Nitric oxide in the vascular system

Question 1

How is nitric oxide synthesised in the vascular endothelium?

Answer 1

• The main regulatory factor = flowing blood
• Shear stress causes the opening of Ca2+ channels
• Ca2+ moves into the endothelium
• Ca2+ bind to calmodulin
• eNOS is activated
• cofactors (biopterin H4, flavin mononucleotide, flavin adenine dinucleotide) aid oxidation and reduction reactions
• acetylcholine in plasma can also activate NO synthesis (open Ca2+ channels)

Question 2

What does nitric oxide do once produced?

Answer 2

• once synthesised, NO diffuses from the endothelium to the smooth muscle
• there it activates guanylate cyclase
• guanylate cyclase converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP)
• cGMP makes muscle relax; it acts through 3 main groups:
  1. cGMP protein kinase: regulate Ca2+ homeostasis and Ca2+ sensitivity of cellular proteins
  2. cGMP cation channels
  3. Phosphodiesterases
• increased cGMP = reduced Ca2+ availability = reduced muscle contraction and increased muscle relaxation

Question 3

What is the main role of NO?

Answer 3

2 main functions:

1. relax and dilate arteriolar smooth muscle = reduced SVR (prevent HTN)
2. prevent unwanted intravascular coagulation (DVT/VTE) –> relax bronchial muscle, balance effects of noradrenaline and angiotensin

• also aids gas exchange
• -> hypoxia = NO released and reacts with oxyhaemoglbin to form nitrosohaemoglobin
• this displaces O2, impairing delivery to tissues

Question 4

How is nitric oxide stored?

Answer 4

NO is a gas = cannot be stored in cells
- after reacting with guanylate cyclase it is though to be converted into nitrous acid and then to nitrite

*nitrite is converted back to NO (via carbonic acid) in hypoxic and acidic conditions

Question 5

How does NO level change during exercise? What is the effect of NO during exercise?

Answer 5

coronary circulation increases ~3 times in exercise –> stimulation via SNS increases the rate and force of contraction

during exercise there is an increase in NO
NO travels to the heart
Increases vasodilation to match the increased workload
results in increased vasodilation and increased ventilation of lungs

eNOS in pulmonary endothelium is very sensitive to ppO2 –> when ppO2 increases, NO production increases

Question 6

How can NO be used to treat babies with pulmonary hypertension of the newborn (PPHN)?

Answer 6

It is thought that there is NOS in the lungs and will only become activated when first breath at birth is taken

In PPHN, this may mean that NOS is not activated
Therefore by administering NO for a couple of weeks, it can enhance the innate NOS

Question 7

What is the effect of NO synthesis on pulmonary resistance?

Answer 7

reduced resistance