Nitric Oxide

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 Nitric Oxide
• Nitric Oxide (NO) is a soluble gas

• An important cell signaling molecule with diverse actions

on cardiovascular, renal and immune cell function.
• NO was formerly knows as endothelial-derived relaxing
factor (EDRF) that is produced by endothelial cells
following activation by agonists (ACh,GABA, or
ADENOSINE)

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 Biosynthesis

• Nitric oxide is produced de novo from the

precursor amino acid L-arginine, the reaction
is catalyzed by the enzyme Nitric Oxide
Synthase (NOS) in presence of molecular
oxygen.
• The products are NO and L-citrulline
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Biosynthesis

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 Nitric Oxide Synthase (NOS)

• Constitutional
– NOS I (n NOS) Neuornal
– NOS III (e NOS) Endothelial

• Inducible
– NOS II or iNOS

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 nNOS (neuronal NOS, NOS I)

• n NOS is found in the brain, peripheral

neurons, some vascular and epithelial
smooth muscle and in skeletal muscles.
• The produced NO functions as
neurotransmitter and neuromodulator.

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 iNOS (inducible, NOS II)

• i NOS is induced by cytokines from different

tissues such as macrophages, glial cells,
hepatocytes, endothelium, cardiac myocytes
and smooth muscles.
• The NO produced eradicates infections and
combats tumors (cytotoxicity).
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 eNOS (endothelial constitutive, NOS III)

• It is expressed in tissues such as endothelium

pulmonary and renal epithelium, cardiac
myocytes and hippocampus.
• The produced NO functions as vascular tone
regulator and regulator of blood supply to
organs.
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Endothelial NOS

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Mechanism of action of NO:

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Mechanism of action

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 Mechanism ofAction
• Increase in cyclic guanosine monophosphate (cGMP),
activates cGMP-dependent protein kinase leading to
– Opening of K+ channels causing hyperpolarization
– Inactivation of operated calcium channels causing
decrease calcium channels causing decrease in calcium
influx
– The resultant effect is vasodilation or muscle relaxation

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 Pharmacological Manipulation of Nitric
Oxide

• Inhibitors of Nitric Oxide Synthesis

• Nitric Oxide Donors

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 Inhibitors of NOS Enzyme
• The majority of these inhibitors are arginine analogs that bind to the

NOS arginine-binding site.

• In inflammatory disorders and sepsis, inhibition of the iNOS isoform is

potentially beneficial.

• However, administration of nonselective NOS inhibitors leads to

concurrent inhibition of eNOS, which impairs its homeostatic signaling

and also results in vasoconstriction and potential ischemic damage.

• Example : N-Monomethyl-L-arginin (L-NMMA)

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 Nitric Oxide Donors

• Nitroglycerine, nitroprusside, nitrite and

nitrates.
• These are clinically effective in angina
pectoris as vasodilators and in other cardiac
diseases.

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Nitric Oxide Donors

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 Thank You

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