Nitric oxide and the vascular system Flashcards
What are the biologically important compounds of nitrogen and oxygen?
- nitric oxide (NO) and nitrous acid (nitrate)
What is Entonox?
A mix of 50% NO and 50% oxygen
- medical anaesthesia gas
- in pre-hospital care and childbirth and emergency medicine
- stable and unreactive
What is the difference between nitrous oxide and nitric oxide?
Nitrous oxide is a mild analgesic (laughing gas)
Nitric oxide is a free radical
How is nitric oxide synthesised?
- 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-
Where is nitric oxide synthase found?
Brain, macrophages, vascular endothelium
What are the different isoforms of nitric oxide synthase?
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
Which 2 forms of nitric oxide synthase are very closely related and similar?
eNOS and nNOS
How is nitric oxide synthesised in the vascular endothelium?
- 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
How does nitric oxide cause an effect?
Diffuses from endothelium into SM -> activates guanylate cyclase -> this converts guanosine triphosphate to cGMP
What is cGMP? What does it do?
- 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
What are the 2 main functions of nitric oxide in the vascular system?
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
What is the role of NO in the respiratory system?
Relaxes bronchial SM, released in lungs
How does blood flow change during exercise?
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
How does skeletal muscle blood flow change during exercise?
- 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
What triggers vasodilation of exercising muscle?
Acidosis - lactic acid production as anaerobic metabolism and ATP depletion, leads to arteriole opening
