nitric oxide Flashcards
is nitrous oxide a free radical?
no
stable and unreactive
what is nitric oxide?
mild analgesic and a free radical
what is a free radical?
compound with an unpaired electron
what is entonox and what is it made of?
medical anaesthesia gas
50% nitrous oxide and 50% oxygen
when is entonox used?
pre-hospital care, childbirth and emergency medicine situations
what enzyme is used to make nitric oxide?
nitric oxide synthase (NOS)
what does nitric oxide synthase do?
NOS converts amino acid I-arginine into citrulline
what condition enhances and inhibits nitric oxide synthase and why?
Reaction makes H+ - enhanced in alkali conditions and inhibited in acidic conditions
where is NOS found?
in the brain, macrophage and vascular endothelium
what are the isoforms of NOS?
NOS type 1
NOS type 2
NOS type 3
what are other names for NOS type 1?
bNOS
nNOS
where is NOS type 1 found and what does it depend on?
o Central and peripheral neuronal cells
o Calcium dependent
where is NOS type 2 found and what does it depend on?
o Most nucleated cells, particularly macrophages – part of the immune system
o Independent of intracellular Ca+2
o Inducible in presence of inflammatory cytokines
where is NOS type 3 found and what does it depend on?
o Vascular endothelial cells
o Calcium dependent
what is another name for NOS type 2?
iNOS
what is another name for NOS type 3?
eNOS
what is the main regulatory factor in endothelial NO synthesis?
flowing blood
how does flowing blood activate eNOS?
- Moving blood causes friction (stress) on the endothelial wall – opens Ca2+ channels (maybe by moving a molecule that sits loosely in the Ca2+ channel – called caveolin)
- Calcium moves into endothelium, binds + activates calmodulin which activates eNOS
name cofactors that help in the oxidation and reduction reactions in NOS?
eg biopterinH4, Flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD)
how can ACh activate NO synthesis?
Ach (& other factors) in the plasma can also activate NO synthesis by binding Ach receptors or endothelium and opening Ca2+ channels
once nitric oxide is activated in the vascular endothelium, what does it do?
- Nitric oxide diffuses from the endothelium into the surrounding smooth muscle – activates guanylate cyclase
- Converts guanosine triphosphate to cyclic guanosine monophosphate cGMP (makes muscles relax)
what are main groups of cellular targets for cGMP?
o cGMP-dependent protein kinases (PKGs) o cGMP-gated cation channels o Phosphodiesterates (PDE)s.
what do proteins modified by PKG normally do?
commonly regulate calcium homeostasis and calcium sensitivity of cellular proteins
what is the net effect of raised cGMP?
reduce calcium availability in muscles –> inhibit contraction
what are the 2 main functions of nitric oxide in the vascular system?
1) NO relaxes and dilates arteriolar smooth muscle - lowers vascular resistance (and prevents hypertension) - maintains low PVR and normal BP
2) NO prevents unwanted intravascular coagulation (eg a DVT/VTE)
what is the effect of NO in the lungs?
relaxes bronchial smooth muscle
how can NO help in gas exchange?
- NO released from vascular endothelium during local hypoxia
- Diffuses into the blood and smooth muscle
- In RBCs it reacts with oxyhaemoglobin to form nitrosohaemoglobin – displaces O2 from Hb improves delivery of O2 to hypoxic tissue
how does blood flow to different organs in the body change during exercise?
- Blood flow in active muscles increases over TEN FOLD
- Heart blood flow increases THREE FOLD
- Kidney blood flow DECREASES by nearly half
- Skin blood flow increases nearly four-fold
- Brain blood flow does not change
how does the SNS reduce local muscle blood flow?
SNS produces general vasoconstriction of arterioles in muscle during exercise mediated by alpha-1 receptors
how does redistribution of blood occur during exercise?
• Vasodilation in active muscle and vasoconstriction in inactive skeletal muscle = effective redistribution to active muscles
what effect does acidosis have on exercising muscle and how?
