Nitric Oxide

Question 1

Actions of NO

Answer 1

Smooth muscle relaxation/vasodilation
Decreased cell adhesion
Inflammatory response

Question 2

Generation of endogenous NO

Answer 2

Oxidation of guanidine group of arginine
Can be generated in macrophages (in response to bacteria)
Vascular enodthelium release vasodilatory EDRF (aka NO)

Question 3

Synthesis of NO

Answer 3

Created by NO synthase
Three isoforms of these enzymes
Some drugs have NO in the molecule, these are known as NO donors

Question 4

Isoforms of NO

Answer 4

Neuronal NOS (NOS1)
Inducible NOS (NOS2)
Endothelial NOS (NOS3)

Question 5

Neuronal NOS

nNOS

Answer 5

NOS1
Neuronal epithelia cells
Constitutive
Requires Ca

Question 6

Inducible NOS

iNOS

Answer 6

NOS2
Macrophages, SMC
TRANSCRIPTIONAL INDUCTION
DOES NOT REQUIRE Ca

Question 7

Endothelial NOS

eNOS

Answer 7

NOS3
Endothelial cells
Constitutive
Requires Ca

Question 8

NO MoA

Answer 8

Interacts with heme moiety of soluble guanyl cyclase

Converts GTP to cGMP (smooth muscle relaxation properties)

Question 9

Inactivation of NO

Answer 9

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

Question 10

Inhibitors of NO

Answer 10

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

Question 11

L-NMMA

Answer 11

Competitive inhibitor, binds ariginine binding site in NOS

Nonselective NOS inhibitor

Question 12

L-NAME

Answer 12

Competitive inhibitor, binds ariginine binding site in NOS

Nonselective NOS inhibitor

Question 13

7-Nitroindazole

Answer 13

Competitive inhibitor, binds both tetrahydrobiop=terin and arginine binding sites in NOS
Partially selective for NOS-1 in vivo

Question 14

BBS-2

Answer 14

Inhibits iNOS dimerization

Weakly inhibits nNOS and eNOS

Question 15

Hemoglobin

Answer 15

NO scavenger

Question 16

Effects of NO

Answer 16

Activation of guanyl cyclase (generation of cGMP)
Smooth muscle relaxation
Vasodilation
Immune regulation
Anesthetic
Anti-athersclerotic responses
PATHOGENIC: free radical formation, nitrosation, irritant effects

Question 17

Vascular Effects of NO

Answer 17

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

Question 18

Immune Effect

Answer 18

Inhibition of WBC adhesion to endothelial surface

Decreases release of adhesion molecules such as the E-selectin on the endothelial surface

Question 19

Respiratory Effects

Answer 19

Improves cardiopulmonary function in pts with pulmonary hypertension (INOmax)
ARDS in children
Bronchodilator

Question 20

Septic Shock

Answer 20

Bacterial infection induces NOsynthase
Results in hypotension, shock, death
Reversed by NO inhibitors (L-NMMA)

Question 21

Athersclerosis

Answer 21

Plaques and endothelial damage impairs NO formation
Decreased NO leads to vascular defects and increased cellular proliferation
L-arginine and NO donors as Tx

Question 22

Platelets

Answer 22

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

Question 23

Organ Transplantation

Answer 23

Platelet activation and cellular proliferation results in ischemic and reperfusion injury
NO is cytoprotective aginet
Dietary arginine is helpful

Question 24

CNS

Answer 24

NO is NT, modulator of receptors, release of other transmitter
NO has impact on stroke and vascular dementia
Mutliple roles in CNS

Question 25

Peripheral Nervous System

Answer 25

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

Question 26

Inflammation

Answer 26

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

Question 27

Nitrates as NO Donors

Answer 27

Nitrates represent the most widely used donors of NO

Question 28

Pharmacodynamics of NO Donors

Answer 28

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)

Question 29

Therapeutic Use of NO

Answer 29

Selective pulmonary vasodilation
Treatment of newborn with persistent pulmonary hypotension
Cardiopulmonary bypass in adults, CHD, primary pulmonary hypertension, PE, lung transplantation, sickle cell crisis