Cardiac Physiology Flashcards
What is membrane potential
In most cells types there is an electrical potential difference between the inside of the cell and the surrounding extracellular fluid. This is termed the membrane potential of the cell
Cell in rest
• When a cell is at “rest”, its membrane potential is called the resting membrane potential; in most cells this is negative i.e. the cell is negative with respect to the outside
Non excitable cells
• In non-excitable cells, the resting potential does not change much over time
• Sinoatrial node cells do not typically have a stable resting potential (but is around -60 mV)
In excitable tissues
• In excitable tissues, like neurons and muscle, stimulation of the cell results in a ‘big’ change in potential, over a short period
An action potential
an action potential – that brings about a functional response
• Nerve impulse
• Contraction of muscle
The action potential
is generated by rapid changes in electrochemical gradients across the cell membrane;
movement of ions into and out of the cell
Chemical gradient – ion will move down its [gradient]
• Electrical gradient – ion will move away from like charge
Movement is controlled by specific ion channels embedded in the cell membrane like
• notable channels/ions = K+, Na+ and Ca2+
Movement of ions generate characteristic changes in potential differences; transmembrane potential (mV)
Depolarization – less negative (becomes positive in muscle)
• Repolarization – a return to the negative resting potential
• Hyperpolarization – become more negative with respect to
typical resting potentials
Heart muscle consists of
cardiomyocytes or myocardial fibres
Heart muscle
• Around 20 x 100 M and branched
Rich in mitochondria 5000-8000 / cell
• Numerous Ion channels and pumps
Fibres
Formed by individual cells joined end-to-end by specialized junctions – intercalated discs
• Ensure tight interactions and mediate electrical coupling
• Fibres often branch to extend the interconnections
• Single central nucleus and an abundance of mitochondria
Cells show a repeating pattern of striations, which are the actin and myosin filaments (plus several other proteins)
• Filaments slide along each other to facilitate contraction
• Contraction is dependent on by calcium signalling
Diagram to illustrate cardiomyocyte structure •
•
Contractions synchronized via the intercalated discs and gap junctions between them; this ensures that individual cardiomyocytes work together and the cardiac muscle functions as a syncytium
Sinoatrial node propagates the
action potential
How Sinoatrial node propagates the action potential
• Excites the right atrium, then left atrium via the Bachmann’s bundle
• Reaches atrioventricular node via right atrium
• Intrinsic rhythm is 60-100 beats/minute
Electrical signalling pathways
Sinoatrial node propagates the action potential
Atrioventricular node passes the signal to bundle of His
This ordered sequence of conduction from atria to ventricles coordinates the specific contraction of the heart chambers ‘
The membrane action potentials of the SA node are different from the contractile myocardial cells
Unstable membrane potential = automaticity of SA i.e., it sets the pace of the heart – the pacemaker
AVN has pacemaker potential——— also ——-between atrial and ventricular conduction
(20-60 bpm);
gate keeper
Bundle of His Branches to form
right bundle and left bundle
What project into and spread
throughout myocardium
Bundles terminate in Purkinje fibres
Atrioventricular node passes the signal to bundle of His
Depolarize the right and left ventricle
Autorhythmic Cells (Pacemaker Cells)
Undergo spontaneous depolarization when a threshold voltage reached
• Unstable membrane potential, which never falls below -60mV
• Transmembrane potential drifts upward to -40mV, forming a threshold or pacemaker potential
• Slow leakage of K+ out and faster leakage of Na+ into cell
• Causes slow depolarization
• Occurs through If channels (f=funny) aka hyperpolarization-activated cyclic nucleotide-gated (HCN) channels;
these open at negative membrane potentials and start closing as membrane approaches threshold potential
• At -55 mV T-type Ca2+ channels (transient opening) open and continue slow depolarization as membrane approaches threshold
• At threshold potential (-40mV), L-type Ca2+ channels (long lasting) open causing more rapid depolarization to 0 mV, then cause ‘overshoot’ up to ~ +20-30 mV; these deactivate shortly after
• Slow or delayed rectifier K+ channels open as membrane depolarizes causing an efflux of K+ and a repolarization of membrane back to -60 mV
10
Auto-rhythmic Cells (Pace
Action potential of the cardiomyocytes (contractile system) composed of what
Composed of 5 distinct phases (0-4); have a stable resting phase unlike the SA node
Phase 4: The resting phase
The resting potential in a cardiomyocyte is −90 mV due to a constant outward leak of K+ through inward rectifier channels
• Na+ and Ca2+ channels are closed at resting transmembrane potential (TMP)
Phase 0: Depolarization
An action potential triggered in a neighbouring cardiomyocyte or pacemaker cell causes
the TMP to rise above −90 mV
• Fast Na+ channels start to open and Na+ enters he cell, further raising the TMP
• TMP approaches −70mV, the threshold potential in cardiomyocytes, i.e., the point at which enough fast Na+ channels have opened to generate a self-sustaining inward Na+
current
• The large Na+ current rapidly depolarizes the TMP to 0 mV and slightly above 0 mV for a
transient period of time called the overshoot; fast Na+ channels close (fast Na+ channels
are time-dependent)
• L-type (“long-opening”) Ca2+ channels open when the TMP is greater than −40 mV and
cause a small but steady influx of Ca2+ down its concentration gradient.
Phase 1:
Early repolarization
• TMP is now slightly positive
• Some K+ channels open briefly and an outward flow of K+ returns the TMP to
approximately 0 mV.
