L37 Pharmacology of Nitric Oxide Flashcards
Nitric oxide is a gaseous signaling molecule that diffuses vascular and cellular sites and regulates a wide range of processes including…
…cardiovascular, cerebrovascular, inflammatory, and immune/neuronal pathways.
What are the 3 major effects of NO?
- Smooth muscle relaxation
- Decreased cell adhesion
- Inflammatory response (pathologically)
What leads to the generation of NO in macrophages?
Exposure to bacterial LPS
When endothelial injury occurs, there is reflex vasoconstriction. What does NO do here?
NO causes relaxation to counteract this effect.
What synthesizes NO?
Nitric oxide synthase (NOs)
What are the 3 isoforms of NOs and where are they found?
- Neuronal NOS (neuronal epithelial cells)
- Inducible NOS (Macrophages, SMCs)
- Endothelial NOS (endothelial cells)
Describe the process of nitric oxide generation.
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.
What is the different between nitric oxide and nitrous oxide?
Nitric oxide (NO) is a vasodilator, platelet inhibitor, immune regulator, and NT. Nitrous oxide (N2O) is used as an anesthetic.
What inactivates NO endogenously?
Heme and superoxide
In cardiovascular diseases and diabetes, cellular levels of glutathione are reduced and contribute to vascular pathology. Why?
Glutathione regulates peroxynitrite, a pathologic form of NO generated by superoxide interaction
What are the inhibitors of NO?
- L-NMMA
- Inhibitors of NO synthase synthesis
- Inhibitor of binding of arginine to NOs
- Scavenger of NO
Most of the inhibitors of NO are ___.
Substrate analogues
What mediates the effects of NO?
Activation of guanylyl cyclase resulting in the generation of cGMP
In sepsis and other inflammatory conditions, what happens regarding NO production?
NOs-2 is induced and NO production is increased
Why are NO inhibitors helpful in the treatment of sepsis related disorders?
Excess production of NO is seen in these conditions; this excess can lead to the production of toxic peryoxynitrite
What are the beneficial effects of NO?
Smooth muscle relaxation, vasodilation, immune regulation, anesthetic, anti-atherosclerosis
What are the pathologic effects of NO?
Free radical formation, nitrosation, and irritant effects
Decreased NO levels in blood vessels may result in a ___ in blood pressure.
Increase
What inactivates cGMP to GMP?
Phosphodiesterase
How does Viagra (Sildenafil) work?
Blocks phosphodiesterase, preventing cGMP from getting broken down and maintaining vasodilatory effects
NO is a potent inhibitor of white cell adhesion in the endothelial surface. How?
It decreases the release of adhesion molecules such as E-selectin on the endothelial surface.
What are the respiratory effects of NO?
Improve cardiopulmonary function in adults with pulmonary hypertension and in children with acute respiratory distress syndrome (bronchodilator)
Vascular plaque and endothelial damage in atherosclerosis result in impaired NO formation. What does this cause?
Leads to vascular defects and increased cellular proliferation
What NO-related drugs are useful in the treatment of atherosclerotic disorders?
L-arginine and NO donors
What is the effect of NO on platelets?
Potent inhibitor of adhesion, activation, and aggregation; also regulates the release of 5-HT, growth factors, and thromboxane from platelets. Platelets also contain NOs.
What is a major cause of graft failure?
Accelerated graft atherosclerosis (due to platelet activation and cellular proliferation causing ischemic and reperfusion injury)
How is NO helpful in organ transplantation?
Cytoprotective agent that prevents cellular and platelet adhesion
What is the role of NO in the CNS?
NT, modulator of receptors, impacts on stroke and vascular dementia
Why is combined use of nitrates and Viagra contraindicated?
Interactions lead to hypotension
What is the role of NO in inflammation?
Involved in edema, vascular permeability, and vasodilation
What are the most widely used donors of NO?
Nitrates
What are the three types of nitrates?
- Nitroglycerine
- Isosorbide dinitrate (sublingual/oral)
- Amyl nitrates (rapid acting, rarely prescribed)
What is the MOA of nitrates?
Produce smooth muscle relaxation by releasing NO, which stimulates guanyl cyclase, increases cGMP, and leads to dephosphorylation of myosin and muscle relaxation
What are the indications of gaseous NO?
- Selective pulmonary vasodilation
- Newborn with persistent pulmonary hypotension
- Cardiopulmonary bypass in adults, CHF, primary pulmonary hypertension, pulmonary edema, lung transplant, sickle cell crisis
