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Cardiovascular Pharmacology > Hormonal Control of Stroke Volume > Flashcards

Hormonal Control of Stroke Volume Flashcards

1
Q

How is cardiac output calculated?

A

CO= HR x SV

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2
Q

How much blood may be pumped per minute in elite athletes?

A

up to 40L

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3
Q

What controls stroke volume?

A

stretch

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4
Q

What is increased venous return a result of?

A
  • increased skeletal muscle activity
  • adrenergic effects on blood vessels
  • respiratory depth and frequency
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5
Q

What system controls cardiac inotropy, lusitropy and chronotropy?

A

sympathetic nervous system

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6
Q

What causes adrenoceptor activation?

A

adrenaline - in vivo
isoprenaline (b1) - linked to PKA in lab
phenylephrine (a1) - linked to PKC in lab

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7
Q

What type of kinases are PKA and PKC?

A

serine/threonine

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8
Q

What are the phosphatases found in the heart?

A

PP1 - phospholamban and ryanodine receptor

PP2a - LTCC, RyR, NCX and Troponin I

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9
Q

What proteins does PP1 target?

A

phospholamban and RyR

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10
Q

What proteins does PP2a target?

A

LTCC, RyR, NCX, Troponin I

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11
Q

How big is PLB?

A

52aa

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12
Q

What is the phosphorylation site of PLB?

A

serine 16 by PKA

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13
Q

What does PKA look for in PLB to phosphorylate?

A

aRginine at -3 and -2 positions relative to serine/threonine

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14
Q

What proteins anchor PKA?

A

A-Kinase Anchoring Proteins (AKAPs)

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15
Q

Which PKA subunit binds the AKAP?

A

the two regulatory subunits

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16
Q

What are the potential sites of action for PKA and PKC?

A

PLB, PLM, LTCC, RyR, NCX, TnI

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17
Q

What is the function of the LTCC?

A

triggers calcium

plateau phase of AP

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18
Q

How is the LTCC regulated?

A

PKA phosphorylation
increases in trigger calcium
CICR

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19
Q

What is the effect of PKA on the LTCC?

A

increases the likelihood of it being open

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20
Q

Which AKAP is important in regulating LTCC PKA?

A

AKAP 18a

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21
Q

Which author and journal discussed AKAP 18a?

A

Fraser et al. EMBO

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22
Q

What prevents AKAP 18a from functioning?

A

mutation of 3aa at the N-termincal

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23
Q

What is the second AKAP to regulate the LTCC?

A

AKAP 79

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24
Q

What happens when AKAP 79 is mutated?

