Summary MG circulatory tract
Lecture 1: Cardiovascular structure and the heart (introduction)
Anatomy of the cardiovascular system
The heart is a pump that delivers blood (containing water, oxygen, carbon
dioxide, nutrients, hormones, ions, and immune cells) to organs. Veins
contain deoxygenated blood and go towards the heart, whereas arteries
contain oxygenated blood and go away from the heart. Blood from veins
enters in the right atrium, then goes to the right ventricle, and towards the
lungs via the pulmonary artery. In the lungs, carbon dioxide is removed, and
oxygen is taken up by the red blood cells. The oxygenated blood enters the
left atrium via the pulmonary veins, after which it goes to the left ventricle
and is pumped into the aorta, from where it is transported to all parts of the
body. The heart has its own blood supply via the coronary arteries, where
also often problems arise. In the organs capillaries are present, and
exchange occurs. The blood is deoxygenated after which it can again go to the heart via veins (that have
valves to prevent backflow). There is a systemic circulation and a pulmonary circulation.
Anatomy of the heart
The veins that enter the right atrium are called the superior and inferior
vena cava. The blood can go from the atrium to the ventricle via the
tricuspid valves. When the right ventricle contracts, the blood goes into the
pulmonary arteries, passing the pulmonary semilunar valves. Oxygenated
blood returns to the heart in the left atrium via the pulmonary veins. When
it enters the left ventricle, it passes the bicuspid (mitral) valves. When the
left ventricle contracts, the blood is pumped into the aorta, passing the
aortic valves. The muscle on the left ventricle is thicker because it must
contract harder to pump blood to the whole body. In diseases, the left ventricle is often affected.
Heart rhythm
There are different events happening during one hear beat:
1. Diastole: the heart is relaxed, and the atria and ventricles fill
with blood. The pulmonary and aortic valves are closed.
2. Atrial systole: the atria contract and force more blood into
the ventricles. The pulmonary and aortic valves are still closed.
3. Isovolumic ventricular contraction: contraction of the
ventricles in which the volume remains the same, but the
pressure increases. All valves are closed.
4. Ventricular ejection: the pressure in the ventricles is so high
that the aortic and pulmonary valves open and the blood is
ejected into the vessels. The tricuspid and bicuspid valves are
closed.
5. Isovolumic ventricular relaxation: the ventricles relax, and
the pressure falls. All valves are closed.
This can also be shown in a diagram, in which the EDV is the
end-diastolic volume and the ESV is the end-systolic volume.
1
,Electrical conduction in the heart
Pacemaker cells determine the beating of the heart and are
present in the SA node. They initiate an electrical current that
is spread over the cardiomyocytes (contractile cells).
Propagation between cardiomyocytes occurs because of the
intercalated disk with gap junctions between the cells. If the
SA node is damaged, there are pacemaker cells in the AV
node, bundle of His or Purkinje fibers that can take over, but
these have a lower frequency. The membrane potential of a
pacemaker cell is unstable due to sodium influx. The action
potential (AP) itself is caused by calcium influx. Repolarization occurs
by outflux of potassium. In contractile cells, the AP is not caused by
calcium, but by sodium influx. Electrical signals go from the SA node via
the internodal pathways to the AV node (with a small delay to lead to
filling of the ventricles), then via the AV bundle (bundle of His) to the
Purkinje fibers that spread out over the ventricles. The heart has a long
refractory period (no new AP can be generated in this time), as
opposed to skeletal muscles. Skeletal muscles can also accumulate
tension, which the heart cannot do. Only after one contraction is
finished, a new one can start: protection of the heart.
Muscle types and their differences
The most important muscle types are smooth muscle, skeletal muscle, and cardiac muscle. These differ in
their action potential mechanism and in their contraction
mechanism. This is important because it can act as a
target for therapy.
