Nitric oxide (NO)
PHARMACOLOGY
Dr. M.S Fageyinbo
INTRODUCTION
Nitric oxide (NO)
• NO is a signaling molecule having
important role in various
pathophysiological conditions.
• It is also known as endothelium derived
relaxing factor (EDRF).
• NO is formed by the action of the enzyme
NO synthase on the amino acid arginine.
Synthesis
• The enzyme NO synthase (NOS) has three isoforms:
Endothelial NOS (eNOS),
Inducible NOS (iNOS)
Neuronal NOS (nNOS).
• Both eNOS and nNOS are expressed constitutively
• iNOS is inducible in many inflammatory conditions.
• Arginine -----NOS-------- NO + Citrulline
Mechanism of action
• NO binds to iron in Heme and causes an
increase in the concentration of cGMP by
stimulating guanylyl cyclase.
• This cGMP is responsible for its vasodilatory
actions.
Nitric Oxide Donors
• NO donors are primarily used for smooth muscle relaxation.
• The important NO donors are:
Organic nitrates: Nitroglycerin and isosorbide dinitrate
are metabolized to NO releasing compounds.
• Rapid tolerance is seen with the vasodilatory properties of
nitrates because of inhibition of the mitochondrial aldehyde
reductase.
Organic nitrites: Amylnitrite also causes relaxation of
vessels (especially arteries) but it does not exhibit
tolerance.
Sodium nitroprusside: It is an antihypertensive drug that
• Hydralazine: It is an antihypertensive drug
that acts partly by releasing NO and partly by
opening the K+ channels.
• Nebivolol: It is a third generation beta-
blocker that contains additional vasodilatory
activities due to the release of NO.
• Alternative drugs: Drugs like sildenafil act
by increasing the duration of NO induced
cGMP elevation in the tissues.
Nitric oxide inhibitors
NG-monomethyl-L-arginine (L-NMA)
• It occurs naturally in living organisms, as it is a
product of the degradation of arginine-
methylated proteins.
• L-NMA is one of the first compounds which
were intuitively employed to inhibit NOSes.
• L-NMA has been used widely as a general tool
to decrease NO bioavailability or to establish
the NO dependency of a physiological process.
L-N 𝜔 ,N 𝜔 -Dimethylarginine (ADMA)
• L- N 𝜔 , N 𝜔 -dimethylarginine (commonly referred
to as asymmetrically dimethylated arginine,
ADMA).
• Similarly to L-NMA, ADMA is a product of the
degradation of arginine-methylated proteins.
• ADMA is considered as a nonspecific competitive
inhibitor of NOSes.
• ADMA to be a potent inhibitor of nNOS with a
submicromolar inhibition
L-N 𝜔 -Nitroarginine (L-NNA) and L-N 𝜔 -
Nitroarginine Methyl Ester (L-NAME)
• L-NNA (also referred to as NG-nitro-L-arginine) is one of
the first synthetic NOS inhibitors.
• Initially L-NNA was recognized as a competitive
inhibitor of all NOSes having high selectivity to eNOS
and nNOS over iNOS.
• A later study, however, indicated only minor selectivity
to nNOS and eNOS.
• Though L-NNA interacts with all NOSes noncovalently,
its coupling with iNOS is immediate and rapidly
reversible with arginine.
• The only limiting factor of L-NNA application in
biological systems is poor solubility (about 4
mmol/L) at neutral pH.
introducing another compound L-N 𝝎 -
• This disadvantage was addressed by
nitroarginine methyl ester (L-NAME).
• L-NAME acts as a weak NOS inhibitor, but it is
readily hydrolyzed by ubiquitously present
esterases to L-NNA in a biological system.
• Both L-NNA and L-NAME have been extensively
used in experimental practice
Nitric Oxide in Health and Disease
Vascular effects: Effect of NO on blood vessels are:
–– Vasodilatation
–– Inhibition of vascular smooth muscle proliferation
–– Inhibition of platelet aggregation
–– Increase in fibrinolysis
Septic shock:
• NO plays an important role in the pathogenesis of septic
shock.
• This is confirmed by the increased urinary excretion of
oxidative products of NO
• (nitrates) and the reversal of hypotension by NO synthase
inhibitors (L-NMMA,7-nitroimidazole) in this condition.
Inflammation: Inhibitors of iNOS have a dose
dependent protective effect on:
• arthritis, psoriasis, inflammatory bowel
disease and asthma.
CNS: NO is involved in the regulation of
synaptic plasticity (the process underlying
memory and behaviour).
Peripheral nervous system: NO is an
important mediator of non-adrenergic,
noncholinergic (NANC) transmission in
neurons of GIT and other areas of the body.
Respiratory diseases: NO can be used
for the treatment of several diseases of
respiratory system.
–– Inhalational NO is used for the
management of
pulmonary artery hypertension.
–– NO inhalation is also beneficial in ARDS
(Adult
Respiratory Distress Syndrome).
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