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Cardiovascular Pharmacology > Nitrous Oxide and the Endothelium > Flashcards

Nitrous Oxide and the Endothelium Flashcards

1
Q

What are the actions of NO?

A

binds to free radicals
combines with oxyhaemoglobin
activates guanylate cyclase in VSMC
lowers IC Ca by SERCA uptake into IC stores

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2
Q

What are the indirect effects of NO?

A

inhibition of PDE
inhibition of ET-1
inhibition of renin-release -> decreased AngII release

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3
Q

What are the actions of NO via cGMP?

A

stimulation of Na-K ATPase
Katp opening
inhibition of Rho Kinase
modulation of Ca

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4
Q

What are the actions of NO on Ca?

A 
downregulation on IP3 formation via PLC
Decreasing Ca mobilisatio through IP3R
promoting Ca uptake by the SR via PKG stimulation of CaATPase
reducing passive Ca influx
increasing Ca efflux
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5
Q

How does NO reduce IP3 formation?

A

inhibiting PLC

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6
Q

How does NO promote Ca uptake by the SR?

A

stimulating the Ca-ATPase

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7
Q

What are the types of NO available for therapeutic use?

A

short and long acting formulations

sublingual tablets, sprays, patches and ointments

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8
Q

Why are effects of NO diminished with chronic use?

A

nitrate tolerance

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9
Q

What are the features of nitrate tolerance?

A

loss of effects
need to increase dose
onset of vascular abnormalities

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10
Q

What are the forms of nitrate tolerance?

A

true tolerance

pseudotolerance

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11
Q

What are the features of pseudotolerance?

A

activation of RAAS
increases in catecholamine levels and release rates
increase in vasopressin levels
volume expansion

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12
Q

What are the features of true vascular tolerance?

A

impaired biotransformation
increased vascular superoxide production
desensitisation of soluble guanylyl cyclase
increase in PDE activity
increased vascular endothelin production
supersensitivity to vasoconstrictors

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13
Q

Which form of tolerance is specific to nitrates?

A

True vascular tolerance

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14
Q

Activation of RAAS - pseudotolerance or true vascular?

A

pseudotolerance

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15
Q

increase in catecholamine levels - pseudotolerance or true vascular?

A

pseudotolerance

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16
Q

increase in vasopressin - pseudotolerance or true vascular?

A

pseudotolerance

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17
Q

volume expansion - pseudotolerance or true vascular?

A

pseudotolerance

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18
Q

impaired biotransformation - pseudotolerance or true vascular?

A

true vascular

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19
Q

increased vascular superoxide production - pseudotolerance or true vascular?

A

true vascular

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20
Q

desensitisation of soluble guanylyl cyclase - pseudotolerance or true vascular?

A

true vascular

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21
Q

increase in PDE activity - pseudotolerance or true vascular?

A

true vascular

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22
Q

increased vascular endothelin production - pseudotolerance or true vascular?

A

true vascular

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23
Q

supersensitivity to vasoconstrictors - pseudotolerance or true vascular?

A

true vascular

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24
Q

What did the study by Munzel et al. find when using GTNs to investigate tolerance?

A

when comparing tolerant vessels with control vessels, the vasopressor phenylephrine and vasoconstrictor AngII showed increased constriction in tolerant vessels.
this can be reversed by the ACE inhibitor Captopril.

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25
Q

When did the study by Munzel take place?

A

2014

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26
Q

How was vasoconstriction reversed in tolerant vessels in the study by Munzel et al?

A

using the ACE Inhibitor Captopril

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27
Q

What are the features of Isosorbide Mononitrate Tolerance?

A
  • no vascular tolerance
  • endothelial dysfunction
  • stimulates vascular superoxide production
  • increased endothelin production
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28
Q

What are the features of Pentaerythritol Tetranitrate Tolerance?

A
  • no vascular tolerance
  • no endothelial dysfunction
  • up-regulates antioxidant enzymes
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29
Q

What are some NO donor drugs?

A

Sodium Nitroprusside
Diethylamine/NO
S-nitrosothiols

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30
Q

What are some features of using sodium nitroprusside?

A

used in acute coronary HF
causes a profound dilation
can’t be given in high doses

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31
Q

What do Diethylamine and S-nitrothiols do?