Action potential skeletal muscle
When an AP is present in somatic motor neurons,
acetylcholine (ACh) is released into the synapse. ACh can
bind nicotinic receptors on the muscle fibers, which are
ligand gated sodium channels. There is sodium influx, that
leads to an action potential. The AP is guided over the
skeletal muscle via T-tubules. DHP (dihydropyridine L-
type calcium channels) are opened, which is coupled to
RyR on the sarcoplasmic reticulum (SR), after which
calcium is released from the SR. Increase in calcium leads
to troponin binding, which displaces tropomyosin to
allow interaction of myosin and actin, which causes
contraction. There is only a short refractory period.
Action potential pacemaker cells
In pacemaker cells there is no true resting potential. Voltage starts at about -
60 mV and spontaneously moves to the threshold of -40 mV via funny
channels (some sodium influx). This depolarization is called the pacemaker
potential. At the threshold, calcium channels open and the ‘real’
depolarization occurs (rising phase). At the peak, potassium channels are
opened, and calcium channels deactivate, leading to repolarization to -60
mV (falling phase). The AP then spreads to the cardiomyocytes.
2
,Action potential contractile cells
Cardiomyocytes have a resting membrane potential of -
90 mV and only depolarize upon stimulation (by
pacemaker or neighboring myocyte). This occurs through
leakage of sodium and calcium ions through the gap
junctions. The threshold of -70 mV is reached, and fast
sodium channels open, leading to rapid sodium influx and
voltage rise (depolarization). At the peak, sodium channels close and fast
potassium channels lead to outflux of potassium, causing the early
repolarization. However, calcium channels are also opened and lead to
calcium influx, creating a plateau. During this phase, calcium induced
calcium release (from the SR) is triggered. After the calcium channels close,
slow potassium channels open and the membrane potential is brought back
to its original state (repolarization). Finally, calcium and sodium balance is
restored.
Skeletal muscle cell contraction
Tendon attaches skeletal muscles to bone. Skeletal muscle is composed of
bundles of muscle fibers. The muscle fibers are surrounded by connective
tissue. In the skeletal muscles also nerves and blood vessels are present. A
skeletal muscle fiber is surrounded by sarcolemma and contains T-tubules, a
large sarcoplasmic reticulum for calcium storage and a lot of myofibrils: a
bundle of contractile and elastic proteins. Myofibrils contain sarcomeres:
composed of myosin and actin.
When they interact, contraction
occurs. In the relaxed state,
myosin head is cocked and
contains ADP and Pi (hydrolyzed
ATP). When calcium binds
troponin, the tropomyosin is
pulled away from the actin
filaments, and the myosin heads
can bind to the actin. When Pi
leaves, the myosin head moves
and leads to a power stroke:
contractions. There is an optimal
overlap between myosin and actin: not too much and not too little.
Smooth muscle cell contraction
In smooth muscle cells, the myosin and
actin filaments are not as nicely organized,
and there are no sarcomeres. Troponin also
lacks from the system. Contraction occurs
slower and different from skeletal muscle
contraction. When cytosolic calcium is
increased (either from the extracellular fluid
or the SR; ACh binds M3 to activate SR
receptors), it can bind to calmodulin to
activate MLCK (myosin light chain kinase).
This compound phosphorylates light chains
in myosin heads and increases ATPase
3
, activity. ATP on the myosin heads is needed for contraction (it’s hydrolyzed to ADP and Pi) by moving along
actin filaments. Later, relaxation can occur by MLCK inhibition or MLC phosphatase activation
(dephosphorylates myosin heads).
Cardiac muscle cell contraction
Cardiac muscle cells resemble both smooth muscles
and skeletal muscles. It is striated and has sarcomeres,
has one nucleus per cell and is induced by calcium. It
contains desmosomes (cell-cell contact), gap junctions,
T-tubules, SR, intercalated disks and cardiac myofibrils.
Action potential opens the L-type calcium channels for
influx from the ECF and activation of the SR to release
calcium into the cytosol by RyR channels. These calcium
sparks leads to calcium binding to troponin, after which
tropomyosin is released from the actin and myosin
heads can bind actin for contraction. Relaxation occurs
because calcium unbinds from troponin and is
transported to the SR and ECF by ion balance
restoration.
Overview most important differences between the muscle cells:
Autonomic nervous system
Both the sympathetic and parasympathetic nervous system can influence frequency, beating strength and
conduction of the AP generated by the pacemaker cells.
