Download Cardio66-ElectricalActivityOfTheHeartI

Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 1 of 10
I.
II.
Electrical Activity of the Heart I
Introduction
 Come to class, read the power points, and read the text and you’ll do well.
 Dr. Tune and Dr. Downey have well-funded cardiovascular research projects.
Stop by and see one of them if you’re interested.
 This lecture builds on the cell science lectures Dr. Downey delivered.
Resting [electrical] Potential across the Cell Membrane
A. Ionic Basis of the Resting Potential
1. Resting potential is negative under resting (diastolic) conditions. Changes
make it fluctuate to cause systolic activation of the heart.
2. It is so negative because the Na+/K+ pump in the membrane maintains high
intracellular [K+] and low intracellular [Na+]
3. Anions are largely non-diffusible because of their association with proteins
in the cell.
4. Calcium dynamics are very important for cardiac activity.
 In the membrane, the ATP consuming Ca2+ pump, Na+/Ca2+ exchanger,
and the sarcoplasmic reticulum (SR) uptake during diastole maintain low
intracellular [Ca2+]
 Resting cell membrane is much more permeable to K+ than to Na+ or
Ca2+. K+ leaks out faster than Na+ or Ca2+ can enter. This makes the
inside of the cell negative.
B. Intracellular and extracellular ion concentrations and equilibrium potentials in
cardiac muscle cells
Extracellular
Intracellular
Equilibrium
concentrations
concentrations
potential
Ion
(mM)
(mM)
(mV)
+
Na
145
10
70
+
K
4
135
-94
Ca2+
2
10-4
132
C. Nernst Equation—Learn how to use this!
1. Computes the equilibrium potential for a specific ion.
2. At the equilibrium potential, the transmembrane electrical potential
exactly balances an opposing transmembrane chemical potential. The
chemical potential is due to the transmembrane concentration difference.
Translation: The electrical potential is the voltage difference
across the cell membrane due to the charge differences of all of the
ions. The chemical potential is due to the concentration gradients
inside and outside the cell. The membrane potential is the voltage
of the membrane that exactly balances the concentration gradient
for the ions.
3. Eion =
61
log
Charge of ion
[ion]outside cell
[ion]inside cell
units are in mV.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 2 of 10

So, using this Nernst equation, compute the equilibrium potential for
the ions in the chart in II.B.

