Cardiac Muscle 1

Question 1

General Features of Cardiac Muscle

Answer 1

Myogenic
Striated
Cells electrically coupled
Mainly oxidative in metabolism
AP triggers synchronised Ca2+ release from internal store SR (CICR)

Question 2

Main cells types

Answer 2

Cardiac Fibroblasts
Myocytes
Endothelial cells
Vascular SM
Neurons

Question 3

Cardiac Fibroblasts

Answer 3

Majority of cells in the heart

Secrete and maintain CT fibres

Question 4

Myocytes

Answer 4

(~30% of all cells)
Majority of myocardial mass
Carry out myocardial work/contractions
Some are v specialised (purkinje&nodal cells)

Question 5

What do myocytes look like?

Answer 5

• Striated (bundles of contractile proteins)
• have EC spaces containing collagen.
• Intercalated discs at intercellular junctions consisting of : Gap junctions, intermedite junctions and desmosomes

Question 6

Extracellular space

Answer 6

-~33% heart volume

~60% vascular
~23% glycocalyx-like substance
7% CT cells
6% empty space
4% collagen

Question 7

T-Tubules

Answer 7

• Formed by invagination of the sarcolemma.
• Allow for propagation of the AP to the centre of the muscle fibre, due to close interaction between the junctional SR and the sarcolemma (SL)
• Rich in DHPRs(slow, L-type calcium)

Question 8

T-tubule ultrastructure, normal vs failing heart

Answer 8

Normal: RyR and DHPR can’t be discerned from one another as the junction between SR and SL is too small (to allow for sufficient CICR)

Failing: may channels that are not associated with the other, alters AP speed etc

Question 9

E-C coupling

Answer 9

Electrical change @ surface membrane > changes intracellular calcium (via DHPRs and RyRs) > activate contraction

Rapid event.

Question 10

Steps of Cardiac E-C coupling

Answer 10

1) Activation of Ica: AP propagates, depolarises membranes via sodium influx, DHPRs activated (L-type calcium channels)
2) Activation of CICR: small inflow of Ca (from DHPRs) activates much large CR, ‘calcium sparks’ from SR (via RyRs). This can occur as the two receptors are so closely associated to one another
3) Force Development: Ca diffuses to contractile proteins within the myocytes, binds to exposed troponin-C sites on the myofilament > X-bridge cycling
4) relaxation; when cytosolic levels of calcium return to normal

Question 11

How does relaxation (returning of cytosolic Calcium levels) occur

Answer 11

1) reuptake by SR ‘SERCA’ (70-90%)
2) Na/Ca exchanger. 3Na in for 1Ca out. Electrogenic.
3) Ca ATPase in surface SL (1-2%)
4) Ca pump in mitochondria

Question 12

Role of DHPRs

Answer 12

• Found on the sarcolemmal membrane (inc T-tubules), activated by membrane depol > carry Ica (inward Ca current)
• Contribute to AP plateau, via a small inward current
• Trigger E-C coupling by activating RyRs by CICR > much larger Ca2+ release
• Inhibited by SR calcium release

Question 13

DHPRs activated by

Answer 13

Depolarisation of >-40mV

Question 14

DHPRs stimulated by

Answer 14

Catecholamine

Question 15

DHPRs inhibited by

Answer 15

Dihydropyridines (Ca channel blockers)
Mg2+
Low plasma

Question 16

SR Role

Answer 16

Reservoir for intracellular Ca

• Ca buffered in SR by calsequestrin, a molecule that allows the SR to store an extraordinarily high amount of Calcium.
• 35-40 Ca ions per calsequestrin molecules

Question 17

SR channels

Answer 17

• Ca release channels (RyRs), CICR > increased calcium transient
• SR Ca ATPase (SERCA) 2Ca:1ATP actively pumps calcium back into the SR (70-90% extrusion)

Question 18

When SR Ca2+ load is high

Answer 18

Increased Ca available for release

-Enhanced gain of E-C coupling between DHPRs and RyRs (amount of Ca released from SR for any given Ica flow)

Question 19

SR release events

Answer 19

Lots of “calcium sparks” from SR (that summate to make the whole calcium transient

The sparks amplitude and frequency determines the Ca transient amplitude

Question 20

Summary of Contraction

Answer 20

1) AP from adjacent cell spreads over sarcolemma
2) DHPRs channels are activated/opened > Ica flow
3) Ica activated RyRs in the SR > Ca sparks which summate to calcium release
4) Calcium ions bind to Troponin-c on actin filaments and initiate x-bridge cycling
5) Contraction

Question 21

Summary of Relaxation

Answer 21

1) Occurs when intracellular [Ca2+] is lowered, and ca2+ unbinds from TnC
2) Bulk of Ca actively pumped back into SR for storage (SERCA), with a small amount leaving the cell in exchange for Na+ (via NCX)
3) intracellular [Na+] gradient maintained by Na/K ATPase

Question 22

Four important Ca transport proteins for Myocyte relaxation

Answer 22

SR Calcium ATPase SERCA (Ca > SR)

SL Calcium ATPase (Ca > out of cell)

SL Na/Ca exchanger (Ca > out of cell)

Mitochondrial uniporter (Ca> into mitochondria)

Question 23

In steady state Calcium influx and efflux is balanced. What happens if Ca efflux is decreased

Answer 23

Calcium will accumulate

1) Higher SR calcium content
2) Next transient has increased extrusion to balance influx

Same will happen if influx is increased

Question 24

SL Ca-ATPase

Answer 24

minor extrusion of Calcium

Uses 1ATP to remive 1 Ca

Likely to be electroneutral

Question 25

Electrogenic NCX

Answer 25

carries one net charge per cycle. 
reverse mode (ca entry) follows depol > affects plateau

Forward mode (Ca extrusion) follow repol

So NCX contributes to the Vm