Cardiac Muscle

Mechanism by which muscles shorten

What is the significance of cardiac muscle’s ability to increase its contractile force with a slight increase in its length

It underlies its ability to control stroke volume

Stroke Volume

the volume of blood ejected from the heart during a single beat

What heart sounds are heard at each of the stars *

Preload

stretched condition of the heart muscle at the end of diastole (EDV)

What does this represent

Starling's Law of the Heart states that the greater the stretch of the heart muscle (myocardium) during diastole, the greater the force of contraction during systole.

What does the starling curve represent

SV’s relationship with EDV

Every point on the starling curve has the same contractility

(Starling's Law of the Heart states that the greater the stretch of the heart muscle (myocardium) during diastole, the greater the force of contraction during systole.)

SV increases/decreases with EDV

Increases

Between what parameters does SV increase with EDV, why

90-200

EDV below 70ml - no SV

EDV above 200ml - SV no further increase - cardiac muscle overstretched

Other than an increased EDV, what can increase SV

An increase in contractility

dP/dt_max

The maximum rate at which VP rises

What is dP/dt_max used to measure

Myocardial contractility

Inotropic agents

Agents that cause an increase/decrease in contractility

Agents that cause an increase in contractility are said to have a positive inotropic effect

Agents that cause a decrease in contractility are said to have a negative inotropic effect

Examples of positive inotropic agents & how they work

noradrenaline, adrenaline : increase Ca2+ influx and uptake by the SR

increased intracellular Ca2+ (also increased extracellular but that’s not the point)

- digoxin : increases intracellular Ca2+ (blocks the Na/K pump which slows Na-Ca exchange)

Examples of negative inotropic agents

hypoxia

drugs: calcium channel blockers, beta adrenergic blockers

Structure of myosin

Thick filament

Contains 2 heads with ATPase activity

Structure of thin cardiac myofilament

Made up of actin, tropomysoin & troponin (TN)

Components of troponin complex

TN-T

TN-I

TN-C

(TIC)

Role of each of the components of troponin complex

TN-T: structural (TNT would cause structural damage🧨)

TN-I: Controls binding of Ca2+ to TN-C (I = In between - goes in between T & C)

TN-C: Ca²⁺ binding

What are the steps that lead to myosin binding to actin

Ca2+ concentration rises and Ca2+ binds to TN-C

Conformation change in tropomyosin

Myosin-binding site on actin is exposed and myosin binds to actin

How do Ca2+ ions come to enter muscle cells

Cells depolarised

Membrane potential rises

Threshold - L-type Ca channels open

Ca2+ ions enter cell

Explain the calcium-induced calcium release (CICR) mechanism in relation to contraction

The Ca2+ ions that enter the cell are only about 25% the amount of calcium needed to induce contraction.

the Ca2+ ions that enter cell “triggers” release of Ca2+ ions from the sarcoplasmic reticulum (SR)

This is enough Ca2+ to cause contraction

How does calcium cause muscle contraction

Ca2+ ions bind to troponin C in troponin complex

Tropomyosin moves

Actin-myosin interaction occurs

Muscle contraction occurs

RYR

Ryanodine receptor

Giant protein with a terminal foot with a T-shaped tube in its centre through which Ca2+ ions are released

(Ryan releases Calcium!)

Where is the density of RYR high

near L-type Ca channels

distance between the Ca channels and the RYR is long/short

short (nm)

Facilitates CICR (Calcium-induced calcium release)

How does calcium relate to muscle relaxation

High Ca2+ conc. inactivates RYR.

The Ca2+ channels close - No further Ca2+ entry (cessation of calcium entry)

No CICR release from SR

(negative feedback)

3 mechanisms by which intracellular Ca2+ is reduced by the cell

In order of importance:

1. SERCA (SR ATP-dependent Ca pump) pumps Ca2+ ions from the cytoplasm into the SR stores

2. Sodium-calcium (Na+-Ca2+) exchanger in the cell membrane powered by the Na+ gradient

3. Cell membrane ATP-dependent Ca pump

What regulates SERCA

SERCA is regulated by the regulatory protein, Phospholamban (PLN), which inhibits Ca2+ uptake by the SR while in its dephosphorylated state

Effect of sympathetic stimulation of cardiac muscle

an increase in active tension

an increase in the rate of tension development

an increase in the rate of tension relaxation

Example of sympathetic stimulation of cardiac muscle

β-adrenergic stimulation

What activates protein kinase A (PKA)

cAMP

(PKA loves going camping!)

What does PKA phosphorylate in muscle cells

L-type calcium channel

Phospholamban (PLN)

Troponin I

Role of PLN in relaxation

PLN reduces inhibition of SERCA which increases the uptake of calcium into the SR, causing relaxation

(PLN ↑SERCA ↑Relaxation ↑Contraction)

How does PLN phosphorylation promote the rate of contraction

PLN phosphorylation promotes the rate of contraction because it increases uptake of calcium into the SR causing relaxation but it also means the SR is loaded with Ca for the next contractions

Role of troponin I in relaxation

troponin I inhibits the binding of calcium to troponin C, causing relaxation

(TN-I is In control of C)

Effect of increased intracellular Ca2+ concentration on muscle cells

increases the force of contraction - positive inotropic effect

Starling’s Law of the Heart

Increased filling of the ventricle causes an increase in SV

Increased muscle fibre length increases the force of contraction

How does Starling’s Law of the Heart work

Increased stretching of the muscle fibre increases the sensitivity of troponin C for Ca2+ • A stronger force of contraction for a given Ca2+ concentration