stimulus for a motor unit is going to be stimulate to contract) what level do we need to reach? How much depolarization do wwe need?As we increase stimulus strength we increase the tension generation until the maximal stimulusWe can increase voltage stimulus but the muscle contraction doesn’t go any higherIncomplete & Complete TetanusIf 2 identical stimuli are delivered to a muscle in rapid succession, the 2nd twitch will be stronger than the 1st, this is wave summationoccurs because subsequently induced contractions occur before muscle can relax summing the contractionsWith increasingly faster rate of stimulation, muscle relaxation is shorter & Cai, leading to incomplete tetanus When a “fusion frequency” of stimulation is reached, with no visible relaxation between successive twitches, complete tetanus is attainedYou can have summation of skeletal muscleSingle muscle twitch (2 identical stimuli notice the second twitch is stronger—we have wave summation In order for you to have a smooth contraction we need to hit threshold and certain frequencyWave summation contributes to force of contraction, but primary function is in generation of a smooth, continuous muscle contraction – reach complete tetaniAchieved by frequency of stimuli without relaxation between contractionsTreppestaircase pattern observed when muscle fibers first stimulated to contractstimulus strength constantdue to:increasing amounts of Ca available in sarcoplasmheat generated from muscle work increases NZ efficiency in musclemuscle more pliable (warm up fibers)—warm up lead to less injury possibly?Force-Velocity Curvelighter objects are moved faster than heavier objectsinverse relationship between force opposing muscle contraction & velocity of muscle shortening380428540386000What does curve represent physiologically? In order for a muscle to contraction, the thin and thick filament needs to contract the shortening velocity determined by the rate of cross-bridges undergo cyclical activity 0 load= maximum shortening velocityIncrease the load we get to a point where there is no shorteningIsotonic isometricSlope = shortening velocity Time is NOT the element but the rate of contraction More load is harder for the cross bridges to interactLength-Tension Relationshipmuscle contraction strength can be influenced by a variety of factorsfiber numbers activated, stimulus frequency, muscle fiber thickness, length of muscle fiber at restan “ideal” resting length for striated muscle fibers that results in maximum force generationRecruit smaller motor units first and then larger motor unitsSarcomere is a defined length– degree of overlap Too far apart- cant connectToo close together- unable to slide There is a region indicated by the graph- there is an optimal length u want your muscle to be at rest to generate the best forceEnergy Requirements for Skeletal Muscle Skeletal muscle cannot “store” ATP, so it must have metabolic mechanisms in place to meet demand once contractile activity begins – works hardOxygen is important for ATP generationFatty acids are the most used energy source- more bang for your buckFrom mild to moderate exercise, glucose is more commonly used because of instant break downSkeletal Muscle Metabolism Creatine phosphate—regenerate ATP from ADPglucose gives us ATP quickly- forming lactic acid to run anerobicallyDesired way– oxidative phosphorylation, make a lot of ATP using many organic molecules (proteins, fats and carbs)You need oxygen (can be get from blood circulation) When muscle fibers contract, blood flow make be limited Myoglobin pigmented protein found in skeletal muscle cells and it binds oxygenAmount dependent on type of skeletal muscleObserve a maximal capacity for aerobic exercise in an individual dependent on the maximum rate of oxygen consumption by the bodyVO2 Max– maximal oxygen uptake/ aerobic capacity (Vo2 max)Males have highest and hit peak at 20Respiration rate doesn’t change when you stop working out– oxygen debtThere is a basal level of oxygen needed to function at restWhen you exercise you pull oxygen from reserves in myoglobin, RBC– needs to be replenishedThe amount of oxygen required needed after exercise is above basal need– oxygen debtThe extra oxygen needed to replace reserves and stores used p during exerciseMuscle Fatiguedefined as any exercise-induced reduction in the ability of muscle to generate force/power (reversible)observe EC K conc during maximal contractionreduces membrane potential, thus interferes with ability to generate APsCauses (due to exercise type):depletion of muscle glycogen Hard working muscle and you only have a certain capacity to generate ATP (run out of glucose)reduced ability of SR to release CaFailure of excitation-contraction couplingIf you cant release Ca (go signal for contraction) the muscle will not contraction“others”…↑ [PO4] & ↓ATP-↑ADPIncrease in phosphate groups- reducing force developed by cross bridgesLevels of ATP drop anything that requires energy to run will not run; ADP raise decrease muscle velocity for shortening in humans, fatigue is experienced BEFORE muscles fatiguecentral fatigue muscle fatigue caused by changes in CNS rather than muscles themselves Shuts things down before muscle completely loses all stores. STOP So we have a base. It is reversibleWhy do we have muscle fatigue? Action potentials increase in extracellular potassium throwing off the ion balances, reducing membrane potential and interfere with making action potentialTypes of Skeletal Muscle Fibers SkM classified on basis of contraction speedfiber typesslow-twitch, or type l fibers (red fibers) suited for prolonged contractionsSlow oxidative fibersSlow to contract; use oxidative phosphorylationFatigue resistantGood for posture (on all the time)Small in diameterintermediate fibersFast- oxidative glycolytic fibersSomewhere in between both typesfast-twitch, or type ll fibers (white fibers)suited for rapid, intense movementsFast-glycolyticUse glycolysisFatigue readily Rapid and intense skeletal movementLarge diameterfibers differ in mechanical & metabolic characteristics (some are resistant to fatigue or fatigue resistant)human muscles are a mixture of fiber typesgives muscle a range of contraction speeds, varying resistance levels to fatigue & performanceNOTE—all muscle fibers associated with a particular motor unit are of the same type Why don’t we have all intermediate fibers (best of both)? They won’t give a range of contractions speed, resistant to fatigue can impact performancea world class sprinter– have more intermediate and fast twitch- larger thicker radius; a world class marathoner– more slow twitch- lean smaller radius (genetically predisposed to be athletic based on their fibers)Spinal injury- loose slow twitch and more fast twitchEXAMPLESextraocular eye muscle (fastes muscles in body, generate tension very quickly; more fast twitch\c – soleus muscle (prolonged contraction- help stabilize posture and balance, slower generation of tension; more intermediate & slow twitch fibersMuscle Damage and RepairLimited capacity to repair skeletal muscle damage- due to presence of satellite cells observe resident stem cells in SkMsatellite cells“leftover” from embryological developmentlocated outside muscle fibersClose proximity to be recruited for repairpermit some degree of repair & limited regenerationability declines with ageSarcopenia decline in muscle mass and strength (resistance training is important) myostatin (transforming growth factor-β family, also known as GDF-8)paracrine regulator inhibits satellite cells & muscle growth (myokine– local chemical messenger)Regulate muscle growth- don’t want too much or too little muscles (helps balance muscle growth)Large slice through the muscle is harder to repair (more damage harder to repair)Damage due to exercise satellite cells are activated by damage and develop into myoblasts that fuse with damaged muscle fibers OR can form new muscle fibers. If damage is extensive limits to ability to repairNeural Control of Skeletal Muscle & ReflexesMuscle tone—state of tension in a resting muscleMuscle stretch- measure degree of stretchMuscle spindle– sensor, made up of intrafusal muscle fibers that has noncontractile center (just at the end there are contractile elements) wrapped by a sensory neuronWhen stretched the afferent neuron increases action potential frequency denoting stretchExtrafusal muscle fibers- contractile elements along its entire lengthMuscle contraction- scrunch middle portion and muscle togetherDecrease in action potentialMake it difficult to gage the degree4488180190500Alpha-gamma coactivation alpha motor neuron innervates extrafusal fibers, gamma motor neuron innervations intrafusal fibers; activate is useful in helping us keep proper tension in that muscleContraction of extrafusal fiber my alpha motor neuron, = intrafusal fibers activate gamma motor neuron reseting spindle Why? Ensures info about muscle length continuously available so adjustments can be made during contractionNoncontractile area is harder to gauge and measure the degree of contractionSUMMARY—Gamma motor neuron activity maintained to keep muscle spindle under proper tensionKnee jerk reflex initiated by stretching patellar tendon, picked up by stretch receptor and look at degree of stretch in muscleIf you Cause of contraction in one muscle compartment (anterior of thigh), need to cause relaxation in other compartment (posterior of thigh) in order for movement to proceedsActivate extensor inhibit flexor so movement can occurReciprocal innervation- from site of stimulus we go back to original- excitatory contraction of extensors and inhibit flexor – one set of muscles we contract the other set of muscles we inhibit Withdrawal reflex— activate one set of muscles and inhibit another (activate flexors- posterior to pick up foot from tack) on the side of stimulusCrossed extensor reflex– on the opposite side of stimulus- back leg needs to prep and get read for weight shift when you pick your leg back up. Cardiac MuscleFunctionally similar to skeletal musclestriated, short branched muscle fibersstriation caused by sarcomeres; arrangement of thin and thick filamentselectrically coupled via gap junctions—intercalated discselectrical impulse conducted along long axis from cell to cell345757522225000one cell depolarized it spreads through all cells it is connected to; once contraction is initiated it acts like one unit due to the gap junctionsfunctional syncytiumbehave as a single functional unitcontract to fullest extentflow from one cell plasma membrane to the