4 - overview of nitrate-nitrite-nitric oxide system Flashcards
high BP increases risk of which types of disease
cardiovascular
examples of reasons why people wouldn’t want to take medication
unnatural
unhealthy
lifestyle recommendations to decrease BP
eat less salt
increase exercise
why is beetroot juice recommended to lower blood pressure
source of inorganic nitrate
function of nitric oxide n cardiovascular system
main regulator of vascular tone lowers BP relaxes vascular smooth muscles dilates blood vessels inhibits aggregation of platelets to prevent thrombosis
when do blood vessels reduce their nitric oxide production
during cv disease states
how is nitrate produced in the body
oxidation of nitric oxide from L-arginine NOS pathway
what is the by-product of nitric oxide oxidation
free radical
how much inorganic nitrate is consumed in the typical western diet per day
1-2 mmmol
mainly from green, leafy vegetables
what is NO2-
nitrite
what is the symbol for nitrate
NO3-
why is nitrite concentration higher in saliva than plasma
nitric oxide is concentrated in the salivary gland
how do you convert nitrate or nitrite back to nitric oxide
reduction reaction
they gain oxygen
where is nitrite reduced to nitric oxide in the body
catalysed by acidic environments e.g. the stomach
why is nitric oxide important in the stomach
increases gastric blood flow
increases mucosal covering
reacts with food
gets absorbed into the bloodstream
which enzymes catalyses reduction of nitrite to NO
xanthine oxidoreductase
which enzyme catalyses production of nitric oxide from L-arginine
nitric oxide synthase
why do blood vessels need nitric oxide
needed to keep blood vessels relaxed and keep blood flow going
how do strokes effect NO
they can prevent nitric oxide synthesis
S-Nitrosothiol
R-SNO
formed when nitrite interacts with other molecules (such as sulfur atom of a thiol) to products alternative products to NO
why does nitric oxide need to be stored in the body in other forms
nitric oxide is an unstable free radical
has a very short half life
rapidly oxidises to nitrite
why is nitric oxide known as a free radical
it contains unpaired electrons
other bodily functions of nitric oxide
increases cerebral blood flow (oxygen to the brain)
important for penile erection
dilates blood vessels –> increases blood flow to the kidney
dilates pulmonary vessels
role of NO in immunity
Modulates T cell-mediated immune response
why might bioavailability of NO be impaired
oxidative stress –> over-production of free radicals
low co-factor availability (low arginine)
retention by altered haemaglobin –>glycated haemaglobin holds onto NO and doesnt release it correctly
what are the 3 forms of nitric oxide synthase
endothelial NOS (eNOS) neuronal NOS (nNOS) inducible NOS (iNOS)
which NOS forms are constitutive
eNOS
nNOS
which forms of NOS have steady levels in th body
nNOS
eNOS
where are eNOS and nNOS found in the body?
endothelial cells, neurons, skeletal muscles, epithelial cells and many other tissues.
how is iNOS induced?
by specific cytokines
often in response to inflammatory conditions
product of nitrite oxidation with oxyhaemaglobin
nitrate
product of nitric oxide directly reacting with oxyhaemaglobin
methhaemaglobin and nitrate
most common nitrosylated product in plasma.
R-SNO
why is production of S-nitrosothiols common
nitric oxide has a high affinity for sulfhydryl groups (thiols)
what is the main storage form of nitric oxide
nitrate (most stable)
role of caveolin-1
modulates NO production
how is cGMP produced
when nitric oxide activates smooth muscle soluble guanylyl cyclase (GC)
how does cGMP effect smooth muscles
Increased intracellular cGMP inhibits calcium entry into the cell
–> decreased intracellular calcium concentration
activation of myosin light chain kinase
both causes smooth muscle relaxation
when is caveolin-1 concentration increased
in cv disease states
which type of blood vessel does nitric oxide effect the most
affects veins more than arteries
80% of blood is found in veins so dilation of veins has bigger effect
where is NO produced
vascular endothelium
which types of NOS are calcium dependent
constitutive NOS (cNOS) (eNOS and nNOS)
2 mechanisms to stimulate NO production
flow-dependent formation
- increase in blood flow stimulates release of Ca2+ and activates cNOS
receptor-stimulated formation
- ligands bind to endothelial receptors stimulating Ca2+ release
2nd messenger in vasodilation
cyclic GMP
- inhibits Ca2+ entry/activates K+ channels –> hyperpolarisation
- activates myosin light chain phosphotase
definition of bioavailabilty
the rate at which molecules enter the systemic circulation and can therefore access the site of action
mechanism of cav-1
intracellular eNOS inhibitor
binds to eNOS and prevents binding of Ca2+ or CM
anchors eNOS in the membrane
reduces its ability to generate NO
bioavailability of orally ingested nitrates
almost 100%
absorbed in the upper GI tract rapidly
bypassed first-pass metabolism in the liver
how does NOS contribute to oxidative stress in mitochondria
NO binds to COX enzyme (competes with oxygen)
results in partial inhibition of mitochondrial respiration
effect of hypoxia
increased conversion of nitrite to nitric oxide (instead of nitrite to nitrate)
dilatory effect enhanced
BH4
co-factor
involved with all 3 NOS isoforms
reduces the haem iron of the enzyme to ultimately form an iron-oxy species that hydroxylates L-arginine to produce NO
effect of increased expression of intracellular inhibitors of eNOS (Caveolin-1)
reduces bioavailability of NO
what % of ingested inorganic nitrates is excreted in urine
60%
what is sGC
soluble Guanylyl-cyclase
role of facultative anaerobes after inorganic nitrates have been ingested
reduce NO3- to NO2- on the surface of the tongue
before NO2- is swallowed
