Exam 3 Study Guide

Chapter 12- MuscleMechanisms of Contraction and Neural Control

• ability to use chemical energy to produce force & movement is present to a limited extent in most cells– in muscle cells, it has become dominant

• force generation and movement by muscle can be used in a variety of ways in the human body– movement within external environment– regulate internal environment– speech– drawing a picture– twiddling your thumbs– typing these notes

• Moving blood through vessels, moving liquids through GI tract- all need musculature.

Structure of Skeletal Muscle• Fibrous Connective Tissue fibers within tendon extend around muscle forming an outer sheath—epimysium• 2 ends of muscle

– Origin attachment to immoveable bone– Insertion attachment to moveable

• Outer fascia that compartmentalizes muscles• Epimysium– outer later wraps around all muscle fibers/fassicles beneath fascia• Cells 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 Units• One muscle is an individual organ • Skeletal muscle (voluntary) somatic nervous system needs to initiate contraction by motor unit• Motor Unit—somatic motor neuron and all muscle fibers it innervates• Neuromuscular 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 fiber– Motor end plate– area with ligand gated sodium channels ,acetylcholine is ligand, binding opens sodium

channels• Resting 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 initiated

• End plate potential = synaptic potential• Graded 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 contraction

• Activated by rapid, asynchronous contractions for smooth, sustained contraction– They don’t contract at the same time– Resilience 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 activate– 5-100– The smaller the motor unit– finer control of skeletal muscle contraction (typing on a computer)– Gross movements large motor units

• Smaller 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 muscle– Recruitment– when you recruit more motor units based on the demand

Mechanisms of Contraction• Contraction refers to the activation of force-generating sites within muscle fibers cross bridges

– Cross bridges also referred to myosin heads on the thick filaments• Sarcomere 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 myofilaments– Myofilaments = actin and myosin– Nuclei are peripherally placed– Sarcolemma- plasma membrane

• Myofilaments are organized into sarcomere – smallest contractile unit• Z line (dark line) – one Z line to the next is one sarcomere• Thick filaments are STATIONARY made of myosin

– Held by the M line and do NOT move• Thin filaments are made of actin + other things

– Connected on to Z line then extend toward the center– Only the thin filaments MOVE

• Arrangement of myofilaments gives sarcomere its dark and light bands– I band = thin filaments (made of two adjacent sarcomere)– A band= thick filaments and little thin filaments for overlap– H band = JUST thick filament

Sliding 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 filaments• When contraction occurs and cross bridges interact the A band disappears, Z line and I band is reduced• H zone is also reduced • A band does not change (it is the length of thick filaments and they don’t move within sarcomere)

Interaction between thin and thick filaments• during contraction, only a portion of cross-

bridges are attached at any given time, thus power strokes are not in synchrony

• WHY? 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 Cycle– Thick filament & myosin heads (2 golf

clubs/headed sperm) must be energized! High energy presentation (sticking straight up) Requires ATP

– ADP 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 STROKE

• High energy to low energy change• ADP is release opening a site for another

ATP to bind• To release the head from actin the ATP

needs to bind • Power Stroke due to the release of phosphate

Regulation of Contraction• Regulation 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)o Tropomyosin—lies within groove between G-actin monomers, covers binding site for myosin

G actin—individual actin molecules F actin—G actin bound together looks like pearls on a string

o Troponin—3 protein complex TnT—binds to tropomyosin TnI- inhibitory portin TnC—binds to calcium

• Calcium is the regulator

Role of Ca in Muscle Contraction• Ca 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 regulated• In 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 o 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. • If 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 Review• A muscle is an organ• Sarcoplasmic reticulum (blue) where calcium is stored

– Terminal cisternae (enlargments) lateral sac– Ttubules (transverse Ttubules) connect up to sarcolemma – PM of muscle cell– Connection between T-tubule and terminal cisternae of SR

• Action 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 Coupling• Muscle 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 o DHP receptor is molecularly linked to ryanodine (calcium release channel)o The ryanodine receptor opens! Ca flows out (10x size of normal receptor)o Calcium flows out of SR channelo Calcium-induced calcium release channels flood the sarcoplasm with calcium. Calcium is going to bind to

troponin then move o tropomyosin causing contraction

• Initiate 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)

o DHP changes shape (open) it pulls ryanodine allowing Ca to flow out Sarcoplasmic Reticulum Localized event

o As Ca increase, we open ca-induced ca channels until we get high enough intracellular ca to cause contraction

o Ca 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

o When AP stops this process stops o Calcium channels shuto As calcium ion decrease in concentration o Pulling ca off troponin and actin and myosin

can not longer interact with each other o Don’t care concentration always pump Ca

into the SR• ATP is not only needed for contraction but also for

relaxation o Need to allow for the heads to detacho Needed for the Ca-ATPase pump to run

• Relaxation = produced by active Ca transport out of sarcoplasm into SR

Mechanism of Skeletal Muscle • SkM contractions typically produce bone movement at joints, which act as levers to move load against which the

muscle tension is exerted– tension is the force exerted on an object-the load-by the contracting muscle– load & tension are opposing forces– load > tension

• no movement– isometric contraction (constant length): muscle is generating tension but it is not

moving– tension > load

• movement– isotonic contraction (constant tension): tension is greater than load and we get

movement» concentric—muscle shortens, tensions is generated by sarcomere shortening

and moving load» eccentric** (lengthening)—muscles never lengthen but length compared to

shortening via concentric » greater control of movement

• Series-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 lengths

– Muscle contraction pulls on CT wrappings tendon bone– Additional elasticity due to the pulling of other parts– When everything relaxes tendon helps us reset our muscle to original length – Absorb some of the tension as muscle contracts

Muscle Twitch• 3 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 calcium– Contraction 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 stimulus• muscle 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 stimulus

– threshold stimulus» Weakest stimulus at which motor unit is stimulated to contract

– maximal stimulus» Strongest stimulus to recruit all motor unit to contract» We can increase voltage stimulus but the muscle contraction doesn’t go any

higher• changing frequency of stimulation

– Proportion of nerve fibers excited (how many motor units are being activated) • Smaller motor units activated first

– Increase 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 stimulus– We can increase voltage stimulus but the muscle contraction doesn’t go any higher

Incomplete & Complete Tetanus• If 2 identical stimuli are delivered to a muscle in rapid succession, the 2nd twitch will be stronger than the 1st, this

is wave summation– occurs because subsequently induced contractions occur before muscle can relax summing the

contractions• With 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 attained• You can have summation of skeletal muscle• Single 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 frequency• Wave summation contributes to force of contraction, but primary function is in generation of a smooth,

continuous muscle contraction – reach complete tetani– Achieved by frequency of stimuli without relaxation between contractions

Treppe• staircase pattern observed when muscle fibers first stimulated to contract

– stimulus strength constant• due to:

– increasing amounts of Ca available in sarcoplasm– heat generated from muscle work increases NZ efficiency in muscle

– muscle more pliable (warm up fibers)—warm up lead to less injury possibly?

