Nitric oxide and the vascular system Flashcards Preview

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Flashcards in Nitric oxide and the vascular system Deck (28)
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1
Q

What are the biologically important compounds of nitrogen and oxygen?

A
  • nitric oxide (NO) and nitrous acid (nitrate)
2
Q

What is Entonox?

A

A mix of 50% NO and 50% oxygen

  • medical anaesthesia gas
  • in pre-hospital care and childbirth and emergency medicine
  • stable and unreactive
3
Q

What is the difference between nitrous oxide and nitric oxide?

A

Nitrous oxide is a mild analgesic (laughing gas)

Nitric oxide is a free radical

4
Q

How is nitric oxide synthesised?

A
  • complex process
  • involved large complex enzyme (nitric oxide synthase) which has oxidase and reductase domains
  • oxygen essential for synthesis so NO synthesis inhibited in hypoxic conditions
  • enzyme converts the amino acid I-arginine into citrulline
  • synthesis produces hydrogen ions so enhanced in alkali and inhibited in acid
  • I arginine + O2 -> citrulline + NO + H+ +e-
5
Q

Where is nitric oxide synthase found?

A

Brain, macrophages, vascular endothelium

6
Q

What are the different isoforms of nitric oxide synthase?

A
NOS type 1 (bNOS or nNOS)
- in central and peripheral neuronal cells
- calcium dependent
NOS type 2 (iNOS)
- most nucleated
- independent of intracellular Ca2+
- inducible in presence of inflammatory cytokines
NOS type 3 (eNOS)
- vascular endothelial cells
- calcium dependent
INOS - part of the immune system
7
Q

Which 2 forms of nitric oxide synthase are very closely related and similar?

A

eNOS and nNOS

8
Q

How is nitric oxide synthesised in the vascular endothelium?

A
  • in well oxygenated tissue main regulatory factor is flowing blood
  • moving blood flow = shear stress on endothelial wall = dislodges caveolin which sits on calcium channel to block it = calcium channel opens = Ca2+ into endothelium = calcium binds to and activates calmodulin = activates eNOS = NO synthesis
  • cofactors required: biopterinH4, flavin mononucleotide, flavin adenine dinucleotide (enzymes aiding in oxidation and reduction of nitric oxide synthase)
  • acetylcholine and other factors also activate NO synthesis by binding to acetylcholine receptors on endothelium and opening calcium channels
9
Q

How does nitric oxide cause an effect?

A

Diffuses from endothelium into SM -> activates guanylate cyclase -> this converts guanosine triphosphate to cGMP

10
Q

What is cGMP? What does it do?

A
  • cyclic guanosine monophosphate
  • like cAMP but has the opposite effect
  • makes the muscles relax
  • acts through 3 main groups of cellular targets (PKGs, PDEs and cGMP gated cation channels) causing net effect of raised cGMP to reduce calcium availability in muscle and inhibit contraction
11
Q

What are the 2 main functions of nitric oxide in the vascular system?

A

1) relaxes and dilates arteriolar SM lowering vascular resistance (balances effects of noradrenaline and angiotensin as made all the time in healthy vascular system maintaining normal blood pressure)
2) prevents unwanted intravascular coagulation
3) NO from endothelium aids in gas exchange between haemoglobin and cells, release during hypoxia, diffuses into blood and SM, in erythrocytes reacts with oxyhaemoglobin forming nitrosohaemoglobin displacing oxygen from haemoglobin improving delivery of oxygen to hypoxic tissue

12
Q

What is the role of NO in the respiratory system?

A

Relaxes bronchial SM, released in lungs

13
Q

How does blood flow change during exercise?

A

CO increases up to 17.5L/min (usually 5L/min)

  • blood flow in active muscles increases > 10 fold
  • heart blood flow 3 fold
  • kidney blood flow < nearly half
  • skin blood flow increases 4 fold
  • brain blood flow doesn’t change
14
Q

How does skeletal muscle blood flow change during exercise?

A
  • SNS produces vasoconstriction of arterioles in muscle during exercise reducing local blood flow
  • Exercising muscles vasodilate as powerful local vasodilator overcomes vasoconstrictor tone and opens up arterioles
  • this combination effectively redistributes blood to active muscles
  • power vasodilator is NO and adenosine
15
Q

What triggers vasodilation of exercising muscle?

