L37 Pharmacology of Nitric Oxide

Question 1

Nitric oxide is a gaseous signaling molecule that diffuses vascular and cellular sites and regulates a wide range of processes including…

Answer 1

…cardiovascular, cerebrovascular, inflammatory, and immune/neuronal pathways.

Question 2

What are the 3 major effects of NO?

Answer 2

1. Smooth muscle relaxation
2. Decreased cell adhesion
3. Inflammatory response (pathologically)

Question 3

What leads to the generation of NO in macrophages?

Answer 3

Exposure to bacterial LPS

Question 4

When endothelial injury occurs, there is reflex vasoconstriction. What does NO do here?

Answer 4

NO causes relaxation to counteract this effect.

Question 5

What synthesizes NO?

Answer 5

Nitric oxide synthase (NOs)

Question 6

What are the 3 isoforms of NOs and where are they found?

Answer 6

1. Neuronal NOS (neuronal epithelial cells)
2. Inducible NOS (Macrophages, SMCs)
3. Endothelial NOS (endothelial cells)

Question 7

Describe the process of nitric oxide generation.

Answer 7

Arginine is converted to Citrulline by NOS. This is inhibited by L-NMMA. Once formed, NO activates guanylyl cyclase via interaction with the heme moiety. This enzyme converts GTP to cGMP. In high amounts, NO can be converted to pathologic substances.

Question 8

What is the different between nitric oxide and nitrous oxide?

Answer 8

Nitric oxide (NO) is a vasodilator, platelet inhibitor, immune regulator, and NT. Nitrous oxide (N2O) is used as an anesthetic.

Question 9

What inactivates NO endogenously?

Answer 9

Heme and superoxide

Question 10

In cardiovascular diseases and diabetes, cellular levels of glutathione are reduced and contribute to vascular pathology. Why?

Answer 10

Glutathione regulates peroxynitrite, a pathologic form of NO generated by superoxide interaction

Question 11

What are the inhibitors of NO?

Answer 11

1. L-NMMA
2. Inhibitors of NO synthase synthesis
3. Inhibitor of binding of arginine to NOs
4. Scavenger of NO

Question 12

Most of the inhibitors of NO are ___.

Answer 12

Substrate analogues

Question 13

What mediates the effects of NO?

Answer 13

Activation of guanylyl cyclase resulting in the generation of cGMP

Question 14

In sepsis and other inflammatory conditions, what happens regarding NO production?

Answer 14

NOs-2 is induced and NO production is increased

Question 15

Why are NO inhibitors helpful in the treatment of sepsis related disorders?

Answer 15

Excess production of NO is seen in these conditions; this excess can lead to the production of toxic peryoxynitrite

Question 16

What are the beneficial effects of NO?

Answer 16

Smooth muscle relaxation, vasodilation, immune regulation, anesthetic, anti-atherosclerosis

Question 17

What are the pathologic effects of NO?

Answer 17

Free radical formation, nitrosation, and irritant effects

Question 18

Decreased NO levels in blood vessels may result in a ___ in blood pressure.

Answer 18

Increase

Question 19

What inactivates cGMP to GMP?

Answer 19

Phosphodiesterase

Question 20

How does Viagra (Sildenafil) work?

Answer 20

Blocks phosphodiesterase, preventing cGMP from getting broken down and maintaining vasodilatory effects

Question 21

NO is a potent inhibitor of white cell adhesion in the endothelial surface. How?

Answer 21

It decreases the release of adhesion molecules such as E-selectin on the endothelial surface.

Question 22

What are the respiratory effects of NO?

Answer 22

Improve cardiopulmonary function in adults with pulmonary hypertension and in children with acute respiratory distress syndrome (bronchodilator)

Question 23

Vascular plaque and endothelial damage in atherosclerosis result in impaired NO formation. What does this cause?

Answer 23

Leads to vascular defects and increased cellular proliferation

Question 24

What NO-related drugs are useful in the treatment of atherosclerotic disorders?

Answer 24

L-arginine and NO donors

Question 25

What is the effect of NO on platelets?

Answer 25

Potent inhibitor of adhesion, activation, and aggregation; also regulates the release of 5-HT, growth factors, and thromboxane from platelets. Platelets also contain NOs.

Question 26

What is a major cause of graft failure?

Answer 26

Accelerated graft atherosclerosis (due to platelet activation and cellular proliferation causing ischemic and reperfusion injury)

Question 27

How is NO helpful in organ transplantation?

Answer 27

Cytoprotective agent that prevents cellular and platelet adhesion

Question 28

What is the role of NO in the CNS?

Answer 28

NT, modulator of receptors, impacts on stroke and vascular dementia

Question 29

Why is combined use of nitrates and Viagra contraindicated?

Answer 29

Interactions lead to hypotension

Question 30

What is the role of NO in inflammation?

Answer 30

Involved in edema, vascular permeability, and vasodilation

Question 31

What are the most widely used donors of NO?

Answer 31

Nitrates

Question 32

What are the three types of nitrates?

Answer 32

1. Nitroglycerine
2. Isosorbide dinitrate (sublingual/oral)
3. Amyl nitrates (rapid acting, rarely prescribed)

Question 33

What is the MOA of nitrates?

Answer 33

Produce smooth muscle relaxation by releasing NO, which stimulates guanyl cyclase, increases cGMP, and leads to dephosphorylation of myosin and muscle relaxation

Question 34

What are the indications of gaseous NO?

Answer 34

1. Selective pulmonary vasodilation
2. Newborn with persistent pulmonary hypotension
3. Cardiopulmonary bypass in adults, CHF, primary pulmonary hypertension, pulmonary edema, lung transplant, sickle cell crisis