Primary role of Cardiac Myocytes?
Contraction , which is initiated by an action potential
Describe the cardiac action potential
a transient change in the polarization of the resting membrane potential that is transferred from the cell to cell based on ionic differences
Cardiac myocytes have an __________________________ between the intracellular and extracellular regions
electrical potential difference
Electrical potential is measured with....
The intracellular region is ______________ charged relative to the extracellular region.
Resting ventricular myocyte has a resting membrane potential of _________ mV while it's extracellular environment is considered _____ mV
-90 mV, 0mV
The cell in its resting state is said to be _________
Major ions (4) involved in determining membrane potential during the cardiac cycle?
The current of the cell membranes is carried by.....
Most important ion in establishing the resting membrane potential?
Define Ohm's law
Voltage difference between 2 points in a material are directly proportional to the current (I) and the Resistance (R)
Inverse of the resistance; notated as g
big resistance = small conductance // small resistance= large conductance
4 factors involved in the membrane potential:
- Cell type
- Ionic concentration differences (chemical gradient/electrochemical forces)
- Permeability of the cell membrane (high conductance for K+= high permeability for K to flow in and out)
- Electrogenic pumps
Describe the chemical gradient for K+
Concentration for K is higher inside than outside; wants to move DOWN it's concentration gradient
Describe the chemical gradient for Na+, and Ca++
Concentrations for both are higher OUTSIDE the cell; want to flow against their gradients to go inside the cell
Why do the ions move according to their concentration differences (high to low)?
How can we calculate the ion equilibrium potentials
Nernst equation practice problems
Net Electrochemical driving force:
- The Ek (potassium potential) is/is not the same as the Em(membrane potential)? Why?
IS NOT THE SAME
- The Em is LESS NEGATIVE than Ek (~90mV compared to -96mV) .....therefore the negative voltage required to stop the outward flow of K+ is NOT STRONG ENOUGH.....SOOO there's a small net electromotive driving force resulting in a steady and slow leakage of K+ from the intracellular phase to the extracellular phase in the resting non pacemaker cardiomyocyte (inward rectifier potassium channel, K11)
Practice problems: What is the net electromotive driving force for Na+, Ca++, and Cl-
What happens to the Em a cell membrane is permeable to more than one ion?
All of the ions will contribute to the Em , so the Em will NOT BE EQUAL to the chemical potential for a resting membrane.
**in contrast, the reason for the resting membrane potential of a non pacemaker cardiac myocyte being so close to Ek is because it's significantly more permeable to K+ than Na+, Ca++ or the Cl- ions**
What 2 terms reflect the migration capacity of a membrane?
Permeability and conductance
- higher the permeability = higher the conductance >> meaning greater the solute transport across the cell membrane
The BETTER model to describe the cardiac cell potential?
Goldman-Hodgkin-katz Equation, this equation is fundamental to cardioelectrophysiology and for understanding the action potential
**not responsible for this, just know there is a better model than Nernst*
Maintaining ionic gradients:
- There are mechanisms to counterbalance the slow leakage of ions into and out of the cells, because over time the concentration gradient for K+ and Na+ would reach 0
- The mechanisms require energy to maintain the concentration gradients
- What are the mechanisms?
Ion pumps which are couples with ATP hydrolysis to drive the pumps
What is the pump that is found at the sarcolemma?
Na+/K+- ATPase pump
What happens if the ATPase pump is inhibited (or fails secondary to hypoxia from infarction) ?
intracellular Na+ increases
- Ions are able to cross the sarcolemma via_____________________.
- The ion channels are protein structures that are/are not selective for specific ions. These protein structures adjust their shape/conformation so ions can _____________________________.
- Can ions have more than one channel?
- Ions are able to cross the sarcolemma via specialized ion channels or pores that penetrate the phospholipid bilayer.
- The ion channels are protein structures that are selective for specific ions. These protein structures adjust their shape/conformation so ions can flow in, out, or not at all.
- Ions can have more than one channel.
Direction of Currents:
- Flux of + charge into the resting cells =
- Flux of + charge out of the resting cells =
- If the cell is depolarized, the outward flux causes =
- Flux of + charge into the resting cells = inward current and depolarization (reducing the - charge/neutralizing charges)
- Flux of + charge out of the resting cells = outward current and hyperpolarization
- If the cell is depolarized, the outward flux causes depolarization (loosing + charges and becoming more -)
****Opposite effects for flux of - charge into and out of the cell****
Structure of ion channels:
- The ion channels are ____________________.
- Each domain consists of _____ _____________ segments.
- The K+ channels has 4 domains that are ___________________________________ in comparison to the Na+ and Ca++ channels
- The Na+ channel have a loop between domains __ and __ that is believed to be the ________________.
- The ion channels are glycosylated proteins with repeating domains.
- Each domain consists of 6 transmemb rane segments.
