Nitric oxide and its role in therapeutics

Dr. Aditi M. Panditrao 1

Nitric Oxide and its role in Therapeutics

Dr. Aditi M. Panditrao

Nitric Oxide – A unique molecule

• Harmful and Helpful

• Discovered – 240 years ago

• Function in body – 28 years ago

Robert Furchgott Louis Ignarro Ferid Murad

Nobel Prize – 1998

What is Nitric Oxide?

• Unstable free radical gas

• Lipid Soluble, very small

• Highly reactive

Biosynthesis

• 3 main mechanisms:

• Via Nitric Oxide Synthase

• From Dietary Nitrates

• Nitric Oxide Donors

Major Pathway

Biosynthesis

via Nitric Oxide Synthase (NOS)

Biosynthesis

Nitric Oxide Synthase (NOS)

Neuronal NOS (nNOS)

Endothelial NOS (eNOS)

Inducible NOS (iNOS)

• Macrophages• Kupffer cells• Neutrophils• Fibroblasts• Vascular smooth

muscle

• Endothelium• Cardiac myocytes• Osteoblasts• Osteoclasts

• Neurons• Skeletal muscle

Constitutive Forms (Physiological)

Pathological

Biosynthesis

Activation of eNOS

Dr. Aditi M. Panditrao 10Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htm

Biosynthesis

Nitric Oxide Synthase (NOS)

• Long Term Potentiation

• Cardiac function, Peristalsis, Sexual arousal

eNOS• Vascular tone,

Insulin secretion, Airway tone, Regulation of cardiac function and angiogenesis

• Embryonic heart development

iNOS• In response to

attack by parasites, bacterial infection and tumor growth

• Causes septic shock, autoimmune conditions

Biosynthesis

• 3 main mechanisms:

• Via Nitric Oxide Synthase

• From Dietary Nitrates

• Nitric Oxide Donors

Pharmacokinetics

• Absorbed systemically after inhalation

• Moves across the pulmonary capillary bed - combines with hemoglobin

• Inactivation – Haem, Oxidation, Superoxide

• Nitrate - excreted in the urine

• No known storage mechanism in humans.

Inactivation

• Haem –Haem + NO → Methaemoglobin + Nitrate (urine)

• Oxidation – 2NO + O2 → N2O4

N2O4 + H2O → NO2- + NO3

- + 2H+

NO2- + HbO → NO3

- + Hb

Inactivation

• Superoxide –

NO(Nitric Oxide)

O2●-

(Superoxide)OONO-

(Peroxynitrite)

SOD(Superoxide Dismutase)

H2O2 + O2(Hydrogen Peroxide)

Cellular Injury

Mechanism of Action

• NO as a signaling molecule• NO in the nervous system• NO in the circulatory system• NO in the respiratory system• NO in the immune system• NO in the digestive system• NO in Cancer

NO – Signaling Molecule

1. Metalloproteins

2. Thiols

3. Tyrosine

Signaling Molecule

• Metalloproteins –

Signaling Molecule

• Thiols – • – SH containing• NO + Thiols → Nitrosothiols• Glutathione• Vascular Glutathione decreased in DM, Atherosclerosis

• Tyrosine Nitration – • Marker of oxidative stress and tissue damage

NO – Nervous System

• Neurotransmitter

• Retrograde Messenger• In learning and memory (non-declarative)

• Vasodilation – • Hypoxia

Nervous System

• Neurotransmitter?Similarities – • Present in presynaptic terminal• Natural removal from synaptic junction

Dissimilarities –

Nitric Oxide Neurotransmitters

Synthesized on demand Constant Synthesis

Diffuses out of cells Exocytosis from vesicles

Enters cell, binds to intracellular sGC

Binds to surface receptor

Nervous System

• Neurotransmitter?

• Assists other neurotransmitters

• Neuroprotective or Neurodegenerative?

NO and Pain

• In spinal cord

• Evidence of increased NO in states of Chronic Pain

• Sensitization of neurons to painful stimulus?

Neurotoxicity

• CNS dementia during AIDS• Multiple Sclerosis• Bacterial Meningitis• Migraine• Alzheimer’s Disease• Huntington’s Disease

NO – Circulatory System

• Vasodilator

• Antiatherosclerotic

• Antithrombotic

• Aids gas exchange between haemoglobin and cells

Smooth Muscle Contraction

Circulatory System

• Vasodilator -

Circulatory System

• Antiatherosclerotic & Antithrombotic

Circulatory System

• Heart • Depresses all cardiac functions

• Pre-eclampsia

• Sickle cell disease

NO – Immune System

• iNOS in phagocytes – NO

• Antibacterial, antiparasitic

• Formation of Reactive species

NO – Septic Shock

• Increased iNOS or NO

• Hypotension, cardiodepression, edema, vascular hypoactivity

• Tyrosine nitration?

NO – Respiratory System

• Bronchodilation

• Increased blood flow

• Shunting

• NO2 – Acute Lung Injury, Pneumothorax

Respiratory System

• Asthma –

• Inflammatory hyperreactivity of airway

• Increased NO production

• Exhaled NO – Biomarker

NO – Digestive System

• Stretching of stomach

• Gut motility

• Protective mechanisms

• Protective in NSAID induced injury?

NO – Cancer

• Pro Cancer –

• Angiogenesis• Invasion• Metastasis• Apoptosis of macrophages

NO - Cancer

• Anti Cancer –

• Cytotoxic

• Suppresses Cellular respiration

• Apoptotic

• Inhibits viral replication

NO - Miscellanous

• Impotence

• Infantile Hypertrophic Pyloric Stenosis

• Wound Healing

• Osteoarthritis

Therapeutic Applications

• Neonatal Hypoxic Respiratory Failure

• Pulmonary Hypertension (Adults)

• Adult Respiratory Distress Syndrome?

• Inhaled NO

• Inhaled NO – • Selective pulmonary vasodilator• Decrease Pulmonary Vascular Resistance• Improve oxygenation• Reduce inflammation• Antibacterial

• Unsatisfactory results from trials

• iNO Problems – • Disproportionate vascular selectivity• Systemic effects• Reacts with Oxygen• Methemoglobin• Prolongation of PT• Rebound Pulm. HTN and Hypoxemia• Infection

• Neonatal Respiratory Failure – • Start at 20 ppm• 5-14 days

• Pulmonary HTN • Heart and Lung Surgery• Asthma• Sickle Cell disease

NO Supplements

• Vasodilatory properties

• Side effects

• Not harmful in prescribed quantities

NO Donors

• Organic Nitrates – Nitroglycerin

• Organic Nitrites – Amyl nitrite

• Sodium Nitroprusside

• Beetroot

• NO releasers – Propofol, Nebivolol

• NO Inhibitors• NMMA (N- mono methyl arginine)• ADMA (Assymetric dimethyl arginine)• L-NAME (N-nitro-l-argenine methyl ester)

• NO potentiators – • PDE V Inhibitors• Statins, ACE-I, Insulin, Estrogens

Recent

• Use of iNO in neonates with surfactant dysfunction

• N-iminomethyl-L-lysine – selective iNOS inhibitor

• 7-nitroindazole-S-methyl-L-thiocitruline – selective nNOS inhibitor

• S-nitrosoglutathione (SNOG)• S-nitrosoacetylpenicillamine (SNAP)

Recent

• Epoprostenol (PGI2) – alternative to iNO

• Diazeniumdiolates – Anticancer(Nanoparticles)

• NO topical

• NO saliva test

• COX – inhibiting NO Donors – Naproxcinod

Thank You!!

Nitric oxide and its role in therapeutics

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