Force-Velocity Curve• lighter objects are moved faster than heavier objects

– inverse relationship between force opposing muscle contraction & velocity of muscle shortening• What 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 velocity• Increase the load we get to a point where there is no

shortening• Isotonic isometric• Slope = shortening velocity • Time is NOT the element but the rate of contraction • More load is harder for the cross bridges to interact

Length-Tension Relationship• muscle contraction strength can be influenced by a variety of factors

– fiber numbers activated, stimulus frequency, muscle fiber thickness, length of muscle fiber at rest• an “ideal” resting length for striated muscle fibers that results in maximum force generation• Recruit smaller motor units first and then larger motor units• Sarcomere is a defined length– degree of overlap

– Too far apart- cant connect– Too 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 force

Energy 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 hard• Oxygen is important for ATP generation• Fatty acids are the most used energy source- more bang for your buck• From mild to moderate exercise, glucose is more commonly used because of instant break down• Skeletal Muscle Metabolism

– Creatine phosphate—regenerate ATP from ADP– glucose gives us ATP quickly- forming lactic acid to run anerobically

– Desired 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 oxygen

– Amount dependent on type of skeletal muscle• Observe a maximal capacity for aerobic exercise in an individual dependent on the maximum rate of oxygen

consumption by the body• VO2 Max– maximal oxygen uptake/ aerobic capacity (Vo2 max)• Males have highest and hit peak at 20• Respiration rate doesn’t change when you stop working out– oxygen debt

– There is a basal level of oxygen needed to function at rest– When you exercise you pull oxygen from reserves in myoglobin, RBC– needs to be replenished– The amount of oxygen required needed after exercise is above basal need– oxygen debt– The extra oxygen needed to replace reserves and stores used p during exercise

Muscle Fatigue• defined as any exercise-induced reduction in the ability of muscle to generate force/power (reversible)

– observe EC K conc during maximal contraction– reduces membrane potential, thus interferes with ability to generate APs

• Causes (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 Ca

• Failure of excitation-contraction coupling• If you cant release Ca (go signal for contraction) the muscle will not contraction

– “others”…↑ [PO4] & ↓ATP-↑ADP• Increase in phosphate groups- reducing force developed by cross bridges• Levels 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 fatigue

– central 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 reversible• Why do we have muscle fatigue? Action potentials increase in extracellular potassium throwing off the ion

balances, reducing membrane potential and interfere with making action potential

Types of Skeletal Muscle Fibers • SkM classified on basis of contraction speed

– fiber types• slow-twitch, or type l fibers (red fibers)

– suited for prolonged contractions– Slow oxidative fibers– Slow to contract; use oxidative phosphorylation– Fatigue resistant– Good for posture (on all the time)– Small in diameter

• intermediate fibers– Fast- oxidative glycolytic fibers– Somewhere in between both types

• fast-twitch, or type ll fibers (white fibers)– suited for rapid, intense movements– Fast-glycolytic– Use glycolysis– Fatigue readily – Rapid and intense skeletal movement– Large diameter

• fibers differ in mechanical & metabolic characteristics (some are resistant to fatigue or fatigue resistant)• human muscles are a mixture of fiber types

– gives muscle a range of contraction speeds, varying resistance levels to fatigue & performance• NOTE—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 performance• a 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 twitch• EXAMPLES

– extraocular 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 fibers

Muscle Damage and Repair• Limited capacity to repair skeletal muscle damage- due to presence of satellite cells • observe resident stem cells in SkM

– satellite cells• “leftover” from embryological development• located outside muscle fibers• Close proximity to be recruited for repair

– permit some degree of repair & limited regeneration• ability declines with age

– Sarcopenia 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 repair

Neural Control of Skeletal Muscle & Reflexes• Muscle tone—state of tension in a resting muscle• Muscle stretch- measure degree of stretch

o Muscle spindle– sensor, made up of intrafusal muscle fibers that has noncontractile center (just at the end there are contractile elements) wrapped by a sensory neuron

When stretched the afferent neuron increases action potential frequency denoting stretcho Extrafusal muscle fibers- contractile elements along its entire length

• Muscle contraction- scrunch middle portion and muscle togethero Decrease in action potentialo Make it difficult to gage the degree

o Alpha-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 muscle

Contraction 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 contraction

Noncontractile area is harder to gauge and measure the degree of contraction

• SUMMARY—Gamma motor neuron activity maintained to keep muscle spindle under proper tension

• Knee jerk reflex initiated by stretching patellar tendon, picked up by stretch receptor and look at degree of stretch in muscle

o If 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 proceeds

o Activate extensor inhibit flexor so movement can occuro Reciprocal 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 stimulus• Crossed 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 Muscle• Functionally similar to skeletal muscle• striated, short branched muscle fibers

– striation caused by sarcomeres; arrangement of thin and thick filaments• electrically coupled via gap junctions—intercalated discs

– electrical impulse conducted along long axis from cell to cell• one cell depolarized it spreads through all cells it is connected to; once contraction is initiated it

acts like one unit due to the gap junctions

– functional syncytium• behave as a single functional unit

– contract to fullest extent– flow from one cell plasma membrane to

the next cardiac muscle fiber’s plasma membrane

• pacemaker cells (found in various locations – right atrium)

– spontaneously depolarize– set contractile rate– modified by autonomic innervation

(sympathetic and parasympathetic)• excitation-contraction coupling

– Ca-induced Ca release

• different 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 reticulum

Smooth Muscle • Fusiform in shape- belly and tapered ends • nonstriated

– no sarcomeres but actin & myosin are present for contraction• thin filaments are long• dense bodies

– sites of attachment for thin filaments– connected by intermediate filaments netting around the cell

• thick filaments vertically stacked– myosin heads along entire length of thick filaments allows sliding along the entire length– myosin tails are all parallel to the axis,

• sliding can occur along entire length of thin filaments– pull the dense bodies close together and pull on the intermediate filament netting– don’t contract but SCRUNTCH

– advantage to arrangement?• ability to contract even when greatly stretched• What we see in urinary bladder

– If 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

• Calcium is an important element but no troponin or tropomyosin- calmodulin

• Sarcoplasmic reticulum is less developed—pull a lot off calcium from extracellular fluid

• Functions are more variable and complex—no T-tubules

– contraction is initiated extracellular calcium comes in through voltage gated channels- the calcium need when contraction.