next cardiac muscle fiber’s plasma membranepacemaker cells (found in various locations – right atrium)spontaneously depolarizeset contractile ratemodified by autonomic innervation (sympathetic and parasympathetic)excitation-contraction couplingCa-induced Ca releasedifferent from Skeletal muscle , no “direct” interaction between T-tubule & SR (ie. no ryanodine R’s)Molecular coupling occurs between DHP receptor and Rvanodine is NOT there in cardiac muscle – just a voltage gated Ca channel that allows Ca to flow into cardiac cell; as Ca rises in sarcoplasm then we open ca-released channels Ca-induced Ca released– need a certain level of intracellular Ca before they open-slower process (no coupling)DHP receptor is the T tubule in voltage gated (calcium from the extracellular fluid)Bulk of calcium comes from sarcoplasmic reticulumSmooth Muscle Fusiform in shape- belly and tapered ends nonstriatedno sarcomeres but actin & myosin are present for contractionthin filaments are longdense bodiessites of attachment for thin filamentsconnected by intermediate filaments netting around the cellthick filaments vertically stackedmyosin heads along entire length of thick filaments allows sliding along the entire lengthmyosin tails are all parallel to the axis, sliding can occur along entire length of thin filamentspull the dense bodies close together and pull on the intermediate filament nettingdon’t contract but SCRUNTCHadvantage to arrangement?ability to contract even when greatly stretchedWhat we see in urinary bladderIf you don’t have a sarcomere (no Z lines) how do we move? Still have the same directional movements we don’t have any limits.. We can only slide so far due to the constriction of the Z line but the smooth muscle we have the entire length to slide due to the lack of sarcomere…stretch even more 36017209715500Calcium is an important element but no troponin or tropomyosin- calmodulinSarcoplasmic reticulum is less developed—pull a lot off calcium from extracellular fluid Functions are more variable and complex—no T-tubulescontraction is initiated extracellular calcium comes in through voltage gated channels- the calcium need when contraction. When voltage gated channels open, calcium Bind to calmodulinCalmodulin and calcium complex activate MLCK which take light chain (myosin head) become phosphorylated– phosphorylation of cross bridge contractionRegulatory even that permits actin and myosin interaction (phosphorylation of cross bridge)ContractionCan have graded contraction through amount of phosphorylationDepends on amount of calcium- more calcium= more phosphorylation= more contractionRelaxationCa-ATPase transport pump found on sarcoplasmic reticulum- continuously running and bring in calcium also pumping it out of the cell. Pump calcium out of cell, calcium will not bind and no complex,, light chain because inactivatedMyosin phosphatase runs continuously; removes phosphate from light-chain on myosin head (cross bridge element)– allowing relaxationCa calmodulin - MLC kinase phosphorylate MLCWhen there is no longer a signal there is no more calcium flowing in and both pumps (SR and plasma membrane) will pump out calciumSlow and sustained contractions: contractions over time; energy consuming!Latch state complex ; smooth muscle can sustain a contraction by utilizing minimal amounts of ATP; suspending animation (efficient) Functional CategoriesSingle unknit smooth muscleMajority/ typical smooth muscleAutonomic nervous systems modifyVaricosities along entire length, gap junctions, synpases en passant--Act like a single unit when contractHave pacemaker cells – similarly to cardiac muscle Multiunit smooth muscle No gap junctionsStimulate via nerve stimulation Ciliary muscles, erector pilli musclesTABLE 12.8Chapter 13- Blood, Heart & CirculationCirculatory Systemfunctional termprefer the use of Cardiovascular System3 partsPump (heart) moves transport mediaBlood the transport mediaConduits- blood vessels Bloodfunction divided into 3 broad areas:transportation- move nutrients, wastes, ions, regulatory elements (hormone)regulation – regulate temperature by moving heat around, hormonesprotection – antibodies, immune function and clottingComposition of Bloodconnective tissue- only fluid tissue in human bodyPlasma—liquid of water and dissolved solutes (esp. sodium), plus varied organic moleculesCellular component – Formed elements Leukocytes, platelets, thrombocytes, erythrocytesHematopoiesisHematopoiesis- process to make formed elements; occurs in RED bone marrowIn adults it will be in sternum, skull, scapula, pelvic, ribs and vertebra– proximal ends of long bones Newborns have more RBCHemocytoblast- pluripotent hematopoietic stem cell gives rise to all the formed elements Lymphoid line: lymphocytesMyloid line: everything elseVarious mechanisms in place regulating formed elements productionInfluenced by cytokines and other regulatory molecules Cytokines– regulates the production of different sub types of leukocytesInterleukins (CSFs) stimulate the development of different white blood cells Erythropoietin assists with RBC formation Thrombopoietin give rise to platelets49002955207000ErythrocytesErythrocytes: Are anucleate, have a longevity of 120 days needs to be constantly replaced Erythropoiesis is a very active process Regulated by Erythropoietin– supportive, stimulates the erythroblast….speeds up, supports and enhances, released by kidney to jump start erythropoiesis Expel the nucleus to form the reticulocyte mature into erythrocytesLiver, spleen and bone marrow remove aged cells, recycle iron and globinWhen erythrocytes get old are recycles to globin(protein portion) and iron ( can be limiting in our diet) Iron can be toxic in its free state (mechanism in place need to be regulated) Required for erythropoiesis– supply of iron, Vitamin B12, folic acidFerroportin channels in enterocytes: allow cells to take up iron and stored; transferrin in plasma move iron throughout the body (stored in liver) Hepcidin regulator of iron (polypeptide made in liver) target enterocytes (cells of GI tract) and macrophages( contain ferroportin channels)Caused the removed of the ferroprotin channels Hormone that promotes the cellular storage of iron Lower blood concentration of iron as wellOnly way to get rid of excess iron – menstruation Blood Typing-- result of distinguishing antigen displayed on cell surfaceGenetically determinedImmune system exhibits tolerance to body’s Red Blood CellsType A- A antigens, antibodies to B antigensType B- B antigens, antibodies to A antigensType AB- A & B antigens, No antibodiesType O – NO Antigens, antibodies to both A and BBlood Clottinghemostasiscessation of bleedingeffective in dealing with injury to small vessels but little help for middle to large vesselsobserve 3 separate but overlapping hemostatic mechanismsvascular spasmformation of platelet plugclot formationVascular Phasevasoconstrictive event- immediate response to injury; occurs in smooth muscle of vessel wallwhen you irate it, responds by contraction or undergoing a vascular spasminherit characteristic of smooth musclefunction: close off vessels, reduce blood loss & allow time for other processes to stop bleeding in larger vessels Aorta does NOT clotPlatelet PhaseNormal condition- platelets repelled from each other and endothelium (simple squamous epithelium that lines inside of blood vessels)Prostacyclin and prostoglandins and nitric oxide produced by endothelium– vasodilators that inhibit platelet aggregationOn surface of cell- CD39, an enzyme that breaks down ADP to promote platelet aggregationADP is a platelet aggregation factor When an injury occurs it exposes collagen in the matrix– release of VWF (bind platelets to collagen- initiate aggregation) both of these activate plateletsPlatelet release reaction- degranulate and released ADP, serotonin, thromboxane A2 which activate more platelets in the plug that begins to form; fibrinogen brought inMore platelets activated and recruited Form a platelet plug organizes for blood clot formation; platelet activate clotting factorsTemporary fix, loose; must be stabilizesPositive feedback event- once initiated it gets bigger and bigger; platelets activate more platelets Coagulation PhasePlatlet plug is forming- RBC and fibrinogen is incorporatedRepresents the transformation of blood from liquid to a gel that results in the formation of a clotConversion of soluble plasma protein, fibrinogen, into an insoluble fibrous protein, fibrin = clottingClotting PathwaysInitiated at the same time- one goes faster than anotherExtrinsicActivated by chemical released from damaged tissues and activating clotting factors Tissue thromboplastinFaster pathwayIntrinsicAll components present in blood, initiated by negatively charged structures & NETS (neutrophil extracellular traps)Collagen, NETs, PolyphosphatesContact pathway because initiated by clotting factors being in contact with negatively charged structuresSlower pathwayCommon Pathway All steps require Calcium and phospholipids from platelets Not all about clotting factors!Factor X- prothrombin activator Both extrinsic and intrinsic come together to activate Factor XConverts prothrombin to thrombin (molecule that converts fibrinogen to fibrin)Fibrin polymerized into big cables to strength the plug at injury site utilizing Factor 13 (fibrin stabilizing factor)Clot retraction element of platelets; contraction within platelet mass to form more compact and effective plug Squeeze out fluid inside = serum (plasma – clotting factor)Bring edges of wound closer together [less real estate to repair]Vitamin K and LiverVitamin K is needed to make many clotting factors Come from symbiotic bacteria in GI tract Deficiency in K or impairment of liver functions can lead to clotting issues Clot Dissolution Activation to pare down the clot so it’s not too big – tears down the clotPlasminogen activates plasmin that tears down fibrin from insoluble cables to soluble fragments Balance to Ensure the clot is just the right sizeKallikrein is a plasminogen activator (happens at same time as intrinsic and extrinsic pathways)3 mechanisms that oppose clot formation:TFPI tissue factor pathway inhibitor released by endothelial cells and blocks clotting Thrombomodulin – receptor for thrombin making thrombin inactivate; when thrombin binds to thrombomodulin it becomes inactivated and becomes Protein C activator and activates Protein C that is a natural anticoagulant- inhibiting clottingAntithrombin III– inactivates clotting factors and thrombinFunction- limit clot formationToo