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Cardiovascular System 7: Nitric Oxide Synthesis & Function
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A detailed summary on the use of Nitrous oxide and the mechanism of action of NO Synthase.
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NITRIC OXIDE SYNTHESIS & FUNCTIONNitric oxide (NO) is a vasodilator produced by endothelial cells and increases blood supply to
the heart. NO is synthesized by NO synthase and has a short half life.
NO Synthase activated by:
ACh/Bradykinin, which increase calcium levels to activate NO synthase.
Protein Kinase B via phosphorylation.
NO synthase catalyses the conversion of L-arginine to NO.
NO then acts on guanylate cyclase to convert GTP to cGMP – conversion causes smooth
muscle relaxation. However, cGMP can be inhibited and converted into linear form (inactive)
by a phosphodiesterase inhibitor.
How does NO act on guanylate cyclase?
Guanylate cyclase has four subunits – two regulatory and two catalytic subunits.
NO binds to the heme group sat in between the regulatory subunits causing a
conformational change and activating the catalytic subunits.
Two other signaling pathways for NO production:
1. By reactive oxygen species as NO reacts with O2- (superoxide) and forms
peroxynitrate (reactive nitrogen species which can lead to mitochondrial damage
and then cell death).
2. By protein nitrosation – add NO group onto protein.
NO Synthase Action
NADPH donates electron to enzyme forming NADP+ + H+.
Electron is then transferred by electron carriers in the enzyme (flavins) until it reaches the
final electron acceptor (O2) so then it can stimulate the conversion of Arginine to NO.
NO Synthase Dimer
Need two NO Synthases to combine to form a dimer for the enzyme (NO Synthase) to be
active. Two dimers are bound by BH4.
For the dimer to be uncoupled and become non-functional – can occur by oxidative stress.
As oxidative stress reduces BH4 levels.
Furthermore, uncoupled NO synthase dimer is damaging as it separated dimer uses O2 to
produce superoxide.
Can BH4 be given as treatment?
Yes, as a hypertensive treatment.
As BH4 increases NO Synthase activation – reducing BP due to vasodilation.
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