Transcript Zool 352 Lecture 34

Cardiac Muscle II
Excitation-contraction coupling in the
heart
There are 3 key differences in excitationcontraction coupling in heart versus skeletal
muscle
• 1. In the myocardium, a significant amount of
Ca++ (about 1/10 of the total) enters through L
Ca++ channels in the sarcolemma, during the
plateau of the myocardial action potential.
• (In comparison, essentially all the Ca++ released
in skeletal muscle comes from the SR and
virtually none enters across the sarcolemma).
2. In the heart, the concentration of Ca++
attained in the sarcoplasm during an action
potential is generally less-than-saturating for
cardiac troponin. Therefore, unlike skeletal
muscle, it is possible to modulate contractile
force by modulating the amount of Ca++ that
enters the sarcoplasm during excitation.
3. Ca++-induced Ca++ release is much more
important in cardiac muscle than in skeletal
muscle
The Ca++ that enters through L channels both
triggers, and tightly regulates, the amount of
Ca++ released from the SR by ryanodine
receptors in Ca++-induced Ca++ release. Each
L channel in the sarcolemma controls a small
number of nearby ryanodine receptors on the
SR.
Opening of an L channel results in a small area
of increased Ca++ that has been termed a
“Ca++ spark” because it appears as a glowing
spot when visualized with fluorescent Ca++
indicators.
Trigger Ca++
Ca++ spark
Ryanodine
receptor
Ca++ from SR
Regulation of myocardial
performance
• Two kinds:
• Intrinsic: stretch increases force - the
degree of stretch of the ventricle wall is
determined by venous return - the
amount of blood that enters the heart
during the interbeat interval
• Extrinsic: Cholinergic input decreases
force; sympathetic input increases it.
These inputs are managed by a reflex
circuit that regulates arterial blood
pressure.
Intrinsic regulation (autoregulation)
• As averaged over several heartbeats,
volume in = volume out
• I.e. cardiac output = venous return
• This is known as the Frank-Starling Law of
the Heart
Some definitions:
• End-diastolic volume EDV: the volume of
the ventricle at the end of filling, equal to
the venous return volume plus the endsystolic volume ESV.
• Stroke volume SV: the amount of blood
ejected during a beat.
• SV = EDV-ESV
Cardiac Output is the volume of blood
pumped by the heart per unit time
= SV X HR
Because of the Frank-Starling Law, the output
of the two ventricles is equal, when averaged
over time intervals of more than a few beats
Venous return
The effect of the FrankStarling Law on cardiac
performance
EDV
Ventricular
stretch
Stroke Volume
Since SV X HR = CO, CO follows VR
The Frank-Starling Law
is the result of the
position of the working
heart on the rising limb
of the length tension
curve. For a time it was
thought that the heart
had parallel elastic
elements that squeezed
the sarcomeres, forcing
them to greater overlap
than in resting skeletal
muscle.
However, recent studies showed that
the slope of the length-tension curve of
cardiac muscle is too steep to be
explained simply as a result of the
overlap of thick and thin filaments.
Even more recent studies published in
2011 (Science 1333, 1440-1445)
showed how stretch is transduced into
an increase in Ca2+ release.
Single-cell studies of Starling’s law
• In these studies, single cardiomyocytes
were glued between two glass rods. One
rod included a force transducer; the other
could apply small increments of stretch.
• The cells were loaded with a fluorescent
Ca2+ probe.
In these figures you can see that stretching leads immediately to an increase
in the number of Ca2+ sparks, represented as spikes on the false-color surface in figure
B. In a real-life situation this would increase the baseline level of Ca2+ that would be
present at the start of a heartbeat. The higher this baseline level is, the higher the peak
level reached in an action potential, and thus the more crossbridges activated. This
effect seems to be able to account for much if not all of the stretch-sensitivity of cardiac
muscle.
Stretch causes regulatory subunits of membrane-associated
NADPH oxidase (NOX2) to be brought in contact with its catalytic
subunits. As a result, reactive oxygen species are released.
The stretch response is altered in genetic disease
The results in the lower figure are from an animal model of Duchenne’s
muscular dystrophy. In this case, stretch results in a wave of increased
Ca2+ that could potentially trigger an arrhythmic heartbeat.
Summary of EC coupling in
heart
Effects of the beta adrenergic
receptor in myocardium
• Increased activity of L Ca++ channels
• Increased sensitivity of troponin to Ca++
• Increased ability to clear Ca++ after a
contraction – through reuptake to the SR
and expulsion across the sarcolemma
Neural regulation of the heart
What factors could increase the peak
intracellular Ca++ concentration attained
during excitation?
•
•
•
•
Simply increasing heart rate
Increased stretch during diastole
Activating Beta1 receptors
Cardiotonic drugs, such as digitalis, that
interfere with Ca++ removal from the
cytoplasm.
The effect of
increased contractility
on the length-tension
relationship
Increasing the
inotropic state of the
myocardium shifts
the cardiac function
curve upward and to
the left. This means
that the heart has
become more
sensitive to stretch.