GENERAL PHYSIOLOGY OF

EXCITABLE TISSUES

Lecture in normal physiology

 Normal Physiology
 studies all the functions and processes,
taking place in an organism (its systems,
organs and tissues); the science also
studies mechanisms of the functions’
regulation, those which make possible
proper activities in different environment
and different inner state of the organism
 Russian Physiologists

I.M. Setchenov (1829 – 1905) I.P. Pavlov (1849 – 1936)

1904 Nobel Prize
 EXCITABILITY
 Irritability - All cells possess the ability to
respond to environmental changes called
stimuli. Response means changing shape,
activity, etc.
 Excitabily – Specific ability of certain cells to
give special response to stimulation: changes
in activity, metabolic processes and electrical
charge.
 Excitation
is a complex biological reaction manifested as a
combination of physical, physico-chemical, and
chemical processes and functional changes; its
imperative sign is a change in the electrical state
of the cell-membrane. When stimulated, a cell
changes from a state of rest to one of the
physiological activity characteristic of it: a
muscle fiber contracts, while a gland cell
secretes. Only in nerve cells and nerve fibers
excitation is encountered in its pure electric
form.
 CELL MEMBRANE
 The cell membrane is a protective sheath,
enveloping the cell body. The thickness of the
cell membrane varies from 75 A to 111 A.
 This membrane separates the fluid outside the
cell called extracellular fluid and the fluid inside
the cell called intracellular fluid.
 The cell membrane is a semipermeable
membrane. So, there is free exchange of certain
substances between the extracellular and
intracellular fluids.
STRUCTURE OF CELL MEMBRANE
 The electron microscopic
study reveals three layers of
cell membrane: one central
electron-lucent layer and
two electron-dense layers.
The two electron-dense
layers are placed one on
either side of the central
layer. The central layer is
called lipid layer as it is
formed by lipid substances.
The outer two layers are
formed by proteins and are
called protein layers. Cell
membrane contains some
carbohydrate molecules.
Lipid Layer of the Cell Membrane
 The central lipid layer is a bilayered structure. This is
formed by a thin film of lipids. The major lipid is
phospholipids. The phospholipids are the lipid
substances containing phosphorus and fatty acids.
 The phospholipid molecules are arranged in two layers.
The outer part of the phospholipid molecule called head
portion is soluble in water (hydrophilic). The inner part is
the tail portion that is not soluble in water
(hydrophobic). The two layers of phospholipids are
arranged in such a way that the hydrophobic tail
portions meet in the center of the membrane. The
hydrophilic head portions of one layer face the
extracellular fluid and those of the other layer face the
cytoplasm.
 THE PROTEIN LAYER
The protein layers of the cell membrane are
the electrondense layers. These layers
cover the two surfaces of the central lipid
layer. The protein layers give protection to
. the watery central lipid layer. The protein
substances present in these layers are
mostly the glycoproteins. Two types of
protein molecules are present in the cell
membrane: the integral proteins and
peripheral proteins.
 MEMBRANE PROTEINS
 The integral proteins are also known as
transmembrane proteins. These proteins pass
through the entire thickness of the cell
membrane from one side to the other side.
These proteins are tightly bound with the cell
membrane.
 The peripheral proteins are otherwise called
peripheral membrane proteins. These proteins
are partially embedded in the outer and inner
surfaces of the cell membrane and do not
penetrate the cell membrane. The peripheral
proteins are loosely bound with the cell
membrane. So, these protein molecules can
dissociate readily from the cell membrane.
 Functions of Membrane Proteins
Integral proteins: Integral proteins provide the structural integrity
of the cell membrane.
Channel proteins: Some integral protein molecules form the
channels for the diffusion of water soluble substances like glucose
and electrolytes. So, these proteins are called the channel proteins.
Carrier proteins: Some protein molecules help in the transport of
substances across the cell membrane by means of active or
passive (facilitated diffusion) transport. These are called carrier
(pump) proteins.
Receptor proteins: Some protein molecules serve as the receptor
sites for hormones and neurotransmitters. Such proteins are known
as receptor proteins.
Enzymes: Some of the protein molecules form the enzymes
which control chemical (metabolic) reactions within the cell
membrane.
Antigens: Some proteins act as antigens and induce the process
of antibody formation.
 Protein Channels