small wont sufficiently plug392557080010Too large will include the vesselCirculation Circuits & the HeartHeart feeds two circuits – pulmonary and systemicPulmonary circuit feed by right hand side of heart – goes to lungs to be oxygenatedSystemic circuit fed by left hands side of heart- takes blood from heart to the rest of the body – back into vena cava to restart the processWe have a closed circulatory pathway (there is equal flow in the circuit) Equal blood flow in circuits- prevents fluid accumulation in lungs and oxygenated blood delivery to bodyA typical humans ha 5.5 L of blood (males have more females have less)Depends on stature and robust Side-by-side pumps – left hand side (systemic) and right hand side (pulmonary) – primer pumps (L, R atria- “top” off ventricles) and power pumps (L, R ventricles)To make sure that they flow in one direction– two sets of valves (NO BACKFLOW)Atrioventricular valves (2) into the pulmonary and systemic circuit via semilunar valves (2)Thin connective tissue flabsFibrous skeleton – dense connective tissue structure stabilize the valves, attaches myocardium so cardiac muscle can pull againstFunctionally and structurally separates the atria and ventriclesElectrically separates the two compartmentsCardiac CycleRepeated cycle/pattern of contraction and relaxation (one contraction and one relaxation = 1 cycle)338963017399000contraction= systolerelaxation= diastole Occurs in both atria and ventricleThe heart spends more time in relaxation/diastole (2/3 of its time) only 1/3 of times in contractionAtrial contraction - atria contract and push blood into the ventricles then move into diastoleIsovolumetric ventricular contraction; pressure is going to rise *all valves are closed*Advantageous because it allows to increase pressure very quicklyEjection- blood out of ventricles Set up so blood flows from atria to ventriclesThe force within the heart has to be great enough to push against the flow within pulmonary and systemic circuits and open the valves to push blood out Ventricles then go into diastoleIsovolumetric ventricular relaxation- even though ventricles are relaxing, pressure is still great that the atrioventricular valves cannot open so ALL VALVES ARE CLOSEDPressure will eventually fall; atrioventricular open and then blood flow into ventricles restarting cycle Relationship between Interventricular Pressure, Volume, & Heart SoundsIsovolumetric contraction– all valves are closed; steep rise in pressureEjection- stroke volume is ejected out from ventricles EDV- end diastolic volume– volume at the end of diastole/relaxationSV- stroke volume, the volume that is ejected outIsovolumetric relaxation- pressure drops quickly in L ventricle and before we ejected blood out we have the end systolic volume. (you don’t pump out every mL of blood)ESV- blood volume that is left within the heart after contractionFirst and second heart sounds are the closure of valvesTo make the first heart sound the atrioventricular valve closes, second heart sound is the semilunar valves close.Electrical Activity of the HeartIsovolumetric contraction– all valves are closed; steep rise in pressureEjection- stroke volume is ejected out from ventricles EDV- end diastolic volume– volume at the end of diastole/relaxationSV- stroke volume, the volume that is ejected outIsovolumetric relaxation- pressure drops quickly in L ventricle and before we ejected blood out we have the end systolic volume. (you don’t pump out every mL of blood)ESV- blood volume that is left within the heart after contractionFirst and second heart sounds are the closure of valvesTo make the first heart sound the atrioventricular valve closes, second heart sound is the semilunar valves close.Pacemaker Potential cells of SA node exhibit slow, spontaneous depolarization, called a pacemaker potentialresult due to channels opening because of membrane events (hyperpolarization from previous AP)channel permits Na to flow into the cell, causes a depolarization event until we hit threshold funny currentdiastolic depolarization- pacemakers use sodium HCN channel due to hyperpolarizationat threshold, voltage-gated Ca channels open for depolarization with repolarization resulting from the opening of voltage-gated K channelsSympathetic and parasympathetic Influence– modifies ONLYWhen sympathetic released epinephrine binds to beta-1 receptors increasing heart rate because the signaling pathway generate cAMP which opens the HCN channels Funny current HCN are hyperpolarization activated, cyclic nucleotide gated channels– open in presence of cAMP and hyperpolarization eventEpinephrine generates cAMP to openParasympathetic released acetylcholine that binds to muscarinic potassium channels; decreasing heart rateMyocardial Action PotentialIn adjacent cardiac muscle cells in the myocardium, initiated by pacemaker cells to produce Apsspread through gap junction to initiating contraction of all neighboring cell Use a fast sodium channel, open up slow calcium channels – repolarize by slow potassium channel causing an elongationThe influx of calcium causes a plateau -- “muscle twitch”Conducting Tissue of the HeartAPs from SA node spread at 0.8-1 m/sec across atriaconduction slows with AV node-delayconduction speeds increase with fastest in purkinje fibers-5 m/sec (make sure contract at a single unit)ventricular contraction begins ~0.1 to 0.2 sec after atrial contraction (delay to make sure atria contract first then ventricles)Send signal across both L and R sides Atrioventricular node– can then activate the ventricles to contractAtria contract first then ventriclesWe have a delay- takes a little bit to get AV node goingAllowing ventricles to contract and relax before automatically contracting themECG- electrocardiogram; hills are generated based on electrical activity inside of heartExcitation-Contraction Couplingnote, a Ca-induced Ca release is observed from the Sarcoplasmic reticulum as seen in skeletal muscle however excitation-contraction coupling is slower due to system not as efficient as in Skeletal muscleSlower in cardiac muscle- no rhysodine receptorsCai is lowered by Ca-ATPase pumps of SR & Na-Ca exchanger on PMunlike SkM & SmM, CM cannot sustain a contraction, with contractions lasting about 300 mseclong absolute refractory period prevents summation of contraction, ensures rhythmic pumping of heart QUESTION: Is summation important to the heart?NO, gap junctions so all cardiac cells are contracted at the same time anyway- functional syncytium. We don’t need summation. There is NO summation in the heartSummation allows us to have sustained contraction (tetani)We have gap junctions in heart so summation is unneeded Frequency of stimuli is NOT important in the heartBlood VesselsBlood Vessels– conduits that form a network throughout body permitting distribution of blood to body tissuesTIME tells you layers of the blood vessel layersInnermost: tunica internaMiddle: mediaOutermost: externaArterial circuit of systemic circuit—DIVERGING– one big one to smaller and smaller oneselastic artery: elastic layer found within tunic and when heart ejection of blood the vessels can expand and contract backMuscular arteries– deliver and control blood flow to organsArterioles– important for organ physiology; adapted for vasoconstriction and vaodilation, regulation and respond to minute by minute changes within organLook at chemicals and signals to direction of blood flow within an organ Capillaries are the smallest blood vessels– EXCHANGE, endothelium with a basement membrane wrapped around them. (don’t have all three tunics) Very important in exchange of nutrients and gasesArteries and veins MOVE blood; Capillaries EXCHANGE nutrients Venous Circuit is CONVERGING Circuit (millions of capillaries into bigger and bigger vessels to return to the heart)Veins: Have the three tunicsVeins walls are always thinner than the robust arteriesCapillaries Smallest blood vessels; endothelium with basement membrane; branch extensivelyWell suited for function of exchangeForm a capillary bed good for exchangeThe functional unit of cardiovascular unit because of the capillaries!Need exchange in and out of transport mediaArteriole– capillary bed--- exit out a venuleDo not function independently but together as a group, referred to as a capillary bed; It doesn’t have to flow through a capillary bed. In arteriole: there is a Shunt can bypass bed (medarteriole) empties into into postcapillary venule Don’t have enough blood for all beds so need shuntsHelp maintain body temperatureFlow into capillary bed controlled by precapillary sphincter; contracts/relaxes in response to tissue needs; observed to follow a cycle, contracting/relaxing at a rate of `5-10 cycles/min in response to tissue activityVasomotion– opening and closing of precapillary sphincter for blood to flow in or be shunted by capillary bed Tissue is hardworking increase rate of blood flow cause we need more blood DuringBasic Types of Capillaries:Continuous“leaky”Most common Endothelium with basement membrane Localized in vascularized tissue – muscle, skin, lungs, Nervous system, adipose tissueIntracellular cleft- regions between individual endothelial cells held together by tight junctionA little space to allow for exchange for ions and fluid (otherwise need to move through vesicle)Fenestrated“leakier”Similar to continuous but contain Fenestration/ pores covered by a membrane called diaphragmAllow for a little more exchange Found where Active absorption or filtration occur (kidney, GI tract, endocrine glands)Sinusoids“leakest”Discontinuous basement membrane, highly modifiedRestricted to certain organs (least common)Suited for Passage of blood cells and large moleculesFound in Bone marrow, liver, lymphatic tissues- spleen, few endocrine organs Veinslarge lumens/diameter & thin wallsaccommodate large blood volume, thus referred to as capacitance vessels (have capacity to serve as a blood reservoir) low pressure, so structural adaptations arose to ensure blood returns to heart:large diameter, low resistancevenous valves- tunica intima, a lot like valves in heart, ensure blood flow in one direction – towards heart; can’t move backwards, cuts the weight of a column (prevalent in limbs)skeletal muscle pumps– contraction of muscles help push blood along in the right directionChapter 14 – Cardiac Output, Blood Flow & Blood PressureCardiac Outputvolume of blood each ventricle pumps (what is being ejected out)L/minReflects pumping ability of the heartCO = HR x SVHR= heart rateSV= volume that is ejected out of ventricle/heartAverage adult: HR= 70 beats/min & SV= 70-80 ml/beatChanges based on build of individualEX. What is the CO for this individual? 