4 - nitric oxide system (disease and therapeutics) Flashcards
why might we have excess nitric oxide
septic and cardiogenic shock
- cause hypotension (NO lowers BP)
dermatological conditions such as psoriasis
- NO is a vasodilator and causes the redness on the skin
neurologies e.g. migraines
- NO increases cerebral blood flow
cancer
- promotes tumour growth by increasing blood supply
important of NOS inhibitor if patient is in shock
shock causes hypotension
NOS inhibitors would revert this
and increase blood pressure of patient
side effects of nitric oxide inhibition therapies
damaging to those with cv diseases
role of NO during ischemic events
NO is cardio-protective
provides increased blood/oxygen supply
causes vasodilation
role of NO inhibitors in chronic kidney disease
causes vasoconstriction
increase in blood pressure
endothelial dysfunction
2 endogenous NOS inhibitors
ADMA
L-NMMA
ADMA
endogenous non-competitive NOS inhibitor
potent
example of NO scavenger
haemaglobin
conditions associated with NO deficiency
hypertension
congenital abnormalities, including achalasia cardia, hypertrophic pyloric stenosis, and Hirschsprung disease
Chronic kidney disease
insufficient nitric oxide in the skin can cause….
psoriasis
by promoting cell proliferation and reducing differentiation of skin cells.
how is nitric oxide related to diabetes
pancreatic beta cells produce NO which may cause apoptosis
damage to beta cells is a cause of type 1 diabetes.
what are organic nitrates used to treat
heart failure (myocardial infarction) angina
what are nitrodilators
drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues
how do nitrodilators work
NO produced acts directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelial-independent vasodilators.
how are inorganic nitrate drugs taken
orally –> under the tongue
disadvantage to inorganic nitrate drugs
tolerance builds up after frequent use which reduces efficacy
need period of time not exposed to drug so nitrate can be liberated
endothelial dysfunction caused
outline experiment showing effect of oral nitrate on plasma nitrite and BP
control vs beetroot juice
oral nitrate decreases systolic BP
changes mirrored in plasma nitrite
reasons why inorganic nitrate supplementation could be useful?
1 - decreases BP
2 - protects against IR (ischemia reperfusion) injury
3 - improves ability to exercise
4 - protects against metabolic syndrome
how does NO effect ability to exercise
reduces amount of O2 needed per workload
increases endurance and efficiency of O2 use
haemoglobinemia
excess of heamoglobin in the blood plasma
what is the DASH diet
low salt diet
reduce dairy and fats
increase fruit and veg intake
try and eat 20mmol nitrate per day to reduce BP
blue babies
caused by methaemoglobinemia
excess NO oxidises haemoglobin to methaemoglobin
babies do not have methaemaglobin reductase so oxygen is not released to tissues
met-haemoglobin reductase
reduces methaemaglobin to haemaglobin so oxygen can be released
not found in infants
nitric oxide affect on haemaglobin
oxides Fe2+ to Fe3+
high affinity for oxygen
low carrying capacity –> does not release in tissues
disadvatnages to supplementing water supply with nitrates
can cause methaemoglobinema –> blue babies who cannot deliver oxygen to tissues
why do babies growing up on rural/agricultural land suffer from blue baby sydrome
bacterial contamination of the water converts nitrates (safe) from fertilizers into nitrites (unsafe)
why do NO drugs need a higher dose to cause arteriolar dilation
NO has less effect on arteries than veins
differences between organic and inorganic nitrates
bacteria and the body process them differently
nitric oxide donor therapeutics
attach drugs to NSAIDs (e..g ibruprofen)
what kind of bacteria convert nitrate to nitrite
facultative anaerobes
why are NOS enzymes unusual
they require co-factors
e.g. FAD, BH4
2 examples of co-factors in NOS signalling pathway
FAD
BH4
FMN
NADPH
why is iNOS calcium insensitive
binds tightly to calmodulin
cGMP
cyclic GMP
inhibits Ca2+ influx into the cell –> smooth muscle relaxation
nitrate/nitrite concentrations in people with cv risk factors
low plasma nitrite (NO2-)
high plasma nitrate (NO3-)
mechanism behind viagra
viagra inhibits breakdown of cGMP
therefore NO-mediated vasodilation is enhances
more blood flow can reach penis
treats erectile dysfunction
effect of superoxide anion
reduces bioavailability of NO
has higher affinty for NO
nitroglycerin
nitrate drug taken to reduce angina (chest pain)
delivery of nitroglycerin
tablet
spray
patch
nitroglycerin mechanism
converted to NO in the body
acts as a vasodilator
give two examples of nitrate vasodilators
Glyceryl trinitrate (nitroglycerin) isosorbide mononitrate
what causes decreased bioavailability of NO in cv disease
endothelial dysfunction