4
Lecture 1: Cardiovascular structure and the heart (introduction)
Anatomy of the cardiovascular system
The heart is a pump that delivers blood (containing water, oxygen, carbon
dioxide, nutrients, hormones, ions, and immune cells) to organs. Veins
contain deoxygenated blood and go towards the heart, whereas arteries
contain oxygenated blood and go away from the heart. Blood from veins
enters in the right atrium, then goes to the right ventricle, and towards the
lungs via the pulmonary artery. In the lungs, carbon dioxide is removed, and
oxygen is taken up by the red blood cells. The oxygenated blood enters the
left atrium via the pulmonary veins, after which it goes to the left ventricle
and is pumped into the aorta, from where it is transported to all parts of the
body. The heart has its own blood supply via the coronary arteries, where
also often problems arise. In the organs capillaries are present, and
exchange occurs. The blood is deoxygenated after which it can again go to the heart via veins (that have
valves to prevent backflow). There is a systemic circulation and a pulmonary circulation.
Anatomy of the heart
The veins that enter the right atrium are called the superior and inferior
vena cava. The blood can go from the atrium to the ventricle via the
tricuspid valves. When the right ventricle contracts, the blood goes into the
pulmonary arteries, passing the pulmonary semilunar valves. Oxygenated
blood returns to the heart in the left atrium via the pulmonary veins. When
it enters the left ventricle, it passes the bicuspid (mitral) valves. When the
left ventricle contracts, the blood is pumped into the aorta, passing the
aortic valves. The muscle on the left ventricle is thicker because it must
contract harder to pump blood to the whole body. In diseases, the left ventricle is often affected.
Heart rhythm
There are different events happening during one hear beat:
1. Diastole: the heart is relaxed, and the atria and ventricles fill
with blood. The pulmonary and aortic valves are closed.
2. Atrial systole: the atria contract and force more blood into
the ventricles. The pulmonary and aortic valves are still closed.
3. Isovolumic ventricular contraction: contraction of the
ventricles in which the volume remains the same, but the
pressure increases. All valves are closed.
4. Ventricular ejection: the pressure in the ventricles is so high
that the aortic and pulmonary valves open and the blood is
ejected into the vessels. The tricuspid and bicuspid valves are
closed.
5. Isovolumic ventricular relaxation: the ventricles relax, and
the pressure falls. All valves are closed.
This can also be shown in a diagram, in which the EDV is the
end-diastolic volume and the ESV is the end-systolic volume.
1
,Electrical conduction in the heart
Pacemaker cells determine the beating of the heart and are
present in the SA node. They initiate an electrical current that
is spread over the cardiomyocytes (contractile cells).
Propagation between cardiomyocytes occurs because of the
intercalated disk with gap junctions between the cells. If the
SA node is damaged, there are pacemaker cells in the AV
node, bundle of His or Purkinje fibers that can take over, but
these have a lower frequency. The membrane potential of a
pacemaker cell is unstable due to sodium influx. The action
potential (AP) itself is caused by calcium influx. Repolarization occurs
by outflux of potassium. In contractile cells, the AP is not caused by
calcium, but by sodium influx. Electrical signals go from the SA node via
the internodal pathways to the AV node (with a small delay to lead to
filling of the ventricles), then via the AV bundle (bundle of His) to the
Purkinje fibers that spread out over the ventricles. The heart has a long
refractory period (no new AP can be generated in this time), as
opposed to skeletal muscles. Skeletal muscles can also accumulate
tension, which the heart cannot do. Only after one contraction is
finished, a new one can start: protection of the heart.
Muscle types and their differences
The most important muscle types are smooth muscle, skeletal muscle, and cardiac muscle. These differ in
their action potential mechanism and in their contraction
mechanism. This is important because it can act as a
target for therapy.
Action potential skeletal muscle
When an AP is present in somatic motor neurons,
acetylcholine (ACh) is released into the synapse. ACh can
bind nicotinic receptors on the muscle fibers, which are
ligand gated sodium channels. There is sodium influx, that
leads to an action potential. The AP is guided over the
skeletal muscle via T-tubules. DHP (dihydropyridine L-
type calcium channels) are opened, which is coupled to
RyR on the sarcoplasmic reticulum (SR), after which
calcium is released from the SR. Increase in calcium leads
to troponin binding, which displaces tropomyosin to
allow interaction of myosin and actin, which causes
contraction. There is only a short refractory period.
