Nitrate-Nitrite-Nitric Oxide Flashcards
What is the effect of NO on blood vessels and what is the mechanism for this?
NO diffuses out of endothelial cells into smooth muscle cells
NO activates guanyl cyclase
Formation of cGMP from GTP
cGMP has many effects which lead to vasodilation
What are the effects of cGMP?
Activation of PKG which inhibits calcium channels, preventing calcium influx
Activation of potassium channels, allow potassium efflux and hyperpolarisation
Activation of cGMP-dependent protein kinase that activates myosin light chain phosphatase
What other vascular effects does NO have?
Inhibition of platelet aggregation
Anti-inflammatory effects
Inhibition of angiotensin II and SNS innervation
Negative ionotropic effects on the heart
Describe how NO is produced from L-arginine
L-arginine from the diet is converted into NO by endothelial nitric oxide synthase, in vascular endothelial cells
Requires co-factors
What are the 3 forms of NOS and when are they expressed?
eNOS in endothelial cells
neuronal NOS within the nervous system - these two both constitutively expressed
inducible NOS expressed by white blood cells in response to infection
What are the co-factors for eNOS?
Oxygen NADPH BH4 (Tetrahydrobiopterin) FAD Flavin adenine nucleotides
Describe how NO is produced in the nitrate-nitrite-nitric oxide pathway
Dietary nitrate absorbed in stomach
Concentrated and secreted in saliva
Undergoes enterosalivary conversion into nitrite by nitrate reductases produced by facultative anaerobe bacteria on the tongue
Nitrite swallowed and re-enters systemic circulation
Nitrite reduced to NO
What are the ways in which nitrite can become reduced to NO?
Acidic stomach environment
By xanthine oxidoreductase
By deoxyhaemoglobin
By NOS
Why is NO more abundant in hypoxic settings and why is this important?
In hypoxic environments there is deoxyhaemoglobin as opposed to haemoglobin
Deoxyhaemobloin reduces nitrite into NO
Important because when there is no oxygen e.g. during a heart attack, NOS cannot synthesise NO as oxygen is a cofactor. However deoxyhaemoglobin will allow NO synthesise from nitrite.
What are two other possible fates of plasma nitrite?
React with molecules to form S-nitrosothiols (R-SNO). Or can form nitrated lipids. Both can act as NO donors/NO storage, or can activate receptors involved in glucose homeostasis.
Why might NO bioavailability become impaired in people with CVD?
Oxidative stress
Limited substrate or co-factor availability
Retention by altered haemoglobin
Increased expression of intracellular eNOS inhibitors
Increased concentration of NOS inhibitors
What are the two types of NO therapeutics (nitrodilators)?
Direct NO donors such as nicorandil or sodium nitroprusside, that spontaneously release NO and activate ATP-sensitive potassium channels
Indirect NO donors such as nitroglycerin are organic nitrates, in which the nitrate group becomes reduced to NO
What are two cons of nitrodilators?
Excessive consumption can lead to hypotension, initiaiting the baroreceptor reflex and tachycardia
Cerebral vasodilation can cause headaches
Name 1 pro and 3 cons of indirect NO donors
Also inhibits platelet aggregation
Quick development of tolerance
Production of superoxide anions that damage the endothelium
Undergoes extensive first pass metabolism, so has variable oral bioavailability
Name 1 pro and 1 con of direct NO donors
No build-up of tolerance
Sodium nitroprusside releases cyanide so can be toxic after prolonged use
