PSIO 603/BME 511
February 19, 2007
1
Dr. Janis Burt
MRB 422; 626-6833
jburt@u.arizona.edu
MUSCLE EXCITABILITY - Ventricle
READING: Boron & Boulpaep pages: 483-507
OBJECTIVES:
1. Draw a picture of the heart in vertical (frontal plane) section. Include the elements of the
conduction system in your drawing.
2. Describe the sequence of activation of the heart. List the three benefits of the sequence in
optimizing cardiac function.
3. Draw an action potential characteristic of ventricular cells, label its phases, describe the
membrane's relative ion permeabilities for each phase, and compare these relative
permeabilities to those of skeletal muscle and nerve.
4. Discuss the significance for cardiac function of the high resting potassium permeability.
5. Relative to an action potential, illustrate the timing of the three refractory periods observed
in a cardiac myocyte. Provide a definition for each refractory period. State which channel’s
activation/inactivation characteristics determine the refractory state of the heart. Graph the
relationship between that channel’s availability and membrane potential. State the
significance of refractory periods to normal pulsatile function of the heart.
LECTURE OUTLINE
I. Sequence of Activation – Overview (Objectives 1, 2)
A. Normal Sequence of Activation:
Sinoatrial node → right atrium, interatrial tracts, and internodal tracts → atrioventricular
node and left atria → atrioventricular node → Bundle of HIS → bundle branches →
Purkinje fibers → ventricle (apex to base, endocardial surface to epicardial surface)
B. Benefits of normal activation sequence
1. Maximizes ventricular filling
2. Optimizes ventricular contraction by stabilizing valve leaflets and septum early in
contraction
3. Maximizes ejection by synchronizing contractile activation in the ventricular wall
II. Excitability of Ventricular Cells:
A. The Action potential - Figure 1&2 (Objectives 3 & 4)
1. Action potential duration is 100x longer than in SKM or nerve with 4 distinct phases.
2. During Phase 4 the membrane potential is dominated by PK (IK1 channels), which are
~10x more numerous than in SKM or nerve.
a) High resting PK: stabilizes the resting membrane potential; minimizes arrhythmias
by necessitating a large stimulus (depolarization of neighboring cells) to result in
successful activation (ventricles are slaves to the pacemaker cells).
b) The resting permeabilities for PK :PNa :PCl are: 1 : 0.05 : 0.1 (note: PNa is 10-50x
higher than in nerve or SKM; PCl is comparable to nerve, 100x less than SKM.
c) The density of Na,K-ATPase enzymes in heart membrane is greater than SKM or
nerve.
3. During phase 0, the action potential upstroke, PNa increases resulting in an influx of
Na+ (Na-channel comparable to nerve and SKM but with slower kinetics).
4. Phase 1, the early repolarization phase, involves a transient increase in PK (resulting
in efflux of K+) and Na-channel inactivation.
PSIO 603/BME 511
February 19, 2007
2
Dr. Janis Burt
MRB 422; 626-6833
jburt@u.arizona.edu
5. Phase 2, the plateau phase, requires an increase in PCa and a decrease in PK (decrease
in IK1 activity).
a) The calcium channel is voltage activated, dihydropyridine sensitive, and regulated
by cAMP-dependent protein kinase.
b) PK decreases as Mg2+ blocks the IK1 channels.
6. Phase 3, repolarization, voltage activated K channels open (IK - delayed rectifiers)
and Ca channels close. As the membrane repolarizes Mg2+ block of IK1 channels is
relieved and resting membrane permeabilities are restored.
7. As heart rate increases action potential duration decreases; however time between
action potentials shortens to a greater extent than the action potential.
B. Refractory periods – Figures 1,3,4 (Objective 5)
1. absolute refractory period - the period of time during which no action potential can
be initiated, regardless of stimulus strength (ARP in Figure 1) and is considerably
longer in duration than observed in skeletal muscle.
2. effective refractory period, the period of time during which no propagated action
potentials can be elicited regardless of stimulus strength.
3. relative refractory period (RRP) the period of time in which a response can be
elicited but the stimulus required is larger than normal and the amplitude of the action
potential is abnormally small.
4. supranormal period (SNP) the period during which a slightly smaller than normal
stimulus elicits a propagated response, although the amplitude of the action potential
is reduced compared to normal.
5. Full recovery time (FRT) represents the time before a normal action potential can be
elicited with a normal stimulus.
6. Refractory properties reflect the recovery of Na-channels to a state from which they
can be activated.
7. The long duration of the action potential and the refractory characteristics of the cell
insure that cardiac cells are nearly completely relaxed by the time they are
repolarized. Cardiac muscle cannot be tetanized because of these membrane
properties.
