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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
When did the study by Munzel take place?
2014
26
How was vasoconstriction reversed in tolerant vessels in the study by Munzel et al?
using the ACE Inhibitor Captopril
27
What are the features of Isosorbide Mononitrate Tolerance?
- no vascular tolerance - endothelial dysfunction - stimulates vascular superoxide production - increased endothelin production
28
What are the features of Pentaerythritol Tetranitrate Tolerance?
- no vascular tolerance - no endothelial dysfunction - up-regulates antioxidant enzymes
29
What are some NO donor drugs?
Sodium Nitroprusside Diethylamine/NO S-nitrosothiols
30
What are some features of using sodium nitroprusside?
used in acute coronary HF causes a profound dilation can't be given in high doses
31
What do Diethylamine and S-nitrothiols do?
liberate NO spontaneously
32
Give some cardiovascular agents which modulate NO bioavailability
``` ACE Inhibitors Calcium Channel Blockers Statins b-blockers PDE Inhibitors ```
33
Give an example of an ACE Inhibitor
Ramipril
34
Give an example of calcium channel blockers
nifidepine
35
Give an example of a statin
simvastatin
36
Give an example of a b-blocker
atenolol
37
Give and example of a PDE Inhibitor
Sildelfanil
38
How do statins work to modulate NO bioavailability?
reduce inflammation and stabilise eNOS mRNA
39
Which naturally occurring molecule blocks NO synthesis?
Asymmetric dimethylarginine - ADMA
40
What Arginine analogues can also be used to inhibit NO synthesis?
L-NMMA | L-NAME
41
What did a study by Vallance et al. 1989 find?
that blood flow was constricted when L-NMMA applied but could be restored by L-Arginine
42
What does the group 'Prostanoids' include?
prostaglandins, thromboxanes and prostacyclins
43
Which COX is constitutively active?
COX1
44
When is COX2 induced?
with inflammation
45
What are the effects of PGI2?
- increase in cAMP -> decrease in Ca -> decrease constriction - prevents platelets forming clots - metabolised quickly
46
What molecule does PGI2 work in conjunction with?
NO
47
What are the effects of PGE2 activation?
inhibition of NA release - NA being a potent constrictor
48
What are the effects of PGG2 and PGH2?
constricting factors however not well understood
49
What is vasoconstriction augmented by?
- decrease in NO | - superoxide production
50
What is EDHF?
Endothelium derived hyper-polarising factor
51
What does EDHF cause?
- increase in endothelial Ca - activation of SKca and IKca channels - hyperpolarisation of endothelial cells -> spreads to SMC
52
What does EDHF cause in neighbouring SMC?
activation of Na/K ATPases and/or K channels
53
What is the function of EDHF postulated to be?
the back up when NO and PGI2 is impaired
54
How many isoforms are there of endothelin and which is the main form?
3, ET-1
55
What induces endothelin production?
AngII, Adrenaline, hypoxia and oxLDL
56
What inhibits endothelin production?
shear stress, NO, PGI2
57
What does ET1 cause constriction via?
ETa receptor which results in production of IP3
58
What can block endothelin converting enzyme?
phosphoramidon
59
What is the effect of endothelin at ETb on endothelial cells?
vasodilation
60
How was it determined that endothelin at ETb causes vasodilation?
Bosetan (ETa/ETb blocker) causes pulmonary arterial hypertension
61
What should a test of endothelial function/NO bioavailability be?
- safe - non-invasive - reproducible - inexpensive - standardised between labs - identifiers of early disease - able to predict CV outcome
62
What are the pros of coronary catheterisation?
- gold standard invasive test - assesses endothelial function at vascular bed of interest - predicts CV outcome
63
What are the cons of coronary catheterisation?
- invasive - expensive - limited to patients who require the procedure
64
What are the pros of venous occlusion plethysmography with brachial catheterisation?
- more accessible than coronary arteries | - correlates with coronary arteries
65
What are the cons of venous occlusion plethysmography with brachial catheterisation?
- invasive - can and has killed before - limited repeatability - difficult to standardise - vascular injury risk
66
What does venous occlusion plethysmography involve?
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
What are the pros of high frequency ultrasound flow mediated dilitation?
- gold standard non-invase test - repeatable - can be standardised for reproducibility - NO dependent
68
What are the cons of high frequency ultrasound flow mediated dilitation?
- expensive equipment - easily affected by physiological factors - extensive training required - high inter-operator variabilit
69
What does the process of high frequency ultrasound flow mediated dilitation involve?
occlusion of blood flow using pressure cuff above the normal systolic pressure ~200mmHg causes reactive hyperaemia which causes the artery to dilate
70
What are the pros of Laser Doppler Flowmetry and Imaging?
- easy to use - non-contact - not operator dependent - measures microcirculation specifically
71
What are the cons of Laser Doppler Flowmetry and imaging?
- depth of detection is uncertain | - spatial heterogeneity with single point instruments
72
What does laser doppler flowmetry and imaging involve
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
What are the two peaks associated with a localised heating ring?
first peak is the heat receptor activation response | second peak is NO dependent
74
What are the pros of EndoPAT?
- non invasive - easy to use - automated analysis - FDA approved
75
What are the cons of EndoPAT?
- expensive consumables - more data needed on reproducibility - digital circulation affected by sympathetic tone
76
What is involved with EndoPAT technique?
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
What are the pros of Pulse Wave Reflection technique?
- non-invasive - easy to use - may reflect basal endothelial function
78
What are the cons of Pulse Wave Reflection technique?
influenced by structural aspects of the vasculature beyond the endothelium
79
What is seen in Pulse Wave Reflection technique?
a decrease in diastolic BP when NO is increased compared with the baseline
80
Describe the process of atherogenesis?
- 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
What are the classic risk factors for CVD?
``` T1/2 Diabetes Mellitus dyslipidemia ageing HBP smoking ```
82
What are the novel risk factors for CVD?
inflammation obesity oxidative stress
83
In which groups of people can NO bioavailability be seen to be reduced?
people with hyperglycaemia and T1 diabetes
84
What does low NO bioavailability and T1 diabetes correlate with?
poor HbA1C
85
Where is low NO bioavailability also seen?
in obese children and children with T1 Diabetes - originates in utero?
86
What is the Barker Hypothesis?
That nutritional deficiencies occurring during critical periods of fetal development and infant life may induce a long term physiological change
87
What evidence is there to support the Barker Hypothesis?
children with low birth weight -> age 9 have lower NO bioavailability which is normalised with nitroglycerin-induced vasodilation
88
Which measure is a good indicator of risk for CV events?
Framingham risk score
89
What are the associated scores for increased risk of CV events?
a ratio of
90
What type of therapy improved childhood T1DM with risk factors?
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
What are the clinical utilities of using NO bioavailability and endothelial function testing?
- 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
What therapies/strategies also improve endothelial function?
- 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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