Nerve and Muscle

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Nerve and Muscle

• Physiology of nerve

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The neuron

• The basic structural unit of the nervous system.
• Structure
• The soma
• The dendrites antenna like processes
• The axon hillock, terminal buttons

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Types of nerve fibers

• a- myelinated nerve fiber
• Covered by myelin sheath, protein-lipid layer,
• secreted by Schwann cells,
• acts as insulator to ion flow,
• interrupted at Nodes of Ranvier
• b- unmyelinated nerve fiber
• Less than 1µ, covered only with Schwann cells, as
  postganglionic fibers

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Electrical properties of a neuron

• Electrical properties of nerve muscle are
• 1-There is difference in electrical potential
  between the inside and outside the membrane
• 2-Excitability the ability to respond to any
  stimulus by generating action potential
• 3-Conductivity the ability to propagate action
  potential from point of generation to resting
  point

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Membrane potential the basis of excitability

• Def electrical difference between the inside
  outside the cell
• Causes selective permeability of the membrane
• more K, Mg2, Ptn, PO4 inside
• more Na, Cl-, HCO3-outside
• Exists in all living cells it is the basis of
  excitability
• Excitability
• Def it is the ability to respond to stimuli
  (change in the environment) giving a response
• The most excitable tissues are nerves muscles
• Stimuli
• Types
• Electrical (preferred), chemical, mechanical, or
  thermal.
• Cathode ( more important) anode

anode
- cathode
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Excitability

• Factors affecting effectiveness of the stimulus
• 1- strength
• effective stimulus
• 2- duration
• a certain period of time, very short duration
  can not excite the nerve
• 3- rate of rise of stimulus intensity
• Rapid increase. Active response
• Slow increase . adaptation

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Strength Duration Curve

• Within limits stronger intensity shorter duration
• Strength
• Threshold stimulus (rheobase) it is the minimal
  amplitude of stimulus that can excite the nerve
  and produce action potential.
• Subthreshold stimulus causes local response
  (electrotonic)
• Duration
• stimuli of very short duration can not excite the
  nerve
• Utilization time is the time needed by threshold
  stimulus (Rheobase) to give a response
• Chronaxie time needed by a stimulus double the
  rheobase to excite the nerve, it is a measure of
  excitability, decrease chronaxie means increase
  excitability

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Strength Duration Curve
Stimulus amplitude
chronaxie
2R
Utilization time
R
duration
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Measuring the membrane potential
Recording by 2 micoelectrodes inserting one
inside the fiber the other on the surface
connected to a voltmeter through an amplifier
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Types of membrane potential

• Membrane potential has many forms
• 1- RMP
• 2- on stimulation
• a) action potential if threshold stimulus
• b) localized response (electrotonic) if
  subthreshold stimulus

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Resting membrane potential (RMP)

• definition It is the difference in electrical
  potential between the inside and outside the cell
  membrane under resting conditions with the inside
  negative to the outside
• Value-90 mv large fibers, -70 in medium fibers,
  -20 in RBCs
• Causes
• 1- selective permeability
• 2- Na-K pump

Recording by 2 micoelectrodes inserting one
inside the fiber the other on the surface
connected to a voltmeter
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Resting Membrane Potential

• Selective permeability of the membrane
  contributes to -86mv
• K, ptn-, Mg2PO4- are concentrated inside the
  cell
• Na, Cl-, HCO3- are found in the extracellular
  fluid
• During rest the membrane is 100 times more
  permeable to K than to Na,
• Ktend to move outward through INWARD RECTFIER
  K channels down their concentration gradient
• The membrane is impermeable to intracellular
  Ptn-other organic ions
• Accumulation of ve charges outside -ve charges
  in
• At equilibrium K in to out is 351
• Na in to out is 1-10

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Potassium equilibrium
-90 mV
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Na-K pump

• Definition carrier protein on the cell membrane
• 3 binding sites inside for Na
• 2 sites outside for K
• 1 site for ATP
• Inner part has ATPase activity
• It is an electrogenic pump Contributes for -4mv
  and helps to keep RMP

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• Nernest equation
• E for K -61 log con inside/ conc outside - 94
• E for Na -61 log con inside/ conc outside 61
• Goldman equation it considers
• 1- Na, K and cl concentrations.
• 2- K permeability is 100 times as that for Na

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Action Potential

• Definition It is the rapid change in membrane
  potential following stimulation of the nerve by a
  threshold stimulus.
• Recording microelectrodes and oscilloscope.