 The characteristic feature of the protein

channels is their selective permeability.
That is, each channel can permit only one
type of ion to pass through it.
 Channel permeability depends on: ion
charge, shape, size, water surrounding
 Regulation of the Channels
 Some of the protein channels are
continuously opened, and most of the
channels may be open or closed.
 Continuously opened channels are called
ungated channels (non-regulated).
 The closed channels open only when it is
required, and those are called gated
channels.
 Gated Channels
The gated channels are divided into three categories:
 voltage gated channels,
 ligand gated channels,
 mechanically gated channels.

Voltage gated channels:

These channels open whenever there is a change in the
electrical potential. That is why these are called voltage
gated channels. For example, in the neuromuscular
junction, when action potential reaches axon terminal,
the calcium channels are opened and calcium ions
diffuse into the interior of the axon terminal from
extracellular fluid in large number.
 The Resting Membrane Potential
 All cells under resting conditions have a potential
difference across their plasma membrane. This
potential is the resting membrane potential.
 By convention, extracellular fluid is assigned a
voltage of zero, and the polarity of the membrane
potential is stated in terms of the sign of the excess
charge on the inside of the cell.
 The magnitude of the resting membrane potential
varies from about 50 to 90 mV, depending upon the
type of cell; in neurons, it is generally in the range of
60 to 75 mV The membrane potential of some cells
can change rapidly in response to stimulation, an
ability of key importance in their functioning.
The magnitude of the resting membrane potential
is determined mainly by two factors :
 (1) differences in specific ion concentrations in
the intracellular and extracellular fluids,
 (2) differences in membrane permeability to the
different ions, which reflect the number of open
channels for the different ions in the plasma
membrane.
In other words, a potential is generated across the
plasma membrane largely because of the movement of
potassium out of the cell down its concentration gradient
through open potassium channels, so that the inside
of the cell becomes negative with respect to the
outside. To repeat, the experimentally measured resting
membrane potential is not equal to the potassium
equilibrium potential, because a small number of
sodium channels are open in the resting state, and
some sodium ions continually move into the cell,
canceling the effect of an equivalent number of
potassium ions simultaneously moving out.
 Action potential
 When a nerve or muscle cell is stimulated,
Na-gated chanals in the plasma
membrane open and Na instantly diffuses
down its concentration gradient into the
cell. These cations override the negative
charges in the ICF, so the inside of the
plasma membrane briefly becomes
positive (up to +20 mV).
 This point Na gates close and K gates open. K
rushes out of the cell, it diffuses down its electrical
and concentration gradient.
 The loss of positive potassium ions from the cell
turns the inside of the membrane negative again.
This quick up-and-down voltage shift, from the
negative RMP to a positive value and then back to
a negative value again, is called an action
potential.
 The RMP is a stable voltage seen in a “waiting” cell,
whereas the action potential is a quickly fluctuating
voltage observed in an active, stimulated cell.
The first manifestation of the approaching action potential is a
beginning depolarization of the membrane. After an initial 15 mV
of depolarization, the rate of depolarization increases. The point at
which this change in rate occurs is called the threshold level.
Thereafter, the tracing on the oscilloscope rapidly reaches and
overshoots the isopotential (zero potential) line to approximately
+35 mV. It then reverses and falls rapidly toward the resting level.
When repolarization is about 70% completed, the rate of
repolarization decreases and the tracing approaches the resting
level more slowly. The sharp rise and rapid fall are the spike
potential of the axon, and the slower fall at the end of the process
is the after-depolarization. After reaching the previous resting
level, the tracing overshoots slightly in the hyperpolarizing
direction to form the small but prolonged after-hyperpolarization.
 Sodium-Potassium Pump
The pump is a primary active transporter, because
it uses the cellular energy of the terminal
phosphate bond of ATP.
The Na+-K+-pump transports 3 Na+ out of the
cell and 2 K+ into the cell for each ATP
hydrolysed. This is a net movement of positive
ions out of the cell, and therefore called an
electrogenic transport. The constant influx of
Na+ is present as well as the leakage of K+ and
Cl-. In a steady state the net transport of each
ion across the resting membrane is zero.
 Absolute Refractory Period.
 During the action potential, a second stimulus,
no matter how strong, will not produce a second
action potential, and the membrane is said to be
in its absolute refractory period.
 This occurs because the voltage-gated sodium
channels enter a closed, inactive state at the
peak of the action potential.
 The membrane must repolarize before the
sodium channel proteins return to the state in
which they can be opened again by
depolarization.
 Relative Refractory Period
 Following the absolute refractory period, there is an
interval during which a second action potential can be
produced, but only if the stimulus strength is
considerably greater than usual. This is the relative
refractory period, which can last 10 to 15 ms or
longer in neurons and coincides roughly with the period
of after hyperpolarization.
 During the relative refractory period, there is lingering
inactivation of the voltage-gated sodium channels, and
an increased number of potassium channels are open. If
a depolarization exceeds the increased threshold or
outlasts the relative refractory period, additional action
potential will be fired.
 Excitability of different
tissues

