Nitric oxide - Importance for a Physician - General Medicine
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This document provides an overview of nitric oxide, including: 1. Nitric oxide is produced in the body through nitric oxide synthase and acts as a signaling molecule through metalloproteins, thiols, and tyrosine. 2. It plays important roles in the nervous, circulatory, immune, respiratory, and digestive systems as a neurotransmitter, vasodilator, and part of the immune response. 3. Therapeutic applications of inhaled nitric oxide include treating neonatal respiratory failure, pulmonary hypertension, and acute respiratory distress syndrome.
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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
- 24. Circulatory System • Vasodilator - 32
- 25. Circulatory System • Antiatherosclerotic & Antithrombotic 34
- 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
- 52. Thank You!!
- 53. ECG FOR TODAY.