Phase 2: The plateau phase
L-type Ca2+ channels are still open and there is a small, constant inward current of Ca2+. This becomes significant in the excitation-contraction coupling process
• K+ leaks out down its concentration gradient through delayed rectifier K+ channels
• These two counter-currents are electrically balanced, and the TMP is maintained at a
plateau just below 0 mV throughout phase 2
Phase 3:
Repolarization
• Ca2+ channels are gradually inactivated
• Persistent outflow of K+, now exceeding Ca2+ inflow, brings TMP back towards resting
potential of −90 mV to prepare the cell for a new cycle of depolarization.
• Normal transmembrane ionic concentration gradients are restored by returning Na+ and Ca2+ ions to the extracellular environment, and K+ ions to the cell interior
The pumps involved include the sarcolemmal Na+-Ca2+ exchanger, Ca2+-ATPase and Na+-K+-ATPase 13
•
Action potential of the cardiomyocytes (contractile system)
Refractory period/plateau
Cardiomyocytes have a longer refractory period than other muscle cells; the plateau from slow Ca2+ channels (phase 2)
Physiological mechanism allow
sufficient time for the ventricles to empty and refill prior to the next contraction
Sarcomere
is the unit of muscle that contracts; many sarcomeres per cell arranged in series
Thin filaments composed
protein actin; thick filaments composed of the protein myosin
• Z-lines
demark each sarcomere (thin filaments connect to Z-line)
• M-Line
defines the middle of sarcomere and middle of thick filament
• I band
is a zone around the Z-lines and includes part of two separate sarcomeres. The I band only has thin filaments.
H band
is a zone around the M-line
A band
is a zone that demarks the length of thick filaments
Myosin
thick filaments with globular heads evenly spaced
along their length; contains myosin ATPase.
Actin
thin filaments consisting of two strands arranged as
an a-helix, between myosin filaments
Tropomyosin
double helix that lies in the groove between actin filaments. Prevents contraction in the resting state by inhibiting the interaction between myosin heads and actin
Troponin
complex with three subunits at regular intervals along the actin strands
Troponin T (TnT)
ties troponin complex to actin and tropomyosin molecules
Troponin I (TnI)
inhibits activity of ATPase in actin-myosin interaction
Troponin C (TnC
binds calcium ions that regulate contractile
Cardiac physiology; part three
process
Contractile proteins – Ca2+ is a key regulator
Calcium-induced calcium release (CICR) is required for excitation-contraction coupling
• Influx of Ca2+ into myocytes through L-type Ca2+ channels during phase 2 of the action potential is not sufficient to trigger contraction of myofibrils; signal is amplified by CICR, which triggers much greater release of Ca2+ from the sarcoplasmic reticulum
• The cell membrane of cardiomyocytes, called sarcolemma, contains invaginations (T-tubules) that bring L-type Ca2+ channels into close contact with ryanodine receptors, specialized Ca2+ release receptors in the sarcoplasmic reticulum (SR)
• When Ca2+ enters the cells through L-type channels, ryanodine receptors change conformation and induce a larger release of Ca2+ from abundant SR store
• Large levels of intracellular Ca2+ act on tropomyosin complexes to induce myocyte contraction.
Initiation
action potential via pacemaker cells to conduction fibers
Excitation
Contraction Coupling
Starts with CICR (Ca2+ induced Ca2+ release)
Action potential spreads along sarcolemma
T-tubules contain voltage-gated L-type Ca2+ channels
which open upon depolarization
Ca2+ entry opens RyR (ryanodine receptors) Ca2+ release channels
Release of Ca2+ from SR causes a Ca2+ release
Calcium binds troponin C and mediates contraction
Contractile proteins – Ca2+ is a key regulator
As with myocyte contraction, the relaxation phase is synchronized with the electrical activity of the cell
• L-type Ca2+ channels inactivate toward the end of phase 2 → Ca2+ influx arrests → CICR trigger is abolished
• Ca2+ is sequestered back into the SR by sarcoplasmic reticulum Ca2+ ATPase (SERCA) and pumped out of the cell to a lesser extent by specialized Ca2+ pumps
• Ca2+ ions dissociate from TnC as intracellular concentration falls, and tropomyosin inhibition of actin-myosin interaction is restored
Cardiac muscle, heartbeat and cardiac cycle
• The autonomic system is anatomically and functionally divided into the sympathetic and parasympathetic components
• Sympathetic system stimulates the heart rate
• Stress, exercise, excitement
• Norepinephrine (adrenoceptors)
• Parasympathetic system relaxes/slows the heart
• PNS dominates autonomic stimulation of heart
• Acetylcholine (muscarinic receptors)
• Hormones, local chemical mediators also contribute to control of myocyte activity
Autorhythmic Cells (Pacemaker Cells)
Altering Activity of Pacemaker Cells; Sympathetic activity
Norepinephrine (and epinephrine) increase If channel activity
Binds to β1 adrenergic receptors which activate cAMP and increase If channel open time Causes more rapid pacemaker potential and faster rate of action potentials
Gap junctions
Gap junctions are intercellular channels 1.5–2 nm in diameter
• Formed by connexin an integral membrane protein; 6 connexin proteins form a connexon or channel, which links with a connexon in neighbouring cell to form the gap junction
• Gap junctions link the cytoplasm of neighbouring cells and enable rapid passage of ions and small molecules
• Permit changes in membrane potential to pass from cell to cell e.g., action potential and sarcomere contraction in the heart
regions/structures within the heart comprised of cells that are similar to cardiomyocytes
Sinoatrial and atrioventricular nodes
• The bundle of His and Purkinje fibres
SA node also called
SA node also called
The heart which originates in the sinoatrial node
intrinsic auto-rhythmicity
• Intrinsic waves of excitation (depolarization) spread from the SA node to the AV node and then to myocytes via other parts of the conduction system; the bundle of His and Purkinje fibres
• While capable of functioning independently, the SA is innervated (as are most parts of the heart and circulatory system) by autonomic nerves and SA activity can be controlled by autonomic nervous system signals
