3. Nitric oxide in the vascular system

Question 1

Effect of nitric oxide (NO)

Answer 1

Makes vascular smooth muscle relax

Question 2

Electronic make up of NO

Answer 2

• Free radical
• BUT more stable than other free radicals
• Stable free radical which neutralises other free radicals e.g. OH

Question 3

Synthesis of NO

Answer 3

Via complicated enzyme Nitric oxide synthase - converts arginine to citrulline and NO, reaction requires O2

Question 4

Different isoforms of Nitric oxide synthase (NOS)

Answer 4

• NOS type 1 is bNOS
• NOS type 2 is iNOS
• NOS type 3 is eNOS

Question 5

NOS type 1

Answer 5

bNOS is found in the brain is calcium dependent

Question 6

NOS type 2

Answer 6

Found in most nucleated cells, especially macrophages
Independent of Ca2+
Inducible in the presence of inflammatory cytokines

Question 7

NOS type 3

Answer 7

Found in vascular endothelial cells

Are also calcium dependent (like bNOS)

Question 8

Synthesis of NO in the vascular endothelium

Answer 8

Via the physical movement of blood agains the endothelial wall -
Activation of proteins that are sticking into the vessel
- attached to the vesssel wall
These proteins are calcium channels or can also be ACh receptors - ACh can activate this
This movement of blood allows the calcium to enter the endothelial cells and allows for a basal release of NO

Question 9

“Calmodulin”

Answer 9

Protein that binds CA2+ and is involved in many regulatory reactions

Question 10

How does the NO cause the vascular smooth muscle to relax?

Answer 10

The NO activates ‘guanylate cyclase’
This converts ‘guanosine triphosphate’ to ‘cyclic guanosine monophosphate’ (cGMP)
The cGMP is what makes the smooth muscle relax

Question 11

Impact of NO on hypertension

Answer 11

Relaxation of the vascular endothelium causes a dilation of smooth muscle and so the blood vessel also dilates
This increases local blood flow and so reduces the local blood pressure

Question 12

What would be the impact of the inhibition of the eNOS system

Answer 12

This would cause the blood pressure to rise - increased constriction of blood vessels and so reduced local blood flow
Results in hypertension

Question 13

General impact of exercise on arterioles

Answer 13

Exercise causes the activation of the sympathetic NS via alpha-1 receptors
This causes the vasoconstriction of arterioles

The actively exercising muscles then release local chemical factors to cause a local vadodilation

Question 14

Impact of NO on exercising muscles

Answer 14

The actively exercising muscles then release local chemical factors to cause a local vadodilation

These are believed to be NO and adenosine

This then overcomes the sympathetic vasoconstriction and hence increases the blood flow

Question 15

How do muscles produce the NO?

Answer 15

Contain O2 which can be used to produce NO BUT this is readily used up

Muscles contain a store of nitrate to allow for the production of NO in the hypoxic condition

The hypoxia results in a shift towards anaerobic metabolism and lactate production which causes a lowered pH

These acidic and hypoxic conditions allow for the conversion of nitrate to NO

Question 16

Conversion of nitrate to NO in hypoxic and acidic conditions

Answer 16

Acidic conditions causes conversion of nitrate to nitrous acid (HNO2)

Hypoxic conditions causes conversion of nitrous acid to NO (and the release of OH)

Question 17

How do the arterials come out of this hypoxic condition?

Answer 17

This production of NO then causes the arterioles to dilate and increases local blood flow

This then causes more oxygen to pass and diffuse through and the hypoxic state is abolished

Question 18

Relate eNOS to angina

Answer 18

Where arteries are damaged or lined with atheromatous deposits, eNOS activity is reduced

If eNOS activity is reduced in the heart, then the vessels cannot dilate enough during exercise and the heart becomes iscaemic/hypoxic - results in acidosis and angina pain

Question 19

Other than smooth muscle, where else can NO have an impact?

Answer 19

NO can also diffuse into the blood rather than into the smooth muscle

Displaces O2 from haemoglobin and so increases the delivery of O2 into hypoxic tissue

(Reacts with oxyhaemoglobin to form nitrosohaemoglobin which displaces the O2)

Question 20

NO production in the lungs - link this to ventilation and perfusion

Answer 20

Pulmonary arterioles are rich in NOS

NO is continually produced in the healthy lung BUT this production is reduced if the lung region becomes hypoxic

In hypoxia, the arterioles constrict (no NO produced) so perfusion is reduced

SO reduced ventilation results in reduced perfusion of blood

Question 21

How is pulmonary resistance decreased during exercise?

Answer 21

The sympathetic NS acts on B2 receptors on the bronchial smooth muscle to cause them to relax and increase the bronchial lumen diameter

This then increases the O2 concentration in the alveoli and causes an increased production of NO and hence causes dilation of smooth muscle and a decreased pulmonary resistance

Question 22

What would be the impact of reduced levels of bNOS?

Answer 22

This would result in reduced cerebral blood flow

Can lead to reversible (brain blood flow falls to about half of normal) or permanent brain damage (blood flow falls lower than quarter of normal)

Question 23

What is the benefit of a basal release of NO from muscle vascular endothelium?

Answer 23

This basal release helps prevent leukocytes and platelets from adhering to the surface of the endothelium and prevents the stagnation of blood