LECTURE NOTES
I. Sequence of Activation (Objectives 1 & 2)
The normally functioning heart follows a specific pattern of activation every time it
contracts. This pattern optimizes function by maximizing ventricular filling, contraction and
ejection. The activation sequence begins with an action potential at the sinoatrial node, the
pacemaker of the heart. The electrical event spreads via gap junctions to the surrounding atria
and along specialized interatrial and internodal conduction pathways to the left atrium and
atrioventricular node (AV node), respectively. The AV node represents the only point of
electrical continuity between the atrium and ventricle. When the excitatory event leaves the
AV node, it passes rapidly along the Bundle of HIS, the bundle branches and the purkinje
network to the ventricles. Activation of the ventricles occurs initially at the septum and apex of
the heart and progresses towards the base of the heart, and from the endocardial surfaces towards
the epicardial surfaces. Activation of the ventricles begins ~ 0.15 sec after the atria. This delay
between atrial and ventricular activation assures maximal ventricular filling. The sequence of
activation within the ventricle insures efficient contraction and ejection by: i) stabilizing the
septum and valve leaflets early in the contraction, and ii) activating from apex-to-base and
endocardium-to-epicardium. The latter results in pushing the blood towards the aortic valve and
PSIO 603/BME 511
February 19, 2007
3
Dr. Janis Burt
MRB 422; 626-6833
jburt@u.arizona.edu
prevents cells located at the epicardial surface from having to contract against "flacid" cells near
the endocardial surface.
How do the electrical properties of the cells of the heart insure that this sequence occurs
beat after beat? When this pathway of normal activation fails, what properties insure a
“back-up” strategy for activation of the heart? What circumstances predispose the heart to
arrhythmias? These are the questions we will address over the next week or two.
II. Excitability in Ventricular, Atrial and Non-nodal Conducting Cells (Objectives 3 & 4)
A. The Action potential: The action potentials of ventricular and non-nodal conduction system
cells last for ~250-300 msec; atrial cell action potentials last ~150 msec. These long duration
potentials are characterized by several phases (0-4) as shown in Figure 1.
Phase 4 -- diastole or rest. The resting permeability of the ventricular cell membrane is
dominated by potassium. Ventricular cells have an approximate ten fold higher resting
permeability to potassium than do skeletal muscle or nerve cells. This high resting potassium
permeability (like the high chloride permeability in skeletal muscle) stabilizes the resting
membrane potential reducing the risk of arrhythmias by necessitating a large stimulus to excite
the cells. The ventricles are thereby rendered slaves to the pacemaker cells of the heart. The
permeabilities of Na and Cl (relative to potassium) are (PK : PCl : PNa) 1 : 0.1 : 0.05. Note that the
ventricular cell is more permeable to Na+ at rest than other excitable cells. As a consequence of
the high Na+ permeability, the density of Na,K-ATPase enzymes in the membrane is high. Since
this pump is electrogenic, its activity contributes several millivolts to the resting membrane
potential.
Phase 0 -- action potential upstroke. As in skeletal muscle and nerve the upstroke results from
an increase in PNa. The voltage gated Na channel Figure 1 Action potential and
expressed in the heart is a different gene product than underlying permeability changes for
that expressed by skeletal muscle or neural tissues.
ventricular and purkinje cells. (modified
from reference 2)
Phase 1 -- early repolarization. The ionic basis of this
phase is a transient increase in potassium permeability
(IK-to) and Na-channel inactivation.
Phase 2 -- plateau. This is the most distinctive feature of
the cardiac action potential. The plateau requires two
changes in membrane permeability: 1) an increase in
calcium permeability through voltage-activated, L-type
Ca channels that are dihydrophyridine sensitive; and 2) a
decrease in potassium permeability. During the plateau
phase potassium permeability is ~ 1/10 the resting
potassium permeability. This decrease in PK is indirectly
voltage dependent – at depolarized potentials Mg2+
enters and blocks the IK1 channels.
1
2
3
0
4
P
0
P
0
2+
Phase 3 -- repolarization. Repolarization occurs as Ca
channels inactivate and voltage activated K channels
open (delayed rectifiers - IK). As repolarization proceeds
the IK channels deactivate and the Mg2+ block of the IK1
channels is relieved, which restores the resting
permeabilities of the membrane.
P 10
0
*
PSIO 603/BME 511
February 19, 2007
4
It is interesting to note that the permeability
of most excitable cells is lowest when the
membrane potential is at the resting level. This
conserves energy by reducing the number of Na+
and K+ ions that need to be pumped. Cardiac
tissue is the exception to the rule. The cardiac
cell’s overall membrane permeability is actually
less during the active phase (dominated by the
plateau) than during the rest phase. In large part,
this difference reflects high resting permeability
to K+ and the block of the underlying potassium
channels (IK1) that occurs with depolarization.
