Nitric oxide

Question 1

what are the main pharmacologic actions of NO

Answer 1

1. Smooth muscle
   
   • relaxation
2. Cell adhesion
   
   • decreased adhesion
3. Inflammatory response

Question 2

Endogenous nitric oxide (NO) is generated from

Answer 2

oxidation of the guanidine group of arginine. It is produced in macrophages and endothelial cells

Question 3

what enzyme synthesizes NO?

Answer 3

Nitric oxide synthase (3 isoforms)

Question 4

what are the 3 isoforms of nitric oxide synthase

Answer 4

NOS-1 (neuronal nNOS)
NOS-2 (inducible iNOS)
NOS-3 (endothelial eNOS)

Question 5

which NOS isoforms are constitutively active

Answer 5

NOS-1 and NOS-3 (neuronal and endothelial) both also require calcium

Question 6

where and when is iNOS (NOS-2) produced

Answer 6

in macrophages and smooth muscle cells. It exhibits transcriptional induction (no Calcium requirement)

Question 7

once NO is generated how does it cause vasodilation

Answer 7

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

Question 8

nitrous oxide N2O

Answer 8

anesthetic

Question 9

what inactivates NO

Answer 9

heme and free radicals superoxide (therefore the enzyme superoxide dismutase may increase NO’s duration of action)

Question 10

4 Inhibitors of Nitric Oxide

Answer 10

1. L-arginine Derivatives (L-NMMA, L-NAME) (competitive inhibitors bind/block the arginine binding site)
2. Inhibitors of nitric oxide synthase synthesis
3. Inhibitor of binding of arginine to NOs
4. Scavengers of NO (heme)

most are substrate analogues

Question 11

for what diagnosis would a NO inhibitor be a useful treatment

Answer 11

sepsis (to reduce peroxynitrite production)

Question 12

excess NO production results in the formation of

Answer 12

peroxynitrite which is toxic to cells

Question 13

what causes the detrimental effects of NO

Answer 13

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.

Question 14

how does cGMP cause vasodilation

Answer 14

it de-phosphorylates myosin light chain leading to muscular relaxation

Question 15

what is the function of phosphodiesterase (PDE)

Answer 15

converts cGMP to GMP which would prevent cGMP’s vasodilation effects

Question 16

how does sildenafil (viagra) work

Answer 16

inhibits phosphodiesterase therefore preventing the break down of cGMP

Question 17

how does NO affect the immune system

Answer 17

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

Question 18

how does NO affect the respiratory system

Answer 18

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.

Question 19

what is the role of NO in shock

Answer 19

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.

Question 20

how does atherosclerosis affect NO

Answer 20

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

Question 21

what is NO’s affect on platelets

Answer 21

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.

Question 22

how is NO helpful in organ transplant

Answer 22

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.

Question 23

Mechanism of Action of NO donnors

Answer 23

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

Question 24

indications of inhaled NO

Answer 24

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.

Question 25

Nitric Oxide (INOMAX) route of adminstration, indications, and side effect

Answer 25

Inhalation, ACS, vasodilation

Question 26

nitroglycerine MOA and route of adminstration

Answer 26

NO doner, sublingual

Question 27

nitroglycerine indications and side effects

Answer 27

indications- pulmonary artery hypertension

side effects - hypotension

Question 28

hydralazine MOA and route of adminstration

Answer 28

NO donor and vasodilator

route- oral

Question 29

sildenafil MOA and route of administration

Answer 29

Phosphodiesterase inhibitor

route - oral

Question 30

sildenafil indications and side effects

Answer 30

hypertesion

side effect- hypotension, and drug interactions

Question 31

L-arginine MOA and route of administration

Answer 31

NO donor

route- oral

Question 32

L-arginine indication and side effect

Answer 32

ACS, vascular disease

side effect - hypotension