Cardiac excitability and excitation-contraction coupling

Question 1

Cardiac conduction system

Answer 1

• Natural pacemaker is sinoatrial (SA) node, which conduct electrical depolarization to the AV node
• From AV node the depolarization travels down the bundle of his and separates into the right and left bundle branches
• The bundle banshees split into purkinjie fibers, specialized muscle cells that have extremely high conduction velocity, allowing for the depolarization to spread to the entire ventricles simultaneously
• Electrical depolarization can travel btwn muscle cells through low-resistance gap junctions (intercalated disks)

Question 2

Cardiac cell action potentials

Answer 2

• Can either be fast (atria, ventricles, purkinjie) or slow (nodes) responses
• Both responses have different phases (0-4) in which various types of channels are opened and closed to generate characteristic polarities within the cell

Question 3

Fast response cells 1

Answer 3

• Begins with rapid depolarization (phase 0) of cardiac cell due to opening of the V-gate, tetrodotoxin (TTX) sensitive fast Na channels (these channels are absent in slow-response cells, which use slow Na channels instead)
• After reaching maximum depolarization, there is partial repolarization (phase 1) due to closure of TTX-Na channels and opening of transient K-channels (Kt)
• Some forms of long QT syndrome are due to mutations in the TTX-Na channels, causing delayed inactivation of these channels and extending the depolarization time

Question 4

Fast response cells 2

Answer 4

• Phase 1 ends when the Kt channels close, delayed rectifier K channels (Kdr) open (slow), and L-type Ca channels open (slow, longer-opened, and dihydropyridine sensitive)
• At this point (phase 2) there is balance btwn K leaving the cell and Ca/Na entering the cell, thus there is a plateau in the membrane potential (Na can enter thru L-Ca channels)
• Some long QT conditions are due to mutations in the Kdr channels not opening properly thus prolonging the phase 2 plateau and leading to long QT

Question 5

Fast response cells 3

Answer 5

• Eventually more Kdr channels open and the L-Ca close, leading to a large repolarization of the membrane (phase 3)
• As the membrane potential approaches resting potential, the Kdr channels close and inward rectifying K channels (Kir) open
• Kir let K in and out of the cell, thus keeping the membrane potential constant at its resting potential (phase 4)

Question 6

Cardiac automaticity

Answer 6

• Slow response cells exist in nodes, and in some degree in purkinje fibers
• These cells provide the basis for cardiac automaticity
• The heart will depolarize due to depolarization of any of these three entities, with the fastest one determining the heart rate
• SA node has intrinsic rate of 80-100/min, which AV is 40-60/min and purkinjie fibers being 30-40/min
• Therefore, SA node will determine the HR unless it is impaired, then the AV node will take over and initiate ventricular contraction

Question 7

Slow response cells 1

Answer 7

• The slow response cells initiate depolarization in a very different way, starting with phase 4 (membrane potential)
• The membrane potential of slow response cells is not static, it slowly increases over time until it reaches threshold (much lower than fast-response cells)

Question 8

Slow response cells 2

Answer 8

• The membrane potential slowly depolarizes during phase 4 due to activation of Na(f) channels (If) which open in response to hyperpolarization (phase 3)
• As Na continuously enters the cell in phase 4, the membrane potential rises until it crosses threshold at which point phase 0 begins
• Phase 0 is due to T-type Ca channels (fast opening, transient, and not blocked by dihydropyridines)

Question 9

Slow response cells 3

Answer 9

• At maximum depolarization, the T-Ca channels close and Kdr channels open slowly due to depolarization leading to phase 1-3 (3 being hyperopolarization)
• Kdr slowly inactivate as membrane potential reaches resting potential, simultaneous to opening of Na(f) and beginning of phase 4

Question 10

Presence of Ca channels in different cardiac tissues

Answer 10

• Cardiac muscle cells (fast response) only have L-Ca
• Nodal cells and purkinjie fibers (slow response ones) have both L-Ca and T-Ca
• Both types are V-gated (respond to depolarization)