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Membrane Permeabilites

• AP is produced by an increase in Na
  permeability.
• After short delay, increase in K permeability.

Figure 7-14
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Shape and Phases of Action Potential

• 1- Stimulus artifact. small deflection indicates
  the time of application of stimulus, it is due to
  leakage of current
• 2- Latent Period isoelectrical interval, time
  for AP to travel from site of stimulation to
  recording electrode.
• 3- Ascending limb (depolarization)starts slowly
  from -90, till firing level-65mv, reaches
  overshoots the isopotential, ends at 35
• 4- Descending limb(repolarization)
• starts rapidly till 70 complete then slows down
• Hyperpolarization in the opposite
  direction
• slight prolonged
• 5- RMP

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Shape and Phases of Action Potential

• 1- Ascending limb
• (depolarization)
• Slow..firing level..rapid.
• 2- Descending limb
• (repolarization)
• rapid then slow
• 3- Hyperpolarization
• slight prolonged
• 4- RMP

35 0 -65 -90
overshoot
depolarization
repolarization
mv
FL
hyperpolarization
Latent period
time
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Duration of Action Potential

• Spike lasts 2msec
• Hyperpolarization 35-40msec

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Ionic basis of action potential

• Depolarization is caused by Na inflow
• Repolarization is caused by K outflow
• Two types of gates
• 1- voltage gated Na channels having 2 gates
  outer activation gate inner inactivation gate
• 2- voltage gated K channels one activation gate
• When the nerve is stimulated
• a- the outer gate of VG Na opens, activating Na
  channel. Na inflow
• b- the inner gate of Na channels closes,
  inactivating Na channels stop Na inflow
• c- K gates open, activating K channels, K
  outflow

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The Action Potential
A stimulus opens activation gate of some Na
channels depolarizing membrane potential,
allowing some Na to enter, causing further
depolariztion If threshold potential is reached,
all Na channels open, triggering an action
potential.
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The Action Potential
1-Depolariztaionoccurs in 2 stages Slow stage
-90 to -65mv some Na channels opened,
depolarizing membrane potential, allowing some Na
to enter, causing further depolarization At
-65mv, the firing level or threshold for
stimulation, all Na channels open, triggering an
action potential. Rapid stage -65 to 35 all
Na channels are opened, Na rush into the fiber,
causing rapid depolarization
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The Action Potential
Within a fraction of msec, Na channel
inactivation gates close and remained in the
closed state for few milliseconds, before
returning to the resting state. 2-
Repolarization Inactivation of Na channels and
activation of K channels are fully open. Efflux
of K from the cell drops membrane potential back
to and below resting potential 3-
Hyperpolarization slow closure of K channels
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The Action Potential
The Na K gradients after action potential are
re-established by Na/K pump Only very minute
fraction of Na K share in action potential
from the total concentration The action potential
is an all-or-none response. (provided that all
conditions are constant, AP once produced, is of
maximum amplitude, constant duration form,
regardless the amplitude of the stimulus ,
however threshold or above Action potential will
not occur unless depolarization reaches the FL
(none) Action potential size is independent of
the stimulus and once depolarization reaches FL,
maximum response is produced, reaches a value of
about 35 mV(all)
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The Action Potential
Both gates of Na channel are closed but K
channels are still open.
Continued efflux of K keeps potential below
resting level.
K channels finally close and Na channel
inactivation gates open to return to resting
state.
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Action potential initiation
S.I.Z.
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Action potential termination
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Action potential in a nerve trunk

