Modulation of Cardiac Ouput

Question 1

In what ways can cardiac output be modulated?

Answer 1

changing contraction frequency: chronotropy (SA node)
changing conduction velocity (AV node)
changing force of contraction: inotropy and lusitropy (ventricle)

Question 2

Which nerves innervate the SAN and AVN and where do they originate?

Answer 2

parasymp: vagus nerve: cardioinhibitory centre
symp: cardiac nerve: cardioacceleratory centre

Question 3

How does the parasympathetic NS modulate heart rate?

Answer 3

slows down hr

accelerates pacemaker potential decay

releases ACh which binds to M2 receptor that is coupled to a Gi protein

GTP binds to G protein, beta + gamma subunits dissociate + bind to K+ leak channels, increases membrane K+ permeability

brings membrane potential towards K+ equilibrium, making it harder to depol

leads to slower pacemaker potential > slower repol of SAN myocytes > less freq APs > hr slower

Question 4

How does the sympathetic NS modulate heart rate?

Answer 4

increases hr

release NA which binds to beta adrenergic receptors on the CSM of SAN/AVN myocytes

b-adr receptors coupled to Gs proteins

GTP binds to G protein, alpha subunits dissociate. alpha subunit binds + activates adenylyl cyclase.

increases adenylyl cyclase activity > more cAMP produced

either binds directly to pacemaker If channel, increasing the likelihood of the channel being open, allowing more Ca2+ into the cell, speeding up depol

or cAMP activates PKA leading to phosphorylation of airtight L type Ca2+ v.g. channels and RyR and K+ channels

more Ca2+ enters the cell from the t-tubules and more is released from the SR

cell more susceptible to depol by funny currents: incr hr

K+ channels open > faster repol therefore frequency of APs increases

faster cardiac cycle

Question 5

What are the 3 courses of action by the sympathetic cardiac nerve that lead to a more forceful contraction?

Answer 5

increasing calcium-induced calcium release
allowing more Ca2+ to be available to RyR
promotes a faster relaxation rate

Question 6

How does the sympathetic cardiac nerve increase Ca-I CR?

Answer 6

SCN innervates ventricular varicosities, the terminal ends release NA

NA binds to beta-adrenergic receptors, Gs protein activates adenylyl cyclase to produce more cAMP

PKA is activated, phosphorylating L-type vg Ca channels, allowing more Ca2+ to enter

Ca2+ binds to RyR leading to a conformational change, opening the pore so more calcium-induced calcium release from SR occurs

Ca2+ binds to troponin complex

myocyte climbs the Ca2+-tension curve leading to a more forceful contraction

Question 7

How does the sympathetic cardiac nerve allow more Ca2+ to be available for the RyRs?

Answer 7

SCN innervates ventricular varicosities, the terminal ends release NA

NA binds to beta-adrenergic receptors, Gs protein activates adenylyl cyclase to produce more cAMP

PKA is activated and phosphorylates phospholamban. This stops the inhibition of the SERCA 2 pump

the reuptake of Ca2+ into the SR is made more effective, meaning more is available in the SR to be release through the RyRs on the next contraction

Question 8

How does the sympathetic cardiac nerve promote a faster relaxation rate?

Answer 8

SCN innervates ventricular varicosities, the terminal ends release NA

NA binds to beta-adrenergic receptors, Gs protein activates adenylyl cyclase to produce more cAMP

PKA is activated and phosphorylates troponin I, which decreases its affinity for Ca2+, which promotes a faster relaxation rate of myocytes

this speeds up the contraction-relaxation cycle which leads to a faster heart rate

Question 9

What is the RMP of ventricular myocytes?

Answer 9

-80mV

Question 10

What causes Ryanodine receptors to open?

Answer 10

influx of calcium from the T-tube

Question 11

what is the ryanodine receptor?

Answer 11

calcium-sensitive release channel

Question 12

Which pump is involved in the reuptake of Ca2+ into the SR

Answer 12

SERCA 2

Question 13

Which pump is responsible for removing the same amount of Ca2+ from the cell as enter through the v.g. Ca2+ channels?

Answer 13

NCX (Na/Ca exchanger)

Question 14

what factors do the contractility depend on?

Answer 14

the cytosolic Ca2+, which is determined by the balanced between:
RyR mediated Ca2+ release from the SR and SERCA mediated Ca2+ reuptake to the SR
and
PMCA (plasma membrane calcium ATPase) and NCX mediated removal of Ca2+ from the cell

Question 15

What does beta-adrenoreceptor stimulation do?

Answer 15

stimulates adenylyl cyclase to increase Calcium Induced Calcium Release from stores
and
inhibits PLB, thus enhancing calcium reuptake

Question 16

How is the Na/K ATPase important in removing calcium from the myocyte?

Answer 16

NCX is linked to NKA, with each balancing the [Na] in the cell
NKA pumps 3 Na+ out, creating a gradient for NCX to pump 3 Na+ in and 3 Ca2+ out

Question 17

How is Ouabain used to generate more forceful contractions in the heart?

Answer 17

Ouabain inhibits NKA, which reduces the Na+ pumped out and increases the [Na+] in the cell

this reduces the Na+ gradient, meaning NCX works less efficiently and more Ca2+ is left in the cell: more Ca2+ is available for contraction

Question 18

How are GPCRs used to amplify adrenaline signals?

Answer 18

say 1 adrenaline (10^-10 M) activates 3 adenylyl cyclases, which produce 5 cAMP molecules (10^-6 M) to activate 5 kinases, each of which phosphorylates 5 targets such as vg. Ca2+ channels and PLB.

Question 19

How does ACh affect K+ channels in myocytes?

Answer 19

ACh binds M2 receptor, causing the Gi heterotrimeric G protein to break into alpha and beta-gamma and activate the I(K-ACh) channel

creates a hyperpolarisation current by allowing K+ to leave: opposes depolarisation throughout cardiac cycle and increases the Ca2+ required for contraction to occur

also inhibits cAMP production

Question 20

Which ion channels contribute to pacemaker action potentials and how?

Answer 20

RMP of pacemaker cell is ~ -65mV, much more +ve than ventricular cell, since they are not stabilised by IK1 channels

early pacemaker current (-65mV to -50mV) = decreasing IKr and IKs, increasing If

late pacemaker current = increasing ICaT and NCX

upstroke = ICaL

recovery = increasing IKr and IKs, decreasing ICaT and ICaL

Question 21

how can changing sympathetic stimulation frequency change cardiac stroke work and increase cardiac output

Answer 21

as sympathetic stimulation frequency increases, stroke work increases for a given atrial pressure
and the curve of increase of stroke work with atrial pressure becomes steeper

except this is causation this is a correlation (that is coincidental?): positive inotropic effect increases contractility independently of F-S

Question 22

what is the Frank Starling effect?

Answer 22

increased stretch occurs with increased filling of the ventricles and increases tension force generated

increases strength of contraction

Question 23

where are neurotransmitters released from in the autonomic NS?

Answer 23

varicosities

Question 24

which side of the ANS does the vagus nerve belong to?

Answer 24

parasympathetic

Question 25

what pre and post-syn receptors does NA bind to?

Answer 25

pre: a1, initiates inhibitory response to stop more NA release
post: b1 and b2 (GPCRs, activate adenylyl cyclase, more freq depolarisations due to PKA)

Question 26

what is a common drug used in the heart to combat the sympathetic NS?

Answer 26

beta blockers

reduce hypertension and treat acute cardiac events (MI)
decrease chronotropy and inotropy

treat hypertension and inhibit smooth muscle relaxation (cause vasoconstriction)