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PHARMACOLOGY
1.4D Nitric OXIDE

OBJECTIVES
Identify sources of Nitric Oxide
Discuss role of NO in diseases

NITRIC OXIDE ACTIVATION SYNTHESIS, SIGNALING MECHANISMS &

ACTIVATION

NITRIC OXIDE
Help its 50 million cells communicate with each other by
tr ansmitting signals throughout the entire body.
Important in the ff cellular activities:
o
Help memory and behavior by transmitting information
between nerve cells in the brain.
o
Assist the immune system at fighting off bacteria and
defending against tumors
o
Regulate blood pressure by dilating arteries
o
Reduce inflammation
o
Improve quality of sleep
o
Increase your recognition of sense (i.e. smell)
o
Increase endurance and strength
o
Assist in gastric motility
Over 60,000 studies done in the last 20 years
1998, The Nobel prize for Medicine was given to 3 scientists who
discovered the signaling role of Nitric Oxide.
A gaseous signaling molecule
Diffuses readily across CM
Regulates physiologic and pathophysiologic processes ie. CVS,
inflammatory and neuronal functions
NO shouldnt be confuse with N20 (Nitrous oxide) and NO2
(Nitrogen dioxide)

3 ISOFORMS of NO SYNTHASE (NOS)

Neuronal, inducible, endothelial NOS
Named after from the initial cell type it was isolated

Property
Other sources
Tissue

ISOFORM
NOS-1
nNOS
(neuronal)
Neurons,
skeletal muscle

Expression

Constitutive

Calcium
regulation

Yes

NAMES
NOS-2
iNOS (inducible)
Macrophages,
smooth muscle
cells
Transcriptional
induction
No

Fig2. Diagram of NO activation synthesis

SIGNALING MECHANISMS
NO mediates its effects by modification of 3 proteins. The 3 major targets are:

Metalloproteins

Thiols

NOS-3
eNOS
(endothelial)
Endothelial cells,
neurons
Constitutive
Yes

Table 15-1 of Basic & Clinical Pharma 12 th Ed.

Fig1. Synthesis & reactions of Nitric Oxide. L-NMMA inhibits NO synthase. NO

complexes with the iron in hemoproteins (eg. Guanylyl cyclase), Activation
on cyclic guanosine monophosphate (cGMP) synthesis Protein kionase G.

During oxidative stress, NO can react with superoxide to nitrate tyrosine, GTP,
guanosine triphosphate.

Tyrosine nitration
INHIBITORS OF NO SYNTHESIS
Reduces NO generation in cells:
HOW? Ar ginine analogs bind to the NOS arginine-binding site.
o
iNOS isoform inhibition is potentially beneficial in
inflammatory disorders and sepsis.
o
nNOS-specific inhibitors may be useful for the tx of
Neurodegenerative conditions.
o
Nonselective NOS inhibitors leads to concurrent
inhibition of eNOS, which impairs its homeostatic
signaling and also results in vasoconstriction and
potential ischemic damage.
NITRIC OXIDE DONORS
Releases NO used to elicit smooth muscle relaxation.
Organic matters
o
Nitroglycerin dilates veins and coronary arteries
o
Have less significant effects on aggregation of platelets,
exhibit rapid tolerance.
Organic nitrites
o
Antianginal inhalant amyl nitrite
o
Are arterial vasodilators, do not exhibit the rapid
tolerance, abused for e uphoric effects.
o
Combining with PDE inhibitors (Sildenafil ex. Viagra), can
cause lethal hypotension. (because of too much
vasodilatation)
o
Re placed by nitrates (Nitroglycerin more easily
administered)
Sodium nitroprusside
o
Dilates arterioles and venules
o
Is used for r apid blood pressure reduction
NO gas inhalation
o
Reduces pulmonary artery pressure and improves lung
perfusion (lowers total peripheral resistance)
o
Is used for pulmonary hypertension, acute hypoxemia
(reduction of oxygenation) and CPResuscitation.
Alternate strategies
o
NO inhibit the phosphodiesterase (eg. Sildenafil) that
degrade cGMP, result in pr olongation of the duration of
NO-induced cGMP elevations.
NITRIC OXIDE IN DISEASES
Vascular effects
o
Are vasodilators and regulate BP, has antithrombotic
effects, protects against atherogenesis, acts as an antioxidant
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Pharmacology

1.4D NITRIC OXIDE

Smoking, hyperlipidemia, DM and HPN are

associated with decreased endothelial NO.

Septic shock
o
Infection widespread generation of NO results in
hypotension (vasodilation), shock, death.

NO reduced by NOS inhibitors (PDE

inhibitors)
Infection and Inflammation
o
Infections induces TNF-a & IL-1 induction of in
leukocytes, fibroblasts synthesis of iNOS
o
NO activates COX-2 erythema, vascular permeability,
edema of inflammation
Prolonged or excessive NO may exacerbate tissue
injury.
Lesions of psoriasis, asthma, IBD have high NO
and iNOS.

iNOS inhibitors beneficial to some acute &

chronic inflammation.
CNS
o
May function as a r etrograde messenger and diffuse to
the presynaptic terminal to enhance the efficiency of
neurotransmitter release
Excesive NO synthesis is linked to excititoxic
neuronal death in stroke, amyotrohic lateral sclera,
and Parkinsons disease

NOS inhibitors to reduce damage

Peripheral Nervous System
o
NO is a mediator of certain NANC (Nonadrenergic,
noncholinergic neurons), some NANC neurons appear
to release NO,
o
Penile erection is caused by the release of NO from
NANC neurons;

NO enhance signaling by inhibiting the

breakdown of cGMP by the PDE isoform 5
inhibitos (Sildenafil, Tadalafil, and Vardenafil)

Inhibitors of NOS prevent erection.

Respiratory Disorders
o
NO through inhalation to newborns with hypoxic
respiratory failure associated with pulmonary
hypertension.

Dilates pulmonary vessels, resulting in

decreased pulmonary vascular resistance and
reduced pulmonary artery pressure

Also improves oxygenation

o
PDE-5 inhibitors causes vasodilation and marked
reduction in pulmonary HPN

END OF TRANS

"Don't wish it were easier. Wish you were better."

Jim Rohn

SUMMARY
Mechanism of Action
o
Activates soluble guanyl cyclase to elevate cGMP levels
in vascular smooth muscles
Effects
o
Vasodilator
o
Relaxes other SM
o
Inhalation increased blood flow to exposed parts to
NO
o
Decreases pulmonary vascular resistance
Clinical Application
o
Hypoxic respiratory failure and pulmonary hypertension
o
PK, Tox, Intrxn

Inhaled gas, Methemoglobulinemia

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