Nitric Oxide Flashcards
Actions of NO
Smooth muscle relaxation/vasodilation
Decreased cell adhesion
Inflammatory response
Generation of endogenous NO
Oxidation of guanidine group of arginine
Can be generated in macrophages (in response to bacteria)
Vascular enodthelium release vasodilatory EDRF (aka NO)
Synthesis of NO
Created by NO synthase
Three isoforms of these enzymes
Some drugs have NO in the molecule, these are known as NO donors
Isoforms of NO
Neuronal NOS (NOS1) Inducible NOS (NOS2) Endothelial NOS (NOS3)
Neuronal NOS
nNOS
NOS1
Neuronal epithelia cells
Constitutive
Requires Ca
Inducible NOS
iNOS
NOS2
Macrophages, SMC
TRANSCRIPTIONAL INDUCTION
DOES NOT REQUIRE Ca
Endothelial NOS
eNOS
NOS3
Endothelial cells
Constitutive
Requires Ca
NO MoA
Interacts with heme moiety of soluble guanyl cyclase
Converts GTP to cGMP (smooth muscle relaxation properties)
Inactivation of NO
Oxidative and reductive rxn (by heme and free radicals)
Formation of variety of oxides of nitrogen
Stable metabolites that can act as NT, immune regulators, etc
Superoxide dismutase can act with NO and form complexes that are regulated by glutathione
In CV and diabetes cellular levels of glutathione are reduced and contributes to vascular pathology
Inhibitors of NO
L-arginine Derivatives (L-NMMA, L-NAME) Inhibitors of NO synthase Inhibitors of arginine binding to NOs Scavengers of NO (heme) Most are substrate analogues
L-NMMA
Competitive inhibitor, binds ariginine binding site in NOS
Nonselective NOS inhibitor
L-NAME
Competitive inhibitor, binds ariginine binding site in NOS
Nonselective NOS inhibitor
7-Nitroindazole
Competitive inhibitor, binds both tetrahydrobiop=terin and arginine binding sites in NOS
Partially selective for NOS-1 in vivo
BBS-2
Inhibits iNOS dimerization
Weakly inhibits nNOS and eNOS
Hemoglobin
NO scavenger
Effects of NO
Activation of guanyl cyclase (generation of cGMP)
Smooth muscle relaxation
Vasodilation
Immune regulation
Anesthetic
Anti-athersclerotic responses
PATHOGENIC: free radical formation, nitrosation, irritant effects
Vascular Effects of NO
cGMP complexes with GC and activates a PKG that activates and enzyme to dephosphorylate MLCK
Causes relaxation
Been shown to protect against ischemic and reperfusion injury
Immune Effect
Inhibition of WBC adhesion to endothelial surface
Decreases release of adhesion molecules such as the E-selectin on the endothelial surface
Respiratory Effects
Improves cardiopulmonary function in pts with pulmonary hypertension (INOmax)
ARDS in children
Bronchodilator
Septic Shock
Bacterial infection induces NOsynthase
Results in hypotension, shock, death
Reversed by NO inhibitors (L-NMMA)
Athersclerosis
Plaques and endothelial damage impairs NO formation
Decreased NO leads to vascular defects and increased cellular proliferation
L-arginine and NO donors as Tx
Platelets
NO is INHIBITOR of platelet aggregation
Regulates release of 5-HT, growth, and thromboxane from platelets
cGMP is important in platelet production
NO indirectly enhances fibrinolysis by inhibiting antiplasmin release from platelets
Organ Transplantation
Platelet activation and cellular proliferation results in ischemic and reperfusion injury
NO is cytoprotective aginet
Dietary arginine is helpful
CNS
NO is NT, modulator of receptors, release of other transmitter
NO has impact on stroke and vascular dementia
Mutliple roles in CNS
Peripheral Nervous System
NANC neurons release NO
Erectile responses are thought to be caused by this
NO donors are useful in impotence
Or inhibitor of cGMP degradation by phoshodiesterase 5
Inflammation
NO has a role in both acute and chronic inflammation
NOS3 is involved in vasodilation and associated with acute inflammation
NO promotes edema and vascular permeability
Nitrates as NO Donors
Nitrates represent the most widely used donors of NO
Pharmacodynamics of NO Donors
Ultra short: Inhaled amyl nitrate (3-5 mins)
Short: Sublingual nitroglycerine or isosorbinde dinitrate (10-30 min)
Intermediary: Oral or sustained release nitroglycerine or iso-sorbide dinitrate (4-8 hours)
Long: Transdermal nitroglycerine (8-10 hours)
Therapeutic Use of NO
Selective pulmonary vasodilation
Treatment of newborn with persistent pulmonary hypotension
Cardiopulmonary bypass in adults, CHD, primary pulmonary hypertension, PE, lung transplantation, sickle cell crisis