ENa+ =
ENa+ =

EK+ =



61 log [Na+] outside = 61 log (145mM)
1
[Na+] inside
(10mM)
+71 mV
61 log (4mM) = - 93 mV
1
(135mM)
There is a lot of K+ inside the cell, but not a lot outside. -93mV
inside will exactly balance the [K+] gradient for this. In
actuality, the EK+ is about -85mV, so K+ passively diffuses out.
ECa+ =
61 log (2mM)
= +131 mV
2
(10-4mM)
Use the Nernst equation to determine which direction an ion will
move due to the chemical and electrical gradients. Equilibrium
potentials for Na+ and Ca2+ are positive and relatively large values;
this is very different than the transmembrane potential. Thus, the
cell membrane conductance is increased resulting in a large driving
force for these to enter.
D. Effect of ionic permeability on membrane potential in a conducting cell (not SA
or AV node)
Na+ and Ca2+ equilibrium
potential makes the
Note that it’s positive
‘ceiling’
and headed for the Na+
equilibrium potential
Plateau
Repolarization—K+ leaves
the cell
Resting membrane
potential
K+ equilibrium potential
makes the ‘floor’
Activation
1. Effect primarily determined by the relative permeability of the membrane to
Na+, K+, and Ca2+. This is dependent on channel proteins.
2. A relatively high permeability of K+ sets the membrane potential close to
the value of the K+ equilibrium potential. A relatively high permeability of
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 3 of 10
Na+ sets the membrane potential close to the value of the Na+ equilibrium
potential.
3. The same is true for Ca2+. However, an equilibrium potential is not
specified for it because, unlike the other 2 ions, its equilibrium potential
changes during the action potential. This occurs because the cytosolic
[Ca2+] changes by a factor of 5 during excitation. During the plateau of the
action potential, the equilibrium potential for Ca2+ is about +110mV.
4. Note that the difference between Em and the respective equilibrium
potentials changes during the action potential. I.e. (Em –EK+) increases, so
during the plateau there is a large driving force for K+ efflux. When K+
channels open, repolarization occurs rapidly.
5. Difference between the actual membrane potential and equilibrium potential
is greater than usual in the plateau (referring to K+)
6. The # of ions crossing a membrane during an action potential is very
small in comparison to the concentration of the ion inside and outside
the cell. Therefore, the values calculated by the Nernst equation and the
concentrations used are stable. This is why the equilibrium potentials can be
drawn as straight lines.
7. At the end of an action potential, is there a lot more sodium inside than
outside the cell? NO! A small increase is seen, but not enough to measure
a change in the concentration.
E. Importance of Normal, Very negative Resting membrane Potential
1. Avoid spontaneous depolarization. If the resting membrane voltage is near
the threshold voltage, a small change can cause the channels to easily open.
2. The more negative the resting potential, more Na+ channels recover from
inactivation—stage produced by previous depolarization.
3. Faster depolarization during Phase 0 when the resting potential is more
negative. During the upslope, the Na+ channels open faster.
4. Greater amplitude of action potential when rising from a more negative
value. The amplitude of the upslope is higher if the starting point is at a
more negative value.
5. More rapid propagation of an action potential through out the heart. This is
needed for an efficient mechanical pump. If it’s inefficient, the heart does
not inject enough blood into the system.
III.
Transmembrane Currents
1. (cell science information)
2. The driving force to move ions across the membrane: The difference between
Em (membrane potential calculated from the Nernst equation) and Ex influences
the magnitude and determines the direction of X current across the cell
membrane.
3. Specific ionic permeabilities (or conductance) influence the magnitude of the
specific ion current by determining the ease with which the ion can cross the
membrane.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 4 of 10
4. The specific ionic current, Ix = Px * (Em – Ex). By definition, positive current
of cations are directed outward across the membrane and negative current
are directed inward. (Text provides graphs of current flux across the
membrane. The pages and figures were not referenced in class.) Na+ is
positive, so it exits the membrane which is negative.
5. If Em = 0, there’s NO flow of ions.
6. For sodium: INa+ = PNa+• (Em - ENa+)
INa+ = PNa+ • [(-90) - (+70)]
INa+ = PNa+ • (-160)
The driving force is a large value for sodium, yet at rest the sodium currents are
very small due to the small permeability term for the resting cell membrane. If
the permeability increases, there’s a huge drive for the influx of sodium.
IV. Cardiac Action Potentials
A. Two types
1. Fast Response
 Rate of rise of initial depolarization
 Depolarizes rapidly like skeletal muscles and neurons
 Atrial and ventricular contractile cells—99% of cardiac mass. So, most
cardiac cells have fast action potentials.
 Rapidly conducting cells—Purkinje fibers—muscle cells with a large
diameter and lots of gap junctions. Facilitate the conduction of action
potentials through the myocardium.
2. Slow Response
 Action potential rises slowly, but the duration of the action potential is
about the same
 Sinoatrial node—initial depolarization
 Atrioventricular node—conduction from atrium to the ventricles
3. Graphical Representation
 From this, appreciate the difference in slope between the fast and
the slow response.