• Nerve trunk is made of many nerve fibers
• The AP recorded is compound action potential,
  having many peaks
• The individual fibers vary in
• 1- threshold of stimulation
• 2-distance from stimulating electrode
• 3- speed of conduction

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• During depolarization, there is ve feed back
  response.
• Repolarization is due to
• 1- inactivation of Na channels( must be removed
  before another AP
• 2- slower more prolonged activation of K
  channels
• Hyperpolarization (undershoot) slow closing of
  K channels, K conductance is more than in
  resting states
• Role of Inward rectifier K channels
• Non gated channels
• Tend to drive the membrane to the RMP
• Drive K inwards only in hyperpolarization
• Re-establishing Na K gradient after AProle of
  Na /K pump
• All or none law

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Electrotonic potentials local response

• Catelectronus at cathode/ depolarization less
  than 7mV/ passive
• Anelectronus at anode/ hyperpolarization/
  passive
• Local response (local excitatory state)
• Stonger cathodal stimuli
• Slight active response
• Some Na channels open, not enough to reach FL
• It is graded
• Does not obey all or none law
• Non propagated
• Excitability of the nerve increased
• Caused by subthreshold stimulus
• Can be summated produce AP
• Has no refractory period

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Local Response (local excitatory change)

• Although subthreshold stimuli do not produce AP
  they produce slight active changes in the
  membrane that DO NOT PROPAGATE.
• It is a state of slight depolarization caused by
  subthreshold cathodal stimulus that opens a few
  Na channels not enough to produce AP

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Local Response (local excitatory change)

• It differs from AP
• It does not obey all or non rule
• Can be graded.
• Can be summated.
• It does not propagate.

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Excitability changes during the action potential

• Up to FL, excitability increases
• The remaining part of action potential, the
• nerve is refractory to stimulation (difficult to
• be restimulated)
• Absolute refractory period
• Def the period during which a 2nd AP can not be
  produced whatever the strength of the stimulus
• Length from FL to early part of repolarization
• Causes inactivation of Na channels
• Relative refractory period
• Def. the period during which membrane can
  produce another action potential, but requires
  stronger stimulus.
• Length from after the ARP to the end of the AP
• Causes some Na channels are still inactivated
• K channels are wide open.

ARP
RRP
FL
Increased excitability
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Factors affecting Membane potential Excitability

• Factors ? excitability
• Role of Na
• 1) ? Na permeability (veratrine low Ca 2).
• Factors ? excitability
• 1)? Na permeability( local anaesthesia high
  Ca2) membrane stbilizers
• Decrease Na in ECF decreases size of AP, not
  affecting RMP
• Blockade of Na channels by tetradotoxin TTX
  decrease excitability no AP
• Role of K
• 1)? K extracellularly (hyperkalemia).
• 2)? K extracellularly (hypokalemia) familial
  periodic paralysis
• 3) blockade of K channels by TEA prolonged
  repolarization absent hyperpolarization
• Role of Na K pump only prolonged blockade
  can affect RMP AP

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Accommodation of nerve fiber

• Slow increase in the stimulus intensity gives no
  response
• 1- inactivation of Na Channels
• 2- opening of K Channels

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Conduction in an Unmyelinated Axon

• The action potential generated at one site, acts
  as a stimulus on the adjacent regions
• During reversal of polarity, the stimulated area
  acts as a current sink for the adjacent area
• A local circuit of current flow occurs between
  depolarized segment resting segments (flow of
  ve charges) in a complete loop of current flow
• The adjacent segments become depolarized, FL is
  reached, AP is generated

Figure 7-18
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Conduction in Myelinated Axon (Saltatory
conduction)

• Myelin prevents movement of Na and K through
  the membrane.
• The conduction is the same in unmyelinated nerve
  fibers Except that AP is generated only at Nodes
  of Ranvier
• AP occurs only at the nodes.
• AP at 1 node depolarizes membrane to reach
  threshold at next node.
• The ve charges jump from resting Node to the the
  neighbouring activated one (Saltatory conduction).

Figure 7-19
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Importance of saltatory conduction

• ?velocity of nerve conduction.
• Conserve energy for the axon.