A

Acidosis - lactic acid production as anaerobic metabolism and ATP depletion, leads to arteriole opening

16
Q

Where does extra NO come from?

A
  • released in hypoxic skeletal muscle after start of exercise
  • synthesis required by oxygen
  • constantly synthesised at low levels in resting vascular endothelium
  • NO gets converted to nitrous acid then nitrate, nitrate can then be converted back to NO in hypoxic acidic conditions
  • so NO synthesised in resting muscle when oxygen is plentiful then stored as nitrate, when muscle is active and hypoxic nitrate converted back to NO
    to dilate arterioles and increase blood flow
17
Q

How does coronary circulation change during exercise?

A

Increases 3 fold
SNS stimulation increase rate and force of contraction
Endothelium in pulmonary arterioles exposed to high PaO2 so more NO made to be stored, excess travels via pulmonary venous blood to heart to coronary arteries
- coronary arterioles particularly sensitive to NO so increased vasodilation during exercise

18
Q

How does GTN work? What is it?

A

Glycerol trinitrate (nitroglycerin)
essential drug for angina and MI treatment as dilates coronary arteries
converted to nitrate in circulation by enzymes and coronary blood vessels reducing nitrate to NO easily
- also opens collateral vessels in heart enabling blood to get to hypoxic tissue from blocked coronary artery

19
Q

What is the meaning of a deleterious effect by a vasodilator?

A

Increase size of already open blood vessels but do not affect those with atheroma blockage
NO from nitrate is opposite as opens collaterals improving perfusion of previously ischemic regions

20
Q

What is the mechanism of nitrate reduction?

A

nitrate to NO
in hypoxic and acidic conditions
HNO2 + H+ + e- -> NO + H2o + 1/2O2
facilitates by some forms of carbonic anhydrase
electron donor needed (reducing agent)
endothelial cells take up reducing agent ascorbic acid (vitamin C)

21
Q

What is persistent pulmonary hypertension of the newborn? (PPHN)

A

Following first breath, no reduction in pulmonary arterial resistance so suffer from hypoxia as lungs not perfused properly and so cannot collect oxygen
- adding NO to inspired gas improves lung function in these children, life saving

22
Q

Why is there rapid drop in pulmonary arterial resistance in a fetus’ first breath?

A

Pulmonary arterioles rich in nitric oxide synthase but requires high PO2
resting state pulmonary arterioles constricted
baby takes first breath and oxygen levels increase so mass synthesis of NO causing vasodilation so pulmonary arterial resistance drops

23
Q

How does NO explain the link between ventilation and perfusion?

A

In adults NO continually produced in healthy lung so vasodilation and low arteriole resistance
If region becomes hypoxic less NO made, vasoconstriction so less perfusion

24
Q

If CO increases 3 fold during exercise how does pulmonary blood flow increase 3 fold?

A

Pulmonary arterial pressure increases slightly but pulmonary arterial resistance decreases to allow increased flow

25
Q

What causes decrease in pulmonary arterial resistance during exercise?

A
  • distension in thin pulmonary arterial walls
  • increased flow increases NO synthesis = vasodilation
  • SNS acts on beta 2 receptors on bronchial SM so they relax and bronchial diameter reduced, this + greater TV increases oxygen conc in alveoli so more NO diffusing from endothelium into alveoli so increased bronchial SM relaxation
26
Q

What is basal release of NO?

A

From vascular endothelium in muscle even at rest
friction of blood passing over inner surface of endothelium activates NO release
helps prevent leukocytes and platelets adhering to endothelial surface

27
Q

What does NO do in the digestive system?

A

green vegetables contain nitrates and ascorbic acid
nitrates converted to nitrites by enzymes in saliva and enter stomach
acidic conditions nitrate reacts with ascorbic acid forming nitric oxide which is bactericidal and kills harmful bacteria in food
NO diffuses into capillary bed of gastric mucosa relaxing vascular SM increasing stomach blood flow and oxygen supply

28
Q

Why should green vegetables be reduced in someone who wants to prevent stomach acidity?

A

Nitrates from them provide lumen with acid, if pH too high nitrites pass through stomach into small intestine and converted to nitrosamines which are carcinogenic