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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
Q

What does forskolin do?

A

increases cAMP

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26
Q

What is the second function of AKAP 79?

A

directs assembly of a macromolecular complex involving PP2B - calcineurin and PKC isoforms

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27
Q

There are at least two subpopulations of LTCC in the cardiac myocyte with their associated AKAPs, what are their potential roles?

A
  • one thought to be responsible for loading SR with Ca

- other thought to be involved with CICR

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28
Q

What is the function of the RyR?

A

Ca channel

CICR from the SR

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29
Q

How is the RyR regulated?

A 
pH
Protein Kinases
Ca on either side of the SR membrane
Stretch/NO
Binding proteins
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30
Q

Where are the primary binding domains of the PP1, PP2A, PKA and calmodulin on the RyR?

A

the cytosolic domains

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31
Q

How many TM segments does the RyR have?

A

6

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32
Q

What is important for RyR opening?

A

Ca - more Ca, more opening

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33
Q

What is the estimated distance of the RyR to the LTCC?

A

15nM

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34
Q

How long does it take for local Ca to rise next to the RyR?

A

10us

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35
Q

What increases the frequency of sparks from the RyR?

A

stretch

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36
Q

Where are sparks found in the cell?

A

at the t-tubules nears the RyR

37
Q

What is found in models of heart disease with reference to the LTCC and RyR?

A

poor coupling between the LTCC and the RyR due to increased distance between them

38
Q

What is the dyadic cleft?

A

the region between the LTCC and RyR

39
Q

What happens with increased distance between LTCC and RyR?

A

slower development of the contraction

40
Q

What happens if RyRs become too leaky?

A

then waves of Ca can occur outside of an AP which can prove lethal

41
Q

How does acidosis affect the RyR?

A

reduces opening

42
Q

Where might acidosis occur?

A

with ischemia

43
Q

How does caffeine affect the RyR?

A

increases Ca sensitivity and thus opening

44
Q

How does NO affect the RyR?

A

it nitrosylates the RyR to increase opening

45
Q

What affect do kinases have on the RyR?

A

b-adrenoceptor mediated activation of PKA -> increased opening
Ca-Calmodulin-depending kinase may increase opening

46
Q

What other proteins in the SR may affect RyRs?

A

calsequestrin, triadin, junctin

47
Q

What other proteins in the cytosol may affect the RyRs?

48
Q

which AKAP is responsible for assigning PKA to the RyR?

49
Q

what other molecules does mAKAP recruit to the RyR?

A

PDE4D3

PP2A

50
Q

How does PKA activate PDE4D3?

A

phosphorylation at serine 54 - doubles activity

phosphorylation at serine 13 - increases affinity for mAKAP

51
Q

What is PDE4D3?

A

a phosphodiesterase - regulates cAMP which regulates PKA activity

52
Q

Where does PKA phosphorylate RyR?

A

serine 2089

53
Q

What is loss of PDE4D3 associated with?

A

leaky RyR and Ca overload

54
Q

What does PP2A dephosphorylate?

A

RyR

PDE4D3

55
Q

What does mAKAP ensure?

A

rapid response to cAMP
transient PKA activation of RyR
Protects against Ca overload

56
Q

What happens in PDE4D3 KO animals

A

hyperphosphorylation of the RyR

hyperactive RyR

57
Q

What does loss of PDE4D3 cause?

A

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
Q

Who conducted the study for PDE4D3 KO?

A

Lenhart et al. Cell

59
Q

What is the cycle that goes on in HF?

A

Ca overload -> contractile dysfunction -> increase sympathetic drive -> more RyR phosphorylation -> Ca overload

60
Q

What is reduced in human HF?

A

PDE4 expression

61
Q

What is the function of SERCA?

A

removal of Ca at the end of a beat

62
Q

How is the SERCA regulated?

A

NO?

PLB (indirectly)

63
Q

What is the role of PLB and SERCA?

A

PLB inhibits SERCA by reducing affinity for Ca

64
Q

What happens when PLB is phosphorylate?

A

SERCA is disinhibited and Ca uptake is accelerated - heart relaxes quicker

65
Q

what happens in a PLB KO?

A
  • 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
Q

Who did the study regarding PLB KO?

A

Wolska et al. Am J of Physiology

67
Q

Which AKAP is responsible for PLB?

68
Q

What may also disrupt SERCA in the heart?

A

caffeine and peptide inhibtor

69
Q

What is the function of the NCX?

A

triggers Ca at the beginning of the beat

removal of Ca at the end of a beat

70
Q

How is NCX regulated?

71
Q

What is the function of the sodium pump?

A

removal of Na at the end of a beat
maintains ion gradients
controls membrane potential

72
Q

What regulates the sodium pump?

A

PLM (indirectly)

73
Q

What activates the sodium pump?

A

PLM phosphorylation by PKC and PKA

74
Q

What is the function of troponin I?

A

part of the thin filament troponin complex

inhibits actin/myosin interaction

75
Q

How is troponin I regulated\?

A

PKA

phosphorylation reduces TnC affinity for Ca

76
Q

What is the major result of TnI phosphorylation?

A

accelerated relaxation, minor reduction in contraction

77
Q

What is the principle determinant of Ca binding TnC?

A

the rate at which it diffuses from the SR not the actual affinity for Ca

78
Q

What is the principle determinant of Ca unbinding TnC?

A

the affinity of TnC for Ca - so Ca unbinds when TnI phosphorylated -> relaxation

79
Q

Why is the cardiac AP not to be confused with the cardiac cycle?

A

relaxation is not influenced by repolarisation

80
Q

What must happen in order to accommodate more bpm?

A

AP and cycle must be shortened

81
Q

What shortens the contractile cycle?

A

PLB phosphorylation

82
Q

What shortens the AP?

A

IKs activation by PKA and PKC

83
Q

What directs PKA to KCNQ1?

84
Q

Where is KCNQ1 phosphorylated?

A

serine 27 or serine 43

85
Q

What is the net result of AKAPs and general regulation of kinases?

A 
increased force of contraction
increased SV
increased ejection fraction
quicker contraction
more bpm
86
Q

What is the effect of adrenergic stimulation?

A

cardiac cycle modification

87
Q

What will change as aresult of increased venous return?

88
Q

What are the typical values for EDV, ESV and EF?

A

EDV - 120ml
ESV - 70ml
EF - 58%

89
Q

What are the typical values for EDV, ESV and EF under adrenergic stimulation?

A

EDV - 160 ml
ESV - 120ml
EF - 75%

Cardiovascular Pharmacology (7 decks)

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