Nitric oxide Flashcards
what are the main pharmacologic actions of NO
- Smooth muscle
- relaxation
- Cell adhesion
- decreased adhesion
- Inflammatory response
Endogenous nitric oxide (NO) is generated from
oxidation of the guanidine group of arginine. It is produced in macrophages and endothelial cells
what enzyme synthesizes NO?
Nitric oxide synthase (3 isoforms)
what are the 3 isoforms of nitric oxide synthase
NOS-1 (neuronal nNOS)
NOS-2 (inducible iNOS)
NOS-3 (endothelial eNOS)
which NOS isoforms are constitutively active
NOS-1 and NOS-3 (neuronal and endothelial) both also require calcium
where and when is iNOS (NOS-2) produced
in macrophages and smooth muscle cells. It exhibits transcriptional induction (no Calcium requirement)
once NO is generated how does it cause vasodilation
NO interacts with the heme moiety of soluble guanyl cyclase in the cytoplasm of the cell activating it. The enzyme then converts GTP to cGMP which causes muscle relaxation
nitrous oxide N2O
anesthetic
what inactivates NO
heme and free radicals superoxide (therefore the enzyme superoxide dismutase may increase NO’s duration of action)
4 Inhibitors of Nitric Oxide
- L-arginine Derivatives (L-NMMA, L-NAME) (competitive inhibitors bind/block the arginine binding site)
- Inhibitors of nitric oxide synthase synthesis
- Inhibitor of binding of arginine to NOs
- Scavengers of NO (heme)
most are substrate analogues
for what diagnosis would a NO inhibitor be a useful treatment
sepsis (to reduce peroxynitrite production)
excess NO production results in the formation of
peroxynitrite which is toxic to cells
what causes the detrimental effects of NO
generatation of several reactive nitrogen derivatives by interacting with molecular oxygen and superoxide radicals.
These oxides of nitrogen are highly reactive and unstable, interact with numerous proteins, lipids, nucleic acids and metabolize.
= free radical formation, nitrosation and irritant effects.
how does cGMP cause vasodilation
it de-phosphorylates myosin light chain leading to muscular relaxation
what is the function of phosphodiesterase (PDE)
converts cGMP to GMP which would prevent cGMP’s vasodilation effects
how does sildenafil (viagra) work
inhibits phosphodiesterase therefore preventing the break down of cGMP
how does NO affect the immune system
inhibits white cell adhesion to the endothelial surface by decreasing the release of adhesion molecules such as E-selectin on the endothelial surface
may protect against ischemic and reperfusion injury
how does NO affect the respiratory system
Nitric oxide improves cardiopulmonary function in adults with pulmonary hypertension and is approved for this indication (INOmax).
It is administered by inhalation.
It is also used in children with acute respiratory distress syndrome (ARDS). Nitric oxide also relaxes airway smooth muscle and acts as a bronchodilator.
what is the role of NO in shock
Bacterial infection and lipopolysaccharide B activate inducible nitric oxide synthase (NOs-2) resulting in hypotension, shock and possible death. This effect is reversed by NO inhibitors such as the L-NMMA.
how does atherosclerosis affect NO
Vascular plaque and endothelial damage in atherosclerosis results in impaired nitric oxide formation.
L-arginine and nitric oxide donors are useful in the treatment of atherosclerotic disorders
what is NO’s affect on platelets
Nitric oxide is a potent inhibitor of platelet adhesion, activation, aggregation and regulates the release of serotonin, growth factors and thromboxane from platelets. Platelets also contain the constitutive and inducible NOs.
NO also indirectly enhances fibrinolysis by inhibiting the release of antiplasmin from the platelets.
how is NO helpful in organ transplant
Nitric oxide acts as a cytoprotective agent and prevents cellular and platelet adhesion. (which prevents ischemic and reperfusion injury to the graft)
Dietary arginine supplements are helpful in the management of transplantation patients.
Mechanism of Action of NO donnors
Primarily produce smooth muscle relaxation by releasing endogenous NO which produces the following effects.
A. Stimulates guanyl cyclase B. Increased production of cGMP C. Dephosphorylation of myosin
indications of inhaled NO
A. Selective pulmonary vasodilation
B. Treatment of newborn with persistent pulmonary hypotension (improves oxygenation)
C. Beneficial effects in cardiopulmonary bypass in adults, congestive heart disease, primary pulmonary hypertension, pulmonary edema , lung transplantation and sickle cell crisis.