A

reduced response to forskolin and cAMP

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25
What does forskolin do?
increases cAMP
26
What is the second function of AKAP 79?
directs assembly of a macromolecular complex involving PP2B - calcineurin and PKC isoforms
27
There are at least two subpopulations of LTCC in the cardiac myocyte with their associated AKAPs, what are their potential roles?
- one thought to be responsible for loading SR with Ca | - other thought to be involved with CICR
28
What is the function of the RyR?
Ca channel | CICR from the SR
29
How is the RyR regulated?
``` pH Protein Kinases Ca on either side of the SR membrane Stretch/NO Binding proteins ```
30
Where are the primary binding domains of the PP1, PP2A, PKA and calmodulin on the RyR?
the cytosolic domains
31
How many TM segments does the RyR have?
6
32
What is important for RyR opening?
Ca - more Ca, more opening
33
What is the estimated distance of the RyR to the LTCC?
15nM
34
How long does it take for local Ca to rise next to the RyR?
10us
35
What increases the frequency of sparks from the RyR?
stretch
36
Where are sparks found in the cell?
at the t-tubules nears the RyR
37
What is found in models of heart disease with reference to the LTCC and RyR?
poor coupling between the LTCC and the RyR due to increased distance between them
38
What is the dyadic cleft?
the region between the LTCC and RyR
39
What happens with increased distance between LTCC and RyR?
slower development of the contraction
40
What happens if RyRs become too leaky?
then waves of Ca can occur outside of an AP which can prove lethal
41
How does acidosis affect the RyR?
reduces opening
42
Where might acidosis occur?
with ischemia
43
How does caffeine affect the RyR?
increases Ca sensitivity and thus opening
44
How does NO affect the RyR?
it nitrosylates the RyR to increase opening
45
What affect do kinases have on the RyR?
b-adrenoceptor mediated activation of PKA -> increased opening Ca-Calmodulin-depending kinase may increase opening
46
What other proteins in the SR may affect RyRs?
calsequestrin, triadin, junctin
47
What other proteins in the cytosol may affect the RyRs?
FKBP
48
which AKAP is responsible for assigning PKA to the RyR?
mAKAP
49
what other molecules does mAKAP recruit to the RyR?
PDE4D3 | PP2A
50
How does PKA activate PDE4D3?
phosphorylation at serine 54 - doubles activity | phosphorylation at serine 13 - increases affinity for mAKAP
51
What is PDE4D3?
a phosphodiesterase - regulates cAMP which regulates PKA activity
52
Where does PKA phosphorylate RyR?
serine 2089
53
What is loss of PDE4D3 associated with?
leaky RyR and Ca overload
54
What does PP2A dephosphorylate?
RyR | PDE4D3
55
What does mAKAP ensure?
rapid response to cAMP transient PKA activation of RyR Protects against Ca overload
56
What happens in PDE4D3 KO animals
hyperphosphorylation of the RyR | hyperactive RyR
57
What does loss of PDE4D3 cause?
increased muscle at 3 months with small chambers 15 months - huge ventricles, increase HW/BW ratio, reduced ejection fraction inability to generate force at right time or relax at the right time
58
Who conducted the study for PDE4D3 KO?
Lenhart et al. Cell
59
What is the cycle that goes on in HF?
Ca overload -> contractile dysfunction -> increase sympathetic drive -> more RyR phosphorylation -> Ca overload
60
What is reduced in human HF?
PDE4 expression
61
What is the function of SERCA?
removal of Ca at the end of a beat
62
How is the SERCA regulated?
NO? | PLB (indirectly)
63
What is the role of PLB and SERCA?
PLB inhibits SERCA by reducing affinity for Ca
64
What happens when PLB is phosphorylate?
SERCA is disinhibited and Ca uptake is accelerated - heart relaxes quicker
65
what happens in a PLB KO?
- calcium transients are bigger and shorter but are not shorter in the presence of isoprenaline - cell twitch is already bigger and shorter but can only get bigger with isoprenaline
66
Who did the study regarding PLB KO?
Wolska et al. Am J of Physiology
67
Which AKAP is responsible for PLB?
AKAP18d
68
What may also disrupt SERCA in the heart?
caffeine and peptide inhibtor
69
What is the function of the NCX?
triggers Ca at the beginning of the beat | removal of Ca at the end of a beat
70
How is NCX regulated?
PKC
71
What is the function of the sodium pump?
removal of Na at the end of a beat maintains ion gradients controls membrane potential
72
What regulates the sodium pump?
PLM (indirectly)
73
What activates the sodium pump?
PLM phosphorylation by PKC and PKA
74
What is the function of troponin I?
part of the thin filament troponin complex | inhibits actin/myosin interaction
75
How is troponin I regulated\?
PKA | phosphorylation reduces TnC affinity for Ca
76
What is the major result of TnI phosphorylation?
accelerated relaxation, minor reduction in contraction
77
What is the principle determinant of Ca binding TnC?
the rate at which it diffuses from the SR not the actual affinity for Ca
78
What is the principle determinant of Ca unbinding TnC?
the affinity of TnC for Ca - so Ca unbinds when TnI phosphorylated -> relaxation
79
Why is the cardiac AP not to be confused with the cardiac cycle?
relaxation is not influenced by repolarisation
80
What must happen in order to accommodate more bpm?
AP and cycle must be shortened
81
What shortens the contractile cycle?
PLB phosphorylation
82
What shortens the AP?
IKs activation by PKA and PKC
83
What directs PKA to KCNQ1?
Yotiao
84
Where is KCNQ1 phosphorylated?
serine 27 or serine 43
85
What is the net result of AKAPs and general regulation of kinases?
``` increased force of contraction increased SV increased ejection fraction quicker contraction more bpm ```
86
What is the effect of adrenergic stimulation?
cardiac cycle modification
87
What will change as aresult of increased venous return?
EDV
88
What are the typical values for EDV, ESV and EF?
EDV - 120ml ESV - 70ml EF - 58%
89
What are the typical values for EDV, ESV and EF under adrenergic stimulation?
EDV - 160 ml ESV - 120ml EF - 75%

Cardiovascular Pharmacology (7 decks)

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