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![ Goodman and Gilman’s, local anaesthetics and therapeutic gases,
chapter 19, the pharmacological basis of therapeutics, 12th edition, 561
Bertram G. Katzung, vasodilators, chapter 12, Basic and Clinical
Pharmacology, 13th edition, 194
H. Sharma, Vasoactive peptides and nitric oxide, chapter 17, principles of
pharmacology, 2nd edition, 238
Stuart-Smith K. Demystified, Nitric oxide [Internet]. PubMed Central
(PMC). 2017 [cited 18 January 2017]. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1187271/
De Oliveira GA e. Inducible Nitric Oxide Synthase in the Carcinogenesis
of Gastrointestinal Cancers. - PubMed - NCBI [Internet].
Ncbi.nlm.nih.gov. 2017 [cited 18 January 2017]. Available from:
https://www.ncbi.nlm.nih.gov/pubmed/27494631
REFERENCES
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Uploaded byDr. Vishal Pawar
Nitric oxide
Nitric oxide (NO) is a unique signalling molecule that diffuses freely and acts as an intracellular and intercellular messenger. NO was discovered in the late 1970s and plays many important physiological roles such as acting as a neurotransmitter, mediating cellular defense, and regulating vascular tone. It is produced from L-arginine by the enzyme nitric oxide synthase (NOS) which exists in three isoforms. NO has various effects in different organ systems such as the cardiovascular, nervous, immune, and reproductive systems. Therapeutic uses of NO include treatment of pulmonary hypertension and angina. Recent research is focused on developing NO-releasing drugs for various conditions.
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Nitric oxide
- 1. NITRIC OXIDE By :Dr. Vishal Pawar JR 1 Dept. of Pharmacology 1
- 2. Nitric oxide(NO) – simple, unique, gaseous, ubiquitous signalling molecule Readily diffuses across cell membranes Acts – intra cellular, cell to cell messenger INTRODUCTION 2
- 3. Neurotransmitter (NonAdrenergic Non Cholinergic) Mediation of cellular defence More recently, NO - implicated in tumor progression, inflammation and cardiac myocytes development from embryonic stem cells 3
- 4. Discovery: Greatestachievement of vascular biology in the latter part of the 20th century Late 1970s, Robert Furchgott began to examine acetylcholine behaviour Awarded Nobel Prize in Physiology and Medicine HISTORY 4
- 5. Furchgott established– arterial relaxation in response to acetylcholine only occurred if the endothelium was present Endothelium dependent relaxing factor (EDRF) and NO were conclusively shown to be the same molecule Moncada’s group showed that NO is derived from the amino acid L-arginine, and that NO synthesis takes place in endothelial cells5
- 6. Shown toinitiate vascular smooth muscle relaxation by stimulation of guanylyl cyclase and a rise in cGMP NO synthase (NOS), the enzyme responsible for the conversion of L-arginine to L-citrulline With the consequent production of NO, was isolated and purified by Bredt and Snyder in 1990 6
- 7. Nitric oxide -diatomic free radical consisting of one atom of nitrogen and one atom of oxygen Lipid soluble and very small, for easy passage between cell membranes Short lived, usually degraded within a few seconds The natural form - gas NITRIC OXIDE 7
- 8. Synthesised L- Arginine and Molecular Oxygen Enzyme – Nitric Oxide Synthase (NOS) NOS present in 3 isoforms Endothelium (eNOS), Neurons (nNOS), Inducible (iNOS) BIOSYNTHESIS 8
- 9.