– When voltage gated channels open, calcium Bind to calmodulin

• Calmodulin and calcium complex activate MLCK which take light chain (myosin head) become phosphorylated– phosphorylation of cross bridge contraction

– Regulatory even that permits actin and myosin interaction (phosphorylation of cross bridge)

• Contraction– Can have graded contraction through

amount of phosphorylation

• Depends on amount of calcium- more calcium= more phosphorylation= more contraction• Relaxation

– Ca-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 inactivated– Myosin phosphatase runs continuously; removes phosphate from light-chain on myosin head (cross

bridge element)– allowing relaxation• Ca calmodulin - MLC kinase phosphorylate MLC• When there is no longer a signal there is no more calcium flowing in and both pumps (SR and plasma

membrane) will pump out calcium• Slow 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 Categories• Single unknit smooth muscle

– Majority/ typical smooth muscle– Autonomic nervous systems modify– Varicosities along entire length, gap junctions, synpases en passant--Act like a single unit when contract– Have pacemaker cells – similarly to cardiac muscle

• Multiunit smooth muscle – No gap junctions– Stimulate via nerve stimulation – Ciliary muscles, erector pilli muscles

• TABLE 12.8

Chapter 13- Blood, Heart & Circulation• Circulatory System

– functional term– prefer the use of Cardiovascular System– 3 parts

• Pump (heart) moves transport media• Blood the transport media• Conduits- blood vessels

• Blood– function divided into 3 broad areas:

• transportation- move nutrients, wastes, ions, regulatory elements (hormone)• regulation – regulate temperature by moving heat around, hormones• protection – antibodies, immune function and clotting

Composition of Blood• connective tissue- only fluid tissue in human body• Plasma—liquid of water and dissolved solutes (esp. sodium), plus varied organic molecules• Cellular component – Formed elements

– Leukocytes, platelets, thrombocytes, erythrocytes

Hematopoiesis• Hematopoiesis- process to make formed elements; occurs in RED bone marrow• In adults it will be in sternum, skull, scapula, pelvic, ribs and vertebra– proximal ends of long bones • Newborns have more RBC

• Hemocytoblast- pluripotent hematopoietic stem cell gives rise to all the formed elements – Lymphoid line: lymphocytes– Myloid line: everything else

• Various mechanisms in place regulating formed elements production– Influenced by cytokines and other regulatory molecules

• Cytokines– regulates the production of different sub types of leukocytes– Interleukins (CSFs) stimulate the development of different white blood cells

• Erythropoietin assists with RBC formation • Thrombopoietin give rise to platelets

Erythrocytes• Erythrocytes: 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 erythrocytes• Liver, spleen and bone marrow remove aged cells, recycle iron and globin

– When 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 acid• Ferroportin 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 well

• Only way to get rid of excess iron – menstruation • Blood Typing-- result of distinguishing antigen displayed on cell surface

– Genetically determined– Immune system exhibits tolerance to body’s Red Blood Cells– Type A- A antigens, antibodies to B antigens– Type B- B antigens, antibodies to A antigens– Type AB- A & B antigens, No antibodies– Type O – NO Antigens, antibodies to both A and B

Blood Clotting• hemostasis

– cessation of bleeding• effective in dealing with injury to small vessels but little help for middle to large vessels• observe 3 separate but overlapping hemostatic mechanisms

– vascular spasm– formation of platelet plug– clot formation

Vascular Phase• vasoconstrictive event- immediate response to injury; occurs in smooth muscle of vessel wall• when you irate it, responds by contraction or undergoing a vascular spasm

– inherit characteristic of smooth muscle– function: close off vessels, reduce blood loss & allow time for other processes to stop bleeding in larger

vessels • Aorta does NOT clot

Platelet Phase• Normal 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

aggregation• On surface of cell- CD39, an enzyme that breaks down ADP to promote platelet aggregation• ADP 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 platelets– Platelet release reaction- degranulate and released ADP, serotonin, thromboxane A2 which activate

more platelets in the plug that begins to form; fibrinogen brought in– More platelets activated and recruited – Form a platelet plug organizes for blood clot formation; platelet activate clotting factors

• Temporary fix, loose; must be stabilizes• Positive feedback event- once initiated it gets bigger and bigger; platelets activate more platelets

Coagulation Phase• Platlet plug is forming- RBC and fibrinogen is incorporated• Represents the transformation of blood from liquid to a gel that results in the formation of a clot• Conversion of soluble plasma protein, fibrinogen, into an insoluble fibrous protein, fibrin = clotting

Clotting Pathways• Initiated at the same time- one goes faster than another• Extrinsic

– Activated by chemical released from damaged tissues and activating clotting factors • Tissue thromboplastin

– Faster pathway• Intrinsic

– All components present in blood, initiated by negatively charged structures & NETS (neutrophil extracellular traps)

• Collagen, NETs, Polyphosphates– Contact pathway because initiated by clotting factors being in contact with negatively charged

structures– Slower pathway

• Common 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 X– Converts 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 Liver– Vitamin 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 clot• Plasminogen activates plasmin that tears down fibrin from insoluble cables to soluble fragments

– Balance to Ensure the clot is just the right size• Kallikrein 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 clotting

– Antithrombin III– inactivates clotting factors and thrombin• Function- limit clot formation

– Too small wont sufficiently plug– Too large will include the vessel

Circulation Circuits & the Heart• Heart feeds two circuits – pulmonary and systemic• Pulmonary circuit feed by right hand side of heart – goes

to lungs to be oxygenated• Systemic 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 process

• We 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 body

• A 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 flabs

• Fibrous skeleton – dense connective tissue structure stabilize the valves, attaches myocardium so cardiac muscle can pull against

– Functionally and structurally separates the atria and ventricles– Electrically separates the two compartments

Cardiac Cycle• Repeated cycle/pattern of contraction and relaxation (one contraction and one relaxation = 1 cycle)

– contraction= systole– relaxation= diastole

• Occurs in both atria and ventricle• The heart spends more time in

relaxation/diastole (2/3 of its time) only 1/3 of times in contraction

• Atrial 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 quickly

– Ejection- blood out of ventricles • Set up so blood flows from atria to ventricles• The 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 diastole• Isovolumetric ventricular relaxation- even though

ventricles are relaxing, pressure is still great that the atrioventricular valves cannot open so ALL VALVES ARE CLOSED

– Pressure will eventually fall; atrioventricular open and then blood flow into ventricles restarting cycle

Relationship between Interventricular Pressure, Volume, & Heart Sounds• Isovolumetric contraction– all valves are closed; steep rise in pressure• Ejection- stroke volume is ejected out from ventricles

– EDV- end diastolic volume– volume at the end of diastole/relaxation– SV- stroke volume, the volume that is ejected out

• Isovolumetric 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 contraction• First and second heart sounds are the closure of valves

– To make the first heart sound the atrioventricular valve closes, second heart sound is the semilunar valves close.

