Physiology-Muscles And Respiration

Front 1

Skeletal Muscle Overview

Back 1

-Striated
-Somatic Innervation, conscious control
-Many nuclei per cell
-HUGE fibers
-Isolated electrically from neighboring cells
-Attached to bone and cause motion of the skeleton

Front 2

Cardiac Muscle Overview

Back 2

-Striated
-Autonomic Innervation, unconscious control
-1, 2, or 3 nuclei per cell, not as multi-nucleated as skeletal muscle
-Connected electrically to neighboring cells
-Located in the heart
-Act to pump blood through body

Front 3

Smooth Muscle Overview

Back 3

-Smooth, no striations
-Mononucleated
-Autonomic innervation, unconscious control
-Can be isolated or connected to neighboring cells
-Surround hollow organs and blood vessels
-Contract and provide vascular resistance

Front 4

Skeletal muscle development

Back 4

-Start as muscle cell precursors, differentiate into myoblasts, to myotubes
-Myotubes undergo sarcomere assembly, develop into muscle fibers

Front 5

Organization of skeletal muscles

Back 5

-Myofibrils (actin, myosin) make up muscle fibers
-Muscle fibers are surrounded by endomysium
--organized into muscle fascicles
-Muscle fascicles are surrounded by perimysium
--organized into muscle belly
-Muscle belly is surrounded by epimysium

Front 6

Skeletal Muscle fascicle

Back 6

-Collection of muscle fibers
-Joined by endomysium connective tissue

Front 7

Skeletal Muscle Fibers

Back 7

-Nuclei are on periphery of fiber/cell
-Sarcomeres give striated appearance
--highly orgnized and regulated

Front 8

Sarcomere

Back 8

-Structural and functional unit of striated muscle contraction
-Z-line to Z-line
-Highly organized and regulated
-Overlapping actin (thin) filaments and myosin (thick) filaments
-Shortening occurs when myosin interacts with actin
--thick and thin filaments slide past each other and distance between Z-disks decreases

Front 9

Actin

Back 9

-"Thin" filaments
-2nd most abundant protein on earth, highly conserved protein sequence
-Monomeric G-actin polymerizes to form helical F-actin filaments
-Barbed ends are anchored to the Z-disk

Front 10

Myosin

Back 10

-"Thick" filaments
-"Superfamily" of molecular motors, Molecular motor in all cells of the body
--myosin II acts in muscle cells
-Bind to and hydrolyzes ATP
-Bind to the actin in thin filaments

Front 11

Myosin II

Back 11

-Molecular motor that powers muscle contraction
-6 polypeptide chains make up molecule
-has globular motor domain, essential light chain, regulatory light chain, and 2 heavy chains
-Polymerizes in bipolar formation
--both sides look the same, heads on outside and tails on inside
--bare zone= no myosin heads, tails only
--essential light chain and regulatory light chain is bound to each heavy chain
-Polymerizes to form filaments

Front 12

Myosin II regulatory domain

Back 12

-Long alpha helix
-Extends from motor domain
-Acts as a lever arm when ATP is hydrolyzed
-Essential light chain and regulatory light chain bind to regulatory domain
-Only part of myosin that really moves
-Rotates to generate "power-stroke"
--moves TOWARDS barbed end of actin filaments

Front 13

Myosin II head domain

Back 13

-Has region that binds to and hydrolyzes ATP
-has region that binds to Actin

Front 14

G-actin

Back 14

-monomeric form of F-actin/actin filaments
--polymerizes to form polarized actin filaments
-Polarized filament, ends are different, gives arrowhead appearance to filaments
--pointed end = -
--barbed end = +
-Binds nucleotide for assembly
-ATP is rapidly hydrolyzed to ADP+Pi
--Pi is released very slowly
--hydrolysis of ATP by actin is for assembly, NOT for muscle contraction
-Monomers associate and dissociate at filament ends ONLY

Front 15

Myosin/Actin orientation in sarcomere

Back 15

-Actin filaments have barbed end anchored to Z-disc
-Myosin filaments are bipolar, oriented to move towards barbed ends of actin and produce shortening

Front 16

Myosin biochemical properties

Back 16

-Catalytic domains bind tightly to actin in absense of ATP
--no ATP, tight binding
-Actin/Myosin interaction is weakened by ATP
--more ATP, weaker interactions
-Myosin ATPase rate is accelerated by actin
--myosin uses ATP faster when actin is present and available
-Muscle myosins move towards barbed end of actin filaments to cause shortening

Front 17

Actin/Myosin interaction overview

Back 17

1. No ATP, actin and myosin are tightly bound
2. ATP binds to myosin head, myosin releases actin
3. ATP is hydrolyzed to ADP+Pi
--reverse power stroke
4. Myosin can interact with actin
--pre-power stroke
5. Pi is released
--Power stroke, force generating step
--to release Pi, myosin must be able to interact with actin
6. ADP is released
--post-power stroke, actin is tightly bound to myosin

Myosin must detach from actin to generate power stroke

Front 18

Strongly bound states of Actin/Myosin

Back 18

-No ATP present
-Post-power stroke, when ADP is bound to myosin head

Front 19

Weakly bound states of Actin/Myosin

Back 19

-ATP bound to myosin head
-During ATP hydrolysis, reverse power stroke
-Pre-power stroke

Front 20

Myosin ATPase activity is increased by actin

Back 20

-ATPase rate increases when actin is present
-No actin, no ATPase activity

Front 21

Tropomodulin

Back 21

-Capping protein
-Regulates actin polymerization and depolymerization
-Acts at pointed end of actin
-prevents erosion or addition of G-actin monomers

Front 22

CapZ

Back 22

-Capping protein
-Acts at barbed ends of actin filaments
--At Z-disk

Front 23

Titin

Back 23

-HUGE protein
-Filamentous protein
-Forms elastic connections between Z-disks and myosin filaments
--Connects myosin to Z-disk

Front 24

intermediate filaments and Z-disks

Back 24

-intermediate filaments align and connect Z-disks to plasma membrane
-Connect Z-disks on different muscle fibers
-Gives organization to muscle fascicle

Front 25

Dystrophin

Back 25

-Works with associated proteins
-Stabilizes plasma membrane of skeletal muscles
-Medically important protein
-Connects sarcomeres to Extracellular Matrix

Front 26

Motor unit

Back 26

-basic functional element of skeletal muscle
-Single neuron innervates many muscle fibers
--muscle fibers of the same type
-Can have large motor units or small motor units
--small motor units are more easily brought to firing threshold
-Fibers belonging to a motor unit are dispersed and intermingle among fibers of other units
-Activation of 1 motor unit will result in weak, distributed contraction
-Activation of many motor units will result in more muscle fiber activation, stronger muscle contraction
-Simple motor unit = 1 muscle fiber
-Complex motor unit = many muscle fibers

Front 27

Muscle Twitch

Back 27

-mechanical response due to a single action potential
-Motor neuron releases Ca++ into cell
--release gets force
-Depolarization of cell gives Ca++ release, gives response
-Increased stimulus will result in increased Ca++ release, increased response
-Occurs in cardiac and skeletal muscle

Front 28

3 activation states of muscles

Back 28

1. relaxation:
-regulatory proteins inhibit actin/myosin interactions, few myosin heads bound to actin
-Sarcomere can be stretched passively
2. Contraction:
-Muscle is activated by calcium
-Thousands of sarcomeres shorten in series, cause muscle to shorten
-ATP is hydrolyzed, force is produced
3. Rigor (dead)
-ATP is depleted, all myosin heads are tightly bound to actin
-Strong actin/myosin interaction prevents muscle stretching

Front 29

Force production

Back 29

-nerve stimulation determine contractile force
-Force generated is determined by number of active motor units and rate of stimulation
-More motor units activated, more muscle cells produce force, more force
-Increased stimulation leads to incresed Ca++ release, leads to increased force

Front 30

Skeletal muscle contraction is activated by calcium

Back 30

-Production of force is activated by calcium
-When only ATP is present, no force is produced
-Need ATP and Ca++ to produce force

Experiment: removed surface membranes from a single muscle fiber
-isometric tension was recorded in presence of ATP and Ca++ concentrations
-As concentration of Ca++ increased, relative force increased

Front 31

Skeletal Muscle contraction is regulated by thin-filament proteins

Back 31

-Tropomyosin
-Troponin
-Regulatory proteins that respond to calcium

Front 32

Tropomyosin

Back 32

-thin filament
-40nm long coiled-coil, identicl alpha-helical polypeptides
-Regulates muscle contraction
-Inhibits actin/myosin interaction sterically
-No ca++ present, tropomyosin sits on top of actin/myosin interaction site and inhibits interaction
-Ca++ binding to troponin stabilizes tropomyosin away from actin/myosin site
--Ca++ binding "opens" actin/myosin binding site

Front 33

Troponin

Back 33

-Compound protein that regulates muscle contraction
-made up of 3 proteins
-Bind to actin and tropomyosin thin filaments every 7 actin sub-units
-TN-C binds o Ca++ and is closely related to calmodulin
-TN-I inhibits actin/myosin interaction
-TN-T binds to tropomyosin, keeps thin filament together

Works with actin and Ca++ to control muscle contraction
-When Ca++ binds to troponin, causes conformational change and stabilizes tropomyosin in a position that is away from actin/myosin binding site

Front 34

Steric Blocking Model for regulation of muscle contraction

Back 34

-Ca++ binds to troponin, causes tropomyosin to move away from myosin binding site on actin
-Without Ca++ present, tropomyosin covers actin binding site and prevents actin from binding to myosin
-Ca++ mediates movement of tropomyosin by binding to troponin (TN-C)

Front 35

Myosin in absence of Ca++

Back 35

-In absence of Ca++, myosin exists in weak binding states
-Cannot really bind to actin
-ATPase function of myosin is very slow in absence of Ca++
-Myosin holds onto ADP+Pi, will not let go and will not be able to bind to actin
--myosin is "off" in a weak binding state
-Actin binding sites are covered by tropomyosin

Front 36

Force production is proportional to the number of sites that can form cross-bridges

Back 36

-More actin/myosin cross bridges, more force
-More overlap of filaments, more force
-Too much overlap will also decrease force due to steric interactions
--will get an optimal plateau
-Different myosins in different muscles have different ATP release
--property that changes rate limiting step in process

Amount of force generated is related to actin/myosin cross-bridges and amount of time myosin stays in a strong binding site

Front 37

Total tension in contraction is the sum of active and passive tension

Back 37

-Stretching a sarcomere is the sum of active and passive tension

Front 38

Active tension

Back 38

-amount of tension that is generated by interaction of actin and myosin and hydrolysis of ATP
-Tension due to contractile interaction between actin and myosin
-Can be isolated by adding protease and cleaving titin elastic elements

Front 39

Passive tension

Back 39

-Tension due to other elastic elements in parallel with the contractile elements
-Titin is a major elastic element
-Amount of force without activation, without Ca++
-Due to a "spring" within the sarcomere
-Does not require ATP
-Resists pulling
-Force is produced without activation, no Ca++ needed

Front 40

Titin and passive tension

Back 40

-Connects Z-line to myosin filaments

Front 41

Force production in muscle contraction

Back 41

-Depends on the number of myosin molecules per cross-sectional area
--more myosin in cross section, more force
-Force production is proportional to fiber diameteer
--sarcomeres in series produces tension of one sarcomere
-Maximum force developed by a muscle depends on number of fibers in parallel, number of sarcomeres in parallel
-Exercise can incresae the diameter of a fiber, can increase force a fiber can produce

Front 42

Force (Tension) as it relates to sarcomeres

Back 42

-A set of uniform sarcomeres in series produces only as much tension as one sarcomere
--force "cancels out"
-Maximum force developed by a muscle depends in number of fibers in parallel or sarcomeres in parallel
--fewer fibers cancel out
-Force depends on cross-sectional area of the fiber

Front 43

Range of muscle fiber

Back 43

-How much a muscle fiber can shorten
-range = (range of 1 sarcomere) x (number of sarcomeres in series)
-Each sarcomere shortens just a little, has additive effect when sarcomeres are in series

Front 44

Velocity of muscle shortening

Back 44

-Velocity of fiber shortening = (velocity of shortening 1 sarcomere) x (number of sarcomeres in series)
-Velocity of shortening is related to the rate of ADP release from Actin/Myosin ADP bound state
-Longer muscles have larger shortening range and faster shortening rates
--compound effect when in series

Front 45

Advantage of long muscle fibers

Back 45

-Long muscle fibers allow stretch to be distributed over a greater number of sarcomeres
-More sarcomeres in series, greater shortening can occur
-Length-tension curve is spread out along the length of the muscle axis
-For a short fiber to shorten the same length, sarcomeres extend beyond the peak tension, results in less effective shortening
--force per cross-sectional area decreases

Front 46

Disadvantage to long muscle fibers

Back 46

-Increasing number of sarcomeres in series does not increase maximum tension
-increses amount of energy required to produce muscle
--actin and myosin fibers take energy to produce and maintain

Front 47

Isometric contraction

Back 47

-Muscle develops force at a constant length
-muscle does not stretch when force is applied
-All available myosin molecules are involved in resisting the opposing force
--no myosin available to allow shortening
--adding more myosin will allow muscle to shorten (not biologically possible in the moment)

Front 48

Isotonic contraction

Back 48

-Muscle shortens under constant load
-Fewer myosins are needed to resist load, extra ccross-bridges are available to shorten sarcomeres
-Rate is limited by rate of ADP release/ ATPase activity
-At very low loads, myosin slides along actin filament, very few myosin are interacting with actin filaments
-Velocity is limited by the rate of ADP release

Front 49

Force-velocity relationship and muscle shortening

Back 49

-Steady state velocity of muscle shortening depends on load
-At maximum tension, have isometric contraction
--muscle is unable to shorten
--Most force is generated at maximum load and minimum velocity
-At maximum velocity, have isotonic contraction
--muscle has no load and is able to move very quickly
--least force is generated at maximum velocity and no load

-Related to ATPase activity

Front 50

Slow fibers vs. Fast fibers

Back 50

-Small diameter vs. large diameter
-Darker color due to myoglobin vs. paler
-Fatigue-resistant vs. easily fatigued
-Endurance muscles vs. sprinting muscles

Front 51

Slow-twitch type I fibers

Back 51

-Low, slow myosin ATPase
-High amount of oxidative enzymes, aerobic metabolism
-Low glycogen content
-small diameter
-Slow twitch speed
-Small motor neuron size, one motor neuron innervates just a few fibers

Front 52

Fast twitch type IIb fibers

Back 52

-Sprinting muscles
-make ATP quickly and fatigue quickly
-Low amounts of oxidative enzymes, mostly anaerobic mechanisms
-large diameter fibers
-Large motor unit size, one motor neuron will innervate many fibers

Front 53

Different muscle fiber types have different force/velocity relationships

Back 53

important for different functions!

