ACh and NA modulation of cardiac activity Flashcards
What is the overall ACh effect on heart?
ACh acts on M2 ACh receptors in cardiomyocytes and pacemakers cells.
M2 is Gi coupled = reduce cAMP by inhibiting AC, reduce PKA.
Negative inotropic and chonotropic effect.
Inotropic = strength of contraction.
Chonotropic = HR.
How are cardiomyocytes connected?
Cardiac myocytes are connected with gap junctions, allowing electricl signals to travel from cell to cell = like an electrical synapse.
Intercalated discs are the attachment areas between muscle cells:
Within intercalated discs, you’ll find desmosomes and gap junctions.
Desmosomes are cadherins which link to intermediate filaments and firmly attach myocytes.
What is the conducting system of the heart?
SA node innervates the atria via internodal pathways and crosses to left heart via Bachmann’s bundle.
At the AV node, down to the apex of the heart via the Bundle of HIs, then up the ventricles via Purkinje fibres.
What is the the pacemaker potential?
Slowly depolarising potential until threshold met for action potential.
If current includes HCN channels activated by hyperpolarisation, until the threshold is met.
HCN channels are permeable to Na+ and K+, but mostly Na+ entry.
At the threshold, VG Ca2+ channels open, and slowly inactivate at +ve EM. At +ve EM, VG K+ channels open, which causes repolarisation but it slowed by Ca2+ entry still.
What causes the pacemaker Funny current?
If current is a result of HCN channels which are activated by depolarisation.
HCN channels are permeable to Na+ and K+, but have predominantly Na+ entry,
What is the ventricular AP?
Rapid opening of Na+ channels and Ca2+ channels = rapid depolarisation.
Plateau phase where slow repolarisation due to closure of Na+ channels, Ca2+ channels open, but repolarisation by K+ channels.
When Ca2+ channels inactivated, K+ channels causing repolarisation.
What is the role of Ca2+ channels in the Ventricular AP?
L-type VG Ca2+ channels open at threshold of -20mV.
Rapid depolarisation phase, as well as sustained depolarisation during plateau phase, until they inactiivate and allow for K+ to repolarise cell.
How is ACh released at the heart?
Paraysympathetic CNS releases ACH at ganglion.
Post-ganglionic neurone releases ACh on the heart via vagus nerve, released at variscosities.
Effect of PNS activity on heart?
PNS releases ACh on heart via post-ganglionic vagus nerve.
Bradycardia/ Negative chonotropic effect = slower HR.
= More durable pacemaker potential
Decreased contraction amplitude = Negative Inotropic effect.
= Reduced ampllitude of Ventricular AP.
What does ACh do in cardiac system (receptor and effect)?
ACh acts on M2 Gi coupled ACh receptor.
Activation of G-protein disociation by exchanging GDP for GTP:
Ga-subunit inhibits AC, to reduce cAMP and PKA activity.
= Reduce Ica and If.
Gb/y subunit directly opens GIRKs = causing the efflux of K+, leading to hyperpolarisation of myocyte..
What are muscarinic agonist and antagonists?
Agonist = Muscarine
Atropine = Antagonist, from Atropa belladona.
How to show ACh acts on K+ channels?
Cell-attached patch clamp, with voltage clamp.
Recording Erev is equal to Ek.
The channel is rectifying as more permeable to K+ efflux at negative EM.
In an inside-out voltage clamp:
K+ current dissappears, so involves second messenger.
ADdition of activated G-protein, causes a constant K+ current.
What are the effects of ACh on ventricular AP and pacemaker potential?
Increase in Ik = Hyperpolarisation of ER, and reduction of length of AP (as also reduces ICa).
Gb/y subunit activates GIRK = K+ efflux
= Ik current is stronger, faster repolarisation and more hyperpolarised ER.
= Negative inotropic effect.
Ga subunit inhibits AC, reducing cAMP, reducing PKA driven phosphorylation of L-type Ca2+ channels.
ICa less durable, means that duration of ventricular AP is shortened.
How does ACh affect the pacemaker potential?
ACh increases the duration of pacemaker potential by reducing If current, thus taking longer to reach the threshold required to cause AP.
= More durable pacemaker potential
= Decreased IF.
HCN channels are regulated by cAMP.
Reduced cAMP decreases channel opening.
= with cAMP, HCN channels open at more negative EM.
Reduced PKA reduces Ica.
How does the sympathetic NS impact the heart?
Sympathetic pre-ganglionic neurone releases ACH in the ganglion. The sympathetic post-ganglionic neurone releases NA at variscosities onto the heart tissue.
