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Nitric Oxide
2
GUIDED BY
DR.SEETARAM N K SIR
ASST PROFESSOR
DEPT OF MEDICINE
KIMS
HUBLI
PRESENTED BY
DR.SURYAKANTH
PG
DEPT OF MEDICINE
KIMS
HUBLI
Nitric Oxide – A unique molecule
• Harmful and Helpful
• Discovered – 240 years ago
• Function in body – 31 years ago
3
Robert Furchgott Louis Ignarro Ferid Murad
Nobel Prize – 1998
4
What is Nitric Oxide?
• Unstable free radical gas
• Lipid Soluble, very small
• Highly reactive
5
Biosynthesis
• 3 main mechanisms:
• Via Nitric Oxide Synthase
• From Dietary Nitrates
• Nitric Oxide Donors
Major Pathway
6
Biosynthesis
via Nitric Oxide Synthase (NOS)
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
8
Biosynthesis
Activation of eNOS
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.
14
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
15
Inactivation
• Superoxide –
NO
(Nitric Oxide)
O2
●-
(Superoxide)
OONO-
(Peroxynitrite)
SOD
(Superoxide
Dismutase)
H O + O2 2 2
(Hydrogen
Peroxide)
Cellular
Injury
16
Mechanism of Action
17
18
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
19
NO – Signaling Molecule
1. Metalloproteins
2. Thiols
3. Tyrosine
20
Signaling Molecule
• Thiols –
• – SH containing
• NO + Thiols → Nitrosothiols
• Glutathione
• Vascular Glutathione decreased in DM, Atherosclerosis
• Tyrosine Nitration –
• Marker of oxidative stress and tissue damage
23
NO – Nervous System
• Neurotransmitter
• Retrograde Messenger
• In learning and memory (non-declarative)
24
25
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
26
Nervous System
• Neurotransmitter?
• Assists other neurotransmitters
• Neuroprotective or Neurodegenerative.
27
NO and Pain
• In spinal cord
• Evidence of increased NO in states of Chronic
Pain
• Sensitization of neurons to painful stimulus.
28
Neurotoxicity
• CNS dementia during AIDS
• Multiple Sclerosis
• Bacterial Meningitis
• Migraine
• Alzheimer’s Disease
• Huntington’s Disease
29
NO – Circulatory System
• Vasodilator
• Antiatherosclerotic
• Antithrombotic
• Aids gas exchange between haemoglobin and
cells
30
Circulatory System
• Vasodilator -
32
Circulatory System
• Antiatherosclerotic & Antithrombotic
34
35
Circulatory System
• Heart
• Depresses all cardiac functions
• Pre-eclampsia
• Sickle cell disease
36
NO – Immune System
• iNOS in phagocytes – NO
• Antibacterial, antiparasitic
37
38
NO – Septic Shock
• Increased iNOS or NO
• Hypotension, Cardiodepression, Edema,
Vascular Hypoactivity.
39
NO – Respiratory System
• Bronchodilation
• Increased blood flow
• Shunting
• Acute Lung Injury
40
Respiratory System
• Asthma –
• Inflammatory hyperreactivity of airway
• Increased NO production
• Exhaled NO – Biomarker
41
42
43
NO – Digestive System
• Stretching of stomach
• Gut motility
• Protective mechanisms
44
NO – Cancer
• Pro Cancer –
• Angiogenesis
• Invasion
• Metastasis
• Apoptosis of macrophages
45
NO - Cancer
• Anti Cancer –
• Cytotoxic
• Suppresses Cellular respiration
• Apoptotic
• Inhibits viral replication
46
NO - Miscellanous
• Impotence
• Infantile Hypertrophic Pyloric Stenosis
• Wound Healing
• Osteoarthritis
48
49
Therapeutic Applications
• Neonatal Hypoxic Respiratory Failure
• Pulmonary Hypertension (Adults)
• Adult Respiratory Distress Syndrome.
50
Therapeutic Applications
• Inhaled NO –
• Selective pulmonary vasodilator
• Decrease Pulmonary Vascular Resistance
• Improve oxygenation
• Reduce inflammation
• Antibacterial
52
Therapeutic Applications
• iNO Problems –
• Disproportionate vascular selectivity
• Systemic effects
• Reacts with Oxygen
• Methemoglobin
• Rebound Pulm. HTN and Hypoxemia
53
51
Therapeutic Applications
• Neonatal Respiratory Failure –
• Start at 20 ppm
• 5-14 days
• Pulmonary HTN
• Heart and Lung Surgery
54
NO Supplements
• Vasodilatory properties
• Not harmful in prescribed quantities
55
56
NO Donors
• Organic Nitrates – Nitroglycerin
• Organic Nitrites – Amyl nitrite
• Sodium Nitroprusside
• Beetroot
• NO releasers – Propofol, Nebivolol
57
• 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
58
Recent
• Use of iNO in neonates with surfactant dysfunction
59
62Dr. Aditi M. Panditrao
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
Thank
You!!