Front 54

parallel muscles

Back 54

-Long fibers arranged in parallel to length of muscle
-Produce a greater range of movement and forces
-biceps, most skeletal muscles in the body

Front 55

Pennate muscles

Back 55

-Shorter fibers arranged obliquely
-Increases cross-sectional area of the muscle
--increases force the muscle can generate
-Angular pull decreases range of motion

Front 56

Convergent muscles

Back 56

-Muscle fibers are spread over a broad area
-Versatile contraction, stimulation of only one portion of muscle can change direction of pull
-When entire muscle contracts, muscle fibers do not pull as hard on the attachment

Front 57

Circular muscles

Back 57

-Muscle fibers are concentrically arranged around an opening or a recess
-Muscle contraction decreases the diameter of the opening

Front 58

Lever Systems

Back 58

1. Fulcrum lies between the effort and the load
-increases speed of movement and overcomes resistance
2. Load lies between the fulcrum and the effort
-overcomes resistance
3. Effort lies between the fulcrum and the load
-load can be moved rapidly over a large distance while point of application moves over a small distance
-rapid movement can be obtained

Front 59

Static Equilibrium

Back 59

F1D1=F2D2

Front 60

General Functions of Ion Fluxes and Ions

Back 60

-Establish membrane potential (Na, K)
-Action potential transmission
-Excitation/contraction coupling
-Secretion and exocytosis
-gene transcription and differentiation

Ion channels are one of the main therapeutic targets of drugs used in medical practice

Front 61

Ion flux and volume regulation

Back 61

-Ion fluxes regulate volume and water balance
-Na, K and Cl ions
-Regulate pH with protin transport
-Regulate adhesion and motility of Ca and K

Ion channels are one of the main therapeutic targets of drugs used in medical practice

Front 62

Myasthenia Gravis

Back 62

-Neuromuscular autoimmune disease
-Caused by antibodies generated against nicotinic acetylcholine receptors
-Antibodies block ACh receptors at post-synaptic neuromuscular junction
--prevents ACh from stimulating muscular contraciton
-Problem is in post-synaptic neuron
-Results in weakness
--no muscle contraction is stimulated
-Tensilon Test: administer tensilon (antiacetylcholinesterase)

Front 63

Lambert Eaton Syndrome

Back 63

-Similar to Myasthenia Gravis
-Antibodies target N-type calcium channels located in neuromuscular junction
--Prevent normal function of calcium channels, prevent release of ACh into synaptic cleft
-No ACh, no contraction
-Problem is in pre-synaptic neuron

Front 64

Channelopathies in Vet med

Back 64

-Epilepsy, seizures, ataxia
--mutations in ligand-gated or voltage-gated ion channels
-Hyperkalemic Periodic Paralysis (Impressive Syndrome)
-Porcine Stress Syndrome

Front 65

Hyperkalemic Periodic Paralysis
(HYPP)

Back 65

-"Impressive Syndrome"
-Affects quarterhorses
-Very strong, muscled horses that have episodes of weakness, collapse, and death
-Characterized by hyperkalemia, high K levels in serum
--due to mutation in Na channel gene, disruption of Na into cell disrupts K also
--more K moves out of cell than should
-Mutation in Na channel gene causes unequal distribution of ions across cell membrane
--voltage across cell membrane is disrupted
-Named for individual horse, "impressive" that was bred repeatedly
--has many descendents
--if Homozygous mutation, horses die

Front 66

Porcine Stress Syndrome

Back 66

-Autosomal recessive inherited neuromuscular disorder
-Mutation in ryanodine receptor gene
-Causes malignant hyperthermia in pigs
-Triggered by stress, exercise, or halothane inhalation
-Abnormal release of Ca++ from sarcoplasmic reticulum
--SERCA ATPases have to work continuously to restore Ca++ back into ER
-Hyperactive RyR, increased opening of RyR channels and more Ca release into sarcoplasm
-Tx: Block RyR and decrease intracellular Ca levels (dantrolene)
--extra ATP burned produces excessive heat, results in lethal increase in body temp
-decreases quality of meat in pigs

Front 67

nAChR

Back 67

-Nicotinic Acetylcholine Receptor
-made up of multiple sub-units
--2 alpha, beta, gamma, delta
-Opening is triggered by ligand binding
--ACh binds to receptor site on alpha receptor, opens to allow Na+ and K+ ions to flood into the cell
-Ionotropic receptor, can pass ions

Front 68

Ion Channel Classification

Back 68

1. Activation/gating mechanism
-voltage gated channels
-extracellular ligand-gated channels
-intracellular ligand-gated channels (AKA 2nd messenger gated channels)
-Stretch activated channels
2. Ion permeability
-plasma membrane Ca++ channels

Front 69

Voltage-gated ion channels

Back 69

-Regulated by changes in membrane voltage
-Made up of alpha pore-forming subunits and accessory sub-units
--Alpha subunits determine ion selectivity, mediate voltage sensing
--Accessory sub-units modulate functions
-Voltage-gated K, Na, and Ca++ channels
-When voltage changes, flaps in channel structure are drawn towards opposite charge and physically open channel

Front 70

Ligand-gated ion channels
Extracellular

Back 70

-Activated by a ligand binding to extracellular surface
-Nicotinic receptors (nAChR)
-Glutamate/GABA receptors
-ATP-gated channels (P2X)

Front 71

Ligand-gated ion channels
Intracellular

Back 71

-AKA 2nd messenger gated channels
-Activated by a ligand binding to intracellular surface
-Transient receptor potential channels (TRP)
-Triggered by G-protein and other small molecules within the cells

Front 72

Stretch Activated Ion Channels

Back 72

-ion channels activated by physical or mechanical stress or stretch

Front 73

Voltage-gated calcium channels

Back 73

-Sit on plasma membrane
-N-type and L-type
-Gated by voltage, open with membrane depolarization

Front 74

L-type calcium voltage-gated channel

Back 74

-Found in muscle and nerves
-Sensitive to dihydropyridine blockers
-Gated by voltage, need membrane depolarization to open

Front 75

N-type calcium voltage-gated channels

Back 75

-Found at pre-synaptic nerve terminals
-Blocked by snail toxins (conotoxins)
-Mediate Ca++ influx required for neurotransmitter release
-Gated by voltage, need membrane depolarization to open

Front 76

Ligand gated Calcium channels

Back 76

-Non-selective cation channels (NSCCs)
-Ion channels are regulated by ligands that bind to either inside or outside of the cell
-Allow movement of Calcium (along with other cations, Na, K, Ca)
--NOT specific for calcium
--Small changes in calcium levels can have a major effect on the cell, other ions have less of an effect on cell overall
-ACh receptors (post-synaptic membrane on muscle fiber, causes local depolarization)
-Purigenic receptor/channels (P2X, gated by nucleotide binding)
-Transient receptor Potential channels (TRP channels, regulated by changes in temperature, pain, osmolarity, olfaction, lipids)

Front 77

Non-specific Calcium Channels

Back 77

-AKA ligand gated calcium channels
-Allow many ions through, calcium concentration changes have the largest effect on the interior environment of the cell
-ACh receptors on post-synaptic terminals
-Purigenic receptor (P2X) gated by nucleotide binding
-Transient receptor Potential (TRP) channels respond to pain, temperature, osmolarity, olfaction, lipids

Front 78

Ions distribution across the plasma membrane

Back 78

-Ions are asymmetrically distributed across the plasma membrane
-Ions act as 2nd messengers
--Stimulate gene transcription
--Stimulate fusion of vesicles with plasma membrane to release neurotransmitters
-Ionic gradients are a direct and indirect source of potential energy
--can be used to power other cellular functions without depleting cell's ATP

Front 79

Electrochemical gradient

Back 79

-Balance between the electrical and chemical potential of an ion across a membrane
--electrical= membrane potential
--chemical= concentration gradient
-Equilibrium: no net ion flux across the membrane
--tendency of an ion to move down its concentration gradient is exactly counter-balanced by an opposing electrical gradient
-Each ion pumps to its own individual gradient across the plasma membrane

Front 80

Typical Myocyte Electrochemical gradient

Back 80

-Lots of K inside, less outside
-Minimal amount of Ca++ inside, more outside, still in small amounts
-Low Na inside, LOTS of Na outside

Front 81

Production of asymmetrical ion distribution across the plasma membrane

Back 81

-Active mechanisms, use ATP to produce asymmetrical distribution
-Active and facilitated transport:
--ATP fueled pumps (ATPases)
--Gradient facilitated transporters/exchangers
-Gradients can be dissipated by passive diffusion through channels
--ions diffuse rapidly over short distances, slowly over long distances
--inefficient transport over long distances

Front 82

Na/K ATPase

Back 82

-Uses ATP to create a concentration gradient
-Direct active transport, energy-dependent
-Consumes a lot of energy
-ATP hydrolysis fuels exchange of 3 Na for 2 K
-Generates an electrical charge, net negative charge on the inside of the cell (electrogenic)
--Energetically unfavorable process, moving across concentration gradient

Front 83

Ca++ ATPase

Back 83

-Active ion transporter
-Plasma membrane Calcium ATPases (PMCA)
-Sarcoplasmic-Endoplasmic Reticulum Calcium ATPases (SERCA)
--on inside of cell, SR membrane
-Important in skeletal and smooth muscle contraction
-Keep calcium concentrations in cytoplasm very low!

Front 84

Indirect Active transporters

Back 84

-Facilitated exchangers/transporters
-Use energy stored in electrochemical gradient to move other ions against concentration gradient
-Na/Ca exchanged: reversible, uses favorable gradient for one ion to move other ion against gradient unfavorably
-Na/H exchanger (Na in, H protons out): used for pH regulation
-Na/Glucose co-transporter

Front 85

Digitalis

Back 85

-Isolated from foxglove plant
-Used to treat "dropsy" (congestive heart failure)
-Potent and specific blocker
--blocks Na/K ATPase, turns pump off
--Na accumulates within the cell
--Causes Na/Ca exchanger to switch directions and pump Na out, Ca in
--Ca accumulates within the cell, leads to enhanced muscle contraction

Front 86

Excitation-Contraction Coupling

Back 86

-Signal transduction mechanism by which extrinsic signals are translated or converted into a mechanical response
-Converting signal from the brain into a mechanical response
-Contraction/relaxation of skeletal or smooth muscle
--DIRECT function of intracellular Ca concentration
-AP is propagated by Na entry into the cell, becomes converted into an elevation in Ca

Front 87

Steps in Excitation-Contraction Coupling

Back 87

1. Synaptic Transmission:
-Action potential propagated down a neuron is converted to initial depolarization of the muscle membrane
-brain generates signal to contract muscles
2. Action potential propagation in muscle:
-Propagation along muscle fiber
3. Excitation-Contraction Coupling
-Results in increase in cytoplasmic Ca

Front 88

Excitatory and Inhibitory signal integration

Back 88

-Neurons integrate excitatory and inhibitory signals
-Fire when activation threshold of Na channels is crossed
-Threshold has to be reached
-All or none response

Front 89

Action potential transmission across synaptic cleft

Back 89

-Action potential activates voltage-gated Ca channels (N-type, at pre-synaptic terminal)
-Ca influx into presynaptic terminal causes vesicles containing ACh to fuse with plasma membrane
-ACh is release in the synaptic cleft
-ACh binds to ligand-gated nicotinic ACh receptors/channels on post-synaptic membrane
--nicotinic ACh receptors open, causes influx of Na into post-synaptic membrane
-Influx of Na causes depolarization, spreads to adjacent membrane areas and activates voltage-gated Na channels
--allows even more Na to flow into membrane, causes depolarizing wave to spread throughout cell

Front 90

ACh in synaptic cleft

Acetylcholinesterases

Back 90

-VERY short-lived
-Allows rapid action and release
-Acetylcholinesterases degrade ACh in the synaptic cleft

Front 91

Tensilon and Acetylcholinesterase

Back 91

-Tensilon (edrophonium chloride) is an anti-acetylcholinesterase
-Blocks acetylcholinesterase, ACh does not break down in synaptic cleft
--Allows ACh to accumulate to a certain extent
-Accumulated ACh has a prolonged effect on ACh receptors
-In Myasthenia Gravis, ACh can stimulate the few ACh receptors for longer
--prolongs muscle stimulation and strength temporarily

Front 92

Action potentials at the NeuroMuscular Junction

Back 92

-Depolarization at the neuromuscular junction results in all-or-none action potential at muscle cell membrane
-All pre-synaptic excitatory or inhibitory activity is integrated in presynaptic nerve
-AP in muscle has a longer hyperpolarizing tail than neuron
--due to influx of Ca through L-type channels at muscle membrane
--K/Ca ligand gated channels repolarize the membrane
--Slower response in muscle cell

Front 93

T-Tubules

Back 93

-Invaginations of the plasma membrane
-Come into close contact with muscle fibers and sarcoplasmic reticulum
-Way to get AP quickly down into the muscle where the fibers are
--allows quick contractions
-Spread AP along the skeletal muscle cell membrane to contraction machinery
-Cause Ca release from sarcoplasmic reticulum
-Close to sarcoplasmic reticulum, but not contiguous
--parallel but separate
-L-type receptors, Dihydropyridine receptors (voltage gated channels

Front 94

Action Potential Triggering

Back 94

-Neuronal signals trigger AP in muscle cells they innervate
-Results in a voltage change that is transmitted through T-Tubules
-Voltage sensing proteins on T-tubules trigger opening of Ca channels in membrane of Sarcoplasmic reticulum
-Results in release of Ca into the cytosol

Front 95

Role of Calcium in skeletal muscle contraction

Back 95

-Skeletal muscle is REVERSIBLE
-Ca channels in sarcoplasmic reticulum membrane open transiently (can open and close)
-ATP-dependent Ca pumps in SR re-sequester Ca after contraction
-As Ca levels fall, Ca dissociated from troponin C
--causes conformational change in troponin/tropomyosin complex, blocks actin/myosin binding sites
-KEEPING Ca LEVELS LOW IS CRITICAL!

Front 96

Calcium concentrations across muscle cell membrane

Back 96

-HUGE difference in concentrations
-10-3 Ca on outside, 10-7 Ca on inside
--MUCH more Ca on outside, tightly regulated
-ATP is used to establish the gradient, direct active transport
--Plasma membrane Calcium pump
--Sarcoplasmic-endoplasmic reticulum calcium pump

Front 97

Triad

Back 97

-Terminal cisternae of SR (2, one on either side) and T-tubules
-Structure formed by T-tubule and terminal cisternae of SR on either side
-Looks like a butterfly
-Highly ordered arrangement of dihydropyridine and ryanodine receptors is the structural basis for depolarization-induced release of Ca from the sarcoplasmic reticulum in skeletal muscle Excitation-contraction coupling
-Contain specialized structures: Ca release units
--4 dihydropyridine receptors, 1 ryanodine receptor
--Crystal-like arrangement

Front 98

Sarcoplasmic Reticulum

Back 98

-Complex network of intercellular membranes within the muscle cell
-Surround myofibrils
-In close proximity to the T-tubules, but not contiguous with T-tubules
--parallel, but separate
-Ryanodine Receptors (RyR

Front 99

Tetrad

Back 99

-Single ryanodine receptor associated with 4 individual dihydropyridine receptors
-highly ordered arrangement for most efficient coupling of Ca release
-Exist within triad
--junction between SR and T-tubule
-In inactive state, DHPRs are waiting in the plasma membrane, waiting for depolarization
--directly coupled to RyR receptors (in closed/inactive conformation)
-With depolarization, receptors are uncoupled from RyR
--Ca can flood sarcoplasm of cell rapidly

Front 100

Ryanodine Receptors (RyR)

Back 100

-Major cellular mediator of calcium-induced release in muscle cells
-Present intracellularly on sarcoplasmic reticulum
-In skeletal muscle, are coupled to L-type dihydropyridine calcium channels
-Can be activated by calcium directly and through structural coupling with DHPRs

Front 101

Direct activation of RyRs via Calcium

Back 101

-Calcium induced-calcium release channels
-Ca directly causes channels to open
-Every other RyR is coupled to DHPR, rest are not coupled but on own
--on own close to coupled receptors
-Ca flows into Sarcoplasmic space, binds to RyR receptors directly and opens them
-Allows RyR to be major cellular mediator of Ca-induced Ca release
-Positive feedback, Ca influx activates one receptor to open and allow Ca influx, which then activates other Ca channels

Front 102

Ion channels involved in skeletal muscle contraction
Review

Back 102

1. Voltage-gated Na channels propagate depolarizing wave down neuronal membrane to NMJ
2. N-type voltage-gated Ca channels open, allow Ca to flow into pre-synaptic terminal
-ACh vesicles are released, fuse with membrane and ACh is released into synaptic cleft
3. ACh binds to ligand-gated nicotinic ACh receptors on post-synaptic membrane
-allows Na to flow into cell, causes local depolarization
4. Voltage-gated Na channels propagate depolarizing wave down muscle cell membrane/sarcolemma and T-Tubules
5. DHPRs/L-type voltage gated Ca channels along T-tubules are activated, allow flow of Ca into sarcoplasm
-L-type voltage-gated Ca channels couple directly with RyR on sarcoplasmic reticulum
--RyR open via conformational change
6. Ca release from Sarcoplasmic reticulum into sarcoplasm further activates RyR directly
-Positive feedback, causes release of large amounts of Ca into sarcoplasm
7. Ca is re-sequestered into sarcoplasmic reticulum by Ca ATPases (PMCA, SERCA) and Na/Ca exchanged

Front 103

Skeletal Muscle growth and hypertrophy

Back 103

-Total number of skeletal muscle fibers is fixed early in life
-During development, muscles grow and develop
--at some point, myostatin gene is turned on and prevents muscles from growing too big
-Mutation in myostatin can lead to hypertrophy, HUGE muscles!