Electrical Activity of the Heart• Isovolumetric contraction– all valves are closed; steep rise in pressure• Ejection- stroke volume is ejected out from ventricles

– EDV- end diastolic volume– volume at the end of diastole/relaxation– SV- stroke volume, the volume that is ejected out

• Isovolumetric 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 contraction• First and second heart sounds are the closure of valves

– To 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 potential• result 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 current• diastolic depolarization- pacemakers use sodium HCN channel due to hyperpolarization• at threshold, voltage-gated Ca channels open for depolarization with repolarization resulting from the opening

of voltage-gated K channels• Sympathetic and parasympathetic Influence– modifies ONLY

– When 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 event

• Epinephrine generates cAMP to open– Parasympathetic released acetylcholine that binds to muscarinic potassium channels; decreasing heart

rate

Myocardial Action Potential• In adjacent cardiac muscle cells in the myocardium, initiated by pacemaker cells to produce Aps

– spread 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

elongation• The influx of calcium causes a plateau -- “muscle twitch”

Conducting Tissue of the Heart• APs from SA node spread at 0.8-1 m/sec across atria• conduction slows with AV node-delay• conduction 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 contract

– Atria contract first then ventricles• We have a delay- takes a little bit to get AV node going

– Allowing ventricles to contract and relax before automatically contracting them• ECG- electrocardiogram; hills are generated based on electrical activity inside of heart

Excitation-Contraction Coupling• note, 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 muscle• Slower in cardiac muscle- no rhysodine receptors• Cai is lowered by Ca-ATPase pumps of SR & Na-Ca exchanger on PM• unlike SkM & SmM, CM cannot sustain a contraction, with contractions lasting about 300 msec• long absolute refractory period prevents summation of contraction, ensures rhythmic pumping of heart • QUESTION: Is summation important to the heart?

o 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 hearto Summation allows us to have sustained contraction (tetani)o We have gap junctions in heart so summation is unneeded o Frequency of stimuli is NOT important in the heart

Blood Vessels• Blood Vessels– conduits that form a network throughout body permitting distribution of blood to body tissues• TIME tells you layers of the blood vessel layers

– Innermost: tunica interna– Middle: media– Outermost: externa

• Arterial circuit of systemic circuit—DIVERGING– one big one to smaller and smaller ones– elastic artery: elastic layer found within tunic and when heart ejection of blood the vessels can expand

and contract back– Muscular arteries– deliver and control blood flow to organs– Arterioles– important for organ physiology; adapted for vasoconstriction and vaodilation, regulation and

respond to minute by minute changes within organ• Look 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 gases• Arteries 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 tunics

• Veins walls are always thinner than the robust arteries

Capillaries • Smallest blood vessels; endothelium with basement membrane; branch extensively• Well suited for function of exchange

– Form a capillary bed good for exchange• The functional unit of cardiovascular unit because of the capillaries!

– Need exchange in and out of transport media• Arteriole– capillary bed--- exit out a venule• Do 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 shunts

• Help maintain body temperature• Flow 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 activity– Vasomotion– 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 – During

• Basic Types of Capillaries:– Continuous

• “leaky”• Most common • Endothelium with basement membrane • Localized in vascularized tissue – muscle, skin, lungs, Nervous system, adipose tissue• Intracellular cleft- regions between individual endothelial cells held together by tight junction

- A 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 diaphragm• Allow for a little more exchange

• Found where Active absorption or filtration occur (kidney, GI tract, endocrine glands)– Sinusoids

• “leakest”• Discontinuous basement membrane, highly modified• Restricted to certain organs (least common)• Suited for Passage of blood cells and large molecules• Found in Bone marrow, liver, lymphatic tissues- spleen, few endocrine organs

Veins• large lumens/diameter & thin walls• accommodate 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 resistance– venous 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 direction

Chapter 14 – Cardiac Output, Blood Flow & Blood PressureCardiac Output

• volume of blood each ventricle pumps (what is being ejected out)– L/min– Reflects pumping ability of the heart

• CO = HR x SV– HR= heart rate– SV= volume that is ejected out of ventricle/heart

• Average adult: HR= 70 beats/min & SV= 70-80 ml/beat– Changes based on build of individual

• EX. 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 body

• Our hearts pumps our entire blood volume once every minute at REST• Changes in HR or SV parameters impact cardiac output

Regulation of Heart Rate • ~100 beats/min

– result of inherent, autonomous discharge rate of SA (sinoatrial) node – not what observed physiologically

• modified by:– Autonomic Nervous System (sympathetic and parasympathetic-RULE innervation)

» cardiac control center» medulla

– Circulating Hormones can change HR• influenced 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 medulla• Change heartrate via pacemaker potential • How do we change HR?