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Orthodromic antidromic conduction

• Orthodromic from axon to its termination
• Antidromic in the opposite direction
• Any antidromic impulse produced, it fails to pass
  the 1st synapse die out

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Monophasic biphasic AP

• Monophasic AP recorded by one microelectrode
  inserted inside the fiber one indifferent
  microelectrode on the surface.
• Biphasic two recording electrodes on the outer
  connected to CRO

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Depolarization repolarization of a nerve fiber

• RMP does not record any change
• Depolarization flows to the ve electrode .....
  Upright deflection (ve wave)
• Complete depolarization ... No flow of current
  (baseline)
• Repolarization to the ve electrode....down
  deflection
• Complete repolarization ... No flow of current
  (baseline)

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Action potential in a nerve trunk

• Nerve trunk is made of many nerve fibers
• The AP recorded is compound action potential,
  having many peaks
• The individual fibers vary in
• 1- threshold of stimulation
• 2-distance from stimulating electrode
• 3- speed of conduction

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Compound AP

• Graded
• Subthreshold no response occurs
• Threshold a small AP, few nerve fibers
• Further increasing AP amplitude increases up to
  a maximal
• Increasing the intensity, supramaximal stimuli,
  no more increase in the AP

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Nerve fiber types

• According to their thickness, they are divided
  into

diameter conduction Spike duration Remarks
A fibers 2-20 micron 20-120m/s 0.5 msec Alpha, beta, gamma delta Most sensitive to pressure
B fibers 1-5 micron 5-15m/s 1msec Preganglionic autonomic f Most sensitive to hypoxia
C fibers lt1 micron 0.5-2m/s 2msec Postganglionic autonomic f Most sensitive to local anesthetics
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Metabolism of the nerve

• Rest nerve needs energy to maintain polarization
  of the membrane, energy needed for Na/K pump,
  derived from ATP. Resting heat
• Activity pump activity increases to the 3rd
  power of Na concentration inside, if Na
  concentration is doubled, the pump activity
  increases 8 folds23 .
• Heat production increases
• 1- initial heat during AP
• 2- a recovery heat, follows activity 30 times
  the initial heat
• Neurotrophins
• Proteins necessary for neuronal development,
  growth survival
• Secreted by glial cells, muscles or other
  structures that neuron innervate
• Internalised retrograde transported to the cell
  body

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Types of muscles

• Skeletal muscle under voluntary control 40 of
  total body mass.
• Cardiac muscle not under voluntary control.
• Smooth muscle not under voluntary control. Both
  are 10 of total body mass

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Skeletal muscles

• Attached to bones
• gt400 voluntary skeletal muscles
• Contraction depends on their nerve supply
• 4 functions
• 1- force for locomotion breathing
• 2- force for maintaining posture stabilizing
  joints
• 3- heat production
• 4- help venous return

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Morphology

• Muscle fibers
• Bundled together by C.T.
• Arranged in parallel between 2 tendenious ends
• Is a single cell
• Closely enveloped by glycoprotein sheath
  (sarcolemma) outside the cell membrane
• Made of many parallel myofibrils embeded in a
  sarcoplasm, between a complex tubular system

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Skeletal muscle

• Each muscle fiber is a single unit. It is made up
  of many parallel myofibrils embedded together and
  a complex sarcotubular system.
• Each muscle fibril contains interdigitating thick
  and thin myofilaments arranged in sarcomeres.
• 2 major proteins
• 1- thick filaments myosin
• 2- thin filaments actin, troponin, troopomyosin
• Troponin trpomyosin regulate muscle contraction
  by controlling the interaction of actin myosin

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The sarcomere

• It is the functional unit of the muscle.
• It ext\ends between two sheets called Z lines.
• Thick filaments (Myosin) in the middle (dark band
  (A)).
• Thin filaments on both sides (light band (I) ).
• Z line in the middle of I band.
• H zone in the middle of A band.
• When the muscle is stretched or shortened, the
  thick thin filaments slide past each other, and
  the I band increases or decreases in size