- The K+ channels has 4 domains that are not bonded together by peptide bonds, in comparison to the Na+ and Ca++ channels
- The Na+ channel have a loop between domains 3 and 4 that is believed to be the inactivation gate
Activation and deactivation of Na+ ion channels:
- Fast Na+ channel has 2 gate; _______________
- Channel is ___________ at the normal resting membrane potential
- When depolarized, the ___________ gate rapidly opens and Na+ flows in
- The ___ gate starts to close when the ___ gates starts to open, then completely closes in a few milliseconds when the cell starts to undergo depolarization.
- Flow of Na+ into cell stops
- Neat the completion of depolarization, the ____ fate opens and the __ gate closes.
- Fast Na+ channel has 2 gate; inner H gate and outer M gate
- Channel is closed at the normal resting membrane potential
- When depolarized, the M gate rapidly opens and Na+ flows in
- The H gate starts to close when the M gate starts to open, then completely closes in a few milliseconds when the cell starts to undergo depolarization.
- Flow of Na+ into cell stops
- Neat the completion of depolarization, the H gate opens and the M gate closes.
Whether an ion channel is in the open or closed state depends on what?
membrane potential (Em)
The 2 general types of cardiac action potentials?
- Nonpacemaker APs (fast response)
- Pacemaker APs (slow response)
Describe Nonpacemaker APs
Triggered by APs in adjacent cells (gap junctions) with depolarizing currents
Describe Pacemaker APs
Spontaneously generates their own APs simultaneously
How are non pacemaker and pacemaker APs of the heart different from APs found in nerve and skeletal muscle cells?
Shape and duration
5 phases of the nonpacemaker cardiac AP?
4 - Resting/polarized (true resting potential, maintained by the inward rectifying Channel Ik1)
0 - Depolarization as a result of temporal increase in Na+ conductance (gNa+) >> resulting in a rush of Na+ from extracellular to intracellular
1 - Repolarization as a result of the opening of the transient outward K+ channel (Ito) and the inactivation of the Na+ channel >> gCa++ increases and slow movement of Ca++ into cardiomyocyte via the L-type calcium channel (Ica, aka the slow, inward, long-lasting current)
3 - Still depolarization but the downward slope is the result of gK+ increases which initiates an outward K+ current through the potassium delayed rectifier (Ikr) >> gCa++ decreases
4 - Resting/poplarzied
Describe the Absolute Refractory Period (ARP)
- Ventricular cells are unexcitable (refractory)during phases 0, 1, and 2
- No new propagation AP are generated because Na+ channels are closed
Describe the Effective Refractory Period
- Includes ARP and some of phase 3
- Only localized action potentials can be generated, but they cannot be propagated , they are weak af and can't go anywhere
Describe the Relative Refractory Period
- Weaker than normal APs ay be generated and conducted
During the supernormal period what the of stimuli can generate APs?
weaker than normal stimuli
Whys is the RP a protective mechanism of the heart?
To allow the heart to go through a full/complete cycle
How can abnormal action potential generation lead to arrhythmias?
If the fast response Na+ channels are blocked pharmacologically or inactivated by depolarization >> the AP upstroke is reduced
Triggered activity and arrhythmias?
Spontaneous depolarizations called afterdepolarizations can be generated by non pacemaker cells during phase 3 or early phase 4; from slow Ca++ channels if the fast response Na+ channels are closed
What happens when depolarization of the resting membrane reduces the conductance of the fast Na+ channels?
It will take more time for the ion current to travel through the tissues >> depression of the slop of phase 0
**when the membrane potential rises to ~55mV= essentially all of the fast Na+ channels are inactivated by the closure of the H gate**
What is the cause of hERG Cardiotoxicity?
Drugs that inhibit the K+ current through the Potassium Delayed Rectifier (Ikr) leading to cardiotoxicity and dangers arrhythmia's
The two potassium delayed rectifier ion channels?
- Rapid (Kr)
- Slow (Ks)
3 Phases of the Pacemaker Cardiac AP?
4 - no true resting potential = what's happening here is the gK+ decreases, gCa++ increases due to transient Ca++ channels, pacemaker current (funny current, If), and the L-type Ca++ ion channels open
0 - Depolarization ,slope is softer than phase 0 some of nonpacemaker APs
3 - Repolarization due to decrease in gCa++ and increase in gK+
What is overdrive suppression?
The higher intrinsic "firing" rate of the SA node controls the there nodes.
**the others can't keep up!
What is the primary pacemaker site?
**SA node > AV node > Bundle of His > Purkinje Fubers
When the SA node is no longer controlling, secondary pacemaker sites (other nodes) will develop >> when this happens, t he new site outside the SA node is referred to as a what?
Regarding the effects on ANS stimulation, what are the 3 mechanisms that can modify the SA node action potential?
- Change slope of Phase 4
- Alter the threshold voltage
- Change the hyperpolarization
Describe the effects of ANS Stimulation; Sympathetic
More quickly reaches threshold and has the AP kick in
Describe the effects of ANS Stimulation; Parasympathetic
Takes longer to reach threshold and have the AP kick in