Lower permeability during activation is
advantageous to the heart during high heart rates
because K+ efflux is spared and the energy
required to restore that K+ to the intracellular
space (via the Na,K-ATPase) conserved for
contraction.
Dr. Janis Burt
MRB 422; 626-6833
jburt@u.arizona.edu
Figure 2 - Epinephrine (black vs. grey curves)
shortens the ventricular action potential by
enhancing ICa-L and IK. (modified from reference 2)
P
0
10
Sympathetic and Parasympathetic Control
P
The ventricles are well innervated by
0
sympathetic fibers that release norepinephrine.
This transmitter binds to β-adrenergic receptors,
which transduce the activation of protein kinase A. This kinase enhances the activity of ICa-L and
IK channels (see figure 2). In addition to delivering more calcium to the contractile apparatus
(stronger contractions), these changes in channel activity cause a shortening of the action
potential’s duration.
ARP
RRP
FRT
SNP
% Na Channels
Available
B. Refractory Periods (Objective 5)
Due to the activation/inactivation characteristics of the voltage-gated Na+ channel underlying
phase 0, cardiac muscle is refractory to stimulation until it is repolarized. At the cellular level,
the period of time during which no action potential can be initiated, regardless of stimulus
strength, is called the absolute refractory period (ARP - Figure 1). At the tissue level, the
absolute refractory period translates into the effective refractory period, which is defined as the
period of time during which no propagated action potentials can be elicited. The ARP lasts until
the membrane potential repolarizes to levels more negative than -65 mV. The ARP is followed
by a period in which an action potential can be elicited
but the stimulus required is larger than normal and the Figure 3 - Na-channel availability
amplitude of the elicited action potential is abnormally determines the refractory properties of
small. This period is the relative refractory period the heart. (modified from reference 2)
Repolarize
(RRP). As the membrane potential repolarizes an
+
increasing fraction of the total Na channels becomes
available for activation (Figure 3). Thus, a stimulus
delivered at the beginning of the RRP will elicit an
action potential of small amplitude, and one delivered
towards the end of the RRP will elicit an action
potential of larger amplitude. The RRP is followed by
the supranormal period (SNP) during which a slightly
smaller than normal stimulus elicits a normal
propagated response. Full recovery time (FRT)
represents the time after which a normal action potential
Membrane
can be elicited with a normal stimulus.
Potential (mV)
5
Figure 4 - Cardiac contraction is nearly
complete with the onset of phase 4 (top panel).
Consequently, tetanus is not possible in this
muscle type. In skeletal muscle, repolarization
occurs early in contraction, making summation
and tetanus possible.
2
0
3
4
Tension
1
+50
Membrane
Potential (mV)
The refractory properties of the cardiac cell
are suited to the function of the organ. The timing
of the electrical and contractile events is such that
the heart relaxes before it can contract again
(Figure 4). At a heart rate of 72 beats/min (bpm)
and action potential duration of ~300 msec, the
time between beats (referred to as electrical
diastole) is around 530 msec. At a heart rate of
200 bpm and an action potential duration of 300
msec the interval between beats would be 0 msec.
Since it is during diastole that the heart has time
to fill with blood, it is clear that in order to be an
effective pump at fast heart rates the duration of
the action potential must decrease. In general, the
duration of the action potential varies inversely
with the frequency. Shortening of the action
potential reflects the effects of sympathetic drive
on Ca and K channel function.
Dr. Janis Burt
MRB 422; 626-6833
jburt@u.arizona.edu
Membrane
Potential (mV)
PSIO 603/BME 511
February 19, 2007
References Cited in Figures:
1. Physiology by L.S. Costanzo. W.B. Saunders Co., Philadelphia, 1998.
2. Physiology of the Heart (2nd ed.) by A.M. Katz, Raven Press, N.Y. 1992.
3. Ionic Channels of Excitable Membranes by Bertil Hille.
Tension
C. Action Potential Duration
0
Action potential duration, even within the
ventricle, varies. The purkinje fibers have the
longest duration (~300 or longer msec at resting
heart rates), atrial cells the shortest (150-200msec
-85
at resting heart rates); within the ventricle cells
3 msec
closest to the chamber have longer duration action
potentials than the those at the epicardial surface.
This latter comparison is worth remembering – the ramifications of this are that despite
depolarizing after ventricular cells near the endocardium, the epicardial cells repolarize first.
How can so many different durations result from the same types of channels? Although all these
cells have the same array of channel types, their relative numbers differ considerably. You might
expect that delayed rectifiers would be more numerous in cells with shorter duration action
potentials, if so, you would be correct. You might also expect that Ca-channel density is lower in
regions with short action potentials, this too is true.