Nitric Oxide Flashcards
NO is also known as…?
EDRF
Endothelium Derived Relaxation Factor
List some pharmacological effects of NO
Smooth muscle relaxation
Vasodilation
Decreased cell adhesion
Inflammatory Response in excess production
NO is produced by what enzymes? What is the substrate and other product of NO synthesis?
NOS (nitric oxide synthase) takes arginine and converts it to citrulline and NO
How does sepsis affect NO production?
Exposure to bacterial endotoxin (LPS) can activates inducible NOS, which causes vasodilation and potentially hypotension in patients with sepsis.
When the vessels are stimulated by acetylcholine and carbachol, how do they respond?
They vasoconstrict in response to Ach and carbachol, but the endothelium will then make and release NO to help vasodilate again and maintain blood flow
Which NOS enzymes are constitutive and inducible?
NOS2 is inducible (pathological)
NOS1/3 are constitutive/housekeeping enzymes
Where is NOS1 located?
Neuronal epithelial cells
Where is NOS2 located?
Macrophages and smooth muscle cells
Where is NOS3 located?
Endothelial cells
Once generated, how does NO produce smooth muscle relaxation?
Interacts with the heme moiety of guanylyl cyclase, converting GTP to cGMP, which is cytoprotective and causes relaxation of muscles
NO Functions
- Binds heme moiety of guanylyl cyclase to make cGMP.
- Nitrosylates tyrosine and cysteine because NO is a free radical
There are many products of redox reactions on NO. List the two most important pharmacologically
Nitrous Oxide (N2O) = Gaseous anesthetic
Nitrate (NO3-) = Used to measure how much NO a person has in their blood
What effect would superoxide dismutase have on NO?
May increase NO’s potency and increase its duration
What effect would glutathione have on NO?
Low glutathione level may contribute to vascular pathology. Endogenous glutathione may help reduce the toxic effects of excessive NO
What are the main inhibitors of NOS?
L-arginine derivatives (such as NMMA, L-NAME) that will competitively bind NOS and inhibit NO production
NO and NO derivatives
Beneficial Pharmacological Effects
Vasodilation
Immune regulation
Anesthesia
Anti-atherosclerosis
Sildenafil
MOA
Inhibit phosphodiesterase.
Allows more cGMP to cause relaxation of blood vessels.
Toxic interactions of sildenafil
Do NOT take sildenafil with nitrates because this combination could cause severe hypotension and shock
Respiratory Effects of NO
Improves cardiopulmonary function in pulm HTN
Acts as a bronchodilator
Anti-atherosclerosis effects of NO
Inhibits adhesion molecules generation
Inhibit plaque formation
Inhibit homing of WBCs to plaque
What NO drugs should be given in treatment of atherosclerotic disorders?
Give L-arginine and NO Donors to allow for more NO production in atherosclerosis
NO
Effects on Platelets
Inhibitor of platelet aggregation, adhesion, activation
NO directly enhances fibrinolysis
Increases prostacyclin production
Why is NO helpful in organ transplants?
NO is cytoprotective and prevents cellular/platelet adhesion. Dietary arginine supplements are helpful in organ transplant patients.
What kind of neurons release NO in the peripheral NS?
NANC Neurons (Non adrenergic, Non cholinergic)
Nitrates primarily serve as…?
NO Donors that cause smooth muscle relaxation
Nitrates MOA
Release endogenous NO
Stimulation of guanylyl cyclase
Increase cGMP production
Smooth muscle relaxation
List some NO Donor Drugs
Nitroglycerin
Hydralazine
L-arginine
Nitroglycerine
Indication
Pulmonary Artery Hypertension
Hydrlazine
Indication
Hypertension
L-arginine Indications
Acute coronary syndrome
Vascular disease
Nitric Oxide (INOMAX) Indications
Acute coronary syndrome
Sildenafil
Indications
HTN
ED
