Modulation of Cardiac Ouput Flashcards
In what ways can cardiac output be modulated?
changing contraction frequency: chronotropy (SA node)
changing conduction velocity (AV node)
changing force of contraction: inotropy and lusitropy (ventricle)
Which nerves innervate the SAN and AVN and where do they originate?
parasymp: vagus nerve: cardioinhibitory centre
symp: cardiac nerve: cardioacceleratory centre
How does the parasympathetic NS modulate heart rate?
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
How does the sympathetic NS modulate heart rate?
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
What are the 3 courses of action by the sympathetic cardiac nerve that lead to a more forceful contraction?
increasing calcium-induced calcium release
allowing more Ca2+ to be available to RyR
promotes a faster relaxation rate
How does the sympathetic cardiac nerve increase Ca-I CR?
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
How does the sympathetic cardiac nerve allow more Ca2+ to be available for the RyRs?
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
How does the sympathetic cardiac nerve promote a faster relaxation rate?
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
What is the RMP of ventricular myocytes?
-80mV
What causes Ryanodine receptors to open?
influx of calcium from the T-tube
what is the ryanodine receptor?
calcium-sensitive release channel
Which pump is involved in the reuptake of Ca2+ into the SR
SERCA 2
Which pump is responsible for removing the same amount of Ca2+ from the cell as enter through the v.g. Ca2+ channels?
NCX (Na/Ca exchanger)
what factors do the contractility depend on?
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
What does beta-adrenoreceptor stimulation do?
stimulates adenylyl cyclase to increase Calcium Induced Calcium Release from stores
and
inhibits PLB, thus enhancing calcium reuptake
How is the Na/K ATPase important in removing calcium from the myocyte?
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
How is Ouabain used to generate more forceful contractions in the heart?
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
How are GPCRs used to amplify adrenaline signals?
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.
How does ACh affect K+ channels in myocytes?
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
Which ion channels contribute to pacemaker action potentials and how?
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
how can changing sympathetic stimulation frequency change cardiac stroke work and increase cardiac output
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
what is the Frank Starling effect?
increased stretch occurs with increased filling of the ventricles and increases tension force generated
increases strength of contraction
where are neurotransmitters released from in the autonomic NS?
varicosities
which side of the ANS does the vagus nerve belong to?
parasympathetic
what pre and post-syn receptors does NA bind to?
pre: a1, initiates inhibitory response to stop more NA release
post: b1 and b2 (GPCRs, activate adenylyl cyclase, more freq depolarisations due to PKA)
what is a common drug used in the heart to combat the sympathetic NS?
beta blockers
reduce hypertension and treat acute cardiac events (MI)
decrease chronotropy and inotropy
treat hypertension and inhibit smooth muscle relaxation (cause vasoconstriction)