Action potential pacemaker cells
In pacemaker cells there is no true resting potential. Voltage starts at about -
60 mV and spontaneously moves to the threshold of -40 mV via funny
channels (some sodium influx). This depolarization is called the pacemaker
potential. At the threshold, calcium channels open and the ‘real’
depolarization occurs (rising phase). At the peak, potassium channels are
opened, and calcium channels deactivate, leading to repolarization to -60
mV (falling phase). The AP then spreads to the cardiomyocytes.
2
,Action potential contractile cells
Cardiomyocytes have a resting membrane potential of -
90 mV and only depolarize upon stimulation (by
pacemaker or neighboring myocyte). This occurs through
leakage of sodium and calcium ions through the gap
junctions. The threshold of -70 mV is reached, and fast
sodium channels open, leading to rapid sodium influx and
voltage rise (depolarization). At the peak, sodium channels close and fast
potassium channels lead to outflux of potassium, causing the early
repolarization. However, calcium channels are also opened and lead to
calcium influx, creating a plateau. During this phase, calcium induced
calcium release (from the SR) is triggered. After the calcium channels close,
slow potassium channels open and the membrane potential is brought back
to its original state (repolarization). Finally, calcium and sodium balance is
restored.
Skeletal muscle cell contraction
Tendon attaches skeletal muscles to bone. Skeletal muscle is composed of
bundles of muscle fibers. The muscle fibers are surrounded by connective
tissue. In the skeletal muscles also nerves and blood vessels are present. A
skeletal muscle fiber is surrounded by sarcolemma and contains T-tubules, a
large sarcoplasmic reticulum for calcium storage and a lot of myofibrils: a
bundle of contractile and elastic proteins. Myofibrils contain sarcomeres:
composed of myosin and actin.
When they interact, contraction
occurs. In the relaxed state,
myosin head is cocked and
contains ADP and Pi (hydrolyzed
ATP). When calcium binds
troponin, the tropomyosin is
pulled away from the actin
filaments, and the myosin heads
can bind to the actin. When Pi
leaves, the myosin head moves
and leads to a power stroke:
contractions. There is an optimal
overlap between myosin and actin: not too much and not too little.
Smooth muscle cell contraction
In smooth muscle cells, the myosin and
actin filaments are not as nicely organized,
and there are no sarcomeres. Troponin also
lacks from the system. Contraction occurs
slower and different from skeletal muscle
contraction. When cytosolic calcium is
increased (either from the extracellular fluid
or the SR; ACh binds M3 to activate SR
receptors), it can bind to calmodulin to
activate MLCK (myosin light chain kinase).
This compound phosphorylates light chains
in myosin heads and increases ATPase
3
, activity. ATP on the myosin heads is needed for contraction (it’s hydrolyzed to ADP and Pi) by moving along
actin filaments. Later, relaxation can occur by MLCK inhibition or MLC phosphatase activation
(dephosphorylates myosin heads).
Cardiac muscle cell contraction
Cardiac muscle cells resemble both smooth muscles
and skeletal muscles. It is striated and has sarcomeres,
has one nucleus per cell and is induced by calcium. It
contains desmosomes (cell-cell contact), gap junctions,
T-tubules, SR, intercalated disks and cardiac myofibrils.
Action potential opens the L-type calcium channels for
influx from the ECF and activation of the SR to release
calcium into the cytosol by RyR channels. These calcium
sparks leads to calcium binding to troponin, after which
tropomyosin is released from the actin and myosin
heads can bind actin for contraction. Relaxation occurs
because calcium unbinds from troponin and is
transported to the SR and ECF by ion balance
restoration.
Overview most important differences between the muscle cells:
Autonomic nervous system
Both the sympathetic and parasympathetic nervous system can influence frequency, beating strength and
conduction of the AP generated by the pacemaker cells.
4
