0624- modulation of action potential- CG Flashcards
Aims
The students should
- know the elements involved in EC coupling in heart;
- be able to describe Ca2+ clearance from PM;
- recognise the receptors involved autonomic control of the heart, incl. which path is normally stronger;
- be able to state the different forms of tropism;
- understand the signalling cascades and the
downstream targets after receptor activation; and
• appreciate how Ca2+ channel blockers affect the heart.
Describe elements involved in EC coupling in heart, and describe its regulation
Unlike skeletal muscle, cardiac requires extracellular Ca2+ (otherwise stop beating)
- Influx of Extracellular Ca2+ into cell via L-type VGCC
- Triggering of Ca2+ release from SR stores- EC coupling
- [Intracellular Ca2+] cause shortening of contractile proteins
(similar to skeletal muscle…Ca2+ bind to troponin C, which makes it bind to tropomyosin and expose actin so myosin can bind to it)
Regulation via 2nd messengers (cAMP), ie stimulating adrenergic receptors (B1) increase Ca2+ influx and increase contractility. Targets include AP, L type VGCC, SERCA, troponin 1
How is calcium cleared from the cytoplasm?
80% is taken up back into the sarcoplasmic reticulum via SERCA transporters
15% is transported out of cell by NCX (3Na to 1 Ca) exchanger- extrudes 1 Ca2+ by transporting 3 na+ into the cell
5% via Ca2+ ATPase (use ATP to actively pump calcium out)
Other membrane transporters include Na/K atpase and Na/H exchanger
Outline the cardiac tropisms affecting the ICS and myocytes
ICS
Chronotropism- re. HR
Bathmotropism- re. AP threshold
Dromotropism- re. AVN conduction delay
Myocyte
Inotropism- re. contractile force
Lusitropism- re. rate of relaxation
How is the heart innervated (efferent pathway)?
Compare SNS and PNS outflow. Which arm predominates?
Autonomic NS, bilateral
Parasympathetic: (vagal, NT=ACh, receptor = adrenergic, HCN..)
fast
Inhibits HR and SV
Innervation restricted to nodes only. Right= SA node, left= AVN
(how does PNS decrease SV if only SAN and AVN affected? shouldn’t decreased HR increase SV?)
Sympathetic (T1-5, NT=Noradrenaline, receptor= M2–>Katp)
slow
Excitatory- increase HR, SV, TPR
Innervation diffuse, over the whole heart.
Right= SAN, left=ventricle
Both SNS and PNS are tonically active, but VA predominates of SY for Heart rate in normal ppl at rest
Describe sympathetic activation in ICS cells and myocytes
ICS- mostly via B1 (some B2)
Over several beats, HR↑, AV conduction↑, AP shortening, AP amplitude↑, rate of pacemaker decay↑ (positively chrono, dromo, bathmotropic) – no additional depolarisation
Myocyte
HR↑, AP duration shortens, larger phase 2, faster phase 3 (spike and dome shape AP), faster Ca2+ rise and decay, larger [Ca2+] amplitude
Contraction: both contractility↑ and rate of relaxation↑ (positive ino- and lusotropic).
• Consequence: diastolic filling considerably curtailed (later)
Outline the sequence of sympathetic signalling cascade (EC coupling)
B adrenergic receptors are Gs receptors
Ga activate adenylyl cyclase –> ↑cAMP –> ↑ If pacemaker current influx. ↑cAMP also activate PKA (protein kinase A), which goes on to phosphorylate a shitload of proteins:
ICS: faster pacing → HR↑
– I(f) ↑ (directly via cAMP; open probability↑) → faster decay of PMP (pacemaker potential) → HR↑.
– I(K DR= repolarisation, K+ efflux)↑ via PKA phosphorylation → faster repolarisation → HR↑.
– ICaL↑ from PKA phosphorylation → faster decay of PMP → HR↑.
• Myocyte: bigger force production
– I(CaL)↑ from PKA phosphorylation: plateau current↑ → bigger force.
– PLB phosphorylated: disinhibits SERCA pump → faster clearance.
– RyR phosphoryl.: store release↑.
Outline the mechanism of PNS signalling
M2 receptor- Gi-linked. AFFECT ICS CELLS ONLY in humans
Ga inhibit adenylyl cyclase –> ↓cAMP –> ↓PKA activity
ICS: slower pacing
– I(f) ↓ → slower decay of PMP
– I(K DR)↓ via PKA activity↓ → slower repolarisation, longer AP.
– I(CaL)↓ from PKA activity↓ → slower Ca2+influx
– Only at high stimulus rates→ small hyperpolarisation
Myocyte: smaller force production (not humans)
Describe how Ca2+ channel blockers affect AP
negatively dromotropic, chronotropic and inotropic (all ICS properties)
ICS-
SAN- Amplitude↓, HR↓ (prolongs PMP decay)
AVN- Amplitude↓, reduce conduction velocity (prolong AP delay)
Myocyte- Amplitude↓, I(CaL)↓ = (Force↓)
How does hyperkalaemia affect AP?
↑ Extracellular K+ = hyperpolarised RMP
Hence I(Na) inactivated in myocytes (can’t depolarise cell)
APs lose phase 0 and 1
How does hypoxia affect AP
ATP↓ → drop in Na+/K+-ATPase activity
Higher extracellular K+ activate I(KATP), triggering K+ influx and hyperpolarising the cell → less Ca2+ influx → contractility↓ → sympathetic activation: HR↑.
store overload: delayed afterdepol. (DAD)
– via sympathetic reflex activation: ICaL↑
– ATP↓ → transporter activity↓ (Na/K-ATPase activity↓ and Na/H-exchanger↓) → [Na+]↑ → NCX in reverse → Ca2+ influx:
» Depolarisation (arrhythmia).
See that consequences of MI lecture
Stricker Summary
- Ca2+ influx via L-type channels triggers EC coupling.
- Contractility and clearance of plasma modulated by 2nd messenger systems.
- Autonomic innervation is diffuse (SYM) and specific (VA).
- Normally, parasympathetic activity predominates in heart.
- β1-AR signal via cAMP↑ to upregulate If, IKDR and ICaL.
- M2-AChR signal via cAMP↓ to downregulate IKDR and ICaL.
- There is a different between action of synaptic & extrasynaptic AChR. (??? is this NMJ AcH vs PNS vaga AcH <–>M2R?)
- Ca2+ channel blockers are neg. ino-, dromo- and chronotrop.
MCQ
Victor Helms, a 26 year-old is admitted to the Emergency Department (ED) after being stabbed in his neck. The ED physician diagnoses that his left vagal nerve may likely have been damaged? Which of the following statements is most consistent with this diagnosis?
Left vagal nerve innervates the AVN, inhibitory effect that decreases HR and SV.
Hence no inhibition of AVN = tachycardia, increased conduction velocity (shorter PR interval)
However
If AVN is destroyed, His/Purkinje initiates pacemaker potential, which is slower with a longer duration…hence Ventricular bradycardia with large P waves. (>?? or is it???)