Front 104

Myostatin

Back 104

-Cytokine
-Member of TFG-beta family
-Synthesized in muscle cells during development
-circulates as a hormone later in life
-Decreases skeletal muscle growth, indicates when muscle has grown enough
--Suppresses skeletal muscle development
-Mutations in myostatin can lead to muscle hypertrophy
--HUGE muscles!

Front 105

Myostatin KO mice

Back 105

-Myostatin knockout mice
-Inactive/mutated myostatin gene
-"Mighty Mice"

Front 106

Myostatin mechanism of action

Back 106

-Inhibits differentiation of myoblsts into mature muscle fibers
-Prevents development of muscle fiber from initial myotube formation
-Inhibits the serine/threonine kinase (Akt)
--inhibits Akt-induced protein synthesis
-No myostatin, Akt-induced protein synthesis continues

Front 107

Myostatin mutation in whippets

Back 107

-Racing whippets are known for myostatin mutations
-Homozygous dominant/wild-type dogs do not have larger muscle mass and are not used for racing
-heterozygous dogs have larger muscles and are used for racing
--desired phenotype and genotype
--Muscle development but not HUGE muscle development
-Homozygous mutant dogs have HUGE muscles and are used for breeding
--"bully-whippets"

Front 108

Belgian Blue Bull and Myostatin

Back 108

-Double muscling phenotype
--muscles grow on top of each other
-HUGE HUGE muscles, lean beef
-Delicacy in brittain
-Do not reproduce very well

Front 109

Smooth Muscle Functions

Back 109

1. Vascular tone and maintenance of blood pressure
2. Muscular sphincters
--control blood distribution in capillary beds
3. Airway diameter in muscular bronchi and bronchioles
4. GI emptying, peristalsis, sphincters
5. Hollow organ size and pressure regulation

Front 110

Smooth Muscle Excitation-Contraction coupling

Back 110

-Contraction is initiated by appearance of free cytosolic Ca
-Ca gets into cell and is regulated by a totally different mechanism from skeletal muscle
-Contraction is under complex local regulation

Front 111

Smooth muscle overview

Back 111

-Involuntary control
-Unstriated, no sarcomere units
-Found in walls of hollow organs and tubes
-Specialized for slow but powerful contractions
-Elongated, spindle-shaped cells
-Mononucleate
-Arranged in layered sheets/bundles (allow for strong contractions)
-Irregular organization of contractile machinery within the cell
--no sarcomeres, t-tubules, or troponin

Front 112

Smooth Muscle Contraction

Back 112

-Contraction appears to be random and less efficient
-Capable of producing just as much force per cross-sectional area as skeletal muscle
-Entire cell contracts towards center of cell
-Myosin lines up with focal plaques/densities on plasma membrane
--Complex network of myosin/actin fibers attached to focal densities
-Can have depolarization AND receptor-stimulation to elevate intracellular Ca

Front 113

Multi-unit Smooth Muscle

Back 113

-Each muscle fiber is innervated by own axon
--Acts independently of other smooth muscle fibers
-Highly innervated
-One or more axon coming into each muscle cell
-Multiple distinct units that function independently of each other
--units must be stimulated by nerves to contract
-Neurogenic Contraction
-Allows for rapid, quick response
-Large blood vessels, large airways, eye muscles (pupil), piloerector muscles

Front 114

Single-unit smooth muscle

Back 114

-Visceral smooth muscle
-One nerve comes and innervates group of cells
-Gap junctions allow electrical communication between cells
--allow for coordinated contraction without simultaneous individual innervation
--Contracts as a single cohesive unit
-Dense sheets facilitate simultaneous contraction
-Self-excitable contraction (myogenic contraction)
-occurs in majority of smooth muscle
-Lines hollow organs (Urinary bladder, GI, uterus, vascular smooth muscle)
-generally sparse innervation
-1 nerve to 1 muscle cells to many muscle cells

Front 115

Self-excitable contraction
Myogenic contraction

Back 115

-Muscle cells do not necessarity require nerve stimulation to fire an AP and contract
-Pace-maker like activity
-Signal/electrical impulse originates within the muscle
-Depolarization occurs through movement of ions that is not due to neurogenic stimulation

Front 116

Spread of action potentials through single-unit smooth muscle cells

Back 116

-Sparse innervation
-Gap junctions allow movement of ions between cells, can allow depolarization

Front 117

Gap Junctions

Back 117

-"holes" in the muscle cell wall
-Facilitate electrical and metabolic coupling of adjacent smooth muscle fibers
-Allows cells to function in a coordinated fashion
-Junctions are opened by Ca, H, or depolarization
-Adjacent gap junctions lie on top of each other and can pass ions directly

Front 118

Local control of muscle contraction

Back 118

-Receptor stimulation
-In smooth muscles
-Allows intracellular Ca to increase without direct neuronal stimulation

Front 119

Ligand-induced intracellular calcium release

Back 119

-Specific to smooth muscle cells
-Extracellular-gated channels (P2X)
-ACh-ligand gated channels
-G-protein coupled receptor activation

Front 120

Mechanisms of Calcium elevation in smooth muscle
Action potentials

Back 120

-Post-synaptic ACh receptors cause local depolarization at neuro-muscular junction
-Local depolarization activates L-type voltage-gated calcium channels
--AP is voltage-gated calcium channel dependent in smooth muscles
--NOT Na mediated, no voltage-gated Na channels in mooth muscle, no T-tubules
-Ca influx due to opening of voltage-gated calcium channels can cause contraction

Front 121

Mechanisms of Calcium elevation in smooth muscle
Local Depolarization

Back 121

-Membrane depolarization occurs due to Chloride channel inactivation
--Cl- charges are not allowed into cell, cell is in a naturally more positive state
-K channel inactivation
--prevent + charges from leaving the cell, results in cell interior being more positive
-If cell charge is already closer to depolarization, takes less stimulus to make cell contract

Front 122

Mechanisms of Calcium elevation in smooth muscle
G-protein coupled receptor signaling

Back 122

-Indirect mechanism
-Mechanism is independent of membrane potential
-Calcium released from stores by IP3 2nd messenger
--IP3 binds to receptor/Ca channel
-Ligand-gated nicotinic receptor (TRP) allows Ca into cell

Front 123

Mechanisms of Calcium elevation in smooth muscle
Direct ligand gating

Back 123

-P2X receptors/channels
-ATP gated channels
-Non-selective channels between monovalent cations
--Ca can permeate
-Mechanism of local regulation of tone

Front 124

Mechanisms of Calcium elevation in smooth muscle

Back 124

1. Action potentials
2. Localized depolarization
3. G-protein coupled receptor signaling
4. Direct ligand-gating

Front 125

Indirect mechanism for calcium release

Back 125

-In smooth muscle cells
-Usually via G-protein coupled receptors and 2nd messengers
-Receptor triggers G-protein, phosphorylates GTP, activates Adenylyl cyclase, forms cAMP, activates IP3, IP3 opens receptor

Front 126

Local regulation of smooth muscle tone

Back 126

-ESSENTIAL for smooth muscle function
-Want varied contraction throughout the system, achievable through local control
-Organs lined by smooth muscle contract differently across the membrane
-Direct gating and indirect gating allows more precise contraction
-

Front 127

Regulation of smooth muscle contraction

Back 127

-Contraction occurs by binding of myosin to actin
-Smooth muscle lacks troponin C
--Ca binds to calmodulin, induces conformational change in calmodulin and allows calmodulin to bind to myosin light-chain kinase
-Myosin light-chain kinase phosphorylates myosin light-chains, activates ATPase activity
-Allows myosin to interact with actin and cause muscle contraction
-Cross-bridge cycling will repeat as long as myosin light-chains are phosphorylated

Front 128

Calmodulin

Back 128

-Protein in smooth muscle contraction
-Calcium binds to calmodulin (no troponin C in smooth muscle)
--Forms calcium-calmodulin complex
--causes conformational change
-After Ca binding and conformational change, calmodulin in active form can bind to myosin light-chain kinase and activate myosin light-chain kinase

Front 129

Myosin Light-chain Kinase
MLCK

Back 129

-Kinase, phosphorylates myosin light chains
-Phosphorylation activates ATPase activity of myosin light chains
--can now bind to actin and cause muscle to contract

Front 130

Regulation of smooth muscle contraction inactivation

Back 130

-Cross-bridge cycling will repeat as long as myosin light-chains are phosphorylated
-2 methods of inactivation
--1. Removal of phosphate by myosin light-chain phosphatase (MLCP)
--Myosin light chain ATPase will remain active until myosin light-chain phosphatase removes phosphate
--2. Dissociation of calcium from calmodulin
--As calcium decreases in the cell, dissociated and inactivates calmodulin

Front 131

Myosin light-chain phosphatase

Back 131

-Active in smooth muscle contraction inactivation
-removes phosphates from myosin light-chains
-Inactivates ATPase activity of myosin light chains
--Myosin can no longer interact with actin
--Smooth Muscle contraction stops

Front 132

High blood pressure and smooth muscle contraction

Back 132

-high blood pressure can be associated to defects with smooth muscle contraction inactivation
-if there is an issue with MLC-phosphatase or calmodulin-calcium dissociation, muscle will continue to contract and cause constriction of blood vessels
--AKA high blood pressure
--Need to be able to relax vessels

Front 133

Calcium removal in smooth muscle contraction

Back 133

-Smooth muscle has relatively slow rate of Ca removal from system (compared to skeletal and cardiac muscle)
-Uses same methods as skeletal and cardiac muscle
--Plasma membrane calcium ATPase (PMCA)
--Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA)
--Na/K exchanger
-Adenylyl Cyclase pathway: Protein Kinase A phosphorylates and activates K channels for repolarization
-K channels to repolarize the cell
--Ca-activated K channel
--Voltage-gated K channel
--ATP-sensitive K channel

Front 134

Potassium channels in smooth muscle cell contraction inactivation

Back 134

-Additional method smooth muscle uses to repolarize cell and stop contraction
-Ca-activated K channel:
--opens by depolarization and increased Ca
--activated by events assoicated with action potential (negative feedback)
-Voltage-gated K channel:
--sets resting membrane potential and limits extent of depolarization
-ATP-sensitive K channel:
--open when ATP levels fall (with contraction)
--negative feedback system

Front 135

Membrane Potential, Action potential and Ca
Skeletal vs. Smooth muscle

Back 135

-Skeletal muscle:
--intracellular stores in SR provide Ca for contraction
--intracellular Ca is released by AP
-Smooth Muscle:
--Voltage-independent (ligand-induced) Ca release from intracellular stores
--Voltage-activated L-type Ca channels increase Ca
--Ligand mediated regulation of tone is predominant means of contraction

Mechanisms of Ca regulation are more complex in smooth muscle than calcium channels

Front 136

Primary Pathologies of Smooth Muscle

Back 136

-Rare!
-Usually are a secondary result of other diseases
-Exist more commonly in human medicine
-Many diseases exist that result in changes in smooth muscle activation or relaxation
--disease affects smooth muscle, but disease is really somewhere else

Front 137

Smooth muscle location in body

Back 137

-Lines hollow organs
-GI tract
-Urinary bladder
-Endothelium and blood vessels (ALL blood vessels have smooth muscle)
-Uterus
-Vas Deferens
-Bronchioles

Front 138

Smooth muscle epithelial lining

Back 138

ALWAYS present, if epithelial lining is absent, something is wrong with the muscle

Front 139

Smooth muscle shape

Back 139

-Fusiform shape, spindle-shaped
-LOTS of nerves (can have pathology associated with innervation)
-Usually exists in an inner circular layer and outer longitudinal layer

Front 140

Smooth muscle innervation

Back 140

-LOTS of innervation and pathology associated with innervation

Front 141

Smooth muscle force generation and length

Back 141

-Smooth muscle generates force over huge changes in fiber length
-LOTS of force needed over a large area
-Excessive stretching will decrease force and damage skeletal muscle, smooth muscles need to be able to stretch a lot

Front 142

Smooth muscle composition and cell geography

Back 142

-Have actin, myosin, and intermediate filaments
-Thin filaments attach to Z-discs, Z-discs attach to many different units at dense bodies
-Allows muscle to generate force throughout the cell body
-Contraction at many angles, not just in parallel lines
-Allows increased force generation

Front 143

Dense Bodies

Back 143

-Locations within smooth muscle cell where a number of actin filaments attach
--analogous to Z-disc in skeletal muscle
-Connect and contract at many angles, not just in parallel lines
-Allows increased force generation during contraction
-Very regulated structure, may appear random but in fact is very regulated

Front 144

Myosin in Smooth msucle

Back 144

-Same as in skeletal muscle
-2 heavy chains
-2 essential myosin light chains (structural support)
-2 regulatory myosin light chains (VERY important and controls activation of the muscle)

Front 145

Myosin in skeletal muscle contraction

Back 145

-Chemical energy in ATP is converted into mechanical energy by myosin protein
-Generates motion and force

Front 146

Isoforms of smooth muscle Myosin

Back 146

-4 total, 2 mutations at each end of the protein
-Tonic smooth muscle: slower, more energy-efficient contraction
-Phasic smooth muscle: faster contracting muscle

Both isoforms produce the same force as skeletal muscle but are orders of magnitude slower

Front 147

Tonic smooth muscle

Back 147

-Slower, energy-efficient contraction of smooth muscle
-Slower hydrolysis of ATP
-Generates force over a long period of time
-Important in vascular endothelium
-Want to conserve energy

Front 148

Phasic smooth muscle

Back 148

-faster muscle contraction in smooth muscle
-Muscle contracts for short period but generates a lot of force for a short period of time
-Less concerned with energy conservation
-Still much slower than slowest skeletal muscle contractions

Front 149

Cardiomyopathy in cardiac muscle

Back 149

-Mutation of myosin heavy chain
--allows quicker contraction
-Muscle burns more ATP to accommodate quick contractions
-Mutation is an energetic detriment
--results in negative energy balance

Front 150

Fast vs. slow twitch muscle

Back 150

-Sprinting is fast-twitch for quick power
--faster muscle fibers produce higher power but require more energy
-Endurance requires slow-twitch
-Cost/benefit to different compositions of muscle
-Composition can be genetically determined

Front 151

Control of smooth muscle activation

Back 151

-Myosin light-chain phosphorylation by myosin light-chain kinase (MLCK)
-intracellular calcium levels control smooth muscle contraction

Front 152

Calcium-calmodulin complex

Back 152

-Complex of 4 Calcium molecules and 1 calmodulin molecule
-Active complex, interacts with myosin light-chain kinase
--Activates myosin light-chain kinase and allows it to phosphorylate myosin light chains
--allows actin-myosin interaction