– CONTROL: Pacemaker potential brings resting membrane potential to threshold in a contractile cardiac muscle cell-- contraction

– Sodium ion and HCN channels (hyperpolarization cyclic nucleotide channels)

– Sympathetic releases epinephrine and noepinephrine bind to Beta-1 receptors an activate cAMP (second messanger) open HCN channels

• B1 receptors cAMP open HCN channels (spontaneously opening and the increase presence of cAMP opening more channels) shortening the pacemaker potential to increase HR

• Shorten pacemaker potential in sympathetic to increase HR• Elongate pacemaker potential in parasympathetic to slow HR

– Acetylcholine 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 event

• chronotropic effect: changes heartrate due to a compound or chemical– positive

• HR– negative

• HR• Overall 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 Volume• defined volume of blood each ventricle ejects during each contraction (systole)• regulated by:

– end-diastolic volume, EDV• How 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 relaxation» Bigger volume more work load

– Stroke volume directly proportional to EDV» EDV increases, SV increases

– total peripheral resistance, total PR• Resistance to blood flow in arteries, result due to friction (slow it down)

– Afterload– pressure in ventricles must push against– SV is inversely proportional to total PR

– contractility• Changing the strength of ventricular contraction

– Functional 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 ml– EF = SV/EDV– Look at clinically to see if you have heart malfunctions– Issues– heart failure

Frank-Starling Law of the Heart• basically, 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 muscle

• result due to a length-tension relationship – There is a set optimal length for a skeletal muscle at rest for optimal fore generation– The reason we can change contractility in heart because at rest the heart is NOT at

optimal length for max contraction – ventricles contract more forcefully during systole when stretched, which is the result of

a greater EDV• linear curve: increase equally as you increase SV and EDV • EDV – sarcomere length, SV- contractile force• Cardiac 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 harder

– You can’t have more blood on one side than the other because one side will callapse – * maintains equality between left and right Cardiac Output

Intrinsic Control of Contraction Strength• Cardiac muscle length has a more pronounced effect on contraction strength than observed in skeletal muscle• Cardiac muscle optimal length not at rest, as ventricles fill myocardium stretched to optimal length permitting

more forceful/stronger contraction to move blood volume– To 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 cells• Time to reach maximum contraction is constant regardless of stretch• Frank-Starling law explains how heart can adjust to a rise in total PR

– A 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 CO

– Also includes Anrep effect• Both 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 system

– Norepinephrine from SNS which increases contractility– Epinephrine from adrenal medulla– Both 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 system

– positive inotropic effect on contractility

• Due to an increase in amount of Ca available• Top Picture

– also causes a positive chronotropic effect- sympathetic nerve stimulation increases heart rate as well– When norepinephrine or epinephrine

bind to Beta-adrenergic receptors initiate a g protein complex which activate acyclase increases cAMP

– cAMP activate a cAMP dependentt protein kinase that open calcium channels in pm of cardiac muscle and sarcoplasmic reticulam

– Calcium channels in pm are DHP receptors

– Calcium channels in sarcoplasmic reticulum are rhidpon receptors

– These 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 contraction

– Increase in sympathetic nerve system activity• Bottom Picture

– Sympathetic nerves when activayed increase HR and contractile strength

• What about PNS innervation??– PNS decrease heart rate– Does 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 lusitropy

– Occurs in Contractile cardiac cell– Chronotropy– heart rate– Inotropy– contractility– Dromotropy– conduction veolocity-- Excitation speed– Lusitropy- relaxation-- Enhances and supports during relaxed state

• Looking at noncontractile cardiac muscle cells in SA and AV nodes– Parasympathetic 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 responses

• Inhibitory G protein activates K channels to open, allowing an efflux of potassium, hyperpolarizing cell

Venous Return• represents blood return to heart via veins

– 60-70% of our blood is housed in our veins• rate atria/ventricles fill dependent on total blood volume (what can be brought back)and venous pressure

– veins 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 pressure• Venous 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

another– pressure differences between thoracic and abdominal cavities

• Negative intrathoracic pressure• Breathing- changing pressure influencing blood to go back to heart

Blood Volume• Represents a compartment within the extracellular compartment• Fluid movement between blood plasma and interstitial fluid determined by balance of opposing forces acting at

the capillaries– Intracellular 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 utilize– Waste & secretory products of cells

• Water excretion and water intake need to be balanced– Take in 1.5—2.5 L– Lose a little water in fecal content– Every time you breath, moisture is lost– Sweat glands and skin release moisture as well

Exchange of Fluid between Capillaries and Tissues• Push and a pull• 2 Forces involved

– Hydrostatic Pressure (P)– push by fluid against something like capillary wall– Colloid osmotic pressure () – pull of water by solutes;

• 2 compartments (capillary and interstitial fluid) and 4 pressures– Hydrostatic pressure is exerted by the blood in the capillary (Pc)– represents blood pressure– Hydrostatic pressure of interstitial fluid push against capillary (Pi) --- negligible value – Colloid osmotic pressure of plasma– Colloid osmotic pressure that pulls in the opposite direction via interstitial fluid – negligible value

• Equation looks at how forces influence movement– Fluid out (Pc +i)– Fluid in (Pi + p)

• What determines the how fluid flow?- difference between hydrostatic pressure of capillary and colloid osmotic pressure of plasma– defining pressures

• Arteriole 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 out• Flow across capillary there is a change because fluid flows out• Venous side of capillary – the push in becomes greater than

push out– Negative value– Net absorption– Lose in hydrostatic pressure– Absorb fluid back

• Continuous exchange• Only 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 wall• Values differ between organs• Oncotic pressure difference between the two colloid

osmotic pressure– Because the colloid osmotic pressure of the interstitial fluid is very negligible- the body works very hard

to keep it there– You really are just looking at colloid osmotic pressure of capillary due to plasma protein– Important because this is how our nutrients are exchanged – fairly efficient

Edema• Is an interstitial Fluid compartment event- excess fluid is found here• excessive accumulation of tissue fluid

– prevented by balance between capillary filtration & osmotic uptake (filtration and absorption), along with proper lymphatic drainage

• result from:– high arterial Blood pressure– venous obstruction– leakage of plasma proteins into IF– Myxedema: excessive mucin production in extracellular matrix– decreased plasma protein concentration– obstruction of lymphatic drainage- influence homeostatic fluid balance

• Why would high arteriole blood pressure cause edema? Throw off balance– If 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 compartment

• READ IN TEXT BOOKEXPLAIN WHY EDEMA HAPPENS THERE MECHANISMS and how they influence capillary exchange

Regulation of Blood Volume by Kidneys• urine formation, like the origination of tissue fluid (interstitial fluid), involve plasma filtration through capillary

pores (fenestrated capillaries in kidneys)

– kidneys produce ~180L filtrate per day• body contains ~5.5L blood, most of filtrate is reabsorbed back into vasculature, is recycled

– therefore, reabsorption impacts blood volume (the ability to reabsorb filtrate)• excrete ~1.5L urine per day, variable

– urine 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 reabsorption

• Regulation by Antidiuretic Hormone– Stimulus is increase in blood osmolality picked up by osmoreceptors in hypothalamus; can occur due to

dehydration (decrease in blood volume) high salt ingestion – Cause 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 osmolality

