Nitrate-Nitrite-Nitric Oxide Flashcards
How much nitrate is generated by our body in a day
1mmol/day
What can act as a storage pool for nitric oxide
Nitrate and nitrite
What are the three isoforms of NOS
- eNOS
- iNOS
- nNOS
Describe the entero-salivary circulation of dietary nitrate
- Nitrate from diet is ingest
- Most of it it rapidly and completely absorbed by the upper GI tract
- About 25% is stored in salivary glands and secreted in the mouth
- In the tongue, nitrate is reduced to nitrite by facultative anaerobes
- Nitrite is swallowed and some of it undergoes acidic reduction in the stomach to form NO while the rest is absorbed
- About 60% of ingested nitrate is lost to urine within 48 hours
Why is arginine relevant to the synthesis of nitric oxide?
NOS relies on arginine as the nitrogen donor
How does the body get arginine?
- from diet
- synthesised endogenously from other amino acids
What lifestyle measures are usually recommended by GPs to improve BP and reduce the risk of CVD?
- weight loss
- low salt diet
- exercise
What is the difference between organic and inorganic nitrate?
organic nitrate contains carbon
Why has beetroot been used to treat angina?
because it’s a natural source of inorganic nitrate
What is nitric oxide a key regulator of?
vascular tone
What can lead to diminished nitric oxide reduction?
- hypertension
- hyperlipidemia
- type 2 diabetes
- chronic kidney disease
How is inorganic nitrate found in nature?
as a salt with potassium or sodium
What is nNOS used for?
CNS signalling
What is iNOS used for?
it’s a damage free radical, produced by WBCs and a part of the immune response
How is nitrate converted to nitrite within the body?
- through facultative anaerobes
What effect will using antibacterial mouthwash have on nitrate levels within the body?
- will increase and be secreted through urine
What is xanthine oxidoreductase?
an enzyme that reduces nitrite into nitric oxide
How is nitric oxide produced
- oxidation of L-arginine by NOS
What is the bioavailability of nitrate?
almost 100%
Can nitrite be reduced to nitric oxide by the stomach?
yes as it undergoes acid reduction in the stomach
What are the local effects of nitric oxide in the stomach?
- keeps the mucus layer thick
- increases gastric blood flow
What are the different routes of nitrite reduction into nitric oxide?
- acid catalysed
- xanthine oxidoreductase
- deoxyhaemoglobin and other haem proteins
- NOS
When are the systems of nitrite reduction to nitric oxide of most benefit?
during hypoxia or acidosis
eg. during heart attack or stroke
What effect does nitric oxide have on blood vessels?
relaxes them to stabilise blood flow
What does nitric oxide synthesis rely on?
oxygen and arginine (nitrogen donor)
When is deoxyhemoglobin more commonly found?
hypoxia
Which are higher; arterial nitrate levels or venous nitrate levels?
arterial
What is vitamin D important for?
bone and vascular health
What is vitamin D associated with?
frailty and mortality
What affect can UV have on the nitrate levels in the body?
UV light can liberate nitrates from stores in the skin
What are nitrosothiols?
storage molecules that can give up NO in certain conditions
What mechanisms can impair bioavailability?
- oxidative stress
- substrate/cofactor availability
- retention by altered haemoglobin
- increased expression of intracellular eNOS inhibitors
- increased inhibitors of NOS
What is the role of nitric oxide in vascular control
- vasodilation
- reduces release of superoxide radicals
What are the substrates and cofactors in nitric oxide synthesis?
arginine and oxygen
How does altered haemoglobin retain nitric oxide?
Glycated haemoglobin retains more nitric oxide
What effect does inorganic nitrate have on blood circulation?
vasodilation
What can organic nitrates be used to treat?
- angina
- heart attack
- heart failure
Name some benefits of NO donor drugs
- lower systematic BP
- rapid onset
- inhibit platelet aggregation
Name some limitations of NO donor drugs
- can lead to endothelial dysfunction
- extensive first pass metabolism (so concentration is greatly reduced)
- susceptible to developing tolerance (need a reset period)
- very high variability
- unsure of specific mechanism by which NO3 => NO2
What are the roles that NO plays in vascular health
- vasodilator
- protects against IR injury
- anti-thrombotic
- anti-inflammatory
- reduces BP
- inhibits platelet aggregation
what are defects in bioavailaibility and endogenous synthesis of NO linked to
metabolic and cardiovascular disease
What can excess NO result in
free radical formation
Describe the NO signalling pathway
- endothelial cells in the lumen of the vasculature express eNOS
- eNOS produces NO
- NO diffuses from endothelial cells into the smooth muscle cells and activates sGC
- sGC converts GTP into cGMP
- cGMP binds to L-type Ca channels and leads to:
- decreased Ca
- decreased MLCK activation
- smooth muscle relaxation
- vasodilation
Name the 2 major sources of nitrates in mammals
- from diet
- endogenous synthesis of nitrates into NO
Name a major source of dietary nitrates
green leafy vegetables and beetroot
Name some benefits of inorganic nitrates
- lowers BP
- protects from reperfusion injury
- enhances athletic performance due to improved oxygen efficiency because of improved mitochondrial function
- protects against metabolic syndromes (mice without NO3 gained weight and developed arthiritis which was cured by nitrate supplementation)
Name some harms of inorganic nitrates
- has been linked to cancer (mice fed high doses of nitrates develop lymphoma)
- can cause blue baby syndrome due to methemoglobinemia (adults have enzyme that converts Fe3+ back to Fe2+ while babies don’t)
What is methemoglobinemia
- a disorder caused by the conversion of haemoglobin to methhaemoglobin (which has decreased deficiency for oxygen)
How do NO donor drugs work
stabilise NO radical until necessary
Name some common organic nitrates used
- Nitroglycerin (acute pain relief in angina)
- ISMN (chronic pain relief in angina, slow release)
- SNP (rapidly lower BP in hypertensive crisis, cyanide groups can be associated with cyanidosis)