Front 153

"All or none" response in smooth muscle

Back 153

-Does not exist, not an all-or-none response
--GRADED response
-Can have 50% phosphorylated, 50% not phosphorylated at maximum
-Will most likely not have less than 10% phosphorylated at any time in the muscle
-Relative activity of MCLK and MLCPhos determine percentage of phosphorylation and dephosphorylation of chains
-more Calcium, more Ca/Calmodulin, more phosphorylation and more force generation
-Relative activation of MLCK and MLCphos determine the amount of force being generated by the muscle
--Balance of contraction, always have baseline tone/contraction
--rarely want maximum contraction, rarely want zero contraction
-Lack of "all or none" response allows therapeutic manipulation of smooth muscle for therapeutic effects

Front 154

Calcium levels in smooth muscle

Back 154

-Calcium must interact with calmodulin to be able to have an effect on smooth muscle cell
--NO troponin C in smooth muscle
-Ca only affects Myosin Light-chain Kinase activity, Only controls forward reaction!
-C does NOT affect Myosin Light-chain phosphatase activity

Front 155

Benefit of no all-or-none response in smooth muscle

Back 155

-Allows therapeutic manipulation of smooth muscle
-Can give medications to get gradual increases in pressure
-Effective in blood pressure medication

Front 156

Smooth Muscle Agonists

Back 156

-Allow smooth muscle contraction
-LOTS of smooth muscle agonists exist, many differe molecules
--NOT one molecule producing an all-or-none response
--very few skeletal muscle agonists, ACh is only one
-All act by affecting Ca, MLCK, MLCPhos

Front 157

Smooth muscle Antagonists

Back 157

-Promote muscle relaxation
-put Myosin light chains into unphosphorylated state

Front 158

Histamine effect on Smooth Muscle

Back 158

-Acts as an agonist AND antagonist
-Constricts certain tissues and dilates others
-produced by mast cells or basophils
-Released due to immune mediated stimulation of basophil or mast cells
-4 different receptors (H1, H2, H3, H4)
--Smooth muscle receptors are H1
-2nd messenger signaling produces a tissue-specific effect
-Worry about excessive response from immune system

Front 159

Adrenergic Agonists

Back 159

-Cause both vasoconstriction (contraction) and vasodilation (relaxation) in vascular smooth muscle
-Requires specificity of drugs in therapy

Front 160

Methods of smooth muscle regulation

Back 160

-Many methods of regulation
-Stretch or shortening
-nerve stimulation
-Sympathetic and parasympathetic innervation
-paracrine signaling
-endocrine signaling

Front 161

Parasympathetic neurotransmitter in Smooth Muscle Contraction

Back 161

-ACh
-Difference occurs in ACh receptor on cells
-Muscarinic receptor is in smooth muscles and CNS
--has a G-protein linked signaling system
-Nicotinic receptor is in skeletal muscle and CNS
--no 2nd messenger

Front 162

Sympathetic neurotransmitter in smooth muscle contraction

Back 162

-Norepinephrine
-Short half-life
-NT form of epinephrine

Front 163

Endothelial-derived Relaxing Factor
NO

Back 163

-Vasodilator (Profound vasodilator)
-Synthesized by NO synthase
-Produced by endothelial lining of the blood vessels
-Paracrine and autocrine effect, local vasodilation
-Meds: nitroglycerine, viagra
-Causes vasodilation through a 2nd messenger pathway
--lowers intracellular Ca

Front 164

All smooth muscle cells have many different cell surface receptors

Back 164

-MMuscarinic, adrenergic, NO
-Smooth muscle can respond appropriately to many different physiological stimuli
-Some conditions will result in an over-expression of receptors (excessive response)

Front 165

Smooth muscle in disease

Back 165

1. Agonist stimulation
--feline asthma
--feline urogenital syndrome
2. Ca signaling
--Canine dystocia
--feline hypertension
3. Intracellular signaling
--diabetic cystopathy

Pathology is usually primarily elsewhere, expression is through smooth muscle

Front 166

Feline Asthma

Back 166

-Type I hypersensitivity reaction to inhaled allergens
-Immune mediated response
-Cat airways are hypersensitive
--results in profound bronchoconstriction after exposure to histamine
-Air is trapped in lung, hyper-inflated lung cannot move air
-Wheezing, coughing, dyspnea
-Potentially fatal
-Tx: glucocorticoids (slow-acting) and bronchodilators (fast-acting)
--have to be careful can kill cat with meds
-Smooth muscle is acting normally, constriction results from immune response due to histamine
--Hypersensitivity reaction

Front 167

Urinary tract obstruction in Cats

Back 167

-Urinary calculi from mechanical obstruction of urethra
-Urine backs up into urinary bladder and into kidneys
-Tx: open bladder and remove to allow urination
--bethanechol
-If blocked for an excessive period of time, will have damage to smooth muscles and nerves
--Primary neuropathy can develop, atonic bladder
--nerves do not stretch as well and recoil like muscle does

Front 168

Bethanecol

Back 168

-Smooth muscle muscarinic agonist
-VERY specific activity, detrusor muscle
-Important to use drugs specific to the organ of interest!!

Front 169

Dystocia in Dogs

Back 169

-Not particularly common
-Occurs when fetuses are over-sized
-Hormonal abnormalities can decrease uterine contraction stimulus
-Results in abnormal delivery of pups
-Dogs can become hypoglycemic and hypocalcemic during long delivery
--no Ca in blood stream and extracellular spaces, no muscle contraction, uterus cannot push out fetuses
-Tx: give calcium SLOWLY
--too much too fast will affect heart

Front 170

Feline hypertension

Back 170

-Associated with renal disease and increased renal renin secretion
--leads to activation of angiotensin II (vasoconstrictor) and aldosterone secretion
-Increase in amount of smooth muscle tone and contraction
-Tx: Amlodipine (Ca channel blocker)
--decreases force in vascular smooth muscle, lowers BP

Tissue specificity is important in Ca channel blockers!

Front 171

Diabetic Cystopathy

Back 171

-Urologic disease
-Rho kinase over-expression, results in calcium sensitization
--MLCPhos is inhibited, ultimately causes muscle to contract independent of calcium levels
-(defect is in calcium degradation, not over-supply of calcium)
-More of a response to same amount of calcium

Front 172

Pharmacological Control over Smooth Muscle Tone

Back 172

-Lack of all-or-none response allows pharmacological increase or decrease in smooth muscle activation
-Ability to generate force over big changes in muscle fiber length is critical
-Tissue-specific activation or relaxation is critical to therapeutic success

Front 173

Respiratory Failure

Back 173

-Can be due to lung failure or pump (heart) failure

Front 174

Lung failure

Back 174

-Gas exchange failure
-Manifested by hypoxemia
-Decreased O2 in circulating arterial blood
-CO2 levels stay the same or drop slightly

Front 175

Pump failure in respiration

Back 175

-Chest wall muscles or brain signaling fails
-Ventilatory failure, not enough O2 is getting to the tissues to allow tissues to metabolize
-Manifested by Hypercapnia (high CO2)
-CO2 in blood increases, O2 stays normal
-CO2 normally stimulates breathing, but of CO2 is high there is an issue with the pump

Front 176

How to increase transport of O2 and CO2 in a body

Back 176

-Increase capacity, both anatomically and functionally
-increase the transport, will increase the capacity

Front 177

Respiratory adaptations to exercise

Back 177

-Increase ventilation (lungs)
-increase cardiac output (heart)
-Goal is to deliver more O2 to the cells
--meet metabolic demands of the cells
-Cardiovascular and respiratory systems must collaborate

Front 178

Limits on O2 consumption

Back 178

-At the whole animal level, O2 consumption is limited
-Limit is characteristic of an organism
--can have a difference due to training
-Energy demands exceeding limit must be covered anaerobically (glycolysis)

Front 179

Oxygen abbreviations

Back 179

V=gas volume
V*= ventilation/minute
V*O2= oxygen consumption/minute

V*O2 is determined by the needs of the metabolizing cells

Front 180

Maximum O2 consumption is characteristic of the species

Back 180

-Large animals have a low maximum O2 consumption
--Steer, lion, human
-Small animals have a high maximum O2 consumption
--Shrew has a HUGE O2 consumption, has to eat 1-2x body weight each day

Front 181

Horse O2 consumption

Back 181

-Outlier in terms of O2 consumption
-Has a huge body weight, and huge O2 consumption
-Circulation increases with activity
-During exercise respiratory system must deliver more O2 to body

Front 182

Lung Blood-gas barrier

Back 182

-Separates alveoli from capillaries (gas from blood)
-Provides for rapid exchange of gasses

Front 183

Characteristics of the Gas exchange membrane

Back 183

-Very large, very thin membrane (.05-2.5 microns)
-Large surface area from internal partitioning
--divides lung into millions of alveoli
--HUGE in a horse
-Surface area is proportional to metabolic rate
-Thin layer of blood is spread out over exchange surface

Front 184

Respiration is about exchange of gasses

Back 184

-between cell and environment
-Between organism and its environment
-Contributes to the nutrient environment of the cell

Respiratory system is "slaved" to the cellular oxidative metabolism of the cell
-The need for O2 is quantitatively linked to ATP synthesis in mitochondria
-Oxygen need in the cell is based on rate of ATP synthesis

Front 185

Oxygen demand in a cell

Back 185

-Directly linked to ATP synthesis
-Higher rate of ATP synthesis, more O2 is needed
-Lower rate of ATP synthesis, less O2 is needed
-Increased number of mitochondria in a cell results in increased need for O2

Environment is the source of all O2

Front 186

Function of the Respiratory system

Back 186

1. Provide proper amount of O2 to cells
--amount of supplied O2 equals demand and consumption
2. Excretion of produced CO2
--lungs exchange CO2 for O2, but do not use the same transport mechanisms
3. Maintain extracellular fluid pH
--excretion of acid via CO2
4. Respiratory Heat Exchange
--warming air as it comes in in cold weather
--expelling hot air in warm weather

Front 187

Environmental O2

Back 187

-Most of inspired gas is N2
-Overall, O2 is a low percentage of total gas inhaled
--Partial pressure of O2 is the key measure

Front 188

Partial pressure

Back 188

-The pressure that the gas would have it if solely occupied the volume of the entire mixture at the same temperature
-Total pressure is the sum of the partial pressures of each individual gas within the mixture
-partial pressure of O2 depends on volume fraction (percentage of the whole) and pressure of the mixture
-Partial Pressure = (total absolute pressure)x(volume fraction of gas component)

Front 189

High Altitude Hypoxia

Back 189

-Pressure is lower at higher altitude
-Pressure of O2 is lower because total pressure is lower
--fraction of O2 is the same, total pressure drops, and partial pressure of O2 drops
-Some animals have adapted to lower pressure at altitude

Front 190

High altitude adaptations

Back 190

-Increased mitochondrial mass in skeletal muscles
-More mitochondria, more ability to utilize O2 and convert it into ATP

Front 191

O2 transport should be adapted to the needs of the cells

Back 191

-If metabolic rate increases, ventilation and cardiac output should also increase
-Metabolic rate has to be determined by functional needs
--not by delivery of substrate
-As metabolic rate increases, ventilation and cardiac output should also increase

Front 192

CO2 production in cells

Back 192

-ALL CO2 in cells comes from oxidative metabolism
-CO2 always exists within body
--do not want to eliminate all CO2, just that is produced
--need to maintain baseline CO2 within body
-Effectively there is no CO2 in the outside air
--do not breathe in CO2
--when hyperventilation occurs, more CO2 goes out than comes back in

Front 193

Inhalation of Air vs. pure O2

Back 193

-Breathing with pure oxygen does not eliminate CO2
-Only other gas level that changes is N2
--do not inhale N2, is replaced by O2
-All other inhaled gasses stay the same

Front 194

Respiratory Quotient

Back 194

-Metabolic exchange ratio
-Measure of tissue metabolism, indicates which fuel is metabolized to supply body with energy
--carbohydrate vs. fat
-Ratio of CO2 produced to O2 consumed
-Carbohydrates are most efficient (1), equal amount of CO2 produced to O2 consumed
-Proteins (0.8-0.9)
-Fat is least efficient (0.7), least CO2 produced for O2 consumer

Front 195

Respiratory Exchange Ratio

Back 195

-Measure of gas exchange
-CO2 that comes out compared to O2 taken in
-Determined by lung gas exchange
-In a steady state, ratios are equal

Front 196

Hyperventilation

Hypoventilation

Back 196

-Hyperventilation: too much CO2 leaves the body
--respiratory alkalosis


-Hypoventilation: CO2 accumulates within the body
--respiratory acidosis

Front 197

Respiratory system as a transport system

Back 197

-Links outside air to interior of cells
-Series of transport systems

Front 198

O2 delivery requirements

Back 198

-Adequate amount
--equal to O2 consumption
-Adequate pressure
--drive diffusion transport, create PO2 gradients

Respiratory system must be able to succeed despite varying requirements (exercise, pregnancy, lactation, growth) and availability (high altitude, disease)

Front 199

Factors affecting Oxygen delivery to tissues

Back 199

1. Capillary partial pressure
2. Blood flow
3. Distance from a capillary
4. Metabolic rate

Front 200

Capillary Oxygen partial pressure

Back 200

-Important role in determining oxygen delivery to tissues
-PO2 decreases from arterial side to venous side of the capillary bed
--PO2 arterial= 100 mmHg
--PO2 venous= 40 mmHg
-Allows O2 to move down-gradient from artery to veins
-Creation of a gradient is ESSENTIAL
-As blood moves from artery to vein across capillary bed, O2 moves out into cells

Front 201

Blood flow on oxygen delivery to tissues

Back 201

-Increased cardiac output will increase blood flow, bring more O2 to tissues
-Mean capillary PO2 is higher
-Increase in bloodflow without increase in metabolic needs will increase venous pressure to be greater than 40

Front 202

Distance of a metabolizing cell from a capillary

Back 202

-Cells closer to capillary gets increased O2 flow, more O2
-Mitochondrial further from arterial O2 will get less O2
-Distance can be changed by opening new capillaries and decreasing the diffusion distance

Front 203

Metabolic rate and Oxygen delivery to tissues

Back 203

-Metabolic rate determines the rate at which O2 is consumed and supplied
-The more a cell metabolizes, the more O2 it consumes
-Determines the tissue PO2 and the concentration gradient

Front 204

Profile of PO2 in tissues

Back 204

-Midpoint between two capillaries is the furthest from blood flow and therefore the furthest from available oxygen
-Midpoint has contributions from each capillary but still gets less O2
-Midpoint can be decreased by:
--lowering capillary PO2
--Increasing metabolic rate
--Increasing distance between capillaries
-The closer to each capillary, the higher the tissue PO2

Front 205

PO2 at the midpoint between capillaries

Back 205

-Midpoint can be decreased by:
--lowering capillary PO2
--Increasing metabolic rate
--Increasing distance between capillaries

Front 206

Critical level of PO2 in tissues

Back 206

-Capillary PO2 must not fall below a certain critical PO2 level
-If PO2 drops, O2 delivery will not be adequate to maintain O2 consumption
--PO2 will drop too much and result in Hypoxia

Front 207

Critical PO2 level experiment

Back 207

1. expose an animal to gas mixtures with progressively lower PO2
-PO2 in arterial and venous blood will gradually decrease
-Measure O2 consumption in resting and contracting muscles
--Large difference between resting and contracting muscles!