– Osmoreceptors 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 peeing

– Also, 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 kidneys

• Functions 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 water

– Another negative feedback loop to assist with homeostasis of blood volume

– Looking at blood volume and osmolality• Renin-Angiotensin-Aldosterone System

– Responds to a blood pressure and blood flow to kidneys, + salt deprivation

– Maintains homestasis through negative feedback control of blood volume and pressure

– Drop 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 pressure

– AND/OR angiotensin 2 adrenal cortex produces aldosterone (influences sodium) aldosterone allows salt and water retention by kidneys increasing blood volume

• Aldosterone: 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 Peptide– In response to increase in blood volume/ water immersion (mimics an increase in blood pressure

• If you are out swimming– need to go to bathroom– Increase in blood volume also increases venous return increase stretch of atrium vagus nerves tells

brain and posterior pituitary to decrease release of ADH• Decrease water reabsorption

– Increase 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 maintain

Vascular Resistance to Blood flow• amount 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 circulation– note that blood is unequally distributed to different organs in an individual at rest

• blood flow through vasculature is affected by resistance to blood flow due to characteristics of the blood vessels• Some 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 pressure• follows a pressure gradient

– rate of blood flow is proportional to the pressure difference, or P• blood flow is inversely proportional to the frictional resistance of blood as it flows through a vessel • THEREFORE

• Standard 120/80 blood pressure • 100 mmHg driving force of blood flow through vasculature• Center 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 ends• resistance 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) •

• The smaller the length of the vessel, the lower the viscosity = easier to flow • Resistance is directly proportional to length but inversely proportional to radius

– As distance increases, resistance increases– As radius decreases, resistance increases

• Blood flow is easier when the resistance decreases (radius increases)• Blood flow is harder when the resistance increases (radius decreases

Poiseuille’s Law• Blood vessel length and blood viscosity do not significantly change in a normal individual • major physiological regulators of blood flow through an organ:

– MAP• mean arterial pressure

– an “average”– driving force

• drop significantly in resistance vessel – vascular resistance

• arterioles– provide greatest resistance due to capacity to Vasoconstriction and Vasodilation–

changes radius– due to change in radius (larger and smaller vessels)

Total Peripheral Resistance• represents sum of all vascular resistance within systemic circulation• observe blood flows through only one set of resistance vessels before returning to heart• arteries arranged in parallel

– hepatic artery supplies nutrient– heaptic protein vein drains into liver– organs not “down stream” from another

• importance? – 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 example

Extrinsic Regulation of Blood Flow• ANS and endocrine control

– endocrine - - - AII (can be a vasoconstrictor) & ADH (antidiuretic hormone, also vasoconstrictive element)

– sympathetic nerves

BLOOD FLOW = Pr4() L(8)

• has a large effect because of the innervation to other areas• sympathoadrenal system stimulation, observe an increase in CO & total PR

– vascular Smooth muscle stimulation (-adrenergic Receptors) via NOREPI in arterioles of skin & viscera

» also 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 & skin

– in 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 receptors

» blood flow to skeletal muscle increases; advantage– parasympathetic nerves always cholinergic & always promote vasodilation in arterioles

• limited distribution thus has less effect

Paracrine Regulation of Blood Flow• blood vessels particularly subject to paracrine regulation

– especially endothelium, which also produces several paracrine regulators that impact Smooth muscles in tunica media

– arterioles tend to be regulated by paracrine because they are more sensitive• paracrine regulators that cause

– Smooth muscle relaxation = Vasodilation• Nitric Oxide, bradykinin & prostacyclin

– Smooth muscle contraction = Vasodilation• endothelin-1

• Table 14.4• Paracrine regulator- Nitric Oxide

– Parasympathetic stimulation activates eNOS (enzyme in endothelium that creates NO)

Intrinsic Regulation of Blood Flow• represents a “built in” mechanism within individual organs to provide localized regulation of vascular resistance

and blood flow• used to maintain relatively constant blood flow rates within organ despite wide fluctuations in BP - -

autoregulation• mechanisms classified as:

– myogenic• response by vascular smooth muscle to keep tissues perfused as well as protection against high

BP– BP increase, & vascular smooth muscle stretched, it responds by contracting, or VC

» Protects vessels downstream from elevated pressure– BP decrease, vessels dilate to retain adequate blood flow

– metabolic• result of chemical environment created by organs metabolism• VD promotion

– O2, CO2, pH, adenosine or K release from tissues (paracrine regulators)» Hyperemia increased blood flow

Blood Flow Distribution during Rest and Exercise• blood flow to organs such as heart &

Skeletal muscle regulated by both extrinsic & intrinsic mechanism’s

• brain, mainly intrinsic mechanisms, requires constant flow

• cutaneous, mainly extrinsic mechanisms, most variation in blood flow

• 25 L/min blood output during heavy exercise

• Skin uses mostly extrinsic – most variation in blood flow

Blood Pressure• resistance to flow within arterial system is

greatest in arterioles, due to their smaller diameter

• flow 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 vessels

– important to slow velocity of blood flow in capillaries, enhances exchange• Allows capillaries to have lower pressure

– preserves “pressure gradient”• Driving force = pressure difference

– Only 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 numbers– although smaller in diameter, capillary bed (greater cross sectional area) presents less resistance, than

arterioles– Capillaries are functional unit of cardiovascular system-where exchange occurs

• variations 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 pressure

• Blood pressure can also be elevated by an increase in Cardiac Output, which is influenced by other factors

• 3 most important variables affecting blood pressure– Cardiac output- pumping efficiency of the heart

• Influenced by Heart rate and stroke volume– Stroke volume (determined by blood volume)- regulates blood pressure; reflecting blood volume

• Stretching, great contractility– Total peripheral resistance- vasoconstriction increases vasoconstriction- impacting blood pressure which

can be dangerous

BP = CO x total PR

• An increase in any of these variables without a compensatory decrease in another will lead to an increase in blood pressure

– All three need to balanced to keep blood pressure in normal ranges• Therefore, blood pressure can be regulated by kidneys, which regulate blood volume and thus stroke volume• Blood pressure can be regulated by the sympathoadrenal system, which increases vasoconstriction leading to an

increase in peripheral resistance thus impacting blood pressure

Baroreceptor Reflex• Baroreceptor Reflex are stretch receptors found in vessels close to the heart (aorta) that monitor blood pressure

– As blood pressure rises they are stretched more. Stretch less when blood pressure falls-action potential falls

– function to counteract BP changes so fluctuations in pressure are minimized• maintain Blood pressure on a beat-to-beat basis – SHORT TERM RESPONSE