Question 11

Na/Ca exchanger 1

Answer 11

• Unique protein that changes 3 Na for 1 Ca
• Direction of ion movement depends on the membrane potential
• When the cell is more negative than -20mV (hyper polarized) the exchanger removes Ca from the cell and transports Na into the cell

Question 12

Na/Ca exchanger 2

Answer 12

• The the membrane potential is greater than -20mv (depolarized), the exchanger reverses its direction and brings Ca into the cell while removing Na
• This exchanger facilitates Ca movement into the cell during depolarization/contraction when Ca needs to be abundant
• It also aids in ridding the cell of Ca when the cell is hyperpolarized/resting

Question 13

Excitation-contraction 1

Answer 13

• Tension (contraction) in the cell rises during phase 2 while the membrane is depolarized and is maintained for as long as the membrane is depolarized
• Phase 3 (hyperpolarization) acts as a trigger for relaxation
• Cardiac muscle is refractory to further stimulation during force generation, thus it cannot reach tetany
• For the Ca required for contraction, 20% is from extracellular sources (L-Ca and Na/Ca exchange) and 80% is from internal stores (SR)
• 70% of the intracellular Ca is moved back into the SR by the SR Ca-ATPase and the remaining 30% is removed from the cell

Question 14

Excitation-contraction 2

Answer 14

• The release of SR Ca is mediated thru Ca influx thru the dihydropyridine receptor (specialized L-Ca) and Na/Ca exchanger
• The elevated Ca levels lead to release of Ca from SR stores
• Ca exits the SR thru ryanodine receptors
• Both external Ca and internal Ca are needed for contraction
• Exchanger moves Ca in during phase 0-2, and moves Ca out during phase 3

Question 15

Rx of long QT syndrome

Answer 15

• L-Ca channel blockers are used
• Blocking the Ca influx during repolarization leads to faster repolarization and thus shortening the QT interval
• This is b/c lowering the Ca influx, which antagonizes the K efflux, leads to shortening of the repolarization period since K efflux dominates

Question 16

Sympathetic influences on heart 1

Answer 16

• NE binds to B1 receptors and leads to increase of AC activity-> increased cAMP-> increased PKA activity
• PKA phosphorylates different proteins including the slow V-gates Ca channels (L-CA), phospholamban, Kdr (Iks) channels, and Na(f) (If) channels

Question 17

Sympathetic influences on heart 2

Answer 17

• Phosphorylation of L-Ca lead to increased Ca conduction at all membrane potentials, leading to increased excitability and force of contraction
• Phosphorylation of phospholamban increases the activity of the SR Ca-ATPase, thus increasing rate of muscle relaxation thru increases Ca uptake into SR
• This allows the heart to relax more quickly after contraction to get ready for another contraction

Question 18

Sympathetic influences on heart 3

Answer 18

• Phosphorylation of Kdr channels in cardiac myocytes increases their activity, thus shortening the action potential by speeding up K efflux
• Phosphorylation of Na(f) increases nodal cells conductance for Na during resting potential, speeding up the time it takes to reach threshold and his speeding up pacemaker rate and HR (increases onset of pacemaker depolarization)

Question 19

Parasympathetic influences on heart

Answer 19

• Acetylcholine binds to muscarinic receptors which causes 2 things to occur
• One is inhibition of AC, thus reducing all of the effects that sympathetic activation would have
• The other is activating the Kdr channels in nodal cells, which increases the time it takes for these cells to reach threshold
• This is because the Kdr channels stay open for longer once the cell reaches resting potential, thus prolonging the time it takes for the Na influx (from Na(f)) to bring the membrane potential to threshold and cause an AP
• The increased time to threshold in nodal cells reduces the heart rate

Question 20

Effects of cardiac glycosides

Answer 20

• Digitalis (cardiac glycoside) is used in the Rx of congestive heart failure (CHF) by inhibiting the Na/K ATPase (pumps Na out, K in)
• Inhibition of the Na/K ATPase leads to elevation of intracellular Na and partial depolarization of the cell
• At the elevated resting potential, there is less Ca efflux thru the Na/Ca exchanger and thus more resting Ca in the cell
• This means less Ca must enter the cell during depolarization to achieve the same strength of contraction