70 x 75 = 5250 ml/min (a little over 5 liters)5 liters is typically the amount of blood we have in our entire bodyOur hearts pumps our entire blood volume once every minute at RESTChanges in HR or SV parameters impact cardiac outputRegulation of Heart Rate ~100 beats/minresult of inherent, autonomous discharge rate of SA (sinoatrial) node not what observed physiologicallymodified by:Autonomic Nervous System (sympathetic and parasympathetic-RULE innervation)cardiac control centermedullaCirculating Hormones can change HRinfluenced by higher brain centers via sensory feedback from baroReceptors (blood pressure readers in carotid arteries close to heart)Hypothalamus- homeostatic control center; send info for modification through cardiac control center in medullaChange heartrate via pacemaker potential How do we change HR?CONTROL: Pacemaker potential brings resting membrane potential to threshold in a contractile cardiac muscle cell-- contractionSodium ion and HCN channels (hyperpolarization cyclic nucleotide channels) 4594125-7600Sympathetic releases epinephrine and noepinephrine bind to Beta-1 receptors an activate cAMP (second messanger) open HCN channelsB1 receptors cAMP open HCN channels (spontaneously opening and the increase presence of cAMP opening more channels) shortening the pacemaker potential to increase HRShorten pacemaker potential in sympathetic to increase HRElongate pacemaker potential in parasympathetic to slow HRAcetylcholine binds to muscarinic receptors Opens potassium channels-elongate- sodium channels open because of hyperpolarization- to counter it potassium channels which is greater than Na coming in– slow depolarizing eventchronotropic effect: changes heartrate due to a compound or chemicalpositive HRnegative HROverall HR set by antagonistic influences of autonomic nervous system- sympathetic or parasympathetic on SA node (where conduction system starts)Decides whether to speed heart rate up or slow it down **Major regulator for HR is sympathetic and parasympathetic and how it influences SA node**Regulation of Stroke Volumedefined volume of blood each ventricle ejects during each contraction (systole)regulated by:end-diastolic volume, EDVHow much you fill influences how much you can eject out. volume of blood in ventricle at end of diastole (relaxation)Preload- workload imposed on ventricles prior to contraction Load on the heart before contraction- how much blood is in the heart at the end of relaxationBigger volume more work loadStroke volume directly proportional to EDVEDV increases, SV increasestotal peripheral resistance, total PRResistance to blood flow in arteries, result due to friction (slow it down)Afterload– pressure in ventricles must push againstSV is inversely proportional to total PRcontractilityChanging the strength of ventricular contractionFunctional synchitum all cardiac cells CONTRACT; how can we contract stronger??Stroke volume directly proportional to contractility (increase ventricular strength)ejection fraction – EF proportion of EDV that is ejected against afterload depends on strength of ventricular contraction At rest, normally sufficient strength to eject 70-80 ml out of total EDV of 100-130 mlEF = SV/EDVLook at clinically to see if you have heart malfunctionsIssues– heart failureFrank-Starling Law of the Heartbasically, two physiologists independently determined that strength of ventricular contraction varies directly with EDV (heart can contract at different strengths)this Frank-Starling mechanism is an intrinsic property of cardiac muscleresult due to a length-tension relationship There is a set optimal length for a skeletal muscle at rest for optimal fore generationThe reason we can change contractility in heart because at rest the heart is NOT at optimal length for max contraction 389674429718000ventricles contract more forcefully during systole when stretched, which is the result of a greater EDVlinear curve: increase equally as you increase SV and EDV EDV – sarcomere length, SV- contractile forceCardiac muscle tissue is not at optimal length as you stretch you bring to optimal length- increase in SV to get max force **AS VR (venous return) increases, automatically forces an increase in CO (cardiac output) by increasing EDV and thus SV and contractility**If more blood comes back to heart, the heart will contract harderYou can’t have more blood on one side than the other because one side will callapse * maintains equality between left and right Cardiac OutputIntrinsic Control of Contraction StrengthCardiac muscle length has a more pronounced effect on contraction strength than observed in skeletal muscleCardiac muscle optimal length not at rest, as ventricles fill myocardium stretched to optimal length permitting more forceful/stronger contraction to move blood volumeTo insure cardiac output from left and right side are in synch with each other Anrep effect an intrinsic myocardial mechanism; sudden increase in afterload leads to ventricular inotropy, or contractility, however, force of myocardial contraction gradually increase over 10-15 mins following stretching (immediate respond and then there is a lag called anrep effect)Anrep effect due to elevated calcium levels in tissues and cellsTime to reach maximum contraction is constant regardless of stretchFrank-Starling law explains how heart can adjust to a rise in total PRA rise in PR causes a decrease in ventricular SV more blood remain in ventricle with EDV greater for next cycle ventricle is stretched to a greater degree in next cycle contracts more strongly to eject more blood permits health heart to sustain normal COAlso includes Anrep effectBoth mechanisms ensure that increase in EDV intrinsically increase contraction strength and SV Important consequences is CO of left ventricles, pumping into systemic circuit with every changing resistances, adjusts to match output of right ventricle Pulmonary circuit is very congenial Ensures blood flow equally between circulation circuits. Extrinsic Control of Contractility ventricular contraction strength depends on activity of sympathoadrenal systemNorepinephrine from SNS which increases contractilityEpinephrine from adrenal medullaBoth of them have positive inotropic effect– increase in contractility due to activation of sympathetic nervous system and/or sympathoadrenal system by sympathetic nerve stimulation Cardiac output affected by sympathoadrenal systempositive inotropic effect on contractilityDue to an increase in amount of Ca availableTop Picturealso causes a positive chronotropic effect- sympathetic nerve stimulation increases heart rate as well33451743748400When norepinephrine or epinephrine bind to Beta-adrenergic receptors initiate a g protein complex which activate acyclase increases cAMPcAMP activate a cAMP dependentt protein kinase that open calcium channels in pm of cardiac muscle and sarcoplasmic reticulam Calcium channels in pm are DHP receptorsCalcium channels in sarcoplasmic reticulum are rhidpon receptors406019030981700These two channels are not molecularly coupled but the protein kinase open BOTH of them Ca binds to troponin and cross bridge cycling increase- increasing velocity and force of contractionIncrease in sympathetic nerve system activityBottom PictureSympathetic nerves when activayed increase HR and contractile strengthWhat about PNS innervation??PNS decrease heart rateDoes not influence ventricular contraction strength (sympathetic innervation does)Increase in EDV occurs due to a slower HR – more time for ventricle to fill- can increase contraction strength through Frank-Strahling mechanisms (stretch)Increase in Stroke volume but not enough to overall compensate for slow HR thus cardiac output is decrease**Sympathetic nerves release epinephrine and noepinephrine binding primarily to Beta-1 adrenergic receptors; tend to have positive effect on chronotropic, inotropic, dromotropy and lusitropyOccurs in Contractile cardiac cellChronotropy– heart rateInotropy– contractilityDromotropy– conduction veolocity-- Excitation speedLusitropy- relaxation-- Enhances and supports during relaxed stateLooking at noncontractile cardiac muscle cells in SA and AV nodesParasympathetic nerves release acetylcholine that bind to muscarinic receptors, initiate negative effect on the parameters Acetylcholine released from vagus nerve bind the muscarinic receptor activating a G inhibitory protein cut down on activation of cAMP (decreasing cAMP) why we see decrease in chronotropy and dromotropy responsesInhibitory G protein activates K channels to open, allowing an efflux of potassium, hyperpolarizing cellVenous Returnrepresents blood return to heart via veins60-70% of our blood is housed in our veinsrate atria/ventricles fill dependent on total blood volume (what can be brought back)and venous pressureveins have a higher compliance than arteries(able to distend more easily when pressure applied- make a great blood reservoir) hold more blood, but also low pressureVenous Return aided by:sympathetic nerve activity initiating increase venoconstriction (veins constrict), thus decreasing compliance (influence venous pressure encouraging VR)SkM pump: contract press on compartments being venous valves to move things from one section to anotherpressure differences between thoracic and abdominal cavitiesNegative intrathoracic pressureBreathing- changing pressure influencing blood to go back to heartBlood VolumeRepresents a compartment within the extracellular compartmentFluid movement between blood plasma and interstitial fluid determined by balance of opposing forces acting at the capillariesIntracellular fluid (bigger compartment than extracellular- cytoplasm) and interstitial fluid exchange State of dynamic equilibrium movement of blood plasma– interstitial fluid– cytoplasm of cells Nutrients and gases utilizeWaste & secretory products of cellsWater excretion and water intake need to be balancedTake in 1.5—2.5 LLose a little water in fecal contentEvery time you breath, moisture is lostSweat glands and skin release moisture as well Exchange of Fluid between Capillaries and TissuesPush and a pull2 Forces involvedHydrostatic Pressure (P)– push by fluid against something like capillary wallColloid osmotic pressure () – pull of water by solutes;2 compartments (capillary and interstitial fluid) and 4 pressuresHydrostatic pressure is exerted by the blood in the capillary (Pc)– represents blood pressureHydrostatic pressure of interstitial fluid push against capillary (Pi) --- negligible value Colloid osmotic pressure of plasmaColloid osmotic pressure that pulls in the opposite direction via interstitial fluid – negligible valueEquation looks at how forces influence movementFluid out (Pc +i)Fluid in (Pi + p)4131907-56600What determines the how fluid flow?