• tonically active– BP leads to an in AP frequency– As blood pressure falls action potential

frequency falls (direct correlation) – Should be around 100

• info sent via Cranial nerves to medulla– vasomotor control centers

• Regulate Vasoconstriction and vasodilation in arterioles

– Assist with total Peripheral resistance regulation

– cardiac control centers • Regulates heart rate

• system 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 pressure

• Baroreceptors immediately sense the change and change their action potential frequency, send info to medulla, activate sympathetic and decrease parasympathetic

– Initiated VC= increase total peripheral resistance

– Increased heart rate = increase in cardiac out – Both of these increase blood pressure

Atrial Stretch Reflexes• other reflexes present to assist with Blood pressure regulation

– Sensory 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 activity• inhibit 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 excretion

» Antagonist to the renin-angiotensin-aldosterone system

Pulse Pressure and Mean Arterial Pressure• Pulse pressure – PP

• Mean arterial pressure – MAP– represents average arterial pressure during cardiac cycle– significant

• difference between MAP and venous pressure (pressure difference) is what drives blood through capillary beds of organs

– hard 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 pressure

• Diastolic is influenced more then systolic pressure for heart rate• Reverse in regards to cardiac output• Influence difference depending on what we do --- all depends on the pressure difference

Application of Concepts

1. 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 variations

• The net result is the ventricle raises its stroke volume output when venous return is increases and lowers its stroke volume when venous return is lowered

• Furthermore, 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 fail

2. 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 elevated• In 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 dangerous• Drinking 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? Explain

• Exercise using isometric muscle contractions would put a greater “strain” on the heart• Isometric 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 pressure

• Also, during this breath holding interval the drop in blood pressure stimulates the baroreceptor reflex, resulting in tachycardia and decreased total peripheral resistance

• When 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 stroke

o Although 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 vessels

• Isotonic exercise is usually not associated with breath holding

Chapter 15-The Lymphatic/Immune SystemThe Lymphatic System

• comprised of:– lymphoid tissues/organs/cells – scattered throughout body

• Thymus, spleen and lymph nodes• Collections 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 vessels

• functions:– fluid balance

• Lymphatic vessels return fluid from interstitial space to circulation via lymphatic capillaries– lymph*

» Transudates/derived from plasma » Contains anything (products or substances) that Is released – hormones, waste,

nutrients- from neighboring cells– 9/10 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 edema– fat absorption

• absorb fats & other fat-soluble substances from digestive system via lacteals (specialized lymphatic capillaries in GI tract)

– Fats first go into lymphatic system before blood circulation– defense

• organs/tissues serve as “filters”– removing microbes & foreign substances– Lymph node

» Design: 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 agents

Lymphatic Vessels• Lymphatic capillaries blunt-ended tubes (conduits) for vast network within intercellular spaces of most organs

– Capillary bed and intersperse in true capillaries are lymphatic capillaries– Due 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 valve

• Filamentous elements attached to extracellular space: when fluid volume builds causing pressure and opens up the porous junctions

– NO work required just designed to meet the needs of the area• One-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 tunics

• Pacemaker cells- lymphatic vessels have rhythmic contraction help to move things through-also have valves– When fluid volume increases & When stretched– increase rate of contraction

• No need for pump• Negative pressure system

• Lymph Node– before returned to venous circulation it will always pass through at least ONE lymph node– Most of the time it is several

Immune System• functional system rather than a structural one• “organs” are represented by individual immune cells & a diverse array of molecules

– Immune cells in lymph organs (spleen, tonsils, etc) • relies upon 2 intrinsic defense systems

– act both independently & cooperatively• Run concurrently but by themselves

– provide resistance to disease, or immunity• Defense Mechanisms

– Innate (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 surface

– external body membranes - are physical barriers

– Secretions- 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 penetrated

– Limit 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) c

• third line of defense is body’s specific defenses– function of lymphocyte activities

Activation of Innate Immunity• distinguishes between “self”, the body’s own cells, and invading/ foreign organisms/molecules

– recognize PAMPs (pathogen- associated molecular patterns– proteins on surface of cells)• unique to invaders• Lipopolysaccharides & peptidoglycan

– ie. particular classes carbohydrates or lipids in microbial cell walls• innate immune cells display receptors for these PAMPs, referred to as pathogen recognition Receptors

– toll-like Receptors• play role in triggering immune response

– recognize invading/foreign organisms– once 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

– Autophagy• Recognize intracellular components

– DAMP’s (danger-associated molecular patterns)• Stimulate innate immune system as well as initiating inflammation

• Complement system integrates innate and adaptive immune response– Help organize defense systems – proteins associated are in an inactive state of blood circulation

Phagocytes• Best 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 groups

– Neutrophils (polymorpho nuclear cells)• most abundant• Look for cells that are not “self” • phagocytic upon encounter with foreign intruder• 1st to enter infected area, are mobile & quick to phagocytize (bad kill destroy)

– mononuclear phagocyte system• Called monocytes in blood circulation, macrophage when in tissues & dendritic cells• Don’t hang in blood but live in tissues to become a macrophage where they spend most of their

life• Dendritic cells– origin unknown; arise from phagocyte stem

– organ-specific phagocytes of liver, spleen, lymph nodes, lungs & brain

• microglia 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)

Phagocytosis• PMN- polymorphonuclear cell (PNM) aka neutrophil roll along endothelium• In 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 integrins– Neutrophil gets caught on CAMs of neutrophil and begin to get activated. Stop rolling and adhere to wall

• Diapedesis 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 phagocytosis

• Migration 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 chemotaxis

– Positive chemotaxis– moving toward infection• Neutrophil can do 2 things…

– Come around and engulf microbe- lysosomes break it down– Encapsulated 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 response

Fever • defined as an abnormally high body temperature• is a systemic response to infection, which involves resetting the body’s “thermostat” in the hypothalamus• accomplished 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 temperature

• fever causes an increase in body’s metabolism, thus accelerating repair processes & impacts bacterial replication– liver & spleen sequester zinc & iron, makes them less available for bacteria (nutrients required for

reproduction)– Only advantageous if it’s for a short period of time– Anything above 103/104 can begin denature proteins in brain

Interferons• small proteins that protect body against viral infections

– short-acting• Naturally produced by viral infected cells• are not virus-specific, so provide protection from a variety of viruses• considered a cytokine:

– chemical messengers released by tissue cells to coordinate local activities

• When 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 cell

– Interferons 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 HORMONE

• Endocrine function (affecting metabolisms of cells in other organs) but not classified as a hormone

Adaptive Immunity• involves the ability to recognize, respond to and remember a particular substance• requires a “meeting” or to be primed by an initial exposure to a specific antigen before it can protect the body• three important aspects of adaptive immune response, distinguish from innate immunity:

– it is specific• ability to recognize and direct response against particular foreign substance that initiate an

immune response– it is systemic

• not restricted to initial infection site– it has memory

• after initial response, it recognizes and mounts an even stronger attack than previous encounter• Advantage!