- Acidosis triggers vasodilation in exercising muscle
- Lactic acid is created in exercising muscle caused by decrease in ATP and a shift to anaerobic metabolism –> local acidity for local vasodilation
- Closed arterioles in the muscle open up
which is more important in producing vasodilation in hypoxic muscle; NO or adenosine?
NO
what happens to NO once it reacts with guanylate cyclase in the muscle?
converted to nitroud acid which is then converted to nitrite
when can nitrite be converted back to NO?
in hypoxic and acid conditions
where is nitrite stored and why?
Endothelium of the arterioles stores nitrite for when hypoxia occurs
what happens to NO in resting and active muscle and why?
- NO synthesised in resting muscle when there’s plenty of O2 and stored as nitrite
- Active muscle: O2 usage > supply, nitrite is converted back to NO to dilate local arterioles and increase local blood flow
why does exercise vasodilation occur?
bc of increased NO in pulmonary venous blood
why does the pulmonary arteriole endothelium continuously make NO?
constantly exposed to PaO2
what is nitroglycerin (GTN)?
drug to treat angina and MIs
what is the effect of nitroglycerin?
• Dilates coronary arteries and opens collateral vessels in the heart so blood can get to hypoxic tissue downstream from a blocked coronary artery
how does GTN work?
• GTN is converted to nitrite by mitochondrial enzymes (e.g. mitochondrial aldehyde dehydrogenase) then some mechanism converts nitrite to NO
why do some vasodilators like dipyridamole have a negative effect in ischaemic hearts?
bc they increase already open BV size and don’t affect those with an atheroma blockage
Shunts blood away from infarcted regions
what is the equation for nitrite to NO?
HNO2 + H+ + e- NO + H2O + ½ [O2]
what is needed for the forward reaction of nitrite to NO?
enzyme reducing agent (electron donor) e.g. ascorbic acid (vitamin C)
why do some newborns suffer from hypoxia?
reduction in pulmonary arterial resistance following first breath doesn’t happen suffer from hypoxia bc inadequate lung perfusion
how are babies with persistent pulmonary hypertension of the newborn treated?
Adding NO to inspired gas dramatically improves the lung function in these children – life saving in some cases
why is there a drop in pulmonary arterial resistance when babies take their first breath?
- Pulmonary arterioles are rich in NO synthase, but synthesis needs high PO2
- When the baby takes their first breath, O2 levels in the lungs rises and triggers massive + rapid synthesis of NO relaxation of vascular smooth muscle vasodilation drop in pulmonary arterial resistance
how do adults maintain low resistance in the arterioles?
NO is constantly produced in healthy adult lungs
why do arterioles constrict in hypoxia?
NO production is reduced
what changes happen to pulm arterial pressure and pulm arterial resistance during exercise and why?
• Pulmonary arterial pressure increases only slightly
• Pulmonary arterial resistance decreases to allow the increased flow
occurs bc all CO passes through the lungs and CO increases 3 fold during exercise
why is there decreased pulmonary arterial resistance during exercise?
- thin pulmonary arterial walls can stretch easily
- increased blood flow in the artrioles increases NO synthesis –> vasodilation = lower resistance
- SNS acts on beta-2 receptors on bronchial smooth muscle to relax them and increase bronchial diameter. This + increased tidal volume = increased O2 conc in the alveoli
how does nitric oxide help anticoagulation?
Basal release of NO helps prevent leukocytes and platelets from adhering to the endothelium surface
why are green vegetables and beetroot good for you?
contains nitrates and ascorbic acid
how is nitric oxide made in the stomach?
- Nitrates nitrites by enzymes in saliva and nitrites enter the stomach
- In acidic stomach conditions, nitrite + acid = nitric oxide
what properties does NO have in strongly acidic conditions?
bactericidal - helps kill harmful bacteria in the stomach
what happens to nitrites if the stomach pH is too high?
nitrites can pass through the stomach into the small intestine where they’re converted to nitrosamines (carcinogenic)