Front 208

Critical PO2 in resting muscle

Back 208

-PO2= 60 mmHg
-O2 consumption falls because some cells stop metabolizing
-Animal needs supplemental O2
-Do not get a very dramatic drop in PO2, but drops

Front 209

Critical PO2 in contracting muscle

Back 209

-PO2= 45mmHg
-Active cells have higher O2 consumption levels
-Contracting muscle is opening new capillaries, O2 supply improves to tissue overall

Front 210

Angiogenesis

Back 210

-Creating new capillaries
-Contracting muscle opens new capillaries to increase blood flow and therefore PO2 in arterial blood to tissues
-Allows contracting muscle to withstand a lower critical PO2 than resting muscle

Front 211

Venous blood PO2

Back 211

-Lowest PO2 to which cells are exposed
-Measurement of cell O2 supply compared to metabolic need
-Indicates how much O2 the cells must extract to meet metabolic needs
--extraction increases up to 90% during exercise
-PO2 can fall even lower if animal has a disease
-Hard to actually get a real value, have to take value from right atrium
-Critical level for venous blood = 35 mmHg

Front 212

Venous PO2

Arterial PO2

Back 212

Venous PO2= how well the tissues are supplied
-effluent from the tissues

Arterial PO2= how well the lungs are working
-effluent from the lungs

Difference between venous PO2 and arterial PO2 increases during exercise

Front 213

Adequate Tissue PO2 is the fixed point about which the respiratory system must adapt

Back 213

-System is slaved to cell metabolism

Front 214

Unicellular organisms and respiration

Back 214

-Can achieve respiratory needs by simple diffusion
-Distance between outside and inside is extremely small
--one thin membrane
--Simple diffusion is enough for exchange of gasses

Front 215

Simple Diffusion

Back 215

-Effective over short distances
-Ineffective over long distances
-Animals are large, cannot accomplish gas transport by diffusion alone
--thin, delicate respiratory membrane is internalized

Front 216

Organ systems of the respiratory system

Back 216

-2 systems arranged in a sequence of 4 linked transport systems
-2 passive diffusion systems
--diffusion in lungs and in tissues
--need adequate concentration gradients
-2 active mechanical pumps
--heart and lungs
--powered by muscle contractions
--maintain concentration gradients
--decrease diffusion distances (brings gas close to metabolizing tissues)

Front 217

4 linked transport systems in respiration

Back 217

1. pulmonary ventilatory pump
-muscles of thorax and supporting structures surrounding the lungs
2. Alveolo-capillary Membrane diffusion
-barrier between gas and blood in lungs
3. Circulatory pump
-the heart
4. Capillary-tissue diffusion
-molecular flow of gas from capillary blood to the cellular oxidation sites (mitochondria)

Front 218

Pulmonary Ventilatory Pump

Back 218

-Muscles of thorax and supporting structures surrounding the lungs
-External air pump, solution of gasses is moved
-Bulk flow of a solution of gas
-Mechanism for changing the gas medium at alveolar epithelial side of exchange surface
--brings O2 in, takes CO2 out
-Must be adequate in volume and distribution (all alveoli are involved)
-Process known as breathing

Front 219

Alveolo-Capillary membrane Diffusion

Back 219

-Barrier between gas on one side and circulating blood on the other side
-Molecular flow of gas across the lung surface
--Large surface area with lots of internal partitioning and small air spaces
--Thin membrane, close contact of both mediums
--Large flow volume on both sides of membrane maintains concentration gradient
--low flow velocity gives enough time for molecules to exchange by diffusion

Front 220

Etruscan Shrew

Back 220

-Very small animal with HUGE metabolic needs
-Very rapid movements
-Eats 1-2x own body weight each day
-Highly partitioned lung with large surface area

Front 221

Important aspects of a good exchange membrane

Back 221

1. Large surface area
2. Thin membrane
--allows close contact between mediums on either side of membrane
3. Large flow volumes on both sides
--Maintains concentration gradient
4. Low flow velocity
--allows adequate time for exchange

Front 222

Circulatory Pump in respiratory system

Back 222

-internal fluid pump, pumps blood
-Bulk flow of a solution of gas within blood
-Aided by a carrier system (hemoglobin, increases O2 content in blood and allows proper delivery to the tissues)
-Must be adequate in volume and distribution
--must interact with all alveoli

Front 223

Capillary-Tissue diffusion in linked transport system

Back 223

-Molecular flow of gas from capillary blood to the cellular oxidation sites (Mitochondria)

Front 224

Flow = quantity/time
Flow = volume/time
Flow = liters/minute

Back 224

Oxygen flow is measured

In a steady state, the flow in each link must be the same
-equal to the metabolic O2 consumption of the animal
-As long as the flow in each link is adequate, animal is healthy
--poor flow usually indicates disease

Front 225

Anatomic Complexity of the respiratory System

Back 225

-Millions of alveoli
-Complex, branching system of airways and blood vessels

Front 226

Simple model of the airway system

Back 226

1. Airway
2. Alveolar Gas Volume
3. Diffusing Membrane
4. Capillary
5. Enclosure (Wall)

Front 227

Airway in respiratory system

Back 227

-Connects alveolus to outside air
-Does not exchange gas
--dead space
-Mechanical properties are tube-like
--offers frictional resistance to flow

Front 228

Alveolus in respiratory system

Back 228

-Gas exchange surfaces
-All gas exchange takes place in alveolus
--in reality, 90%
-Mechanical properties are like a balloon
--elastic resistance to stretch
--in reality, does not stretch, more like folding like a paper bag (folds and unfolds)
--lung in its entirety stretches, individual alveoli fold

Front 229

Capillary in respiratory system

Back 229

-Contains flowing blood
-Rich network of blood vessels in wall of alveolus
-Covers surface of alveolus to facilitate O2 and CO2 exchange

Front 230

Enclosure in respiratory system

Back 230

-Surrounds alveolus, blood vessels, most of the airway
--everything within the thorax
-Walls contain muscles that provide forces for ventilation
-Muscles = main force for ventilation
-Ventilatory forces generated by enclosure are applied to alveoli, airways, blood vessels, and all organs within enclosure (heart, esophagus)

Front 231

Respiration at rest

Back 231

-Major active muscles are inspiratory
--expiration is passive
-Diaphragm and intercostal muscles, mostly diaphragm
-highly athletic animals can actively use expiratory muscles
--horse, dog

Front 232

Inspiratory Muscles

Back 232

-Contract to enlarge the thorax
-Create a negative pressure pump
-Lungs are attached to thorax via pleural fluid linkage and cohesive forces
--lung is pulled out with thorax expansion, follow movement of the thorax

Front 233

Negative pressure pump

Back 233

Increasing the volume of the thorax and lungs creates negative pressure that brings gas into the lung
-Air is sucked into the lungs
-Contraction of inspiratory muscles reduces pressure in intrapleural space
--reduction in pressure is transferred to aveoli

Front 234

Functional Consequences of thoracic enclosure

Back 234

-Ventilatory forces generated by the enclosure are applied to all structures within enclosure
--alveoli, airway, blood vessels, esophagus, heart
-Vessel and organ diameter will increase during inspiration, decreases resistance
--diameter will decrease during expiration, increases resistance
-High pressure generated within thorax may cause airway collapse

Front 235

Forced expiratory movements during exercise

Back 235

-Diameter of blood vessels inside thorax decrease
--restricts venous blood return
-Diameter of airways decreases
--limits ability to ventilate

Front 236

Tidal Flow

Back 236

-Single conducting airway means that gas flow must be tidal
-Air flows in and out same passage
-Not circulatory
-Alveoli are only ventilated during inspiration
-Expiration can be considered to be a period of "breath holding"
--no O2 is coming in
-Tidal volume is only a small part of normal resting lung volume
-Variations are minimized by buffer volume of gas

Front 237

Ventilation is characterized by the volume of inspired gas per unit time

Back 237

-Functional consequence of thoracic enclosure
-Ventilation = volume of gas/unit time
= tidal volume x frequency of breath

Front 238

Consequence of periodic ventilation

Back 238

-Gas composition inside alveolus will change between inspiration and expiration
-Mean values stay the same
--buffer volume of gas keeps mean values fairly constant
-pO2 increases during inspiration, drops steadily during expiration as blood continues to pick up O2 from alveolus
-pCO2 is opposite, drops during inspiration and steadily increases during expiration as CO2 is delivered continually to alveolus

Front 239

Functional Residual Capacity

Back 239

-Buffer volume of gas within the lung
-Minimizes variations in tidal volume during inspiration and expiration
-Minimizes change by making total volume very large

Front 240

"Dead Space" during respiration

Back 240

-Combination of fresh air and dead space means that only part of gas entering the alveolus during inspiration is fresh air
-Have to clear "dead space" of stagnant air with each breath
-Ex: cold shower
-Presence of dead space is a limiting factor in ventilation efficiency
-Larger dead space leads to decreased efficiency of breathing
-Reduce dead space by narrowing airways

Front 241

Alveolar Ventilation

Back 241

-Volume of fresh air that enters the alveoli per unit time
-Va= Vt-Vd
-With low tidal volume, need increased frequency to get enough fresh air

Front 242

Mechanical problems in chronic pulmonary disease

Back 242

-Leading cause of chronic pulmonary disability
-As ventilation increases, patient have increase in work of breathing
--Have to spend a lot of energy to breathe
-Concentration of CO2 increases, concentration of O2 decreases
-Work of respiratory muscles increases

Front 243

Pressure-Volume relationships

Back 243

-Ventilatory pump functions on basic pressure-volume relationships
-Have to create a difference in pressure to cause air to flow
-Stretching walls of enclosure requires extra force
-If pressure is applied, air flows into the enclosure and stretches walls until recoil force equals applied force

Front 244

Lung ventilation

Back 244

-To ventilate the lung, must produce a different in pressure between inside and outside environments
-Animals cannot change exterior air pressure, have to change interior air pressure
--Pressure inside alveolus is lowered
-Acts as a negative pressure pump, sucks air in

Front 245

Inspiratory forces

Back 245

-All inspiratory forces are generated by muscles
-All muscle forces are transmitted to the intrapleural space
-Acts to stretch the lungs and lower alveolar pressure

Decrease in alveolar pressure causes gas to flow into the lungs

Front 246

Fundamental respiratory pressures

Back 246

1. barometric pressure (atmospheric pressure)
--responsible for lung expansion and keeping alveoli open
2. Transthoracic pressure (trans chest-wall)
--responsible for expansion and contraction of the chest wall
3. Perductal pressure (pressure along the airway)
--responsible for airflow in and out of lungs

Front 247

Lung volume changes as a secondary act

Back 247

-Change in volume of the thorax leads to change in volume of the lungs
-respiratory muscles cause gas to move in and out of the lungs by changing the volume of the thorax

Front 248

Sequence of Inspiration

Back 248

1. Inspiratory muscles contract
--thorax is enlarged and volume is increased
2. Lung volume follows thoracic volume change (passive expansion)
--lung parenchymma is stretched, intrapleural pressure decreases
3. Alveoli expand in size
4. Gasses inside alveoli expand, gas pressure on alveoli decreases, becomes less than atmospheric pressure
5. Difference in pressure causes atmospheric gasses to flow into the lungs

Front 249

Stretching of the lung parenchyma

Back 249

-Lung parenchyma is attached to thoracic wall by cohesive forces
--Pleural fluid
-Allows for passive expansion of the lung when the thoracic cavity expands
-passive expansion
-Pleural fluid maintains attachment
-Airways are also expanded with lung parenchyma
--become wider and longer

Front 250

Lung recoil

Back 250

-Increases when lung expands with the thoracic cavity on inhalation
-Lung parenchyma wants to recoil away from the thoracic cavity
-Allows for passive exhalation in most mammals

Front 251

Inertia in Inspiration

Back 251

-Muscle force is needed to overcome inertia
-Important during exercise
--during exercise, ventilation increases and work of breathing increases
-Allows acceleration of gas and tissue
-inertia is small at rest, usually neglected

Front 252

Lung stretch and elastic work

Back 252

-Inspiratory muscle force is needed
-Lungs are trying to recoil from thoracic cage
-In quiet breathing, most of the work is involved in elastic work

Front 253

Frictional work in inspiration

Back 253

-Inspiratory muscles are used to overcome frictional work
-Most important during exercise
-most of friction is in upper airway resistance

Front 254

Airway widening and resistance

Back 254

-Increases in ventilation during exercise result in airway widening
-Leads to decreased resistance
-Adaptation to exercise
-increased ventilation leads to increased cross-sectional area, leads to decreased resistance

Front 255

Elastic forces in the Lung

Back 255

-Lungs behave like elastic structures
--resist deformation and tend to return to resting shape after deformation
-Obey Hooke's law
-more stretch results in greater tendency to return to normal
-Expansion of the lung will result in elastic recoil pressure
-Lung is normally expanded even at rest
-Lungs always recoil inwards

Front 256

Hooke's law

Back 256

-The extension of a spring is directly proportional to the load applied to it
-Relevant to lung elastic forces
-Change in length of a spring varies with the force applied
--greater the stretch, the greater the tendency to return to resting length

Front 257

Pneumothorax

Back 257

-Break in the seal of the lungs
-Lung is no longer adhered to the thoracic chest wall by cohesive forces
-Lung can return to original resting shape
--VERY small, very low volume
-Lung will no longer move when thorax moves
-Effectively stops all ventilation in that lung

Front 258

Alveolar pressure vs. intrapleural pressure vs. atmospheric pressure

Back 258

-Alveolar pressure is always higher than intrapleural pressure
-Intrapleural pressure is always less than atmospheric pressure
-Result of recoil
-Lung recoils inwards, puts tension on the fluid

Front 259

Tidal volume and lung recoil

Back 259

-The larger the tidal volume, the more the lungs stretch
-The more the lungs stretch, the more they will recoil
-The more lungs recoil, the lower the intrapleural pressure gets
-Intrapleural pressure will become more negative with respect to atmospheric pressure
--more sub-atmospheric

Larger volumes have lower intrapleural pressure

Front 260

Ways to measure lung stiffness

Back 260

1. Change pressure in ling and measure change in lung volume
2. Add volume of gas to lung (cause stretch) and measure recoil force (intrapleural pressure)
-Easy to do in horses

Front 261

The larger the lung volume the lower the intrapleural pressure

Back 261

-

Front 262

Pressure-volume curve

Back 262

-measure of pressure within the lung
-Lung volume vs. transpulmonary pressure
-At low lung volume, transpulmonary pressure is also low
-At high lung volume, transpulmonary pressure is high
-In between is area of rapid growth, ideal compliance
-Can extrapolate compliance
--stiffness of the lung

Front 263

Compliance

Back 263

-Change in volume over change in pressure
-Slope of the pressure-volume curve
-Defines ability to distend the lung (stiffness)
-Low compliance = less steep curve
--need more effort to increase volume
--Occurs at low and high lung volumes
-Low lung volume, lung tends to collapse
-High lung volume, more effort to take a deep breath

Front 264

Low lung volume and lung collapse

Back 264

-Low lung volume tends to lead to lung collapse
-Hard to open lung against cohesive forces of fluid
-Requires a higher difference in pressure to be able to open lung

Front 265

Lung Compliance and disease

Back 265

-Fibrotic lung: stiff lung
--takes a lot of pressure to change lung volume
--Results in small lungs with a dome-shaped diaphragm

-Emphysema: loss of elastic recoil in lung
--lung is very easy to expand
--loss of lung tissue results in loss of recoil
--No recoil in lung
--Large lungs with flat diaphragm

Front 266

Lung tissue and lung recoil

Back 266

-Lung is a meshwork of elastic and collagen fibers
-Fibers themselves to not stretch
-Lung prenchyma stretches
--Due to geometric arrangement of lung fibers (weave)

Front 267

Liquid-gas interface of alveoli and lung recoil

Back 267

-alveoli are lined by layer of liquid, are filled with gas
-Liquid molecules are more attracted to each other than to gas molecule
--results in high surface tension
-Surface tension leads to reduction in surface area
-Increased pressure could result in alveolar collapse

Front 268

Laplace Law

Back 268

-relates wall tension, pressure, and radius
-As radius increases, pressure decreases (tension is held constant)
-Results in all bubbles having same wall tension
--large bubbles have low pressure
--small bubbles have high pressure
--Small bubbles have a higher tendency to collapse due to higher pressure

Front 269

How much pressure is generated within a bubble?