Purkinje fibers are the conducting path and have the longest action
potential.
The atrium has the shortest action potential. This leads to
vulnerability for fibrillation (inappropriate excitation) in the atrium.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 5 of 10
slow
fast
fast
fast
slow
fast
B. Pathologic Conditions
1. Ischemia and other conditions can convert fast response action potentials to
slow response action potentials.
 Remember that ischemia is inadequate blood flow. It kills many and is
often caused by coronary artery disease which limits blood to parts of
the heart.
2. This alters myocardial conduction of electrical excitation, and can cause
cardiac arrhythmias and decrease efficiency of ejection. This converts a fast
response to a slow response.
3. These conditions damage the Na+/ K+ pump so that normal ion gradients
don’t exist, thus eliminating the rapid upslope of the fast response.
4. Ca2+ can provide a slow response. This is bad, though, because the slow
response causes slow conduction between cells. This in turn causes cardiac
arrhythmias and decreases the mechanical function of the heart.
C. Testing to see how a fast response can change to a slow response
1. A drug is given to block fast channels.
2. The channel then changes to slow depolarization as more drugs are given.
3. Slow response is produced by opening of Ca2+ channels. Note that Na+
does NOT play a role in the rise of the action potential in a slow
response cell.
4. The following figure shows the progression from fast to slow response after
the drug was administered.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 6 of 10
D. Phases of Action potentials
1. Remember the phase numbers, where they are on the graph, and what
is happening at that point.
2. Fast Response
Phase 0—rapid upstroke/upslope
Phase 1—brief partial, transient
repolarization
Phase 2—plateau
Phase 3—rapid (deep) repolarization
Phase 4—diastolic/resting potential—
this is constant in a healthy
cell

