3. Nitric oxide in the vascular system Flashcards
Effect of nitric oxide (NO)
Makes vascular smooth muscle relax
Electronic make up of NO
- Free radical
- BUT more stable than other free radicals
- Stable free radical which neutralises other free radicals e.g. OH
Synthesis of NO
Via complicated enzyme Nitric oxide synthase - converts arginine to citrulline and NO, reaction requires O2
Different isoforms of Nitric oxide synthase (NOS)
- NOS type 1 is bNOS
- NOS type 2 is iNOS
- NOS type 3 is eNOS
NOS type 1
bNOS is found in the brain is calcium dependent
NOS type 2
Found in most nucleated cells, especially macrophages
Independent of Ca2+
Inducible in the presence of inflammatory cytokines
NOS type 3
Found in vascular endothelial cells
Are also calcium dependent (like bNOS)
Synthesis of NO in the vascular endothelium
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
“Calmodulin”
Protein that binds CA2+ and is involved in many regulatory reactions
How does the NO cause the vascular smooth muscle to relax?
The NO activates ‘guanylate cyclase’
This converts ‘guanosine triphosphate’ to ‘cyclic guanosine monophosphate’ (cGMP)
The cGMP is what makes the smooth muscle relax
Impact of NO on hypertension
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
What would be the impact of the inhibition of the eNOS system
This would cause the blood pressure to rise - increased constriction of blood vessels and so reduced local blood flow
Results in hypertension
General impact of exercise on arterioles
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
Impact of NO on exercising muscles
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
How do muscles produce the NO?
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
Conversion of nitrate to NO in hypoxic and acidic conditions
Acidic conditions causes conversion of nitrate to nitrous acid (HNO2)
Hypoxic conditions causes conversion of nitrous acid to NO (and the release of OH)
How do the arterials come out of this hypoxic condition?
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
Relate eNOS to angina
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
Other than smooth muscle, where else can NO have an impact?
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)
NO production in the lungs - link this to ventilation and perfusion
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
How is pulmonary resistance decreased during exercise?
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
What would be the impact of reduced levels of bNOS?
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)
What is the benefit of a basal release of NO from muscle vascular endothelium?
This basal release helps prevent leukocytes and platelets from adhering to the surface of the endothelium and prevents the stagnation of blood