- 10. eNOS, nNOS– present constitutively various tissues nNOS – peripheral, central neurons eNOS – cardiac myocytes, platelets, osteoblasts, osteoclasts, renal mesangial cells, endothelium 10
- 11. Activation –requires Ca++ and binding with Calmodulin Shear mechanical stress, Acetylcholine, Bradykinin, Substance P increased Ca++ activation eNOS, nNOS Generates – pico molecules of NO 11
- 12. For ashort duration Inhibitors eNOS : L Nitro Arginine Methyl Ester (L-NAME) nNOS : 7 Nitro Indazole 12
- 13. iNOS Expressed macrophages, kupffer cells, fibroblasts, vascular smooth muscle cells, endothelium Induced response to pathological stimuli, invading micro organisms and resulting cytokines (interferon Gamma) Inhibited glucocorticoids, cytokines (transforming growth factor Beta) 13
- 14. activity independent- intracellular Ca++ Generation of NO: large amounts, long duration Expression on demand during inflammation, governed transcription factor eNOS: membrane bound enzyme nNOS, iNOS: cystolic soluble enzymes14
- 15. NO -relatively labile free radical - half-life of less than 5 s - NO cannot be stored in free form Must generally be synthesized on demand Activity of NOS enzymes - carefully controlled activation and inactivation - developed through multiple interconnected mechanisms 15
- 16. Oxygenated nitroprusside– spontaneously – NO Organic nitrates, nitrites – presence of thiol compound (cysteine) – NO NO or stable form (R-SNO) interacts haem moiety of soluble Guanylate Cyclase, in cytoplasm Promotes conversion GTP cGMP NO DONORS 16
- 17. cGMP vascular relaxation by Ca++ Dephosphorylation of myosine light chain – PO4 (MLC-PO4) to MLC Prevents interaction of myosine and actin Smooth muscle relaxation 17
- 18.
- 19. Phosphodiesterase Vinhibitors like sildenafil Prolong duration of NO induced cGMP elevation in erectile tissue Hence used for treatment of erectile dysfunction 19
- 20. Combination withhaem of Haemoglobin or oxidation to nitrate or nitrite excreted urine Scavenger of superoxide anion – superoxide dismutase protect degradation NO Thus enhancing potency and prolonging duration of action NO INACTIVATORS 20
- 21. NO +Superoxide Anion = Peroxynitrite (ONOO) More toxic – inhibits –SH containing enzymes Glutathione reduces this toxicity DM, Atherosclerosis, cerebral vasospasm vascular glutathione cardiovascular complications 21
- 22. NO +Glutathione (physiological) stable S-Nitrosoglutathione – longer acting adduct/carrier NO + Haem Nitrate + Methhaemoglobin, presence of oxygen 22
- 23. SYSTEM PHYSIOLOGICAL PATHOPHYSIOLOGICAL Smoothmuscle Via eNOS - Vasodilation - Bronchodilation - GI motility OVERPRODUCTION - Hypotension - Ischemia - Reperfusion injury INADEQUATE - Hypertension - Atherosclerosis Cardiovascular Via eNOS Maintenance of vascular integrity, inhibit platelet aggregation, inhibit smooth muscle and fibroblast proliferation, anti-atherosclerotic action Central nervous Via nNOS and eNOS - Neurotransmitter - Nociception - Improved learning, memory Neurotoxicity - huntingtons - ischaemic stroke - dementia CELLULAR AND BIOCHEMICAL EFFECTS OF NO 23
- 24. Peripheral nervous Via nNOS and eNOS -Neurotransmitter in NANC neurons - increased gastric emptying - Pulmonary vasodilation Portal Cirrhosis - Erectile Dysfunction - Hypertrophic pyloric stenosis - bronchial asthama - Renal failure Immune Via iNOS, large amounts of NO - Antibacterial - Antiviral - Antifungal - Antiprotozoal - Antiparasitic - Tumorocidal - Apoptosis - Nonspecific immunity - Bacterial sepsis - Transplant rejection 24
- 25.
