0624 - AP Modulation in the Heart - RM

Question 1

What are the elements involved in EC coupling in heart?

Answer 1

AP opens L-type Ca2+ Channel, requires extracellular Ca2+ to maintain action

potential (10-25% of Ca2+). Some channels electrochemically coupled to RyR2 on SR (Calcium spark - Calcium-induced calcium release – 75-90%). Ca2+ causes shortening of sarcomeres (cross-bridge cycle).

Force production is regulated by 2nd messenger systems (phospholamban – inhibits SERCA). When troponin 1 is phosphorylated, inhibits troponin C, increased force, faster cross-bridge cycling.

Isoproterenol agonises ß-1 Receptors, much larger Ca2+ influx, and bigger force, faster rate of shortening.

Question 2

Describe Ca2+ clearance from the cardiac plasma membrane.

Answer 2

Clearance modulated by 2nd messenger systems.

SERCA returns 80% of Ca2+ to SR where it is sequestered by calsequestrin. (inhibited by phospholambin)

Plasma pumps (NCX – 3Na/1Ca – 15%), Ca2+ATPase (5%) do the rest.

Question 3

Recognise the receptors involved in autonomic control of the heart, incl which path is normally stronger

Answer 3

Parasympathetic is normally stronger (SA node natural pacemaker is100BPM).

Parasympathetic via Vagus (restricted) innervates SA (R) and AV (L) nodes, sympathetic (diffuse) innervates whole heart – R = nodes, L = ventricles. Effect mostly on SA node – via M2 muscarinic receptors (Vagus) or ß1-adrenoreceptor (Sympathetic).

Question 4

Outline the signalling cascade and downstream targets after SY cardiac receptor activation.

Answer 4

Sympathetic Signalling – noradrenaline hits ß-1 receptor, starts Gs signaling cascade, directly increasing cAMP (caffeine has same effect by inhibiting cAMP breakdown), and activating PKA. cAMP directly opens I(f) channels, speeding up pacemaker. PKA opens I(k) and I(CaL), also increasing heart rate. I(CaL) speeds up pacemaker potential decay (funny current).

In the myocyte, increased I(CaL) increases plateau current (thus force), phosphorylated phospholambyn increases SERCA clearance, and phosphorylated RyR increases Ca release. Signalling turned off via phosphatase activity (blocks cAMP). Steadily Increased HR, shorter APs (spike and dome), faster Ca rise and decay, and increased [Ca], positive ino and luso-tropic. Diastolic filling considerably curtailed.

Question 5

Outline the signalling cascade and downstream targets after Parasymp cardiac receptor activation.

Answer 5

ACh hits M2 receptor, instant drop in HR (only in ICS, not myocytes) caused by slower pacemaker potential decay (i.e. the funny current), hyperpolarisation (cause controversial), and lower AP amplitude. Does this by M2 receptor inhibiting cAMP, directly lowers funny current open probability (slower funny current), and via PKA leads to slower repolarisation (I(k)), and slower decay of PMP (funny current again (I(CaL))

Question 6

State the different forms of tropism

Answer 6

INS:
Chronotropism – Heart Rate
Bathmotropism – AP threshold (bathmos = staircase, can change the height/threshold)
Dromotropism – AVN conduction delay (dromos = delay)

Myocytes:
Inotropism – Contractile force (inos = force)
Lusitropism – rate of relaxation (if faster, positively lusitropic, if slower, negatively lusitropic).

Question 7

How do Ca2+ channel blockers affect the heart?

Answer 7

Ca2+ blockers are verapamil, nifedipine, and any other –ipine drugs.

In SAN, prolong PMP decay, and slightly lowers amplitude, therefore lower heart rate (negative chronotropic).
In AVN, reduces amplitude and shortens the AP – fewer currents for depolarising surrounding cells (negative dromotropic)

In Cardiac myocyte, lowers the shoulder and the amplidude (less I(CaL)). Also lowers force (negative ionotropic).

In hyperkalaemia, I(Na) is deactivated, and myocyte APs resemble those in the ICS (no phase 0 or 1).

In hypo/anoxia, less ATP, less Na/KATPase, more I(KATP), shorter AP, less Ca influx, lower contractility. You get sympathetic innervation to increase HR.