Flashcards in Cardiac Excitation Deck (43):
How is the heart innervated?
Largely parasympathetic of atria, SA, and AV node, but not ventricles
sympathetic of atria, SA and AV node, and ventricles
What are the phases of ventricular action potential?
4- resting phase (-85mV)
0- beginning of action potential
1- small decrease
2- plateau phase
What is the resting potential maintained by?
The principal active channel during the resting phase is Kir2.1 (aka K1), assisted by two other K channels (IKATP and IKAch). These channels set the resting potential at close to the K reversal potential, i.e. about -85 mV.
What causes phase 0?
Phase 0 is induced by rapid Na channel activation (inward current shown by downward yellow tracing), simultaneously with K channel inactivation (up to +20mV).
What causes phase 1?
However, this is transient and is followed by activation of Ito channel activation (transient outward K channel; all K channels are shown in green) which slightly repolarizes the cell membrane during phase 1
What causes phase 2?
During Phase 2, a voltage dependent inward Ca2+ current is balanced by 3 outward K+ currents (Ikur, Ikr and Iks). Lasts about 400 ms
What causes phase 3?
Reactivation of K1 at the end of phase 2, together with reactivation of two other K channels (IKATP and IKAch) induces repolarization of cells (phase 3). It is important to note that Na channels need to have a potential close to -85 mV in order to “reset” for the next cardiac cycle.
What other channels exist in the atria and nodes?
there are two other channels, one of which is inhibited by ATP and when the ATP:ADP ratio drops, the channel activates and the channel can help with re-polarization
The other channel is sensitive to ACh and is important in regulating the SA and AV node potentials
How do fast Na channels work?
The channel has two gates activated at different voltages. The V gate opens at membrane potentials more positive than -40 mV, whereas the inactivation gate opens at membrane potentials more negative than -65 mV. At rest, the V gate (V for voltage) is closed because the cell membrane is at the resting level (-85 mV). However, the inactivation gate is open because the channel is experiencing a voltage of -85 mV.
When cells reach the threshold potential, the V gate opens rapidly before the inactivation gate has time to close. This allows Na influx to occur and to rapidly further depolarize cells in a feed forward manner (both gates are open and more gates open as the membrane voltage becomes more positive).
A few milliseconds later, the inactivation gate swings shut, because of the positive membrane potential.
Eventually, when the cells repolarize in phase 3, the V gate closes whereas the inactivation gate opens.
In sinoatrial cells (pacemaker cells), the fast Na channel is permanently in the inactivated state because of the relatively more positive resting membrane potential in these cells, which keeps the inactivation gate closed.
Defective Na channels lead to what?
What is the maximal negative membrane potential in SA node cells?
-65 mV, as compared to -85 mV in ventricular myocytes.
What is the resting membrane potential in SA node cells?
unstable. This is due to the fact that these cells have an inward Na+ current (known as the “funny” current) which is activated by NEGATIVE membrane potential (i.e. during re-polarization), unlike the fast Na current which is activated by POSITIVE membrane potential.
Are there a lot of fast NA channels in SA cells?
No, there are few fast Na channels active in SA cells because the relatively positive membrane potential (-65 mV) suppresses fast Na channel “resetting” event which needs a membrane potential more negative (-85 mV) than the cells provide
Is there a 'plateau' phase for SA cells?
No, there is no plateau phase for SA node cell action potential
What else is different about the action potential of SA cells vs ventricular myocytes?
Fifthly, note that in ventricular myocytes, K channel activity is decreased during phase 2 but is not zero, due to activation of several K channels with low activity, thus balancing the inward Ca current, and causing the plateau phase in ventricular myocytes.
What happens when Na+ influx via funny current in SA cells causes depolarization to about -40mV?
voltage dependent calcium channels open (called T channels)
Ca channels that open late during the pacemaker potential are T-type channels that open and then close rapidly. At the threshold, L-type Ca channels open. The slope of the action potential is less steep in these cells than in ventricular cells because Ca channels are slower in conducting current than are fast Na channels that open in ventricular cells. At the peak of the action potential, Ca channels begin to close and delayed rectifier voltage-gated K channels begin to open.
What is the absolute refractory period?
The absolute refractory period is the time when no stimulus, regardless of strength, can induce an action potential. This is dependent on refractory fast Na channels. Exists from phase) to about midway into phase 3
What is the effective refractory period?
The effective refractory period is the time when no stimulus generated by surrounding cells can elicit an action potential. Exists from phase 0 to further into the phase 3 re-polarization
What is the relative refractory period?
The relative refractory period is the time when a very strong stimulus can elicit an action potential that is weaker than a normal action potential. Exists from end of ARP to close to -85 mV
the action potential here will have a smaller positive slope than normal because not all Na channels are reset yet
What is the supranormal period?
The supranormal period is the time when a weaker than normal stimulus can elicit an action potential. The SNP is dependent on refractory K channels that have not fully activated and thus are unable to clamp the resting voltage in the face of a stimulus (cause of arrhythmia)
Exists right as re-polarization occurs
What sets the heartbeat?
the SA node has the highest rate of spontaneous discharge and thus normally sets the rate of the heartbeat
What sets the heartbeat if the SA node is defective?