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Internal organization
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Striations
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Myofilaments

• 1- thick filaments (myosin)
• 300 myosin molecules
• 2 heavy chains 4 light chains
• Each myosin molecule has two heads attached to a
  double chains forming helix tail.
• myosin head contain actin binding site, an
  ATP- binding site and a catalytic site (ATPase).
• Each myosin head protrude out of the thick
  filaments forming cross bridges that can make
  contact with the actin molecule
• 2- Thin filaments (actin)
• Actin, tropomyosin, troponin.
• Actin is a double helix that has active sites for
  combines with myosin cross bridges.
• Troponin 3 subunits I for Actin binding, T for
  tropomyosin binding, C for Ca binding.
  
  

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Sarcotubular system

• Consists of T-tubules and Sarcoplasmic reticulum.
• T tubules consists of network of transverse
  tubules surround each myofibril, at the junction
  of the dark and light bands.
• T tubules are invaginations from cell membrane.
• T tubules contain extracellular fluid.r
• T tubules transmit the AP from the surface to the
  depth of the muscle fiber.
• Sarcoplasmic reticulum surrounds each myofibril,
  run parallel to it
• Sarcoplasmic reticulum extends between the T
  tubules.
• Sarcoplasmic reticulum are the sites for Ca
  storage.
• Sarcoplasmic reticulum ends expands to form
  terminal cistern, which makes specialized contact
  with the T tubules on either side
• Foot processes span the 200 A0 between the 2
  tubules
• SR contains protein receptor called Ryanodine
  that contains the foot process and Ca channel
• T tubule contains voltage- senstive
  dihydropyridine receptor that opens the ryanodine
  channel

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The muscle protein

• Myosin protein
• Thick filaments 300 myosin molecules
• Myosin molecule is made up of 2 heavy chains coil
  around each other to form a helix.
• Part of the heliix extends to side to form an
  arm
• Terminal part of the helix with 4 light chains
  combine to form 2 globular heads
• The arm head are called cross bridges, flexible
  at 2 hinges, one at the junction between the arm
  leaves the body, the 2nd at the attachment of the
  head with the arm
• The myosin heads contain an actin binding site,
  catalytic site for hydrolysis of ATP

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Myosin thick filaments
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Thin filaments

• Backbone is formed of 2 chains of actin, forming
  helix, has active site, 300-400 molecules
• Tropomyosin long filaments, located in the
  groove between the 2 chains of actin, covers the
  active sites, 40-60 molecules.
• Troponin small, globular, formed of 3 parts
  1-TI 2-TT 3- TC
• Actin tropomyosin Ca2

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• a actinin binds actin to the Z line

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Neuromuscular Junction

• Def it is the area lies between the nerve
  ending of the alpha motor neurons and skeletal
  muscle.
• Structure of the NMJ
• 1) terminal knobs 2)Motor End Plate
  (MEP) 3)Synaptic cleft
• contain Ach vesicle contain Ach
  receptors contain choline estrase
• Steps Of Neuromuscular Transmission
• 1) Arrival of action potential ? permeability
  to Ca2 .. Rupture of vesicles.
• 2) Postsynaptic response ? conductance to Na and
  K more Na influxend plate potential
• 3) EPP graded, non propagated response that act
  as a stimulus that depolarizes the adjacent
  membrane to firing level AP. Muscle
  contraction.
• 4) Acetyl choline degradation

end plate
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Neuromuscular junction

• Properties of neuromuscular transmission
• 1) unidirectional from nerve to muscle
• 2) delay 0.5msec
• 3) fatigue exhaustion of Ach vesicles.
• 4) Effect of ions ?Ca.. ? release of Ach
• ? Mg.? release of Ach
• 5) Effect of drugs
  
  Drugs stimulate NMJ
• Ach like action Metacholine, carbachol, nicotine
  small dose.
• inactivating choline esterase neostigmine,
  physostigmine, diisopropyl phlorophosphate.
  
