Nitric oxide - Importance for a Physician - General Medicine

1. Nitric Oxide
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GUIDED BY
DR.SEETARAM N K SIR
ASST PROFESSOR
DEPT OF MEDICINE
KIMS
HUBLI
PRESENTED BY
DR.SURYAKANTH
PG
DEPT OF MEDICINE
KIMS
HUBLI

2. Nitric Oxide – A unique molecule
• Harmful and Helpful
• Discovered – 240 years ago
• Function in body – 31 years ago
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3. Robert Furchgott Louis Ignarro Ferid Murad
Nobel Prize – 1998
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4. What is Nitric Oxide?
• Unstable free radical gas
• Lipid Soluble, very small
• Highly reactive
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5. Biosynthesis
• 3 main mechanisms:
• Via Nitric Oxide Synthase
• From Dietary Nitrates
• Nitric Oxide Donors
Major Pathway
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6. Biosynthesis
via Nitric Oxide Synthase (NOS)
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7. 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
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8. Biosynthesis
Activation of eNOS
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9. 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.
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10. Inactivation
• Haem –
Haem + NO → Methaemoglobin + Nitrate (urine)
• Oxidation –
2NO + O → N O2 2 4
N O + H O → NO2 4
-
2 2
-
+ NO3
-
+ 2H+
NO2 + HbO → NO3
-
+ Hb
HAEM
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11. Inactivation
• Superoxide –
NO
(Nitric Oxide)
O2
●-
(Superoxide)
OONO-
(Peroxynitrite)
SOD
(Superoxide
Dismutase)
H O + O2 2 2
(Hydrogen
Peroxide)
Cellular
Injury
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12. Mechanism of Action
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14. Role?
• 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
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15. NO – Signaling Molecule
1. Metalloproteins
2. Thiols
3. Tyrosine
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16. Signaling Molecule
• Thiols –
• – SH containing
• NO + Thiols → Nitrosothiols
• Glutathione
• Vascular Glutathione decreased in DM, Atherosclerosis
• Tyrosine Nitration –
• Marker of oxidative stress and tissue damage
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17. NO – Nervous System
• Neurotransmitter
• Retrograde Messenger
• In learning and memory (non-declarative)
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19. 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
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20. Nervous System
• Neurotransmitter?
• Assists other neurotransmitters
• Neuroprotective or Neurodegenerative.
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21. NO and Pain
• In spinal cord
• Evidence of increased NO in states of Chronic
Pain
• Sensitization of neurons to painful stimulus.
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22. Neurotoxicity
• CNS dementia during AIDS
• Multiple Sclerosis
• Bacterial Meningitis
• Migraine
• Alzheimer’s Disease
• Huntington’s Disease
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23. NO – Circulatory System
• Vasodilator
• Antiatherosclerotic
• Antithrombotic
• Aids gas exchange between haemoglobin and
cells
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24. Circulatory System
• Vasodilator -
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25. Circulatory System
• Antiatherosclerotic & Antithrombotic
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27. Circulatory System
• Heart
• Depresses all cardiac functions
• Pre-eclampsia
• Sickle cell disease
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28. NO – Immune System
• iNOS in phagocytes – NO
• Antibacterial, antiparasitic
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30. NO – Septic Shock
• Increased iNOS or NO
• Hypotension, Cardiodepression, Edema,
Vascular Hypoactivity.
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31. NO – Respiratory System
• Bronchodilation
• Increased blood flow
• Shunting
• Acute Lung Injury
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32. Respiratory System
• Asthma –
• Inflammatory hyperreactivity of airway
• Increased NO production
• Exhaled NO – Biomarker
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35. NO – Digestive System
• Stretching of stomach
• Gut motility
• Protective mechanisms
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36. NO – Cancer
• Pro Cancer –
• Angiogenesis
• Invasion
• Metastasis
• Apoptosis of macrophages
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37. NO - Cancer
• Anti Cancer –
• Cytotoxic
• Suppresses Cellular respiration
• Apoptotic
• Inhibits viral replication
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38. NO - Miscellanous
• Impotence
• Infantile Hypertrophic Pyloric Stenosis
• Wound Healing
• Osteoarthritis
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40. Therapeutic Applications
• Neonatal Hypoxic Respiratory Failure
• Pulmonary Hypertension (Adults)
• Adult Respiratory Distress Syndrome.
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41. Therapeutic Applications
• Inhaled NO –
• Selective pulmonary vasodilator
• Decrease Pulmonary Vascular Resistance
• Improve oxygenation
• Reduce inflammation
• Antibacterial
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42. Therapeutic Applications
• iNO Problems –
• Disproportionate vascular selectivity
• Systemic effects
• Reacts with Oxygen
• Methemoglobin
• Rebound Pulm. HTN and Hypoxemia
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44. Therapeutic Applications
• Neonatal Respiratory Failure –
• Start at 20 ppm
• 5-14 days
• Pulmonary HTN
• Heart and Lung Surgery
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45. NO Supplements
• Vasodilatory properties
• Not harmful in prescribed quantities
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47. NO Donors
• Organic Nitrates – Nitroglycerin
• Organic Nitrites – Amyl nitrite
• Sodium Nitroprusside
• Beetroot
• NO releasers – Propofol, Nebivolol
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48. • 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
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49. Recent
• Use of iNO in neonates with surfactant dysfunction
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50. 62Dr. Aditi M. Panditrao

51. References
1. 14TH ED, KATZUNG PHARMACOLOGY
2. 8TH ED, SATYANARAYAN BIOCHEMISTRY
3. GANONGS TEXTBOOK OF PHYSIOLOGY
4. ROBBINS TEXTBOOK OF PATHOLOGY, 10TH ED
5. RECENT ARTICLES FROM NCBI

52. Thank
You!!

53. ECG FOR TODAY.