The next lower discharge rate belongs to the AV node which can become the pacemaker in the event of an ineffective SA node pacemaker.
Moreover, in the event of complete heartblock, i.e. no conduction across the AV node, the bundle of His or Purkinje cells can assume the role of pacemaker, albeit at rates that are not adequate in the long term.
Sympathetic and parasympathetic efferent nerves emanate from two different areas of the medulla. What determines the levels of sympathetic drive? What determines parasympathetic drive?
the cardioacceleratory center
the cardioinhibitory center
How is sympathetic activity transmitted to the heart? Parasympathetic?
sympathetic activity is transmitted via the sympathetic cardiac nerve which influences the SA node, the AV node and the ventricular cells.
Parasympathetic activity which is transmitted via the vagus nerve influences the SA and AV nodes but NOT ventricular cells
What is parasympathetic action in the heart dependent on?
activation of K channels and inactivation of Ca2+ channels
What are some ways parasympathetic activity can decrease the action of SA node cells (and decrease HR)?
- decreased If (funny) current by decreasing cAMP
- more negative maximal diastolic potential “MDP”, mediated by increased K channel activity (via ACh).
- increased threshold for Ca opening via decreased cAMP levels
How does depolarization begin in the heart?
Starts at SA and goes to the AV node in just a few milliseconds
How long does it take for the depolarization wave to cross the AV node?
40 milliseconds (para/sym drugs affect this- so remember that CV drugs not only influence induction but conduction as well)- then to the bundle of His
Once in the bundle of His, the speed of conduction picks up again
What is dromotropy?
increased speed of conduction
What is the intrinsic rate of activation of the normal SA node?
Even though a typical normal heart rate at rest is 60 to 70 beats/min, the intrinsic rate of activation of the normal SA node is considerably higher, around 100 beats/min as there is tonic sympathetic and parasympathetic activity at rest.
How do we know there is tonic parasympathetic activity in the heart?
administration of atropine (cholinergic M2 receptor antagonist) increases the heart rate up to 120 bpm at maximal dosage
How do we know there is tonic sympathetic activity in the heart?
If propranolol (a beta adrenergic antagonist) is given, heart rate drops to about 50 beats/min, indicating modest tonic adrenergic activity.
How does contraction of heart muscle occur?
Intracellular Ca is the critical activator of cardiac muscle contraction similar to that in all other muscle types;
Ca channels are activated in the plateau phase: phase 2; shortly after intracellular Ca reaches a peak concentration, contraction begins; subsequently, as intracellular Ca is decreased, contraction returns to baseline
What activates Ca channels to initiate contraction? Is Ca entry enough to initiate contraction?
Depolarization activates Ca channels; however, entry of Ca via channels is insufficient to activate the contractile machinery by itself
What else does contraction require?
Contraction requires supplemental Ca release from an intracellular Ca reservoir, the SR (sarcoplasmic reticulum). Faster and larger Ca influx cause more SR Ca release
Contraction is a property that is graded based on the intracellular Ca concentration
What is the other major factor controlling contractility?
fiber length- in turn related to preload volume which stretches fibers.
How does influx of ca release more Ca from the SR?
Ca binding to RyR (ryanodine receptor) in SR releases sufficient Ca to cause myofilament activation.
How is Ca removed from myocytes after contraction?
Ca is removed via the cell membrane pumps and exchangers (3Na in for 1Ca out- no ATP needed here- but can work in other direction- BAD), the SR and the mitochondria.
It should be noted however that mitochondria (beat to beat) are the least important in this regard although they may play a role in the long-term, as Ca reservoirs.
How do catecholamines (Epi or Nor) act in the heart?
They bind to Beta adrenergic receptors, which associates with a G protein called Gs which activates adenylate cyclase to produce cAMP which releases PKA from its regulator. PKA then phosphorylates the calcium channel activating it (more Ca in) and the RYR receptor on the SR causing increased Ca release during the response
Ca is taken back up in the SR via an ATP dependent pump (with a subunit called phospholamban which when phosphorylated via PKA from catecholamine binding actually inhibits the pump)
What is the Frank Starling mechanism?
increased sarcomere length results in increased active tension, up to a physiological limit (the maximum of the active tension curve). I.e. stretching the ventricles= increased tension and stroke volume
T or F. Up to a physiological limit, the normal heart will pump out any end diastolic volume (EDV) and reach the same end systolic volume (ESV), thus causing increased stroke volume.
T. Linear relationship
The greater the EDV, the greater the SV
How does an increase in length translate into increased cardiac force generation?
Increasing the length of the fibers makes the fibers more sensitive to Ca (up to a point where it plateaus) and a slow response to stretch exists involving activation of calcium channels by stretch (so more Ca comes in and the filaments become more sensitive to it)
whereas the inverse is true for shortening