- difference between hydrostatic pressure of capillary and colloid osmotic pressure of plasma– defining pressuresArteriole side of capillary- leads to NET filtration (push out is greater than pull in)Note that the i and the Pi are low are meant to be that way thus defining pressures are Pc and p.Fluids are pushed outFlow across capillary there is a change because fluid flows outVenous side of capillary – the push in becomes greater than push outNegative valueNet absorptionLose in hydrostatic pressureAbsorb fluid backContinuous exchangeOnly absorb 9/10 of volume; lymphatic system takes care of then other 1/10 of volume (left out in interstitial fluid)Starling Forces– opposing forces that influence the distribution of fluid across the capillary wallValues differ between organsOncotic pressure difference between the two colloid osmotic pressureBecause the colloid osmotic pressure of the interstitial fluid is very negligible- the body works very hard to keep it thereYou really are just looking at colloid osmotic pressure of capillary due to plasma proteinImportant because this is how our nutrients are exchanged – fairly efficientEdemaIs an interstitial Fluid compartment event- excess fluid is found hereexcessive accumulation of tissue fluidprevented by balance between capillary filtration & osmotic uptake (filtration and absorption), along with proper lymphatic drainageresult from:high arterial Blood pressurevenous obstructionleakage of plasma proteins into IFMyxedema: excessive mucin production in extracellular matrixdecreased plasma protein concentrationobstruction of lymphatic drainage- influence homeostatic fluid balanceWhy would high arteriole blood pressure cause edema? Throw off balanceIf we have higher hydrostatic pressure then as we go through capillary it may not get small enough for the colloid osmotic pressure to be greater- we don’t absorb as much and the fluid is left in interstitial fluid compartmentREAD IN TEXT BOOKEXPLAIN WHY EDEMA HAPPENS THERE MECHANISMS and how they influence capillary exchange Regulation of Blood Volume by Kidneysurine formation, like the origination of tissue fluid (interstitial fluid), involve plasma filtration through capillary pores (fenestrated capillaries in kidneys)kidneys produce ~180L filtrate per daybody contains ~5.5L blood, most of filtrate is reabsorbed back into vasculature, is recycledtherefore, reabsorption impacts blood volume (the ability to reabsorb filtrate)excrete ~1.5L urine per day, variableurine volume excreted can be varied by changes in filtrate reabsorption, THUS, can adjust to needs of the body by action of specific regulatory molecules, like Hs, on the kidney (regulatory site to get more water/reabsorb water from filtrate- release water because we have too much)Hormones serve important function in regulation of cardiovascular system, since they influence blood volume via impacting filtrate reabsorptionRegulation by Antidiuretic HormoneStimulus is increase in blood osmolality picked up by osmoreceptors in hypothalamus; can occur due to dehydration (decrease in blood volume) high salt ingestion 453071315942900Cause neurosecretory cells that terminate in posterior pituitary release ADH– causing water to be retained in the kidney by opening water channels in the kidney by reclaiming more water = increasing blood volume and decreasing blood osmolalityOsmoreceptors initiate thirst (comes about when you are in initiate stages of dehydration – delayed response) NOTE consumption of excessive amount of water without salt does not prolong increase in blood volume and blood pressure water absorbed via intestines, elevate blood pressure but will also dilute blood osmolality, thus inhibiting ADH release thus water lost via urine, thus water is acting as diuretic Excessive amount of water could be a diuretic esp without salt– more peeingAlso, with an elevation in blood volume, ADH secretion is decreased due to stretch receptors (in left atrium, aorta, an carotid sinus) send sensory info to inhibit ADH release, water eliminated from blood by kidneys477472231377200Functions conversely, with a 10% decrease in blood volume reduces stimulation of these receptors leading to an increase in ADH secretion Stretch receptors responding to blood volume- more blood volume, they will extend, higher the pressure. There is an optimum degree of stretch.. Below a level we want to reclaim water, above level we want to get rid of waterAnother negative feedback loop to assist with homeostasis of blood volume Looking at blood volume and osmolalityRenin-Angiotensin-Aldosterone SystemResponds to a blood pressure and blood flow to kidneys, + salt deprivationMaintains homestasis through negative feedback control of blood volume and pressureDrop of blood pressure sensed by kidneys release Renin (enzyme) convert angiotensinogen to angiotensin 1 capillaries have ACE which convert angiotensin 1 to angiotensin 2 (signaling molecule works through carious mechanism to increase blood pressure) vasonstriction of arterioles to increase blood pressureAND/OR angiotensin 2 adrenal cortex produces aldosterone (influences sodium) aldosterone allows salt and water retention by kidneys increasing blood volumeAldosterone: Stimulate Na reabsorption in kidneys and indirectly promotes water retention; move Na and water in proportionate amounts, blood osmolality NOT changed but maintained Atrial Natriuretic PeptideIn response to increase in blood volume/ water immersion (mimics an increase in blood pressureIf you are out swimming– need to go to bathroomIncrease in blood volume also increases venous return increase stretch of atrium vagus nerves tells brain and posterior pituitary to decrease release of ADHDecrease water reabsorptionIncrease stretch of atrium cause release from the noncontractile myocardial cells in atria increase in ANP (atrial natriuretic peptide) which increases sodium and water excretion Eliminate extra volume in an increase of urine volume – decreasing blood volume and back to homeostatic balance More hormones and pathways to regulate something the more important it is for the body to maintainVascular Resistance to Blood flowamount of blood pumped by heart is equal to rate of Venous Return (amount of blood returned to the heart through each cycle), which is equal to the rate of blood flow through the entire circulationnote that blood is unequally distributed to different organs in an individual at restblood flow through vasculature is affected by resistance to blood flow due to characteristics of the blood vesselsSome organs are going to heavily perfuse at rest and others are not due to unequal distribution of systemic blood flow throughout organs (conduits are not the same size—different lengths)Physicals Laws Describing Blood Flow (systemic circulation)blood flow, in part, due to pressure difference between 2 ends of the tube (start and end of vasculature)flow moves from an area of high pressure to one of lower pressurefollows a pressure gradientrate of blood flow is proportional to the pressure difference, or P1190625131253blood flow is inversely proportional to the frictional resistance of blood as it flows through a vessel 27113022372080THEREFOREStandard 120/80 blood pressure 100 mmHg driving force of blood flow through vasculatureCenter of the flow is the best, near the edges of the flow there are resistance Laminar flow- center flows faster than the flow near the endsresistance to bold flow is directly proportional to the length of the vessel (L) & bld viscosity ()of physiological importance, vascular resistance is inversely proportional to the 4th power of the vessels radius (r) 206271630840345720059The smaller the length of the vessel, the lower the viscosity = easier to flow Resistance is directly proportional to length but inversely proportional to radiusAs distance increases, resistance increasesAs radius decreases, resistance increasesBlood flow is easier when the resistance decreases (radius increases)Blood flow is harder when the resistance increases (radius decreasesPoiseuille’s LawBlood vessel length and blood viscosity do not significantly change in a normal individual 319091245481BLOOD FLOW = Pr4() L(8)00BLOOD FLOW = Pr4() L(8)major physiological regulators of blood flow through an organ:MAPmean arterial pressure5536194163415an “average”driving forcedrop significantly in resistance vessel vascular resistancearteriolesprovide greatest resistance due to capacity to Vasoconstriction and Vasodilation– changes radiusdue to change in radius (larger and smaller vessels)Total Peripheral Resistancerepresents sum of all vascular resistance within systemic circulationobserve blood flows through only one set of resistance vessels before returning to heartarteries arranged in parallelhepatic artery supplies nutrientheaptic protein vein drains into liverorgans not “down stream” from anotherimportance? – resistance within only affects blood flow in that organ (NOTHING DOWNSTREAM)Vasodilation in large organ (blood is shunted/pulled into organ), decrease total Peripheral Resistance and thus decreasing MAP (mean arterial pressure)compensatory mechanisms counter, ie CO and VC in other areas- shunt blood flow to that organ and slow down blood flow to other areas because unneeded at the time. exercise, an exampleExtrinsic Regulation of Blood FlowANS and endocrine controlendocrine - - - AII (can be a vasoconstrictor) & ADH (antidiuretic hormone, also vasoconstrictive element) sympathetic nerveshas a large effect because of the innervation to other areassympathoadrenal system stimulation, observe an increase in CO & total PRvascular Smooth muscle stimulation (-adrenergic Receptors) via NOREPI in arterioles of skin & visceraalso observe smooth muscle tone via adrenergic sympathetic fibers at rest - - basal level of VC throughout body activation of fight-or-flight reaction, VC produced in digestive tract, kidneys & skinin skeletal muscle, observe cholinergic sympathetic fibers activate arteriole smooth muscle to VD during fight-or-flight reaction, along with EPI from adrenal medulla that causes VD via -adrenergic receptorsblood flow to skeletal muscle increases; advantageparasympathetic nerves always cholinergic & always promote vasodilation in