Back 269

-All bubbles have the same wall tension (tension is a constant)
-Pressure changes with changing radius
-Larger bubbles have lower pressure, larger radius
-Smaller bubbles have larger pressure, smaller radius

Front 270

Alveolar collapse tendencies

Back 270

-Small alveoi tend to collapse on expiration
-Collapse tendency gets larger as size gets smaller
--pressure is higher in smaller alveoli
--air is pushed out of small alveoli into airways
-Small alveoli are hard to open during inspiration
--have to work harder against cohesive forces of fluid

Front 271

Problem with pressure differences in alveoli

Back 271

-Small alveoli have high pressure
-large alveoli have low pressure
-Gas will flow from high pressure to low pressure
-Will result in "one big alveolus" for lung if all gas from smaller alveoli flow into larger alveoli
-Larger alveoli are easier to expand during inspiration
-Ventilation will become uneven

Front 272

How to avoid pressure issues in alveoli

Back 272

1. Alveoli are not independent units
--share connective tissues and walls
--Forces in one direction are counter-balanced by forces in another direction
2. Surfactant lines alveoli and lowers surface tension

Front 273

Surfactant

Back 273

-Film of Complex phospholipid-protein (lipoprotein)
-In alveolar surface lining
-Main component is dipalmitoylphosphatidylcholine (DPPC)

Front 274

Role of surfactant

Back 274

1. Lowers surface tension
2. Stabilizes alveoli of all sizes

Front 275

Surfactant and surface tension

Back 275

-Surfactant lowers surface tension
-Separates air phase from the liquid phase
-acts as a detergent to disrupt cohesion of water molecules
-Decreases elastic recoil
-Makes lung easier to expand, more compliant
-Reduces collapse tendency at low volumes
-Makes re-opening collapsed airways easier
-Acts as an anti-glue, breaks cohesive forces

Front 276

Surfactant and alveoli stabilization

Back 276

-Stabilizes alveoli by causing surface tension to vary in proportion to alveolar size
-Adjust surface tension depending on size of alveoli
-keeps small alveoli from collapsing
-keeps larger alveoli from distending

Front 277

Benefit of stable alveolar volumes

Back 277

-All alveoli fill and empty uniformly
-All alveoli participate equally in ventilation
-Gas does not flow from one alveoli to another, all have equal gas pressure

Front 278

Surfactant stabilizes gas pressure within alveoli

Back 278

-Causes 2T/r to be a constant, constant pressure with changing radius and tension
-Surface tension is not proportional to the radius or size of the alveolus
-All alveoli will have same internal pressure, same stability
-All alveoli will have same collapse tendency (empty uniformly)
-All alveoli will have same ease of expansion (fill uniformly)
-Results in uniform filling and emptying of the lung

Front 279

Surfactant and Dynamic State

Back 279

-Dynamic state during breathing brings more stability to alveoli
--tendency to collapse is eliminated
-Surfactant at alveolar gas-liquid interface causes surface tension to decrease
--decreases in proportion to its ratio to alveolar surface area
-When alveolus size decreases, surfactant per alveolar surface area increases (ratio increases)
--effects of surfactant increase
-Number of surfactant molecules does not change with size of the alveolus

Front 280

Surfactant molecules during breathing

Back 280

-On inspiration, surfactant molecules move further apart
-Molecules from below surface come to the surface, thinner layer of surfactant
-On expiration, surface will be packed with surfactant molecules
--Surface tension drops, goes to zero

Front 281

Lung and thorax are linked springs

Back 281

-Lung wants to recoil inwards, thorax wants to recoil outwards
-Both act on each other, exert force on each other
-Linked springs have different resting positions
--when together, thorax wall stretches the lung and the lung compresses the thoracic wall
--Equilibrium resting position occurs that is a combination of both resting positions

Front 282

Resting position and lung stretch

Functional Residual Capacity

Back 282

-Resting position: equilibrium where stretch of the lung balances stretch of the thorax
-All respiratory muscles are relaxed
-End of normal expiration
-Functional residual capacity = everything is at rest

Front 283

Functional Residual Capacity

Back 283

-Everything in lung is at rest
-Equilibrium resting position between thoracic wall and lung resting positions
-Position at the end of a normal expiration
-Can be used diagnostically to identify disease
-Horses and dogs have lower end expiratory volume than volume with all muscles relaxed

Front 284

Horse and dog functional residual capacity

Back 284

-Horses and dogs have lower end-expiration volume
-Volume is lower than functional residual capacity
-Highly athletic animals with active expiration

Front 285

Functional Residual Capacity in Emphysema

Back 285

-LARGE functional Residual Capacity
-reduced lung recoil
-large lung, flat diaphragm
-Loss of elastic fibers and alveoli in lungs

Front 286

Functional Residual Capacity in Fibrotic Lung

Back 286

-Small Functional Residual Capacity
-Small lung
-Hard to stretch lung
-Increased lung recoil
-Breathing at low tidal volumes, compensated by high frequency (rapid shallow breathing)
-Lung cannot be stretched, cannot reach full capacity

Front 287

Airway Obstruction

Back 287

-Increased airway resistance due to narrowed airways
--all air cannot get out in normal length of time
-Large functional residual capcity due to gradual build-up of air in the lungs
--air cannot escape due to obstruction
-Lung volume increases until the lung is stretched enough to recoil and push gas out
-May cause airway dilation due to over-stretch

Front 288

High Functional Residual Capacity

Back 288

-High lung volume
-Flat diaphragm
-Inefficient, short diaphragm
--cannot capitalize on full stretch of diaphragm to inflate the lung
--No room to move
--Muscle shortens, individual fibers get shorter and less efficient, cannot generate enough tension

Front 289

Shortening of Diaphragm

Back 289

-Decreases efficiency of the muscle
-Muscle shortens, fibers get shorter, cannot generate enough tension
-Diaphragm becomes a flatter arc, segment of a larger circle
--Laplace's Law: as radius increases, pressure decreases when tension is held constant
-Normal diaphragm is dome-shaped, flattening makes diaphragm inefficient

Front 290

Frictional Resistance in Airways

Back 290

-Ventilatory muscles must exert force to overcome frictional resistance in the airway
-Resistance = pressure difference/volume flow
-Increased volume will result in increased resistance
-Total force needed during inspiration = transpulmonary pressure + perductal pressure
-Resistance decreases as total cross-sectional area increases
--terminal bronchioles have less resistance than bronchus and bronchioles

Front 291

Friction during motion (basic)

Back 291

-On a frictionless surface, force vs. distance is a linear curve
-On a surface with lots of friction, force vs. distance is not linear
--need more force during motion to overcome force of friction to go the same distance
--Expend more force to create same stretch

Front 292

Transpulmonary pressure

Back 292

-Difference between alveolar and interpleural pressure
-Force developed by the inspiratory muscles to stretch the lung
-Accounts for muscular force needed during inspiration
-Total force needed to inhale = transpulmonary pressure + perductal pressure

Front 293

Perductal Pressure

Back 293

-Pressure exerted on lung due to frictional resistance in the airway
-Force needed to overcome frictional resistance in the airways
-Total force needed to inhale = perductal pressure + transpulmonary pressure

Front 294

Pressures on the lung during the breathing cycle

Back 294

-At start, alveolar pressure = 0
-Need alveolar pressure to drop to create inward flow
--Action of inspiratory muscles creates negative pressure

Front 295

Intrapleural pressure during breathing

Back 295

-At start of cycle, negative pressure in intrapleural space (negative relative to atmospheric pressure)
-Need to create extra effort to create negative pressure
-Forced expiration may cause intrapleural pressure to rise above atmospheric pressure

Front 296

Airway resistance during breathing

Back 296

-Dynamic property
--no movement, will not have any dynamic friction
-Function of airway diameter
-Smaller diameter leads to increased resistance
-Pressure is proportional to the length of the tube, diameter, and flow
--decreased diameter leads to increased resistance and increased pressure

Front 297

Effects of Histamine on lung airway diameter

Back 297

-Histamine causes contraction/constriction of airway

Front 298

Asthma

Back 298

-Animals with asthma will have increased airway resistance
-Asthmatic airways have overgrowth of smooth muscle and excess of mucus
-Smooth muscle + mucus leads to constricted airway and increased airway resistance

Front 299

Airway obstruction

Back 299

-increased airway resistance
-Results in more work needed to breathe
-Greater pressure is required for the same flow
-Animals will breathe at larger lung volume to achieve wider small airways
-Tx: bronchodilators, inhaled medication

Front 300

Rate of gas flow

Back 300

-Effort needed to cause flow is related to the flow itself and to the resistance
-More flow requires more resistance
-Smaller diameter, larger resistance
-Flow = difference in pressure/resistance

-Increased flow requires increased effort
-Decreased diameter requires increased resistance

Front 301

Division of airways

Back 301

-As airways divide, total cross-sectional area increases
-Sum of the diameters of next generation branches is larger than the parent branch diameter
-In respiratory zone, cross sectional area doubles with each generation
--each new branch has the same diameter as the parental branch
-Results in a dramatic increase in cross-sectional area growth of airways
-Resistance decreases with subsequent divisions of airways

Front 302

Factors controlling airway diameter

Back 302

1. passive factors: (based on lung functions, are lung-specific)
-volume
-Bronchial compliance
-transbronchial difference in pressure
2. Neural factors
-parasympathetic system constricts
-Sympathetic system dilates
-Irritation of airway causes constriction
--cold, volatile gasses, tobacco smoke, air pollutants
3. Chemical factors:
-Neurotransmitters and synthetic analogs
-Inflammatory mediators
-Drugs

Front 303

Lung volume

Back 303

-Airway resistance decreases as lung volume increases
--Airways are embedded in lung parenchyma, are pulled open by radial traction as alveoli expand during inhalation
-Inhalation has wider airways
--unfolded, radial traction pulls airways open
-Expiration has narrower airways
--folded, airways are relaxed

Front 304

Bronchial Compliance

Back 304

-How easily airways are expanded with changes in lung volume or transbronchial pressure
-Smooth muscle contraction decreases compliance
--airways get stiffer, cannot expand as much during inspiration
--resistance is increased
-Occurs with certain diseases
--fibrosis, edema in walls

Front 305

Transbronchial difference in pressure

Back 305

-Difference between the inside and outside of bronchi
-Intrabronchial vs. peribronchial pressure
-largest effect is on large airways
-Pressure inside airway depends on air flowing in or out and breathing effort
-Changes in outside pressure re always larger than changes in inside pressure
-Airways expand on inspiration and constrict during expiration

Front 306

Forced expiration during exercise

Back 306

-Have increased intrapleural pressure
-Also have increased alveolar pressure
-Can reach a point where transbronchial pressure becomes zero
--airway can collapse due to extra pressure during forced expiration

Front 307

Expiration is always a limiting factor in the ability to ventilate

Back 307

-During forced expiration, pleural pressure can exceed bronchial pressure
-Effort by muscles can cause airway compression
-Greater effort results in greater compression with no change in air flow
-Compression starts at equal-pressure point in cartilage-free airways in lung

Front 308

Equal pressure Point in the lung

Back 308

-Point where pleural pressure is equal to bronchial pressure
-can cause airway collapse
-Obstructions can cause early equal-pressure point
-Pursed-lip breathing pushes equal-pressure point out further, beyond lung

Front 309

Variations in bronchial smooth muscle contraction

Back 309

-Controlled by autonomic nervous system
-Wall diameter and wall compliance are regulated by bronchial smooth muscle contractions
-Adrenergic stimulation dilates airways
-Bronchodilation increases volume and decreases resistance of airways

Front 310

Air flow velocity and resistance

Back 310

-Air flow velocity is low in small airways
--little effort to overcome resistance
-High velocity in large airways
--more effort needed to overcome resistance
-If flow remains constant, when area is increased, velocity is decreased

Front 311

Laminar Flow

Back 311

-Low flow rates
-Flow lines are parallel, no mixing
-Minimal resistance of flow
-Flow is directly proportional to the pressure gradient
-Coefficient of resistance does not change

Front 312

Turbulent flow

Back 312

-Occurs at high levels of effort and flow
-Higher flow rates, more turbulence generated
-Flow rate is proportional to the square root of the pressure gradient
-Flow is not parallel, increased resistance
-Flow becomes turbulent when reynolds number >2000

Front 313

Reynold's Number

Back 313

-Re= (density x velocity x diameter)/viscosity
-Really proportional to diameter and velocity in the body
-Turbulent flow starts above critical value of 2000
--upper airways (trachea)
-Narrowing of airways during expiration causes quicker deviation from linearity of flow

Front 314

Bulk flow in the lungs vs. diffusion

Back 314

-Bulk flow occurs in conducting zone (to terminal bronchiole)
-Diffusion predominates in respiratory zone
--respiratory bronchioles to alveolar sacs

Front 315

Respiratory Zone

Back 315

-Respiratory bronchioles to alveolar sacs
-Characterized by a large cross-sectional area
--cross-sectional area doubles with each new generation, each new branch has same diameter as parental branch
-Velocity decreases in respiratory zone, small airways
-Still some mass flow, but more diffusion
-Diffusion occurs in all directions
--makes alveoli composition uniform

Front 316

Particle deposition in airways

Back 316

-Large particles are deposited in upper airways
--heavy, gravity pulls them out
--sedimentation
-Smaller particles are deposited in airways when they stick to walls
-Very small particles tend to deposit in alveoli
--via diffusion
--no cilia to remove particles

Front 317

Chronic lung disease

Back 317

-Caused by very small particles accumulating in the alveoli
-Coal, silica, asbestos

Front 318

Alveolar gas as an isolated compartment

Back 318

-Sits between atmospheric air and pulmonary capillary blood
-Separated from atmospheric air by conducting airways
-Separated from blood by alveolar membrane

Front 319

Change in concentrations of gasses in alveolar compartment

Back 319

-Concentrations of gasses in compartment are determined by amount of ventilation and blood flow
-Blood flow continuously removes O2 and adds CO2
-More ventilation leads to closer similarity between alveolar gas and atmospheric gas

Front 320

Normal Lung partial pressures

Back 320

-Air PO2: 159 mmHg
-Alveolar PO2: 100 mmHg
-Alveolar PCO2: 40 mmHg
-Air PCO2: 0 mmHg

-P alveolar total= PCO2+ PO2+ PN2+ PH2O
-PaCO2+PaO2 is a constant
40mmHg + 100 mmHg = 140 mmHg
-If CO2 or O2 component changes slightly, other component must accommodate to maintain constant
-Cannot wash out CO2 component, stays in lungs no matter what

Concentrations are kept constant through various feedback mechanisms

Front 321

Water vapor pressure

Back 321

-Determined by body temperature

Front 322

Gas concentration variation over time

Back 322

-Due to large total size of alveolar compartment, gas concentrations very relatively little over time
-PO2 varies between 98 and 201 mmHg
-pCO2 varies between 38 and 44 mmHg
-Concentration of gas varies minimally
-Alveolar ventilation is proportional to metabolism
--O2 consumption and CO2 production

Front 323

In a steady state, all CO2 produced by the cells must be excreted in expired gas

Back 323

-All produced CO2 must go out
-No residual/baseline CO2 should go out
-All expired CO2 comes from alveoli
-Percent CO2 expired must be equal to the metabolic production of CO2

Front 324

Variations in Ventilation

Back 324

-Ventilation can increase or decrease
-Altered by:
--disease
--altitude
--excitement
--Exercise

Front 325

Hypoventilation

Back 325

-Ventilation decreases and CO2 increases, arterial blood CO2 increases
-Ventilatory volume fails to keep up with CO2 production
-Insufficient volume of fresh air entering the alveoli relative to metabolic rate
-Temporary insufficient excretion of CO2, not enough CO2 out
-CO2 accumulates in body, alveolar PCO2 increases and PO2 decreases
-In new steady state, need to have higher concentration of CO2 out
-PUMP failure