 Excitability is the capacity of tissue to

respond to stimulation consequently to
generate an action potential
 QUALITIES OF STIMULUS
To excite a tissue, the stimulus must
possess three characters :
 1. Intensity or strength
 2. Duration
 3. Steepness of increase in stimulus
strength ( accommodation)
 The intensity of stimulus is of five
types:
Subminimal stimulus
Minimal stimulus
Submaximal stimulus
Maximal stimulus
Supramaximal stimulus
 The stimulus whose strength (or voltage)
is sufficient to excite the tissue is called
threshold or minimal stimulus.
The measure of excitability is the minimum
strength of stimulus that produces
excitation, and is known as the threshold
of stimulation.
 The higher the minimum strength of
stimulus needed to cause a reaction, (the
higher the threshold of stimulation) the
lower the excitability; conversely, the
lower the threshold of stimulation, the
higher the excitability.
 THE ALL-OR-NONE LAW
 Through study of the relationship of stimulation
effects to stimulus strength an all-or-none law was
established, according to which subthreshold
stimulation produces no excitation, while threshold
stimuli immediately produce maximum excitation
unaffected by a further increase in stimulus strength.
 For a long time the all-or-none law was erroneously
interpreted as the general principle of the reaction of
excitable tissue. It was supposed that none meant
the complete absence of excitation in response to a
subthreshold stimulus, while all was considered a
manifestation of the complete exhaustion of the
potentials. Later research has shown that a stimulus
of near-threshold strength causes a local excitation
not capable of spreading, a local response, directly in
the area stimulated.
 Local potentials are
1. Graded,
meaning that they vary in magnitude
(voltage) according to the strength ofthe
stimulus. A more intense or prolonged
stimulus opens more ion gates than a
weaker stimulus. Thus, more Na+ enters
the cell and the voltage changes more
than it does with a weaker stimulus.
 Local potentials are
2. Decremental,
meaning they get weaker as they spread from the
point of stimulation. The decline in strength
occurs because as Na+ spreads out under the
plasma membrane and depolarizes it, K+ flows
out and reverses the effect of the Na+ inflow.
Therefore, the voltage shift caused by Na+
diminishes rapidly with distance. This prevents
local potentials from having any long-distance
effects.
 Local potentials are
3. Reversible,
meaning that if stimulation ceases, K+
diffusion out of the cell quickly returns the
membrane voltage to its resting potential
STRENGTH-DURATION CURVE
 The excitability curve demonstrates the exact
relationship between the strength and the duration of a
stimulus. The shape of the curve is similar in almost all
the excitable tissues. Following are some of the
important points to be studied in the excitability curve:
 Rheobase =Threshold: This is the least possible,
minimum strength (voltage) of stimulus which can excite
the tissue. The voltage below this cannot excite the
tissue, whatever may be the duration of stimulus.
 Utilization time: It is the minimum time required for a
threshold strength stimulus to excite the tissue.
 Chronaxie: It is the minimum time, at which a stimulus
with double threshold strength can excite the tissue.
The measure of excitability is the minimum
time of doubled stimulus that produces
excitation, and is known as the
chronaxie.
 The higher the chronaxie of stimulus
needed to cause a reaction the lower the
excitability; conversely, the lower the
chronaxie, the higher the excitability.
 ACCOMMODATION
 Means the steepness of increase in
stimulus strength.
 The level of the threshold of nerve or
muscle excitability depends not only on
stimulus duration but also on the
steepness of its increase.
The stimulus threshold is at its lowest value with rectangular
current impulses characterized by maximum rapidity of increase in
strength. If, however, stimuli increasing linearly or exponentially
are used instead, thresholds prove to increase in inverse
proportion to the rate of increase in current strength When the
steepness of the rise is reduced below a certain minimum, no
action potential appears, no matter how great the final strength of
the current, because of the fact that during the period of increase
in stimulus strength active changes occur in the tissue raising the
threshold and interfering with stimulation. This phenomenon of
adaptation of excitable tissue to a slowly increasing stimulus is
known as accommodation.
Stimulus increase
 Accomodation curves of a
nerve fibre, measured by
means of linearly increasing
currents. Abscissa -
duration of increase in
current strength; ordinate -
values of thresholds in
milliampers. The inclination
of the thin lines to the
abscissa corresponds to the
rate of increase of the
stimuli.
 Stimulation by direct electric
current
Electrical stimulus is commonly used for experimental and
clinical purposes because of the following reasons:
 It can be handled easily
 The intensity of stimulus can be easily adjusted
 The duration of stimulus can be adjusted
 The stimulus can be applied to limited area on the
issues
 Damage caused to tissues is nil or least.