arterioleslimited distribution thus has less effectParacrine Regulation of Blood Flowblood vessels particularly subject to paracrine regulationespecially endothelium, which also produces several paracrine regulators that impact Smooth muscles in tunica mediaarterioles tend to be regulated by paracrine because they are more sensitiveparacrine regulators that cause Smooth muscle relaxation = VasodilationNitric Oxide, bradykinin & prostacyclinSmooth muscle contraction = Vasodilationendothelin-1Table 14.4Paracrine regulator- Nitric OxideParasympathetic stimulation activates eNOS (enzyme in endothelium that creates NO)Intrinsic Regulation of Blood Flowrepresents a “built in” mechanism within individual organs to provide localized regulation of vascular resistance and blood flowused to maintain relatively constant blood flow rates within organ despite wide fluctuations in BP - - autoregulationmechanisms classified as:myogenicresponse by vascular smooth muscle to keep tissues perfused as well as protection against high BPBP increase, & vascular smooth muscle stretched, it responds by contracting, or VC Protects vessels downstream from elevated pressureBP decrease, vessels dilate to retain adequate blood flowmetabolicresult of chemical environment created by organs metabolismVD promotion O2, CO2, pH, adenosine or K release from tissues (paracrine regulators)Hyperemia increased blood flow 2961050103Blood Flow Distribution during Rest and Exerciseblood flow to organs such as heart & Skeletal muscle regulated by both extrinsic & intrinsic mechanism’sbrain, mainly intrinsic mechanisms, requires constant flowcutaneous, mainly extrinsic mechanisms, most variation in blood flow25 L/min blood output during heavy exerciseSkin uses mostly extrinsic – most variation in blood flowBlood Pressureresistance to flow within arterial system is greatest in arterioles, due to their smaller diameterflow through the arterioles must be equal (between arterioles and those around them) to flow through larger vessel that give rise to them, flow is reduced according to Poiseuille’s law, therefore, pressure and blood flow are reduced in capillaries downstream (prevent rupture and allow exchange) with pressure increase upstream in larger vesselsimportant to slow velocity of blood flow in capillaries, enhances exchangeAllows capillaries to have lower pressurepreserves “pressure gradient”Driving force = pressure differenceOnly issue is constriction(systemic side)Blood pressure and flow further (not as much as arterioles) reduced in capillaries due to total cross-sectional area is greater as compared to arteries & arterioles that give rise to them large numbersalthough smaller in diameter, capillary bed (greater cross sectional area) presents less resistance, than arteriolesCapillaries are functional unit of cardiovascular system-where exchange occurs-472989435884BP = CO x total PRBP = CO x total PRvariations in arteriole diameter, Vasoconstriction or Vasodilation, thus affect capillary blood flow but also simultaneously impact arterial Blood pressure upstream, therefore, an increase in total Peripheral resistance due to arteriole Vasoconstriction can raise arterial Blood pressureBlood pressure can also be elevated by an increase in Cardiac Output, which is influenced by other factors3 most important variables affecting blood pressureCardiac output- pumping efficiency of the heartInfluenced by Heart rate and stroke volumeStroke volume (determined by blood volume)- regulates blood pressure; reflecting blood volume Stretching, great contractilityTotal peripheral resistance- vasoconstriction increases vasoconstriction- impacting blood pressure which can be dangerousAn increase in any of these variables without a compensatory decrease in another will lead to an increase in blood pressureAll three need to balanced to keep blood pressure in normal rangesTherefore, blood pressure can be regulated by kidneys, which regulate blood volume and thus stroke volumeBlood pressure can be regulated by the sympathoadrenal system, which increases vasoconstriction leading to an increase in peripheral resistance thus impacting blood pressureBaroreceptor ReflexBaroreceptor Reflex are stretch receptors found in vessels close to the heart (aorta) that monitor blood pressureAs blood pressure rises they are stretched more. Stretch less when blood pressure falls-action potential fallsfunction to counteract BP changes so fluctuations in pressure are minimizedmaintain Blood pressure on a beat-to-beat basis – SHORT TERM RESPONSE376841610747000tonically activeBP leads to an in AP frequencyAs blood pressure falls action potential frequency falls (direct correlation) Should be around 100info sent via Cranial nerves to medullavasomotor control centersRegulate Vasoconstriction and vasodilation in arteriolesAssist with total Peripheral resistance regulationcardiac control centers Regulates heart ratesystem more sensitive to decrease changes than increase, and sudden changes rather than gradual changes why hypertension creeps up on individuals (system just accommodates and doesn’t panic)EX. Go from lying down to standing or sitting to standing– drop venous return, drop EDV, drop SV, cardiac output falls = decrease in blood pressureBaroreceptors immediately sense the change and change their action potential frequency, send info to medulla, activate sympathetic and decrease parasympatheticInitiated VC= increase total peripheral resistanceIncreased heart rate = increase in cardiac out Both of these increase blood pressureAtrial Stretch Reflexesother reflexes present to assist with Blood pressure regulationSensory receptors s present in atria respond to stretch or to in VR to the heart by:stimulate reflex tachycardia (heart rate anything over 100 beats per minute) sympathetic nerve activityinhibit ADH release urine excretion, blood volume…bringing blood pressure down secretion of ANP (atrial natriutic peptide)lowers Blood pressure by lowering blood volume via increasing urinary salt & water excretionAntagonist to the renin-angiotensin-aldosterone systemPulse Pressure and Mean Arterial PressurePulse pressure – PP Mean arterial pressure – MAPrepresents average arterial pressure during cardiac cyclesignificantdifference between MAP and venous pressure (pressure difference) is what drives blood through capillary beds of organshard to estimate since heart does not spend equal time in diastole and systole (spends more time in diastole)rise in total Peripheral resistance and Heart rate increases diastolic pressure more than systolic pressure, however, increase in Cardiac output raises systolic pressure more than diastolic pressureDiastolic is influenced more then systolic pressure for heart rateReverse in regards to cardiac outputInfluence difference depending on what we do --- all depends on the pressure difference-2108205905500Application of Concepts1. According to Frank-Starling law of the heart, output of the right and left ventricles are matched. Explain why this is important and how this matching is accomplished.Since the return of venous blood to the right ventricle varies considerably throughout the day, the Frank-Starling law operates so that the right ventricular contraction strength and thus, the stroke volume will adjust instantly to these preload variationsThe net result is the ventricle raises its stroke volume output when venous return is increases and lowers its stroke volume when venous return is loweredFurthermore, when the left ventricle subsequently receives the newly altered volume of blood, it too will adjust its stroke volume to match that of the right ventricle.In this way the heart can intrinsically compensate for the moment-to-moment fluctuations in the return of blood to the heart. If the stroke volumes were not matched, one ventricle, or the other would soon be depleted of blood and the pump would fail2. You are participating in a 75-mile cycling benefit race and it’s a typical summer day in SC- hot and humid. You’ve consumed your water supply and in the last miles of the race are thirsty. Should you accept water or a sports drink?You are thirsty because you are dehydrated and your blood plasma osmolality is elevatedIn this endurance race, your blood sodium and total blood volume have been lowered by the increased need to sweat while racing for subsequent evaporative heat loss. The resulting low blood pressure is very dangerousDrinking pure water may not be the answer in this extreme case. This is because blood sodium is lost in sweat, so that a lesser amount of water is required to dilute the blood osmolality back to normal When the blood osmolality is norm, the urge to drink is extinguished. Therefore, on prolonged endurance races such as this one, you should accept the sports drink offered by race volunteers providing it contains only a weak solution of sodium and carb concentrations and providing you drink it following a predetermined schedule (rather than waiting until thirsty)3. Which type of exercise, isotonic or isometric contractions, puts more “strain” on the heart? ExplainExercise using isometric muscle contractions would put a greater “strain” on the heartIsometric contractions occur when great force is applied without appreciable movement of the muscle, such as during very heavy weight lifting. TO accomplish heavy lift, people often employ the Valsalva’s maneuver in which a deep breath is taken with an expiratory effort against a closed glottis. Performance of this maneuver transiently increases the intrathoracic pressure that, in return, reduced venous return, lowers stroke volume, decreases cardiac output, and lowers arterial blood pressureAlso, during this breath holding interval the drop in blood pressure stimulates the baroreceptor reflex, resulting in tachycardia and decreased total peripheral resistanceWhen the glottis is finally opened, the intrathoracic pressure and cardiac output return to normal. However, the decrease in peripheral resistance is still in effect causing a transient, explosive, flow of blood to dilated capillaries, possibly causing rupture (hemorrhage) or if in the brain, a strokeAlthough the baroreceptor reflex will eventually respond and compensate for the blood pressure changes, the fluctuations that occur during isometric muscular exercise can be dangerous in people predisposed to cardiovascular disease and/or weakened blood vesselsIsotonic exercise is usually not associated with breath holding Chapter 15-The Lymphatic/Immune SystemThe Lymphatic Systemcomprised of:lymphoid tissues/organs/cells – scattered