Front 326

Causes of hypoventilation

Back 326

-PUMP failure
-Increased CO2 and decreased O2 in arterial blood

1. Damage to CNS (drugs, trauma)
2. Peripheral nerve Damage
3. Damage to heart (muscle paralysis, trauma to chest, bloated abdomen, increased pressure of diaphragm)
4. Lung resisting inflation (airway obstruction, decreased lung compliance, tumor)

Front 327

Hyperventilation

Back 327

-Ventilatory volume rises more than CO2 production, too much CO2 goes out with exhalation
-Alveolar PCO2 decreases, PO2 rises
-Excess volume of fresh air entering the alveoli relative to the metabolic rate
-Increased alveolar ventilation with decreased PCO2
-In new steady state, Decreased concentration of CO2

Front 328

Causes of hyperventilation

Back 328

-Anxiety
-Excitement
-Pain
-Hypoxia, leading to increased ventilation, leading to decreased CO2
-Drugs (epi, progesterone)
-Improper mechanical ventilation

Front 329

Hyperpnea

Back 329

-Ventilatory volume rises in parallel with CO2 production
-Increase in volume of fresh air entering the alveoli in proportion to the metabolic rate
-Occurs during exercise
-Alveolar PCO2 stays constant

Front 330

The single most important blood gas measurement that enables a clinician to determine how well ventilation is providing for the metabolic gas exchange requirements of an animal

Back 330

Arterial PCO2

BEST gas measurement to determine relationship between ventilation and metabolic gas exchange

Front 331

Combination of alveolar ventilation and blood flow (perfusion) will determine the concentration of gas in the alveolus

Back 331

How well the blood is arterialized

Front 332

Role of ventilation

Back 332

-Increase alveolar PO2 above venous blood
-Decrease alveolar PCO2 below venous blood

Allows exchange to continue to happen

Chief purpose of the lung is to arterilaize the blood

Front 333

Effects of Altering ventilation/perfusion ratio

Back 333

-Airway obstruction: concentration of alveolar gas becomes equal to venous blood
--no gas exchange occurs
--CO2 is highest, O2 is lowest

-Blood flow obstruction: alveolar gas concentration becomes equal to atmospheric gas
--No perfusion, no gas exchange
--O2 is highest, CO2 is lowest

Front 334

Effects of a Shunt

Back 334

-Blood from right ventricle bypasses ventilation and returns to the left atrium
-No ventilation
-O2 is lowest, CO2 is highest
-Va/Q= zero
-Airway obstruction
-Alveolar collapse
-Complete airway obstruction
-Pneumonia
-Surfactant deficiency

Front 335

Effects of Dead Space

Back 335

-Alveolar dead space, alveoli receive ventilation but no perfusion
-O2 is highest, CO2 is lowest
-Va/Q= infinite
-Obstruction of blood vessels
-Destruction of pulmonary vasculature
-Pulmonary hypotension
-Increased pressure on pulmonary vessels

Front 336

Anatomic Dead Space

Back 336

Airways leading to alveoli
-Conducting zone

Front 337

Alveolar dead space

Back 337

-Ventilated areas in the lung without blood flow
-Clot, blockage, etc.

Front 338

Mechanical dead space

Back 338

-Artificial airways
-Ventilator circuits

Front 339

Total Dead space

Back 339

Anatomic dead space + alveolar dead space + mechanical dead space

Front 340

Partial Shunt

Back 340

-Hypoventilation or hyperperfusion
-Blood continues to flow, ventilation is not at maximum
-0<Va/Q<1
-Va/Q is decreasing
-O2 is low, CO2 is high

Front 341

Partial dead space

Back 341

-Hyperventilation or Hypoperfusion
-Not enough perfusion
-Enough ventilation
--1<Va/Q<infinity
-Va/Q is increasing
-O2 is high, CO2 is low

Front 342

Hypoxemia

Back 342

-decreased O2 in arterial blood
-Can be the result of a ventilation mis-match
--Alveolar unit is ventilated but not perfused (alveolar dead space)
--Alveolar unit is partially ventilated (shunt)

Front 343

Effects of gravity on lung volume and perfusion

Back 343

-Hydrostatic gradient of pressures
-Regional differences in gas exchange
-Distortion of the lung by its own weight
-Bottom of lung:
--blood flow is greater than ventilation
--Blood accumulates in bottom of lung
--decreased "ventilation"
--Low Va/Q (O2 is low, CO2 is high)
-Top of Lung:
--ventilation is greater than blood flow
--increased "dead space"
--Va/Q is high (O2 is high, CO2 is low)
-Ideal is inbetween, where blood flow equals ventilation
-Both ventilation and perfusion are higher near bottom, but ratio is off

Front 344

Effects of gravity on lung compression

Back 344

-Lung compresses under its own weight
-Pressure on lung parenchyma changes over the length of the lung
-At bottom, alveoli are smaller
--more vessels per unit volume
--hydrostatic pressure is increased
--Decreased efficiency
-Creates regional differences in gas exchange

Front 345

Pulmonary Tuberculosis

Back 345

-Tends to occur in upper areas of the human lung
-Areas with increased ventilation and decreased relative perfusion

Front 346

Alveolar-Arterial gradient and PO2

Back 346

-Higher PO2 from upper areas of lung are not able to compensate for decreased blood flow
-cannot compete with Hb-bound O2
--less blood flow results in less Hb
-PO2 will be lower in pulmonary veins from upper lung
--PO2= 97, vs. 100when optimal

Front 347

Blood flow to lower lung

Back 347

-Most blood flows to ower lung
-Va/Q is less than 1, suboptimal blood arterilaization

Front 348

Regional perfusion in horse lung

Back 348

-Horses have large numbers of blood vessels in upper part of lungs
-Adaptation to compensate for effect of gravity on the lung
-Regional perfusion can be induced by exercise

Front 349

Anesthesia and ventilation-perfusion mis-match

Back 349

-Produce respiratory depression, decreased ventilation
-Produce hypotension
--at some point, perfusion at top of the lung may drop to critical levels
-Dependent lung determined where gravity has the most effect, more perfusion
-Dorsal recumbency is no good, ventilation of both lungs is limited by abdominal viscera
--dorsal lung field is dependent, larger vessels with higher flow
--Va/Q is impaired most, produces huge shunt
--Perfusion of unventilated lungs
-Lateral recumbency is better, Va/Q mismatch is less severe

Front 350

Dependent Lung Field

Back 350

-Lowest point of the lung where gravity has the most effect
-Important during anesthesia
-Want dependent lung field to have adequate ventilation

Front 351

Pulmonary Gas Transfer

Back 351

-Exchange of gas between alveolar compartment and blood by passive diffusion
-Pulmonary diffusion
-Molecular flow of gas across the alveolo-capillary membrane
-continuous process

Front 352

Flow

Back 352

=difference in pressure/ resistance

3 locations for diffusion barriers: (impede flow)
1. terminal alveolar unit
2. Alveolo-capillary membrane
3. Chemical reactions inside RBC

Front 353

Driving Force for O2 transfer

Back 353

-Difference in partial pressure
-Alveolar vs. mean capillary pressure
-Difference is highest at entry
-Allows blood to pick up O2 and release CO2
--blood will pick up O2 until PO2=100
-Rate at which O2 is picked up depends on:
--change in pressure at each point along capillary
--Shape of HbO2 dissociation curve
-Pressure gradient is highest at start, decreases with increased transit time in capillary

Front 354

Driving force for CO2 transfer

Back 354

-Driving force for movement of CO2 is much smaller
-Blood continues to lose CO2 until its equilibrium of partial pressures occurs
--PCO2=40 at equilibrium

Front 355

Factors affecting diffusion in the gas phase

Back 355

1. Absolute temperature
-increased temperature, increased thermal motion of molecules
2. Molecular weight of the gas
-O2 is lighter than CO2, diffuses faster
3. Diffusion distance
4. Area
5. Mean free path (how far the molecule travels before it hits another molecule)
-Long mean free path, molecules are far apart

CO2 and O2 diffuse very rapidly in gas phase

Front 356

Factors affecting diffusion in the liquid phase

Back 356

1. Absolute temperature
2. Molecular weight of the gas
3. Solubility of the gas in the tissue
-Unique factor for alveolo-capillary membrane
-High solubility leads to more gas molecules in the membrane
4. Thickness of the membrane
5. Area

Front 357

Henry's Law

Back 357

-The amount of gas dissolved is proportional to the partial pressure of the gas

Front 358

Capacity of tissue for CO2

Back 358

-VERY large capacity
-CO2 can flow quite readily across alveolo-capillary membrane
-Needs a very small change in pressure to be able to diffuse, small pressure gradient
-CO2 is 24x more soluble than O2!!!

Front 359

Fick's Law

Back 359

-The amount of gas transferred is proportional to:
--area
--diffusion constant
--difference in partial pressures across membrane
-inversely proportional to thickness

CO2 is very soluble!

Front 360

Importance of membrane thickness

Back 360

-membrane thickness is important!
-Relates to length of the diffusion path, how far stuff has to go
-Most diffusion takes place in the thin parts of the membrane
-Relatively little diffusion takes place in the thicker parts of the membrane due to larger diffusion barrier
-Membranes in the lung are very thin!
-Disease can change the thickness of membranes
--edema can also increase membrane thickness
-Thick membranes results in decreased rate of gas transfer

Front 361

Importance of membrane area

Back 361

-Larger area allows for easier diffusion
-Alveolar gas must contact blood for transfer to take place
-If area of functioning alveoli in contact with capillaries containing flowing blood is greater, more transfer will happen
-Actively diffusing area can vary as capillary beds open and close
-Area can triple in size during exercise
-Disease can decrease functional area of the membrane

Front 362

Locations for barriers to diffusion

Back 362

1. Terminal Alveolar unit
2. Alveolo-capillary membrane
3. Chemical reactions inside the RBC

Act to impede flow
-Depends on the time required for various chemical reactions of O2 and CO2 with Hb

Front 363

RBC component factors

Back 363

-RBC component depends on

1. chemical reaction rates
-temperature is important, higher temps increase rxn rate
2. Volume of blood in the capillaries
-more blood = more transfer
-Decrease in capillary blood volume will decrease diffusing capacity
-Volume of blood increases during exercise

Front 364

Time in gas transfer

Back 364

1. Contact time: time that a RBC spends in the exchange capillary
2. Equilibration time: time needed to achieve equilibrium between blood and gas

Relationship between equilibration time and contact time determines extent of alveolo-capillary gas exchange
-If blood flow is too fast, equilibrium might not happen
-In exercise, cardiac output may increase 5x, blood velocity becomes limited by opening more capillaries

Front 365

Contact time in gas transfer

Back 365

-Time that a single RBS spends in exchange capillary
-RBC makes only one pass through exchange membrane before entering systemic circulation
-All exchange must take place during the limited contact time
--time varies between species
-Contact time varies with blood flow velocity

Front 366

Equilibration time in gas transfer

Back 366

-Time needed to achieve equilibrium between blood and gas
-Depends on amount of gas to be transferred
--depends on metabolic rate
-Difference in partial pressures/driving force plays a role
--larger difference in partial pressures, greater driving force, faster transfer
-Chemical reaction rates change with temperature

Front 367

Pulmonary diffusion capacity
Transfer Factor

Back 367

-Measure of the has conductance across he lung
-Volume of gas transferred per mmHg of alveolar partial pressure
-Takes into account area, thickness of membrane, gas solubility, molecular weight of gas, blood volume
-Diffusion capacity for CO2 is 20x more than diffusion capacity for O2
--CO2 is 24x more soluble than O2
-Change in diffusion capacity indicates a change in dimensions of the lung

Front 368

Carbon Dioxide Retention

Back 368

-Inadequate PCO2 removal
-Results from hypoventilation
-Never results from a diffusion impairment by itself
--diffusion block will lead to decreased arterial PO2, increased arterial PCO2

-Decreased PO2 and increased PCO2 cause an increase in ventilation and decrease in arterial CO2

Front 369

CO2 and O2 in the Blood

Back 369

-once O2 enters blood it can be transported to other areas of the body in arterial blood
-CO2 is transported from tissues to lungs in venous blood

Front 370

Transport

Back 370

-The portion of O2 and CO2 that is exchanged in the lungs or tissues
--Differences in content of the gasses between arterial and venous blood
-Involves movement of blood and the content of gas in the blood

Front 371

Movement of blood

Concentration of gas

Back 371

blood flow= volume/time

Concentration= content/unit volume

Front 372

How to increase O2 delivery to tissues

Back 372

1. increase amount of gas carried
2. Increase flow/cardiac output
3. increase extraction to decrease cardiac output for same O2 delivery to tissues

Front 373

Extraction

Back 373

-Difference between content of arterial O2 and venous O2
-Extraction will increase with pulmonary or cardiac disease
-Increased extraction will save cardiac work
--cheap way to provide O2 to tissues with high metabolic rates
-During exercise, extraction and cardiac output will increase
--slaved to cell metabolism
-All animals increase extraction during exercise

Front 374

Measurable variables of ability of blood to transport O2

Back 374

1. Oxygen capacity
2. Oxygen affinity
3. Bohr Shift

Front 375

Oxygen affinity

Back 375

-Affinity of hemoglobin for oxygen
-Can be measured in arterial blood in a steady state
-Want Hb to have strong affinity for O2, but not too strong
--needs to be able to release it in tissues

Front 376

Bohr Shift

Back 376

-The change in the affinity of hemoglobin for oxygen
-Occurs during transitions
--From arterial to venous blood in tissues
--From venous to arterial blood in lungs

Front 377

Oxygen Capacity

Back 377

-Oxygen is not very soluble in water, blood, or tissues
-Amount of o2 that can be carried in a physical solution is very small
-Would require a HUGE cardiac output to have all O2 transported in solution
--Need a carrier to effectively transport O2 in solution

Front 378

Ways to increase O2 capacity

Back 378

-If animal breathes atmospheric air, O2 content is only 21%
--very low, blood content of dissolved O2 is very small
-Animal breathing pure O2 has increased dissolved O2 content, but still a small amount
-Animal in hyperbaric oxygen chamber has considerably increased O2 carrying capacity
--total pressure increases, dissolved O2 increases dramatically

Front 379

Oxygen capacity and Hemoglobin

Back 379

-Oxygen capacity depends on Hemoglobin concentration
-Changes in Hb concentration will change the ability of blood to transport O2
-More Hb, more O2 can be transported
-O2 capacity is proportional to Hb concentration

Front 380

Polycythemia

Back 380

Polycythemia:
-Increased RBC mass
-More RBC, more Hb, more ability to transport O2

Anemia:
-Decreased RBC mass
-Fewer RBCs, decreased Hb, decreased ability to transport O2

Front 381

Factors that increase RBC

Back 381

-high altitude
-Increased exercise
-Doping

Front 382

Horse and elevated RBC

Back 382

-In horses, large spleen elevates arterial hemoglobin and arterial O2 content

Front 383

Renal sensing mechanism and RBC count

Back 383

-RBC mass is regulated by renal sensing mechanism
-Maintans balance between O2 supply and O2 requirements of renal tissue
-During imbalance, kidney releases EPO
-EPO stimualtes bone marrow to produce more RBC
--increases carrying capacity of blood

Front 384

Oxygen Affinity

Back 384

-Ability of Hb to act as a carrier of O2
-Hb must be able to load and unload O2 in appropriate places
--pick up O2 in lungs
--release O2 in tissues
-Has to form loose chemical combination with O2
--easy to add, easy to remove
-Vary amount combined with O2 depending on level of PO2
-In mammals, affinity of pure Hb for O2 is large
--would prevent O2 release at normal tissue tensions
--NOT a good carrier for O2
-Hb must be modified to bind to O2 appropriately