A

liberate NO spontaneously

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32
Q

Give some cardiovascular agents which modulate NO bioavailability

A 
ACE Inhibitors
Calcium Channel Blockers
Statins
b-blockers
PDE Inhibitors
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33
Q

Give an example of an ACE Inhibitor

A

Ramipril

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34
Q

Give an example of calcium channel blockers

A

nifidepine

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35
Q

Give an example of a statin

A

simvastatin

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36
Q

Give an example of a b-blocker

A

atenolol

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37
Q

Give and example of a PDE Inhibitor

A

Sildelfanil

38
Q

How do statins work to modulate NO bioavailability?

A

reduce inflammation and stabilise eNOS mRNA

39
Q

Which naturally occurring molecule blocks NO synthesis?

A

Asymmetric dimethylarginine - ADMA

40
Q

What Arginine analogues can also be used to inhibit NO synthesis?

A

L-NMMA

L-NAME

41
Q

What did a study by Vallance et al. 1989 find?

A

that blood flow was constricted when L-NMMA applied but could be restored by L-Arginine

42
Q

What does the group ‘Prostanoids’ include?

A

prostaglandins, thromboxanes and prostacyclins

43
Q

Which COX is constitutively active?

A

COX1

44
Q

When is COX2 induced?

A

with inflammation

45
Q

What are the effects of PGI2?

A
  • increase in cAMP -> decrease in Ca -> decrease constriction
  • prevents platelets forming clots
  • metabolised quickly
46
Q

What molecule does PGI2 work in conjunction with?

A

NO

47
Q

What are the effects of PGE2 activation?

A

inhibition of NA release - NA being a potent constrictor

48
Q

What are the effects of PGG2 and PGH2?

A

constricting factors however not well understood

49
Q

What is vasoconstriction augmented by?

A
  • decrease in NO

- superoxide production

50
Q

What is EDHF?

A

Endothelium derived hyper-polarising factor

51
Q

What does EDHF cause?

A
  • increase in endothelial Ca
  • activation of SKca and IKca channels
  • hyperpolarisation of endothelial cells -> spreads to SMC
52
Q

What does EDHF cause in neighbouring SMC?

A

activation of Na/K ATPases and/or K channels

53
Q

What is the function of EDHF postulated to be?

A

the back up when NO and PGI2 is impaired

54
Q

How many isoforms are there of endothelin and which is the main form?

A

3, ET-1

55
Q

What induces endothelin production?

A

AngII, Adrenaline, hypoxia and oxLDL

56
Q

What inhibits endothelin production?

A

shear stress, NO, PGI2

57
Q

What does ET1 cause constriction via?

A

ETa receptor which results in production of IP3

58
Q

What can block endothelin converting enzyme?

A

phosphoramidon

59
Q

What is the effect of endothelin at ETb on endothelial cells?

A

vasodilation

60
Q

How was it determined that endothelin at ETb causes vasodilation?

A

Bosetan (ETa/ETb blocker) causes pulmonary arterial hypertension

61
Q

What should a test of endothelial function/NO bioavailability be?

A
  • safe
  • non-invasive
  • reproducible
  • inexpensive
  • standardised between labs
  • identifiers of early disease
  • able to predict CV outcome
62
Q

What are the pros of coronary catheterisation?

A
  • gold standard invasive test
  • assesses endothelial function at vascular bed of interest
  • predicts CV outcome
63
Q

What are the cons of coronary catheterisation?

A
  • invasive
  • expensive
  • limited to patients who require the procedure
64
Q

What are the pros of venous occlusion plethysmography with brachial catheterisation?

A
  • more accessible than coronary arteries

- correlates with coronary arteries

65
Q

What are the cons of venous occlusion plethysmography with brachial catheterisation?

A
  • invasive
  • can and has killed before
  • limited repeatability
  • difficult to standardise
  • vascular injury risk
66
Q

What does venous occlusion plethysmography involve?

A

applying pressure to a vein
this causes blood build up due to arterial input being the same
swelling occurs which is measured by a strain guage

67
Q

What are the pros of high frequency ultrasound flow mediated dilitation?