  Drugs block NMJ curare competes
  with Ach for its receptors

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Motor end plate is a highly specialized region of
the muscle plasma membrane.
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Myasthenia Gravis (MG)

• Serious may be fatal disease of neuromuscular
  junction
• Characterized by weakness of skeletal muscle,
  easy fatigability may affect the respiratory
  muscles and cause death
• More in female
• It is suspected to be a type of autoimmunity (the
  patient antibodies attack the acetyl choline
  receptors at the neuromuscular junction)
• Treatment
• Adminestration of drugs as neostigmine,
  inactivating acetylcholinesterase

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Changes that occurs in the skeletal muscle after
its stimulation

• 1- electrical changes action potential
• 2- Excitability changes ends before the
  beginning of contraction
• 3- chemical changes at rest during activity
• 4- mechanical changes contraction

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Electrical changes
Nerve action potential Muscle action potential
RMP -70mV -90mV
Rate of conduction According to myelination 5m/sec
duration shorter longer
After AP Release of acetyl choline Contraction after 2msec

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35
-70
-90
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Excitability changes

• It is like changes that occurs in the nerve
  during action potential (increased excitability,
  ARP, RRP, Supernormal excitability, subnormal
  excitability, normal)
• The refractory period ends at the time of
  beginning of contraction, so during contraction,
  the excitability is normal, can respond to
  another stimuli

Mechanical changes
AP
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Electrical changes in the muscle

• Similar to nerve action potential
• RMP -90mv
• AP lasts 2-4msec precedes muscle contraction by
  2msec
• Single muscle fiber obeys all or none rule

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Muscle Twitch

• a single action potential causes a brief
  contraction followed by relaxation
• The twitch starts 2msec after the start of
  depolarization, before the repolarization is
  complete

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Excitability changes

• It is like changes that occurs in the nerve
  (refractory) during action potential
• The refractory period ends at the time of
  beginning of contraction, so during contraction,
  the excitability is normal, can respond to
  another stimuli

Mechanical changes
AP
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Mechanical changes excitation-contraction
coupling

• Action potential produce muscle contraction in 4
  steps
• 1- release of Ca2 AP pass through T tubules,
  causing Ca release from the terminal cistern into
  the cytoplasm
• 2- activation of muscle proteins Ca2 binds
  troponin, moves tropomyosin away from active site
  of actin, actin binds with myosin, contraction
  starts
• 3- generation of tension binding, bending,
  detachment, return
• 4- relaxation active process, when Ca is removed
  frrom the cytoplasm actively pumped into the SR

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Action Potentials and Muscle Contraction
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Mechanism of muscle contraction
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Cross-bridge formation
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Types of Muscle Contractions

• Isotonic Change in length (muscle shortens) but
  tension constant
• Isometric No change in length but tension
  increases e.g. Postural muscles of body
• Muscle contraction in the body is a mixture of
  both types e.g. when person lifts a heavy object,
  the biceps starts isometric, then isotonic
  contraction

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Factors affecting muscle contraction

• 1- type of muscle fiber
• Slow red fiber Slow contraction relaxation,
  rich in myoglobin, not easily fatigued, adapted
  for prolonged weight bearing, e.g. soleus muscle
• Rapid pale fiber rapid contraction relaxation,
  poor myoglobin, easily fatigued, adapted for
  skilled movements, e.g. hands extraocular
  muscles
• 2- type of load
• Preload load applied to the muscle before
  contraction changing its initial length, within
  limits, the more the initial length, the more the
  tension in isometric contraction
• Afterload load added to the muscle after it
  starts contraction the more the after load, the
  less will be the velocity of contraction
• 3- stimulus factor
• Stimulus strength the more strength of the
  stimulus, the more the fibers stimulated, the
  more force of contraction
• Stimulus frequency
• low frequency separate twitches
• Medium frequency clonus
• High frequency tetanus
• 4- fatigue repeated stimulation of the muscle
  results in fatigue due to
• Depletion of ATP,CP glycogen consumption of
  acetyl choline
• Accumulation of metabolites decreased O2
  nutrient supply