ECG FOR TODAY.

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Nitric oxide - Importance for a Physician - General Medicine

  • 1. Nitric Oxide 2 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 3
  • 3. Robert Furchgott Louis Ignarro Ferid Murad Nobel Prize – 1998 4
  • 4. What is Nitric Oxide? • Unstable free radical gas • Lipid Soluble, very small • Highly reactive 5
  • 5. Biosynthesis • 3 main mechanisms: • Via Nitric Oxide Synthase • From Dietary Nitrates • Nitric Oxide Donors Major Pathway 6
  • 6. Biosynthesis via Nitric Oxide Synthase (NOS) 7
  • 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 8
  • 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. 14
  • 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 15
  • 11. Inactivation • Superoxide – NO (Nitric Oxide) O2 ●- (Superoxide) OONO- (Peroxynitrite) SOD (Superoxide Dismutase) H O + O2 2 2 (Hydrogen Peroxide) Cellular Injury 16
  • 13. 18
  • 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 19
  • 15. NO – Signaling Molecule 1. Metalloproteins 2. Thiols 3. Tyrosine 20
  • 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 23
  • 17. NO – Nervous System • Neurotransmitter • Retrograde Messenger • In learning and memory (non-declarative) 24
  • 18. 25
  • 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 26
  • 20. Nervous System • Neurotransmitter? • Assists other neurotransmitters • Neuroprotective or Neurodegenerative. 27
  • 21. NO and Pain • In spinal cord • Evidence of increased NO in states of Chronic Pain • Sensitization of neurons to painful stimulus. 28
  • 22. Neurotoxicity • CNS dementia during AIDS • Multiple Sclerosis • Bacterial Meningitis • Migraine • Alzheimer’s Disease • Huntington’s Disease 29
  • 23. NO – Circulatory System • Vasodilator • Antiatherosclerotic • Antithrombotic • Aids gas exchange between haemoglobin and cells 30
  • 26. 35
  • 27. Circulatory System • Heart • Depresses all cardiac functions • Pre-eclampsia • Sickle cell disease 36
  • 28. NO – Immune System • iNOS in phagocytes – NO • Antibacterial, antiparasitic 37
  • 29. 38
  • 30. NO – Septic Shock • Increased iNOS or NO • Hypotension, Cardiodepression, Edema, Vascular Hypoactivity. 39
  • 31. NO – Respiratory System • Bronchodilation • Increased blood flow • Shunting • Acute Lung Injury 40
  • 32. Respiratory System • Asthma – • Inflammatory hyperreactivity of airway • Increased NO production • Exhaled NO – Biomarker 41
  • 33. 42
  • 34. 43
  • 35. NO – Digestive System • Stretching of stomach • Gut motility • Protective mechanisms 44
  • 36. NO – Cancer • Pro Cancer – • Angiogenesis • Invasion • Metastasis • Apoptosis of macrophages 45
  • 37. NO - Cancer • Anti Cancer – • Cytotoxic • Suppresses Cellular respiration • Apoptotic • Inhibits viral replication 46
  • 38. NO - Miscellanous • Impotence • Infantile Hypertrophic Pyloric Stenosis • Wound Healing • Osteoarthritis 48
  • 39. 49
  • 40. Therapeutic Applications • Neonatal Hypoxic Respiratory Failure • Pulmonary Hypertension (Adults) • Adult Respiratory Distress Syndrome. 50
  • 41. Therapeutic Applications • Inhaled NO – • Selective pulmonary vasodilator • Decrease Pulmonary Vascular Resistance • Improve oxygenation • Reduce inflammation • Antibacterial 52
  • 42. Therapeutic Applications • iNO Problems – • Disproportionate vascular selectivity • Systemic effects • Reacts with Oxygen • Methemoglobin • Rebound Pulm. HTN and Hypoxemia 53
  • 43. 51
  • 44. Therapeutic Applications • Neonatal Respiratory Failure – • Start at 20 ppm • 5-14 days • Pulmonary HTN • Heart and Lung Surgery 54
  • 45. NO Supplements • Vasodilatory properties • Not harmful in prescribed quantities 55
  • 46. 56
  • 47. NO Donors • Organic Nitrates – Nitroglycerin • Organic Nitrites – Amyl nitrite • Sodium Nitroprusside • Beetroot • NO releasers – Propofol, Nebivolol 57
  • 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 58
  • 49. Recent • Use of iNO in neonates with surfactant dysfunction 59
  • 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