Antigens• Antigen (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 reactions

• Once lymphocytes are activated and become B cell thus releasing antibodies, these cells must react to the antibodies

• Greater the complexity, more immunogenic – When we look at an antigen, an activated lymphocytes will only make a product directed to ONCE

antigenic determinates• Hapten 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 anymore

– Start making antibodies on self and attack self because haptens make it look like its not self• Immunocompetence- the ability for a lymphocytes to mount a response

– Recognize specific antigen or foreign intruder and mounts a response• Immunological tolerance—tolerating yourself antigens; system attacks everything but ignore self

– Haptens get around them and create antibodies against self

Functions of B Lymphocytes• exposure 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

invader• Immunocompetent 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 immunoglobulins• If we coat a microbe with antibodies its easer to see and engulf

– Once antibodies bind to antigen, pathways are signaled to get rid of them• Observe 5 subclasses (TABLE 15.6)

– IGA- dimers, secretory antibodies (found in secretions such as saliva, tears) breast milk– IGM– first response, pentamores (5), first to be secreted

– IGG– secreted for a secondary response, monomer; most abundant and most common

– IGD- monomers, found on surface of B cells, antigen receptors for B cells

– IGE- monomers, associated with allergic reactions

• Two light chains and two heavy regions + two regions

• FC region-stem, constant region, determines the subclass and functionality

– Chains held to together by disulfide bonds

– Effector region, dictate cells (functionality*)

– Chemical elements like antibodies and other cells or complements can bind to this region

– Involved 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 make

• Ability to identify antibodies are predetermined and planned within genetics• Antigen independent diversification: bone marrow

» We don’t see antigen » Recombination of DNA (make up a bunch of combination) when lymphocytes are

developing• Antigen dependent diversifation- proliferation of B cell

» Secondary lymphoid organs (lymph node)» Mix things up genetically se we can get more combination» Somatic hyper-mutation and change genetics during proliferation of mitosis to get more

combinations– Ability 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 are

Complement• Represent group of plasma proteins, Found in an inactive state in blood circulation• Respond to antibodies bind to antigen

– Binding to cell wall of bacterium = opsonization • Antiskid makes it easier to grab hold• Start initiating the complement system

• Upon activation, via either the classical or alternative pathway, the final product is a MAC, that causes ell lysis– MAC= membrane attack complex

• Activate a series of complement proteins insert themselves into cell’s plasma membrane puts a hole in cell wall of bacterium causing lysis- killing it

• In addition, other fragments created which serve to initiate chemotaxis, phagocytosis and histamine release

• Classical 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)

– MAC• C4a- chemotaxic agent• C3a & 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,

• C3B- facilitate phagocytosis• Alternative pathway

– Initiated by polysaccharide of bacterial wall/call

– another mechanism by which to assist and get rid of intruder

• Classic pathway is rapid and efficient.• Alternative pathway is less rapid and efficient

Functions of T Lymphocytes• T cells are a diverse lot and more complex

than B cells in both classification & function– Observe 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 cells• CD8 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 hand– Keep 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 destruction– Requires physical contact with victimized cell

• Perforins – form pore in victim cells Plasma membrane– Punch holes and cause lyses– cell death

• granzymes – enter victim cell and via capsases activation pathway destroy DNA• immunocompetence occurs in thymus

– Recognize specific antigens – Occurs very early in our development (preschool)

T-Lymphocyte Activation• B 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 chemokines• Dendritic 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 clones

– follow chemoattractants trail so activated T cells can find original site of infection• Antigen 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 cell

Histocompatibility Antigens• MHC 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 self– class I MHC– expressed by any cell of body– class II MHC– only be presented by APC

• 2 pathways: endogenous and exogenous structures– Endogenous: virus that comes into cell; proteasomes break down into fragments; ER take in fragments

through TAP• TAP- transporter associated with antigen processing

» Take processed antigen into ER putting it on to MHC Type 1, (putting out a flag)• ALL CELLS

– Exogenous• Endocytose antigen- put them in vesicle (phagolysosome) with an MHC type 2 already inside• MHC class 2 are waiting for something to be added to them• CLIP– blocker protein, block binding site • Everything happens out in cytoplasm• APCs

• Restriction element= ability to restrict T-cell activation/receptor-binding, only occurs if antigen complexed to MHC protein

T-Cell Activation• Antigen 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 identity

• Cytokine signaling- APC release chemical signal to proceed – Interleukin 1- stimulate proliferation and division of T cells

• T helper cell release other cytokines that assist the cytotoxic cell with its activation– Bind to antigen on class 1 – everything is check and stimulation of the T helper cell to verify the intruder– Produce clones or memory cells – Detach from victimized cell and go to another infected cell

• Why cause proliferation if T-cell bound to virus-infected cell? – If there is one virus there is probably more than one– Proliferation ensures we take care of all the virus infected cells.

Inflammation• a localized event, involves aspects of innate & adaptive immunity• neutrophils 1st to scene, release chemical signals to recruit other immune cells• as 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 intruders• Main Points

– Job is protective response– Involve both innate and adaptive immunity – To any site of injury – neutrophils are first to site and signal to bring in other immune cell

• Take care of intruder and clean area up• Designed to contain and eliminate

– Mast cell release chemoattractants… eliminates that are released give you 4 cardinal signs of inflammation

• Histamine Vasodilator, make capillary more permeable

Active & Passive Humoral Immunity

• Immunity acquired by artificial (vaccine) and natural

• Active – involves B cells being exposed to antigen; immunological memory develops; long-term protection

• Passive 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 Memory• Begins with a Primary response- first time your body sees an antigen/original exposure

o Lag time: the time that Bb cells differentiate and see the antigen o See rise in presence of antibodies to detected antigen

• represented by memory cells & responsible for what occurs during next exposure to a particular Ag• At 28 days exposure to a new antigen and second exposure to the original antigen

o secondary immune response Rapid, prolonged and more efficient response

• Do this for each antigen determinate sites

49 multiple choice

1 short answer (sequencing)