Front 385

Modifications to O2 in RBC

Back 385

-Hb must be modified in RBC to bind to O2 appropriately
-Environmental factors inside RBC allow for modification
--low pH
--presence of CO2
--2,3-diphosphoglycerate
--Temperature
-Increase in concentration of ligands decreases affinity of Hb molecule
--favors O2 release

Front 386

Factors contributing to Hb and O2 association

Back 386

1. pH
--increased pH, more Hb saturation
2. PCO2
--decreased PCO2, increased Hb saturation
3. Temperature
--Decreased temp, increased Hb saturation
4. DPG

Changes in affinity are cheapest and most reliable means for adaptation to low O2 during exercise, disease, or hostile environments

Front 387

HbO2 dissociation Curve

Back 387

-Relationship between PO2 and the degree of O2 binding
-O2 affinity changes with changing PO2 levels
--Higher PO2, lower affinity
--Lower PO2, higher affinity
-At normal arterial point, PO2=100
--Hb is 97% saturated
-At normal venous point, PO2= 40
--Hb is 75% saturated
--Only 25%of O2 is used, rest is in reserve
-P50, or 50% saturation point, PO2= 25
--Hb is 50% saturated
--Change in affinity results in a change in P50

Front 388

Critical PO2 point

Back 388

-If PO2 is less than 60 mmHg, supplemental O2 may be needed

Front 389

Sigmoid shape of PO2 curve
PO2 10-70

Back 389

-between PO2= 10-50, curve is steep
--large amounts of O2 can be picked up or dropped off with a relatively small change in PO2
--Behaves as an O2 reserve, used during exercise or disease
--Additional O2 can be extracted from blood without a large fall in PO2
-Lots of "bang for your buck" in picking up O2
--with minimal increases in PO2, get dramatic increase in O2 content

Front 390

P50 in animals with high metabolic rates

Back 390

-Animal with higher metabolic rates will have higher P50
-Lower affinity of Hemoglobin for O2
-Can extract extra O2 without a large fall in PO2
-Keeps driving force for diffusion in tissues high
--O2 diffuses into tissues easily

Front 391

Sigmoid shape of Hb curve
PO2 above 70

Back 391

-Curve is relatively flat
-O2 content of blood increases slowly as PO2 rises
-Cannot add more O2 to blood, efforts will be wasted
-Alveolar PO2 can vary a bit, arterial O2 content changes little
-Negligible increase in O2 content for large increases in PO2

Front 392

Cause of alveolar-Arterial difference in PO2
A-a gradient

Back 392

-Most blood flow goes to lower lung lobes
--leads to sub-optimal blood arterialization
-Higher PO2 from the upper lobes cannot compensate
--less blood flow results in less available Hb
-PO2 is 97 in pulmonary veins
-Uneven ventilation and blood flow within the lung results in uneven Hb dissociation

Front 393

Bohr Shift

Back 393

-Hb binding affinity to o2 depends on CO2 content and pH
-Decreased pH and Increased CO2
--Hb will release O2
-Increased pH, decreased CO2, bind more loosely
--Hb will pick up more O2, bind tighter
-Lots of H ions (low pH), H competes with O2 for binding sites, affinity decreases

Front 394

CO2 is the carrier of the pH change

Back 394

-CO2 can readily permeate the RBC membrane
-H cannot pass through RBC membrane
-CO2 is hydrated inside the RBC, forms carbonic acid
--carbonic acid dissociates into H ion and HCO3-

Front 395

Carbonic Anhydrase

Back 395

-Enzyme that speeds up Bohr effect
-Needed to make reaction very rapid
-Creates more H ions in RBC
-Allows conversion of CO2+H2O into H2CO3, into HCO3- and H+

Front 396

Hb as a carrier for CO2

Back 396

-Hb is not limited in how much CO2 it can carry
-Not characterized by saturation
-Nearly linear binding curve in physiological range
-Can carry TONS of CO2

Front 397

CO2 in venous blood

Back 397

-CO2 is transported in venous blood in physical solution
--Dissolved in plasma and intracellular fluid in RBC
--CO2 is 24x more soluble than O2 in tissue
-CO2 capacity is increased by chemical combination and buffering

Front 398

Carbamino-Protein

Back 398

-Direct combination of CO2 with a free amino group in an amino acid or a protein
-Deoxy-Hb forms carbamino cpds more readily than HbO2, leads to increased transport of carbaminoHb in venous blood
--release of O2 from Hb makes binding of CO2 easier, even though occupy different sites
-Carbamino formation accounts for 10-20% of CO2 transported
-Venous blood is a better transporter of CO2

Front 399

Bicarbonate Ion

Back 399

-Most abundant form of CO2 in the blood
-Formed inside RBC
-CO2 diffuses into RBC, is hydrated to form Carbonic Acid
--carbonic acid dissociates to form H ions and bicarbonate
-Rapid reaction due to presence of carbonic anhydrase
-Products of rxn do not accumulate in RBC
--bicarbonate (HCO3-) diffuses out of RBC into plasma
--H is buffered by Hb in RBC to minimize pH change

Front 400

Buffering within RBC

Back 400

-Important for H ions created with bicarbonate to be buffered within RBC
-H ions are buffered by Hb
-Hb is the most important buffer of H
--acts quickly
-Buffering capacity of Hb is increased in tissues by removal of O2 from Hb
--deoxy-Hb is a weaker acid and better buffer
--venous blood is a better buffer than arterial blood

Front 401

Deoxy-Hb vs. HbO2

Back 401

-Deoxy-Hb is a better buffer of H ions
--weaker acid, better buffer
--Can accommodate more H ions without changing pH
-Binding more H ions will decrease change in pH in
solution
-Results in venous blood being a better buffer than arterial blood

Front 402

Haldane Effect

Back 402

-Deoxygenated Blood can buffer and carry more CO2 than oxygenated blood
-Hb acts as an important transporter for O2 and CO2
-Metabolic processes that consume O2 are the same that produce CO2
-Removal of O2 creates a buffer
--buffer facilitates transport of the waste product of oxidative metabolism (CO2)
-With oxygenation, more CO2 is released from Hb in lung

Front 403

Function of the Respiratory System

Back 403

-Maintain proper gas exchange and pH to keep up with metabolic demand
-O2 uptake in the lungs should equal metabolic O2 consumption
-CO2 excretion should equal metabolic CO2 production
-Alveolar ventilation should be proportional to the metabolic rate

Front 404

Goal of the respiratory system

Back 404

-Adequate level of ventilation for gas exchange needs
-Ventilation must change in proportion to the metabolic rate

Front 405

Challenges of the respiratory system

Back 405

1. Maintain proper gas exchange over a wide range of metabolic rates
2. Be able to accomodate considerable changes in mechanical loading
3. Function in conjunction with other demands on the system
--speech/vocalization, exercise, panting, etc.
4. Be able to accommodate abnormal situations
--high altitude, disease, anemia

Front 406

Functional levels in the control of ventilation

Back 406

1. Respiratory cycles
-involuntary rhythmic breathing movements initiated by network of neurons
2. Automatic functions
-Level of ventilation
-Adjustment of tidal volume and frequency
3. integrated activities
-Ventilation must be integrated with other motor functions
-Integration takes place in brainstem or spinal cord

Front 407

Pacemaker for breathing

Back 407

-In ventrolateral medullary regions of brain?

Front 408

Automatic Function Control in Respiratory System

Back 408

1. Level of ventilation (volume per minute)
-Adjusted to the metabolic demands for gas exchange
-Info from chemoreceptors, somatic afferents, motor collaterals
2. Adjustment of tidal volume and frequency
-Nervous system sets balance between tidal volume and frequency
-Balance between adequate ventilation and minimum amount of work

Front 409

How brain controls Ventilation

Back 409

1. Peripheral and central chemoreceptors
2. Somatic afferent innervation from muscles and joints
3. Motor collateral innervation from motor areas of the brain

Movement signals excite respiration during increased skeletal muscle activity
-At rest, the major control of the brain is over inspiration, specifically the diaphragm

Front 410

Effect of CO2 in brain on ventilation

Back 410

-increasing CO2 in brain increases inspiratory neuron activity
-Brain senses increased CO2 levels
--sends signal to increase respirations

Front 411

Brain control of the diaphragm

Back 411

-Brain controls diaphragm contractions to control inspiration
-Brain drives phrenic motor neurons
--causes diaphragmatic contraction, leads to lung expansion
-Increased phrenic nerve firing and activity leads to increased inspirations
--increased lung volume

Front 412

Rate of inspiration and chemical drive

Back 412

-Rate of inspiration is determined by the level of chemical drive
--Set by chemoreceptors and movement signals
-Chemoreceptors sense PCO2 in alveolar air

Front 413

Disease and chemoreceptors

Back 413

-During disease, drive set by chemoreceptors cannot always be translated into an increase in ventilation
-Result of pump failure
-Increasing CO2 as a result of pump failure

Animals with pulmonary disease have high PCO2 but low ventilation
-unable to translate high CO2 signal into an increase in ventilation
-Can be a result of damage to CNS, peripheral nerve injury, damage to the pump, airway obstruction, decreased lung compliance

Front 414

Pump failure

Back 414

-Problem with brain or muscles associated with making the heart function
-Increased CO2, decreased O2

Front 415

"Turning Off" Inspiration

Back 415

1. Intrinsic Clock
-Pontine Clock neurons act like inspiratory neurons
-Activate inspiration off switch
2. Extrinsic Mechanism related to lung volume
-Mediated by intrathoracic airway stretch receptors

As inspiration proceeds, clock neurons build in activity
-airways stretch and have increased pulmonary stretch receptor firing
--builds up excitation to turn-off
-When afferent firing reaches threshold level, inspiration is shut off

Front 416

Pulmonary Stretch Receptors

Back 416

-Extrinsic Mechanism for turning off inspiration
-Intrathoracic airway stretch receptors give signal to stop inspiration
-Diameter of airway and lung increases during inspiration
-Neurons fire in proportion to airway stretch and lung volume
--increased lung volume, increased rate of firing in pulmonary stretch receptors

Front 417

Hering-Breuer Reflex

Back 417

-Mechanism for terminating inspiration
-Can be used to optimize balance between elastic effort and non-elastic effort in breathing (optimizes total effort)

1. provides off-switch for inspiration
2. Compensates for mechanical loads
3. Adjusts tidal volume and frequency to achieve work optimization wile inhaling

Front 418

Threshold for turning off inspiration

Back 418

-Starts high at beginning of inspiration
-As inspiration progresses and neurons are signaled to fire, threshold decreases
-At start, need a large volume input to stop inspiration
-late in inspiration pontine clock contribution has increased and a smaller volume is needed to reach threshold
-Cumulative effect of signals serves to decrease threshold of "off" as time goes on

Front 419

Increased chemical drive and movement signals in turning off inspiration

Back 419

-Results in a fast rate of rise of inspiration
-larger tidal volume
--threshold is high
-Increased chemical drive leads to increased muscular activity
--increased drive to breathe, and increased tidal volume

Front 420

Expiration

Back 420

-Following switch off of inspiration, expiration starts
-Main expiratory force is passive lung recoil (at rest)
-Recoil is usually "braked" or "retarded"
--diaphragm contracts with diminished force during expiratory period,
--contraction of laryngeal muscles resists outward flow

Front 421

Expiration during exercise

Back 421

-"Brakes" are removed from expiration
-Larynx becomes wider, do not resist outward flow
-Diaphragm stops contracting totally, no brakes
-Active expiration starts
--abdominal muscles contract to create additional pressure

Front 422

Optimization of the work of breathing

Back 422

1. Effort to stretch the lung (elastic work)
-At low frequency of inspiration, need large tidal volume
--LOTS of effort to stretch the lung
-As frequency increases, tidal volume and effort to stretch decreases
2. Effort to overcome frictional resistance (resistive work)
-At high frequencies, need a lot of effort to overcome frictional resistance
--dead space ventilation is high
-As frequency of inhalation decreases, effort to overcome airway resistance decreases

Effort to overcome stretch is high at low frequencies
Effort to overcome frictional resistance is high at high frequencies
-Need a balance between to be optimal

Front 423

Breathing to Minimize Effort

Back 423

-All animals breathe to minimize effort
-Elastic work + non elastic work = total work (want to minimize total work)
--Find lowest sum of elastic+non elastic work

Front 424

Decreasing lung compliance

Back 424

-increases amount of elastic work needed
-Total work increases
-Tidal volume and lung stretch decrease

Front 425

Increasing lung resistance

Back 425

-Results in additional work needed to overcome resistance/friction
-Need higher tidal velocity to maintain normal ventilation
-Non-elastic work increases, total work increases
-Low frequency, high tidal volume

Front 426

Optimization of Inhalation

Back 426

-If lungs are stiff, compliance is decreased, airways are stretched more
--results in fast, shallow breathing (increased frequency, decreased tidal volume)
-If airways are stiff, lungs are stretched more
--results in slow, deep breaths (decreased frequency, increased tidal volume)

Front 427

Chemical Control of ventilation

Back 427

-Alterations in PCO2, PO2, or pH will alter ventiilation
-Ventilation responds to changes in a way that minimizes change
-Strongest chemical driver to increase ventilation is CO2
--CO2 usually also determines pH
-At normal PCO2, ventilation responds strongly to small increases in PCO2
--HIGHLY sensitive
-Below normal CO2 levels, ventilation becomes independent of CO2
--driven by other factors
-Above normal CO2 levels, ventilation becomes independent of CO2
--If CO2 concentration continues to increase, CO2 acts like an anesthetic gas and depresses ventilation

Front 428

Alterations to response to CO2

Back 428

1. Hypoxia: causes an increased sensitivity to CO2
-combined effect on peripheral chemoreceptors
-Low O2 or poor blood flow results in CO2 sensitivity
--Slope increases
2. Change in pH
-Alkalosis or acidosis will change ventilation with no change in CO2 sensitivity
3. Exercise increases ventilation with no change in slope of response to CO2

Front 429

Intracranial Chemoreceptor

Back 429

-Receptor for CO2H
-Important receptor for mediating effects of CO2H
-Respond to changes in CO2H of the brain extracellular fluid
-Changes in ventilation act to restore brain pH to normal
--Brain uses lungs to control pH of fluid surrounding the brain
--Increased H (decreased pH), increased ventilation

Front 430

Brain extracellular fluid pH

Back 430

-pH is determined by PCO2, cerebral blood flow, and cerebral metabolism
-pH is mediated through the lungs
--decreased pH, increased ventilation (increased CO2 out, H+ ions go to HCO3- instead of into fluid)

Front 431

Receptors for HCO2

Back 431

-Peripheral chemoreceptor in carotid and aortic bodies
-Respond to changes in the CO2-H of arterial blood
-Not separated from blood by a barrier, can diffuse freely
-Respond rapidly to changes in pH

Front 432

Peripheral Chemoreceptor

Back 432

-Located in carotid and aortic bodies
-Have an extremely high blood flow
-Receptors are sensitive to changes in CO2 from 20-60 mmHg
-Linear increase in response of receptors with increases in CO2
-Sensitivity of the receptor is increased by hypoxia

NO appreciable change to ventilation until PO2 falls to 60 mmHg
-much longer to cause a response

Front 433

Hypoxic Drive

Back 433

-Normally accounts for 10-20% of resting ventilation
-Have some natural hypoxic drive to breathing
-Response to hypoxia increases ventilation, causes a secondary decrease in PCO2 as a result
--more CO2 is blown off
--removes source of central respiratory drive, decreases respiratory drive
--As hypoxic drive increases, CO2 drive decreases
-Increase in response when PO2 falls below 50 mmHg

Front 434

Anemia and CO poisoning

Back 434

-Cause very little stimulation to ventilation
-Arterial PO2 is normal, chemoreceptors respond ormally
--only respond when PO2 is below 60 mmHg or changes in PCO2