A
  • gold standard non-invase test
  • repeatable
  • can be standardised for reproducibility
  • NO dependent
68
Q

What are the cons of high frequency ultrasound flow mediated dilitation?

A
  • expensive equipment
  • easily affected by physiological factors
  • extensive training required
  • high inter-operator variabilit
69
Q

What does the process of high frequency ultrasound flow mediated dilitation involve?

A

occlusion of blood flow using pressure cuff above the normal systolic pressure ~200mmHg
causes reactive hyperaemia which causes the artery to dilate

70
Q

What are the pros of Laser Doppler Flowmetry and Imaging?

A
  • easy to use
  • non-contact
  • not operator dependent
  • measures microcirculation specifically
71
Q

What are the cons of Laser Doppler Flowmetry and imaging?

A
  • depth of detection is uncertain

- spatial heterogeneity with single point instruments

72
Q

What does laser doppler flowmetry and imaging involve

A

measuring the blood flow by laser beam reflection off of RBCs
used alongside iontopheresis where a drug of charge (i.e. ACh + is driven through the skin with a positive electrode)
useable with occlusion hyperaemia or localised heating ring

73
Q

What are the two peaks associated with a localised heating ring?

A

first peak is the heat receptor activation response

second peak is NO dependent

74
Q

What are the pros of EndoPAT?

A
  • non invasive
  • easy to use
  • automated analysis
  • FDA approved
75
Q

What are the cons of EndoPAT?

A
  • expensive consumables
  • more data needed on reproducibility
  • digital circulation affected by sympathetic tone
76
Q

What is involved with EndoPAT technique?

A

measuring changes in finger tip volume
measures size of pulse before and after occlusion
extent of response is NO dependent
all compared to non-occluded finger

77
Q

What are the pros of Pulse Wave Reflection technique?

A
  • non-invasive
  • easy to use
  • may reflect basal endothelial function
78
Q

What are the cons of Pulse Wave Reflection technique?

A

influenced by structural aspects of the vasculature beyond the endothelium

79
Q

What is seen in Pulse Wave Reflection technique?

A

a decrease in diastolic BP when NO is increased compared with the baseline

80
Q

Describe the process of atherogenesis?

A
  • endothelium starts to produce adhesion protein markers
  • markers are pulled into arterial intima -> blood monocytes
  • produces fatty streaks and foam cells to produce a plaque
  • causes a clump of platelets
  • dislodges which may cause a CV event
81
Q

What are the classic risk factors for CVD?

A 
T1/2 Diabetes Mellitus
dyslipidemia
ageing
HBP
smoking
82
Q

What are the novel risk factors for CVD?

A

inflammation
obesity
oxidative stress

83
Q

In which groups of people can NO bioavailability be seen to be reduced?

A

people with hyperglycaemia and T1 diabetes

84
Q

What does low NO bioavailability and T1 diabetes correlate with?

A

poor HbA1C

85
Q

Where is low NO bioavailability also seen?

A

in obese children and children with T1 Diabetes - originates in utero?

86
Q

What is the Barker Hypothesis?

A

That nutritional deficiencies occurring during critical periods of fetal development and infant life may induce a long term physiological change

87
Q

What evidence is there to support the Barker Hypothesis?

A

children with low birth weight -> age 9 have lower NO bioavailability which is normalised with nitroglycerin-induced vasodilation

88
Q

Which measure is a good indicator of risk for CV events?

A

Framingham risk score

89
Q

What are the associated scores for increased risk of CV events?

A

a ratio of

90
Q

What type of therapy improved childhood T1DM with risk factors?

A

intensive insulin therapy where the use of insulin and its dose is monitored intensively compared with a group who go about their business as normal

91
Q

What are the clinical utilities of using NO bioavailability and endothelial function testing?

A
  • identification of novel risk factors
  • investigation into pharmacological mechanisms for vascular dysfunction and artheroscelerosis
  • evaluating pharmacological interventions
  • monitoring response to primary/secondary prevention therapies and strategies
92
Q

What therapies/strategies also improve endothelial function?

A
  • statins
  • tuna oil over a period of weeks
  • lowering oxidative stress via blackcurrant juice -> increased FMD production

Cardiovascular Pharmacology (7 decks)

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