Nitric Oxide Flashcards
What are 3 actions of NO?
1) relax smooth muscle
2) decrease cell adhesion
3) evoke inflammatory response
Endogenous nitric oxide is generated from the oxidation of the ___________ group of __________.
guanidine group of arginine
True or false: exposure of LPS results in generation of NO in the macrophage
TRUE
When is NO normally, physiologically released by the endothelium?
upon stimulation with Ach and carbachol
What is the role of NO in the face of injury?
counteracts vasoconstriction
What enzyme family makes NO?
nitric oxide synthase
Which form of NOS is inducible?
NOS-2
inTWOcible
What does it mean to be for NOS to be inducible?
triggered by disease (like sepsis)
NOS-2 is in macrophages and smooth muscle cells
What are the 2 endogenous, normal NOS?
NOS-1 and NOS-3
Which NOS is also called eNOS (found in the endothelial cells)?
NOS-3
3 rhymes with e
Which NOS is the neuronal NOS?
NOS-1 (brain is #1)
What is the substrate for NOS?
L-arginine
What inhibits NOS?
arginine analogues (N-monomethyl L-arginine)
How does nitroprusside differ from nitroglycerin?
nitroprusside: spontaneously generate NO
nitroglycerin: require presence of thiol compound such as cysteine
What is the mechanism of action of NO?
interacts with heme moiety of soluble guanyl cyclase in cytoplasm of cell
guanyl cyclase converts GTP to cGMP
NOS converts arginine to ______________ and NO
citrulline
Once formed, NO can do what 2 things?
nitroslyate proteins (NO is a free radical) or complex with heme of guanylyl cyclase
The most stable form of nitric oxide is _____ and it is used as a measure for how much NO is produced
NO3
What inactivates NO?
heme and free radical superoxide
How does superoxide dismutase affect the duration of NO action?
prolongs it by scavenging superoxide, NO’s inactivator
How does glutathione play a role in NO regulation?
glutathione regulates peroxynitrile which is the product of NO and superoxide
peroxynitrile complexes with sulfhydral group of many key enzymes
WANT HIGH LEVELS OF GLUTATHIONE TO MITIGATE DANGEROUS NO FORMATIONS
What are 4 ways to inhibit NO?
1) L-arginine derivatives (block formation of NO)
2) inhibitors of nitric oxide synthase
3) inhibitor of binding of arginine to NO
4) scavenger of NO
What is the danger of excess production of NO?
generation of peroxynitrite which is toxic to cells
Why are NO inhibitors important for the treatment of sepsis related disorders?
reduce formation of peroxynitrite
NO’s major effects are mediated by the activation of _______ _______ which results in the generation of _______.
guanyl cyclase resulting in the generation of cyclic GMP
In addition to activating guanylyl cyclase, NO can generate several reactive nitrogen derivatives by interacting with molecular radicals. Why are these oxides dangerous?
they are highly reactive and unstable and alter the physio disposition of cells and tissues
The beneficial effects of NO are __________________, ___________, and _______________
smooth muscle relaxation
vasodilation
immune regulation
The negative effects of NO are _____________
free radical formation, nitrosation, irritant effects
Decrease NO can result in _____________ blood pressures
elevated
What is the danger of NO interaction with sildenafil (viagra)?
viagra also increases cGMP by inhibiting phosphodiesterase (which converts cGMP to GMP) leading to massive amounts of cGMP/vasodilation
True or false: NO is a potent inhibitor of WBC adhesion to the endothelial surface?
TRUE; decreases release of adhesion molecules such as E-selectin on endothelial surface
True or false: NO can protect against ischemic and reperfusion injury
true
What are the clinical applications of NO for the respiratory system?
improves cardiopulm function for patients with pulm hypertension
What form of NO is given to patients with pulm hypertension?
INOmax
What is responsible for producing hypotension in septic shock patients?
LPS activation of iNOS-2
What reverses septic shock?
L-NMMA (NO inhibitor)
What are the dangers of too much NO?
ischemia and perfusion defects
How does atherosclerosis affect the formation of NO?
impairs it (plaques and endothelial damage block it) leading to increased cellular proliferation and exacerbating athero
How can you treat the decreased NO formation in athero patients?
L-arginine and NO donors (like nitroprusside and nitroglycerin)
What effect does NO have on platelets?
inhibitor of platelet adhesion, activation, aggregation
How can NO be used in organ transplants?
acts a cytoprotective agent to prevent cellular and platelet adhesion in new grafts (since accelerated graft atherosclerosis after transplant is a major cause of graft failure)
Why are graft patients recommended to be on dietary arginine supplements?
arg is a substrate for NOS and increases NO formation which prevents cellular adhesion and accelerated graft athero
What is the relationship between NO and the PNS?
nonadrenergic, noncholinergic neurons release NO which assists erectile responses
Viagra + NO donors is a dangerous combo because it causes massive ___________
hypotension
Which NOS is associated with acute inflammation found in IBD, arthritis, etc?
NOS-3
What are the 3 NO donor drugs?
1) nitroglycerin
2) isosorbide dinitrate
3) amyl nitrates
What is the longest acting of the NO donor drugs?
nitroglycerin (transdermal)
What is the shortest acting NO donor?
inhaled amyl nitrate
sublingual nitroglyc
isosorbide dinitrate
How does an increase in cGMP lead to vasodilation?
dephosphorylation of myosin
inhaled NO is administered mostly in the management of _______________________
primary pulm hypertension
