Nitric Oxide in the Vascular System

Question 1

What type of molecule is nitric oxide?

Answer 1

A free radical (there is an unpaired electron on the outside of the molecule)

Question 2

What are free radicals? Give an example.

Answer 2

Molecules with an unpaired electron which therefore seek another electron from another molecule so that they can combine to form a more stable compound, and are therefore oxidising agents. Superoxide (O2-) is a free radical found in the body

Question 3

How many forms of nitric oxide synthase are there?

Answer 3

Three, NOS type I, II and III

Question 4

Describe the location and action of nitric oxide type I

Answer 4

NOS type I is found in the brain and is present in the central and peripheral neuronal cells. This type of NOS is calcium-dependent

Question 5

Describe the location and action of nitric oxide type II

Answer 5

NOS type II is also known as inducible NOS (iNOS) as it is found in macrophages and can be induced by the presence of inflammatory cytokines and action is independent of calcium levels.

Question 6

Describe the location and action of nitric oxide type III

Answer 6

NOS type III is found in the vascular endothelium and it is calcium-dependent

Question 7

Which nitric oxide synthase enzymes are calcium-dependent?

Answer 7

NOS I and NOS III, but NOS II is calcium-independent

Question 8

Explain the process of nitric oxide synthesis

Answer 8

In endothelial cells, the ‘shear stress’ caused by blood flow causes calcium channels to open so Ca2+ enters the endothelial cell. This calcium influx activates calmodulin which then activates the eNOS (within the presence of many cofactors) which then converts L-arginine into nitric oxide and citrulline.

Question 9

Explain how nitric oxide can lead to vasodilation

Answer 9

After nitric oxide has been produced in the endothelial cell it diffuses into the smooth muscle of the tunica media of the blood vessel where it activates guanylate cyclase (GC) which then converts GTP into cGMP which then acts directly to relax the vascular smooth muscle

Question 10

Outline the vascular actions of endothelial nitric oxide

Answer 10

Direct vasodilation, anti-thrombotic effect as it inhibits platelet adhesion to endothelium, anti-inflammatory effect as it inhibits leukocyte adhesion to the endothelium and anti-proliferative effect as it inhibits smooth muscle hyperplasia

Question 11

Explain why resting blood pressure would rise if eNOS was inhibited in the whole body

Answer 11

NO synthesis balances the vasoconstrictor effects of noradrenaline and angiotensin on the blood vessels in order to maintain a healthy bP

Question 12

How is nitric oxide involved in increasing coronary collateral circulation?

Answer 12

Nitric oxide increases coronary blood flow by opening up collaterals in the coronary circulation which acts to supplement the endogenous NO release and bypass arteries that are stenosed by atheromatous plaques

Question 13

How does nitric oxide aid in oxygen delivery?

Answer 13

Nitric oxide that is released from vascular endothelium can also diffuse into the blood (as well as smooth muscle), and in the RBC it reacts with oxyhaemoglobin to form nitroshaemoglobin which displaces the oxygen from the haemoglobin in the RBC and therefore makes it readily available to diffuse into the tissues. (oxyhaemoglobin + NO oxygen + nitroshaemoglobin)

Question 14

Explain how nitric oxide is involved in ‘blood shunting’ during exercise

Answer 14

During exercise, the sympathetic nervous system produces a general vasoconstriction of the arterioles in muscles during exercise (mediated by alpha-1 receptors). This tends to reduce local muscle blood flow. However, the muscles which are activity exercising/respiring will release powerful local chemical factors such as nitric oxide and adenosine, which counteract the sympathetic tonal vasoconstriction and instead lead to a local vasodilation.

Question 15

How is nitric oxide synthesised at the beginning of exercise when oxygen levels are depleted?

Answer 15

Normal synthesis of NO cannot occur due to hypoxia (as oxygen stores become depleted quickly) and therefore muscles contain a store of nitrite (NO2-) which becomes nitrous acid due to anaerobic respiration (lactate production) and then the nitrous acid is converted to nitrous acid by combining the acid with an electron from ascorbic acid; this NO will hen diffuse into the smooth muscle of the tunica media and cause activation of GC –> GTP to cGMP –> vasodilation

Question 16

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

Answer 16

This is a condition whereby a new-born doesn’t experience a reduction in the pulmonary arterial resistance following the first breath and as a result they suffer from hypoxia as their lungs aren’t properly perfused and therefore they cannot collect oxygen

Question 17

How may persistent pulmonary hypertension of the newborn (PPHN) be treated?

Answer 17

Adding nitric oxide to the inspired gas given dramatically improves the lung function in these children and can be life-saving

Question 18

How is nitric oxide involved in shunting away from poorly perfused regions of lung?

Answer 18

In adults, nitric oxide is continuously produced in the healthy lung in order to maintain a low resistance in the pulmonary arterioles, however, if a lung region becomes hypoxic, nitric oxide production is reduced and therefore the arteriole constricts. Therefore, if ventilation (pressure of oxygen) is low, then hypoxic vasoconstriction will occur due to the reduced synthesis of nitric oxide.

Question 19

Explain how nitric oxide is involved in the reduction of pulmonary arterial resistance during exercise

Answer 19

• During exercise the sympathetic nervous system acts on beta-2 receptors on the bronchial smooth muscle to relax them and increase bronchial diameter, and therefore this increased diameter alongside a greater tidal volume leads to an increased oxygen concentration in the alveoli
• The eNOS in the pulmonary endothelium is sensitive to the oxygen partial pressure and therefore when it rises, so does the production of nitric oxide
• The drop in pulmonary resistance during exercise is therefore mainly due to an increased pulmonary synthesis of nitric oxide

Question 20

What factors slow cerebral blood flow?

Answer 20

Alkalosis and inhibition of bNOS

Question 21

What factors promote cerebral blood flow?

Answer 21

Brain pH acidosis and increased local neuronal activity

Question 22

Outline the role of iNOS in the bacterial response

Answer 22

iNOS is produced in monocytes/macrophages when fighting infections, and is induced by the presence of bacteria or bacterial toxins in the body. The nitric oxide produced is used as a bactericidal weapon as the released NO can diffuse into trapped bacteria and trigger toxic free radical formation to destroy the bacteria