The mechanism by which electricity stimulates is identical

in principle for all types of stimuli, but is most distinctly
seen when direct current of rectangular wave form is
used.
LAW OF POLARITY OF STIMULATION

 Direct current has a polar action on

excitable tissue; when the direct current
circuit is closed excitation always arises in
a nerve or a muscle only at the anode (+),
and when the circuit is opened only at the
cathode (-).
 ELECTROTONUS
 Means changes in tissue excitability during the
passage of direct current
 According to the law of polarity of stimulation, action
potential arises at the cathode when the circuit is open, and
at the anode when it is closed but, as Pflueger showed, an
electric current not only excites tissue but can also change its
excitability. During the passage of direct current through a
nerve or muscle the stimulus thresholds in the cathode
region (under the cathode and in the adjacent area)
decrease, that is, excitability grows, and conversely, in the
anode region thresholds are heightened, that is, excitability is
reduced.
 These changes, which are most striking immediately under
the cathode and anode and gradually diminish with distance
from the poles, are known as electrotonic changes in
excitability, and are closely associated with the electrolonic
changes in membrane potential.
 Lability
 Under the natural conditions of existence of an organism,
however, rhythmic rather than isolated discharges of action
potentials pass along nerve fibres. The discharge frequency
of impulses in excitable tissues may vary within wide limits
according to the strength of the stimulus applied, the
properties and condition of the tissue, and the rate at which
individual acts of excitation occur in the rhythmic series.

 To characterize this rate Vvedensky formulated the concept

of lability (functional mobility), which he understood as "the
higher or lower rate of the elementary reactions that
accompany the physiological activity of a given apparatus".

 In his view the measure of lability is the largest number of

action potentials an excitable substrate is capable of
generating per second in response to frequently recurring
stimuli.
It was initially supposed that the minimum interval
between the impulses in a rhythmic series would
correspond to the length of the absolute refractory
period. To reproduce the rhythm of stimulation in a
series of stimuli the interval between them must be
somewhat longer than the absolute refractory period.
In the motor nerve fibers of warm-blooded animals the
absolute refractory period is about 0.5 millisecond,
whereas the maximum rhythm of stimulation is only
about 1,000 per second; in the nerve fibers of
crustaceans the absolute refractory period lasts about
one millisecond, while the maximum rhythm of
stimulations is approximately 500 impulses per second.
In the sensory fibres of the acoustic nerve and in
Renshaw inhibitory cells more than 1,000 impulses per
second have been recorded.