throughout bodyThymus, spleen and lymph nodesCollections of tissues and cells: Tonsils, bone marrow, MALT- mucosa associated lymphatic tissue – payer's Patch’s (part of Gut associated lymphatic tissue, also found in lungs)lymphatic vessels – meandering network of vesselsfunctions:fluid balance Lymphatic vessels return fluid from interstitial space to circulation via lymphatic capillarieslymph*Transudates/derived from plasma Contains anything (products or substances) that Is released – hormones, waste, nutrients- from neighboring cells9/10 of fluid volume of out is pulled back in– too much fluid in causes edema/swelling, so the remaining 1/10 is pulled bback by lymph so we don’t get edemafat absorptionabsorb fats & other fat-soluble substances from digestive system via lacteals (specialized lymphatic capillaries in GI tract)Fats first go into lymphatic system before blood circulationdefenseorgans/tissues serve as “filters”removing microbes & foreign substancesLymph nodeDesign: There are more inlets than outlets in a lymph nodes (lymph comes into lymph nodes and meander through channels- serving as a filter)Cells: provide immunological defense against disease-causing agentsLymphatic VesselsLymphatic capillaries blunt-ended tubes (conduits) for vast network within intercellular spaces of most organsCapillary bed and intersperse in true capillaries are lymphatic capillariesDue to construction, porous junctions (also called loose junction), wide array of molecules as well as wandering cells can enter and move through them Lymphatic capillaries Designed the same way as a blood capillaries but do not lining up end to end as a blood capillaries but have overlap The epithelial cells overlap lymphatic capillaries to pull cells apart – mini valveFilamentous elements attached to extracellular space: when fluid volume builds causing pressure and opens up the porous junctionsNO work required just designed to meet the needs of the areaOne-directional flow– there is no PUMP (unlike blood circulaton)Towards venous circulation near the superior and inferior vena cava Larger to larger sympathetic vessel as you move out of capillaries – looking at veins with three tunicsPacemaker cells- lymphatic vessels have rhythmic contraction help to move things through-also have valvesWhen fluid volume increases & When stretched– increase rate of contractionNo need for pumpNegative pressure system Lymph Node– before returned to venous circulation it will always pass through at least ONE lymph nodeMost of the time it is severalImmune Systemfunctional system rather than a structural one“organs” are represented by individual immune cells & a diverse array of moleculesImmune cells in lymph organs (spleen, tonsils, etc) relies upon 2 intrinsic defense systemsact both independently & cooperativelyRun concurrently but by themselvesprovide resistance to disease, or immunityDefense Mechanisms3677886118865Innate (Nonspecific) Defenses: are nonselective and act immediately; do not distinguish one threat from another; present at birth (BAD/ FOREIGN = DESTROY)first line of defense - external body membranes (skin and mucosa- lining open organ systems) & chemical element defenses at body surfaceexternal body membranes - are physical barriersSecretions- mucosoa, antibodies, sweat second line of defense - utilize antimicrobial proteins, phagocytes & other specialized cells that act to inhibit further invasion; includes inflammation; is signaled by chemicals released when 1st line of defense is penetratedLimit how much damage that microbe could perpetrate Adaptive (Specific) Defenses: represents body’s ability to mount an attack against specific foreign invaders (designed for a particular microbe) cthird line of defense is body’s specific defensesfunction of lymphocyte activitiesActivation of Innate Immunitydistinguishes between “self”, the body’s own cells, and invading/ foreign organisms/moleculesrecognize PAMPs (pathogen- associated molecular patterns– proteins on surface of cells)unique to invadersLipopolysaccharides & peptidoglycanie. particular classes carbohydrates or lipids in microbial cell wallsinnate immune cells display receptors for these PAMPs, referred to as pathogen recognition Receptorstoll-like Receptorsplay role in triggering immune responserecognize invading/foreign organismsonce activated-phagocytes & macrophages, release chemokines & cytokines (signaling molecules) which promote inflammation, initiate phagocytosis, fever, attract WBCs to area of infection When bind to receptor, activate immune cell to respond to the presence of foreign molecule NOD-like Receptors (nucleotide- binding oligomerization domain)activate gene transcription to promote defenses AutophagyRecognize intracellular componentsDAMP’s (danger-associated molecular patterns)Stimulate innate immune system as well as initiating inflammation Complement system integrates innate and adaptive immune responseHelp organize defense systems proteins associated are in an inactive state of blood circulationPhagocytesBest defenders out there phagocytes are cells that have the ability to ingest and destroy particulate substances (toxin or microbes)perform janitorial & police services in peripheral tissues by removing cellular debris (dead cells) & responding to invasion (bring into infection site when first barricade is penetrated)observe 3 major groupsNeutrophils (polymorpho nuclear cells)most abundantLook for cells that are not “self” phagocytic upon encounter with foreign intruder1st to enter infected area, are mobile & quick to phagocytize (bad kill destroy)mononuclear phagocyte systemCalled monocytes in blood circulation, macrophage when in tissues & dendritic cellsDon’t hang in blood but live in tissues to become a macrophage where they spend most of their lifeDendritic cells– origin unknown; arise from phagocyte stem 40487602413000organ-specific phagocytes of liver, spleen, lymph nodes, lungs & brainmicroglia in brain tissue kupffer cells in liver – reticuloendothelial cells Fixed and Free (refer to macrophages and macrocytes)Fixed: cells spends entire life span in lymph node (nonmobile)Free: cell move around in tissues of an organ (mobile)PhagocytosisPMN- polymorphonuclear cell (PNM) aka neutrophil roll along endotheliumIn an area of infection, blood flow is slowed…neutrophil rolls along in a vessel (capillary or post capillary venule- where a lot of cells leave from)At site of infection, endothelial cells express CAMs (cell adhesion molecules). The endothelial cells display selectin, and surface of neutrophil are integrinsNeutrophil gets caught on CAMs of neutrophil and begin to get activated. Stop rolling and adhere to wallDiapedesis out of capillary into surroundings tissue (aka extravasation) will probably follow chemotaxic trail to the site of infection and once they see the cell they will undergo phagocytosisMigration of white blood cells form circulation into tissues Recruited to an area of infection by chemical attractants called chemokines, a subclass of cytokines (cell signaling molecule), creating a chemical trail for phagocytes to follow, process referred to as chemotaxisPositive chemotaxis– moving toward infectionNeutrophil can do 2 things…Come around and engulf microbe- lysosomes break it downEncapsulated microbes make It difficult to be engulfed– it released enzymes out of the cell “free enzymes” that break down microbes and contribute to elements of inflammation or signals to the inflammatory responseFever defined as an abnormally high body temperatureis a systemic response to infection, which involves resetting the body’s “thermostat” in the hypothalamusaccomplished by the release of pyrogens from activated macrophages & leukocytes when exposed to foreign substances (referred to as endogenous pyrogens- derived from something that is within the cell)exogenous pyrogens- LPS’s and other molecules produced/ released from pathogenic intruder Pyrogens from two different directions to reset temperaturefever causes an increase in body’s metabolism, thus accelerating repair processes & impacts bacterial replicationliver & spleen sequester zinc & iron, makes them less available for bacteria (nutrients required for reproduction)Only advantageous if it’s for a short period of timeAnything above 103/104 can begin denature proteins in brain Interferons44848335397500small proteins that protect body against viral infectionsshort-actingNaturally produced by viral infected cellsare not virus-specific, so provide protection from a variety of virusesconsidered a cytokine:chemical messengers released by tissue cells to coordinate local activitiesWhen a virus infects a cell, it takes over the cells genetic material and become a factory to make more viruses; activating genes that produce interferons released by host cellInterferons can attack to adjacent cell and turn on cell’s to produce antiviral protein to block virus replication and assembly Idea was to protect cell from virus in area Come in different classes Release of interneurons can be a paracrine factor (affect an adjacent cell)If it gets in blood circulation it can affect metabolism of another cell–acting like a HORMONEEndocrine function (affecting metabolisms of cells in other organs) but not classified as a hormoneAdaptive Immunityinvolves the ability to recognize, respond to and remember a particular substancerequires a “meeting” or to be primed by an initial exposure to a specific antigen before it can protect the bodythree important aspects of adaptive immune response, distinguish from innate immunity:it is specificability to recognize and direct response against particular foreign substance that initiate an immune responseit is systemicnot restricted to initial infection siteit has memoryafter initial response, it recognizes and mounts an even stronger attack than previous encounterAdvantage!AntigensAntigen (Ag)– any foreign molecule that can trigger a specific immune response against itself or the cell bearing it Display antigenic determinates at surface- structure difference as the surface at antigen that we respond to (see them as foreign or nonself)To be an antigen you need to be immunogenicity & reactivity Immunogenicity ability to stimulate production of specific lymphocytes (activate lymphocytes)Reactivity– ability to react with products of these reactionsOnce lymphocytes are activated and become B cell thus releasing antibodies, these cells must react to the antibodiesGreater the complexity, more immunogenic When we look at an antigen, an activated lymphocytes will only make a product