There is a refractory period where it’s impossible or very difficult to
repolarize the cell. So, if inappropriate early depolarization is attempted,
the mechanical event (contraction) has occurred and the cardiac muscle
can’t react.
 This important so that the heart muscle can relax to allow the chambers
to refill before the next excitation.
 Stating the obvious, but very important: contraction lags behind the
action potential (just as in skeletal muscle), but the contraction and
action potential last longer in cardiac muscle than in skeletal muscle.
This is also true for the slow response.
3. Slow Response
 Note that there’s no Phase 1—no transient partial repolarization.
 Phase 0 is much slower than a fast response Phase 0.
 There’s no clear plateau, although it’s still called Phase 2. It’s the next
stage after the depolarization.
 Phase 3 is the rapid repolarization.
 Phase 4 is the diastolic potential. This can gradually rise toward the
threshold to initiate depolarization in slow response cells.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 7 of 10
V.
Series of events during action potentials—trying to separate the electrochemical
force into its components.
A. Phase 0—upslope
Diffusion
Electrical
gradient
1. Initially, the m-gate blocks the channel.
 H-gate, the inactivation gate, is out of the way—it takes a very negative
membrane potential (-90mV) to move it out of the way. If this is not
reached, the h-gate remains in the channel, even if the m-gate has moved
because its threshold has been reached. Na+ entry is blocked by the hgate. (In ischemia, this value is only -60mV, so the h-gate stays in the
channel and blocks Na+ entry.)
 The channel is ready to be activated when the h-gate is out of the way.
2. M-gate begins to swing open at about -65mV. This voltage also initiates the
closure of h-gates, which operate more slowly than m-gates.
3. Na+ enters the cell moving down both its electrical and chemical gradients.
This reduces the negative charge inside the cell and causes more Na+
channels to open, increasing the Na+ influx.
4. As the cell depolarizes, the electrical gradient decreases, and the
electrostatic force attracting Na+ into the cell is neutralized and the electrical
gradient favoring Na+ to leave is large.
5. The chemical gradient stays constant because the inside ion concentration
does not change significantly (see II.D.7) So, the Na+ continue entering the
cell causing the membrane voltage to become positive.
6. When the membrane voltage is about +20mV, Na+ continues to enter the
cell slowly due to the diffusional forces (60mV) which exceed the opposing
electrostatic forces (20mV). This movement is slow because many of the
inactivation gates have closed.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 8 of 10
B. Phase 1—Brief partial repolarization
1. When the membrane potential is 30mV, the h-gates are all closed and block
the Na+ channel. The m-gates are still out of the way. They remain in this
state for the first ½ of repolarization. During the second half of
repolarization, the m- and h-gates move so that the m-gates block the
channels and the h-gates are out of the way.
2. Na+ influx ceases.
3. The loss of cations from the cytosol creates a large force for K+ to leave the
cell. When the K+ channels open, briefly, there’s an efflux of K+ down an
electrical and a concentration gradient.
C. Phase 2—Plateau
1. Na+ channels are closed
2. K+ channels are closed
 These channels decrease conductance (close) to a value that’s lower than
the conductance of the resting membrane = rectification.
 There’s a very small amount of K+ efflux because the channels are not
conducting—no repolarization occurring.
3. Ca2+ channels open
 These are voltage sensitive and have threshold of about -60mV.
 They are slow opening and stay open a long time.
4. Ca2+ enters the cell because a large concentration gradient across the cell
overcomes a small electrical gradient.
D. Phase 3—Rapid repolarization
1. K+ conductivity increases. So, there’s a more rapid loss of K+ generating a
repolarizing current (outward current).
2. There’s a decrease in the Ca2+ inward current because Ca2+ channels are
closing.
Note that rectification is a conduction change with respect of an electrical
driving force.
E. Phase 4—Diastolic potential
1. There’s a return to normal. As the membrane repolarizes, the m-gate
blocks the channel. H-gate moves away if repolarization is sufficiently
negative.
2. Concentrations are maintained
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 9 of 10
3. Net efflux of K+ passively leaving cell due to the electrical and
concentration gradients.
4. Na+ leaks in
5. Na+/ K+ pump actively bring K+ back in while expelling Na+
F. Summary
 Shows thresholds for
ions
 Na+ efflux is early in
the fast response
 Ca2+ influx takes
place over a longer
period of time and
wanes over the
plateau
 K+ efflux during
rapid repolarization
VI. Action Potential Currents
A. Ventricular Cells
1. Na efflux early in the action potential
2. Ca takes place later—wanes during plateau
3. Cardiac action potentials last
 200ms—atrial
 up to 300ms—ventricle
4. These are much longer than action potentials for skeletal muscles and
neurons.
B. Graphical representation
1. g stands for conductance (or permeability)
2. Brief, explosive increase in Na+ conductance
3. Slower rise, longer lasting rise in Ca2+ conductance
4. There is a ‘blip’ of increased K+ conductance during Phase 1. This is
ignored by the text.
5. K+ conductance decreases during plateau (Phase 2)—most important thing
from this drawing. Different from conductances of other tissues. This
decrease aids in maintaining the plateau.
6. Rise in K+ conductance responsible for repolarization. This rises from a
lower value than the baseline.
Cardio #66
Wed, 01/22/03, 8am
Dr. Downey
Jennifer Uxer for Sue Fair
Page 10 of 10
Blip of K+
conductance
C. Inward Rectification of K+ Current
1. Won’t as a test question on the definition of rectification. Understand the
concept. This is included because K+ is described by rectification—it is
increased compared to the resting phase. It doesn’t increase because
conductance decreases
2. During phases 0 – 2, the driving force K+ efflux increases (Em – EK+
increases compared to phase 4), but outward K+ current does not increase
because the conductance decreased.
3. The voltage related change in membrane conduction is called rectification.
The change in the voltage changes the conductance.
4. The rectification is inward since the same driving force, when directed out
of the cell causes the efflux of K+, now produces a very large inward K+
current (influx) when the force is directed inward.
Translation: The channels have a low conductance when the force is
directed outward. When that same force is directed inward, they conduct
rapidly.
VII. Physiologic moderator of Ca2+ conductance
 Positive effects—increase conductance
 Amount of Ca2+ in a cell during systole (activation) affects the amount of force
the muscle can generate
A. Catecholamines
1. Released by sympathetic nerves
2. Norepinephrine—Adrenergic neurotransmitter
3. Epinephrine—Adrenal medullary hormone
B. Sympathicomimetic drugs
1. Mimic physiologic factors
2. These agents bind to Beta Adrenergic Receptors on the cell surface,
stimulate Adenylyl Cyclase, increase Cyclic Adenosine Monophosphate
(cAMP), and enhance activation of L-type (slow type) Ca2+ channels.
3. More channels are open for more of the time when the agents are present.
4. There’s an increase in the amount of Ca2+ entering the cell and an increase
in the duration of channel opening.