Nitric Oxide

Endothelium REF: Guyton’s physiology 22nd edition page 199

Nitric oxide should not be confused with nitrous oxide (N20), an anesthetic and greenhouse gas, or with nitrogen dioxide (NO2), a brown toxic gas and a major air pollutant.

Nitric oxide, known as the ‘endothelium-derived relaxing factor’, or `EDRF’, is biosynthesized endogenously from L-arginine, oxygen and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow.

Acts through cAMP [Ref: Ganong 22/e p598; http://hyperahajournols.org/cgi/content/abstract/35/6/1237; hup://www. trdrp.org/research/PageGrant.asp?grimt_id=1550]

• Nitric oxide acts through cGMP.
• Nitric oxide (NO) is an important signaling molecule that acts in many tissues to regulate a diverse range of physiological and cellular processes. Its role was first discovered by several groups who were attempting to identify the agent responsible for promoting blood vessel relaxation and regulating vascular tone. This agent was termed endothelium-derived relaxing factor (EDRF), and was later known to be nitric oxide.

Nitric Oxide Synthesis

• Nitric oxide is produced by a group of enzymes called nitric oxide synthases. These enzymes convert arginine into citrulline, producing NO in the process. Oxygen and NADPH are necessary co-factors

Biological Role

• Nitric oxide is a short-lived, highly reactive molecule (with a half-life of a few seconds) These attributes make nitric oxide ideal for a transient signal molecule between adjacent cells and within cells.
• Nitric oxide, acts by stimulating the production of cyclic GMP.
• Nitric oxide has been demonstrated to play a role in a variety of biological processes including neurotransmission, immune defence, the regulation of cell death (apoptosis) and cell motility.
• Nitric oxide has been suggested to play an anti-inflammatory role by inhibiting the expression of the genes for inflammatory cytokines.
• NO has important role in producing penile erection by causing vasodilation and hence engorgement of corpora cavernosa.( Erection is caused by parasympathetic impulses that pass from sacral portion of spinal cord.
• These parasympathetic nerve fibres in contrast to most other parasympathetic fibres are believed to secrete nitric oxide and/or vasoactive intestinal peptide in addition to acetylcholine.)

Sildenafil, popularly known by the trade name Viagra, stimulates erections primarily by enhancing signaling through the nitric oxide pathway in the penis.

• Recent studies have provided important information on the use of inhaled nitric oxide for the management of several diseases characterized by the presence of abnormal pulmonary vascular tone, such as persistent pulmonary hypertension of the newborn.
• Cigarette smoking decreases endogenous NO formation and hence increases the risk of cardiovascular disease through increased hypertension and platelet aggregation.

Nitric oxide is a neuro transmitter, in the gaseous for which is considered to have an effect in mood disorders. NOS expressing neurons are well represented in the areas implicated in depression. SSRIs is thought to directly inhibit NOS activity.

Ref: Kaplan and Sadock, 10th Edition.

Nitric oxide, known as the ‘endothelium-derived relaxing factor’, or ‘EDRF’. Endothelial cells contain the constitutive form of nitric oxide synthase, which produces moderate amounts of nitric oxide by metabolizing L-arginine. The endothelium of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow.

Functions: Endothelium-derived nitric oxide inhibits contraction and proliferation of the underlying vascular smooth muscle, adhesion of blood cells and platelets, and platelet aggregation.

Ref: Hypertension Primer: The Essentials of High Blood Pressure By Joseph L Izzo, Jr, Henry R Black, M.D., Theodore L. Goodfriend, 2003, Page 44; Guyton’s physiology, 22nd edition, Page 199

Nitric oxide acts in paracrine manner on target cells through induction of cGMP which in turn initiates a series of intravascular events leading to relaxation of vascular smooth muscle.

A i.e. Endothelium

Nitric oxide is synthesized from arginine by the enzyme NO synthetase (NOS) in endothelial cellsQ. It causes vasodilation.

B i.e. Acts by increasing C- AMP level

A i.e. NO is synthesized from arginine

A i.e. Free radical; B i.e. Vasodilator; C i.e. Oxidizing agent

Ans. is ‘d’ i.e., Fenoldopam

o NO donors, which release NO are used to elicit smooth muscle relaxation. Drugs are –

1.  Organic nitrates (nitroglycerine)               3. Sodium nitroprusside                     5. Nebivolol

2.  Organic nitrites (Isoamylnitrite)               4. Hydralazine

Ans. is ‘d’ i.e., For reducing pulmonary hypertension

According to Goodman Gilman

“Inhaled nitric oxide has been approved by FDA for use in newborns with persistent pulmonary hypertension and has become the first line therapy for this disease. In this disease state NO inhalation has been shown to reduce, significantly, the necessity for extracorporeal oxygenation”

Ans. is ‘b’ i.e., Newborn with pulmonary hypertension

A i.e. Formed from L-arginine by NO Synthetase; B i.e. Causes vasodilation of all vessels; C i.e. Used in portal hypertension

A i.e. Used in pulmonary hypertension

B i.e, Dilates pulmonary arteries 

C i.e. Nitric oxide

Nitric oxide (NO) or endothelium derived relaxing factor (EDRF) is synthesized from L-arginine by nitric oxide synthase (NOS) enzyme in endothelium of blood vesselsQ. Physiologically it causes vasodilation & decreases vascular resistance throughout the bodyQ. It activates guanylyl cyclase producing C-GMP and binds rapidly to Hb & gets inactivatedQ.

Whereas inhaled NO is a selective pulmonary-vasodilator decreases pulmonary artery pressure in infants & adults and improves V/P ratioQ. So it is used in treatment of pulmonary artery hypertensionQ. It has no systemic vasodilatory effectQ. Systemic effects of breathing NO includes platetlet & leukocyte inhibition and oxidation of extraerythrocytic hemoglobin.

Inhaled NO decreases vascular smooth muscle cell hyperplasia & increases alveolarization in the injured developing limb. This pulmonary vascular & alveolar developmental effect of NO is used to prevent or ameliorate pulmonary hypertension in infants with congenital heart disease and chronic lung disease in premature infants.

Pyrogens

• A pyrogen is a substance that induces fever.
• These can be either internal (endogenous) or external (exogenous) to the body.
• The bacterial substance lipopolysaccharide (LPS), present in the cell wall of some bacteria, is an example of an exogenous pyrogen.
• Endogenous Pyrogens
  • IL 1
  • TNF
  • PGs
• Depyrogenation may be achieved through filtration, distillation, chromatography, or inactivation.

Ans. is ‘a’ i.e., Nitric Oxide

Ans:D.)Arginine.

NITRIC OXIDE (NO)/ENDOTHELIUM DERIVED RELAXING FACTOR (EDRF)

• Nitric oxide, a vasodilator is formed by the action of nitric oxide synthase on Arginine. Synthesis:
• NO is formed by the action of Cytosolic enzyme NO synthase in endothelial & neuronal cells.
• Substrate: Arginine, O 2 , NADPH
• Coenzyme: NADPH, FAD, FMN, Heme, tetrahydrobiopterin
• Product: Citrulline, NO

Features

• Reacts with oxygen & superoxide  peroxynitrite which decomposes to form highly reactive OH-radical
• It stimulates guanyl cyclase (cGMP)

Functions

• Relaxes smooth muscles
•  Prevents platelet aggregation
• Functions as neurotransmitter in brain
• Mediates tumoricidal, bactericidal actions of macrophages
• Involved in penile erection; (sildenafil affects this process by inhibiting a cGMP dependent phosphodiesterase)