directed to ONCE antigenic determinatesHapten are small protein molecule that on their own are not immunogenic but are vey reactive and bind with other proteins (albumin in plasma) that are already there, binding to proteins making them “foreign” & no longer self anymoreStart making antibodies on self and attack self because haptens make it look like its not selfImmunocompetence- the ability for a lymphocytes to mount a response Recognize specific antigen or foreign intruder and mounts a responseImmunological tolerance—tolerating yourself antigens; system attacks everything but ignore self Haptens get around them and create antibodies against selfFunctions of B Lymphocytesexposure of B cells to appropriate Ag initiates growth, forming memory cells (impt in active immunity) and plasma cells (produce Ab’s specific to Ag)binding of Antibody to antigen serves to ID the enemy as well as activate defense mechanisms to destroy invaderImmunocompetent B cell that can recognize a specific antigen antigen binds to receptor on cell B cell undergoes a grow spurt (proliferation by mitosis and produce clones) clones can become plasma cell (spit out antibodies) and memory cell (active immunity) Antibodies can also be called immunoglobulinsIf we coat a microbe with antibodies its easer to see and engulf Once antibodies bind to antigen, pathways are signaled to get rid of themObserve 5 subclasses (TABLE 15.6)IGA- dimers, secretory antibodies (found in secretions such as saliva, tears) breast milkIGM– first response, pentamores (5), first to be secreted3246000-6900IGG– secreted for a secondary response, monomer; most abundant and most commonIGD- monomers, found on surface of B cells, antigen receptors for B cells IGE- monomers, associated with allergic reactionsTwo light chains and two heavy regions + two regionsFC region-stem, constant region, determines the subclass and functionality Chains held to together by disulfide bondsEffector region, dictate cells (functionality*)Chemical elements like antibodies and other cells or complements can bind to this regionInvolved with antigen elimination FAB region- variable region; houses the antigen binding site and recognize antigenic determinant of antigen Class switch recombination we can go from making IGM to IGG; Ab diversity- there are about 10 20th power of antibodies we can makeAbility to identify antibodies are predetermined and planned within geneticsAntigen independent diversification: bone marrowWe don’t see antigen Recombination of DNA (make up a bunch of combination) when lymphocytes are developingAntigen dependent diversifation- proliferation of B cellSecondary lymphoid organs (lymph node)Mix things up genetically se we can get more combinationSomatic hyper-mutation and change genetics during proliferation of mitosis to get more combinationsAbility to recognize antigen were determined a long time ago (within genetics) Ensure that individual can recognize and respond to it. Cross reactivity between antibodies and antigens depending on how close they areComplementRepresent group of plasma proteins, Found in an inactive state in blood circulationRespond to antibodies bind to antigenBinding to cell wall of bacterium = opsonization Antiskid makes it easier to grab holdStart initiating the complement system Upon activation, via either the classical or alternative pathway, the final product is a MAC, that causes ell lysisMAC= membrane attack complexActivate a series of complement proteins insert themselves into cell’s plasma membrane puts a hole in cell wall of bacterium causing lysis- killing itIn addition, other fragments created which serve to initiate chemotaxis, phagocytosis and histamine releaseClassical Pathway Antigen-antibodies complex (antibody binds to antigen) activates C1 C1 cleaves and activates C4 C4B inserts itself into the cell wall: complement fixation activates complement protein to from MAC complex C4A comes a chemotaxic agent (proteins that attract neutrophils to site of infection)MACC4a- chemotaxic agentC3a & C5a – stimulate mast cells and basophils (release histamine)Histamine- causes membrane to become leaky allowing fluid exchange, vasodilator, make it easier for neutrophil to leave capillary, 314261514381900C3B- facilitate phagocytosisAlternative pathwayInitiated by polysaccharide of bacterial wall/call another mechanism by which to assist and get rid of intruderClassic pathway is rapid and efficient.Alternative pathway is less rapid and efficient Functions of T LymphocytesT cells are a diverse lot and more complex than B cells in both classification & functionObserve 2 major populations of effector T cells, based on CD proteins, CD4 & CD8 (cell surface Receptors; are not T-cell Antigen receptors-just an identification mechanism)CD4 cells are helper T cellsCD8 cells are cytotoxic T cells“does the damage”CD25 are regulatory T cells (also contain CD4)On periphery so the process doesn’t get out of handKeep process/system contained T cells most efficient against microorganisms that live inside the cells of the body*Defend against viral and fungal infections, responsible for transplant graft rejections and provides immunological surveillance against cancer (our own way of fighting cancer, just can’t keep up with dividing)utilize cell-mediated destructionRequires physical contact with victimized cellPerforins– form pore in victim cells Plasma membranePunch holes and cause lyses– cell deathgranzymes – enter victim cell and via capsases activation pathway destroy DNAimmunocompetence occurs in thymusRecognize specific antigens Occurs very early in our development (preschool)T-Lymphocyte ActivationB cells have IGD on surface that recognize antigen and activate them T cells do NOT recognize free antigen, thus antigen must be “presented” to a T cell via an APC, or antigen-presenting cell APC release chemokinesDendritic cell can be APC cell come in contact with antigen & process it display on marker dendritic ell leave its location, move into lymphatics to find a lymph node to find a T cell activate T cell by presenting antigen to it=-> T cell is activated and move back to site of infections activated T cells divide and some clones migrate to infection via chemoattractants or others fin memory cells divide/form clonesfollow chemoattractants trail so activated T cells can find original site of infectionAntigen presenting cells presented on mHC (major histocompatibility proteins (class II) by dendritic cells but are other cells can serve as APCs, such as a macrophage or B cellHistocompatibility AntigensMHC proteins, are also known as HLA, or human leukocyte-associated antigens coded by a group of genes called the major histocompatibility complex; represent cellular “identity tags”, genetic markers of biological selfclass I MHC– expressed by any cell of bodyclass II MHC– only be presented by APC2 pathways: endogenous and exogenous structuresEndogenous: virus that comes into cell; proteasomes break down into fragments; ER take in fragments through TAPTAP- transporter associated with antigen processingTake processed antigen into ER putting it on to MHC Type 1, (putting out a flag)ALL CELLSExogenousEndocytose antigen- put them in vesicle (phagolysosome) with an MHC type 2 already insideMHC class 2 are waiting for something to be added to themCLIP– blocker protein, block binding site Everything happens out in cytoplasmAPCsRestriction element= ability to restrict T-cell activation/receptor-binding, only occurs if antigen complexed to MHC proteinT-Cell ActivationAntigen presentation by APC (antigen presenting cell)Present on a MHC class 2 activating T helper cell– Co-stimulation: just present an antigen lets cross check and matching (lock and key) verify identityCytokine signaling- APC release chemical signal to proceed Interleukin 1- stimulate proliferation and division of T cellsT helper cell release other cytokines that assist the cytotoxic cell with its activationBind to antigen on class 1 – everything is check and stimulation of the T helper cell to verify the intruderProduce clones or memory cells Detach from victimized cell and go to another infected cellWhy cause proliferation if T-cell bound to virus-infected cell? If there is one virus there is probably more than oneProliferation ensures we take care of all the virus infected cells. Inflammationa localized event, involves aspects of innate & adaptive immunityneutrophils 1st to scene, release chemical signals to recruit other immune cellsas immune cells “gear up” for combat & then clean up, a variety of chemicals are released that lead to the characteristic signs of inflammation: redness & warmth (histamine-stimulated VD), swelling (edema) and pain (free nerve endings are activated)is a protective response, designed to contain & eliminate harmful intrudersMain PointsJob is protective responseInvolve both innate and adaptive immunity To any site of injury – neutrophils are first to site and signal to bring in other immune cellTake care of intruder and clean area upDesigned to contain and eliminate Mast cell release chemoattractants… eliminates that are released give you 4 cardinal signs of inflammation Histamine Vasodilator, make capillary more permeableActive & Passive Humoral Immunity404889779375Immunity acquired by artificial (vaccine) and natural Active – involves B cells being exposed to antigen; immunological memory develops; long-term protectionPassive humoral immunity – administration of antibodies; does not convey memory; no B cell challenged; short lived protection Serum given to individuals who will be dead in 24 hours or less. 00Immunity acquired by artificial (vaccine) and natural Active – involves B cells being exposed to antigen; immunological memory develops; long-term protectionPassive humoral immunity – administration of antibodies; does not convey memory; no B cell challenged; short lived protection Serum given to individuals who will be dead in 24 hours or less. Immunological MemoryBegins with a Primary response- first time your body sees an antigen/original exposureLag time: the time that Bb cells differentiate and see the antigen See rise in presence of antibodies to detected antigenrepresented by memory cells & responsible for what occurs during next exposure to a particular AgAt 28 days exposure to a new antigen and second exposure to the original antigen secondary immune responseRapid, prolonged and more efficient responseDo this for each antigen determinate sites49 multiple choice1 short answer (sequencing) ................
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