- 26. Release ofNO around the glomeruli of the kidney Increases blood flow through them increasing Rate of filtration Urine formation KIDNEY FUNCTION 26
- 27. NO believed toplay a role in long term memory Synthesis mechanism involving Ca/Calmodulin activates NOS-I NO travels from postsynaptic neuron back to presynaptic neuron which activates guanylyl cyclase, the enzyme that catalyzes cGMP production This starts a cycle of nerve action potentials driven by NO NITRIC OXIDE IN THE NERVOUS SYSTEM 27
- 28. NO affectssecretion from several endocrine glands For examples, it stimulates the release of Gonadotropin-releasing hormone (GnRH) from the hypothalamus Release of pancreatic amylase from the exocrine portion of the pancreas Release of adrenaline from the adrenal medulla EFFECTS ON SECRETION 28
- 29. Birth NO inhibitscontractility of smooth muscle wall of uterus As moment of birth approaches, production of NO decreases Nitroglycerine helped some women at risk of giving birth prematurely to carry their baby to full term OTHER ACTIONS ON SMOOTH MUSCLE 29
- 30. Acrosome attip of sperm heads activates its NO synthase when it enters the egg Resulting release NO in the egg is essential for triggering next steps Blocking the entry of additional sperm Orienting the pronuclei for fusion NO AND FERTILIZATION 30
- 31. Erection ofpenis during sexual excitation mediated by NO released from nerve endings close to the blood vessels of the penis Relaxation of vessels causes blood to pool in blood sinuses producing an erection Three popular prescription drugs Sildenafil (Viagra) Vardenafil (Levitra) Tadalafil (Cialis) PENILE ERECTION 31
- 32. Nitrovasodilator Drugs Drugs Affecting NOS mRNA and/or Protein Levels Drugs Affecting NOS Activity: NOS Inhibitors NO potentiators PHARMACOLOGIC INTERVENTION IN NO PHYSIOLOGY 32
- 33. Nitrovasodilator Drugs Glyceryltrinitrate (nitroglycerin) Isosorbide dinitrate Sodium nitroprusside Nitrovasodilators - management of coronary artery disease, angina pectoris, and congestive heart failure 33
- 34. Drugs AffectingNOS mRNA and/or Protein Levels Cardioprotective drugs: Statins Angiotensin-converting enzyme inhibitors (ACEI) Angiotensin receptor blockers (ARB) Calcium channel blockers (CCB) (DHP &BTP)34
- 35. Drugs AffectingNOS Activity: NOS Inhibitors Antagonists of the cofactors Calmodulin antagonists Calcium chelators Phosphatases and kinases 35
- 36. Inhaled –selectively dilated pulmonary vasculature Minimal cardiovascular effects due to its rapid inactivation by oxyhaemoglobin in pulmonary circulation Ventilation perfusion matching – preserved or improved because only distributed to ventilated areas of lungs THERAPEUTIC USES 36
- 37. Inhaled NO(iNO) : elevated pulmonary artery pressure and pulmonary vascular resistance, often improves oxygenation Inhaled NO – FDA approved only for persistant pulmonary hypertension of newborn NO mediated guanyly cyclase activation inhibits platelet aggregation and relaxes smooth muscle in bronchi and GIT 37
- 38. Nitrites, Nitrates,Nitroglycerine, Nitroso compounds, useful - Angina, Myocardial Infarction, Hypertension Phosphodiesterase V inhibitors, used for erectile dysfunction Inducible Nitric Oxide Synthase – Carcinogenesis of Gastrointestinal Cancers 38
- 39. Cardiac catheterization– safely, selectively evaluate pulmonary vasodilating capacity, patient with heart failure, infants with congenital heart disease Diffusion capacity across alveolar-capillary unit Measurement of fractional exhaled NO (FeNO) – non invasive marker for airway inflammation, utility in asthma, respiratory tract infections, chronic lung diseases DIAGNOSTIC USES 39
- 40. Important requirementsfor safe NO inhalation therapy Continuous measurement NO concentration Intermittent analysis of Methhaemoglobin levels Use of certified NO tanks Administration of lowest possible NO concentration required for therapeutic effect 40
- 41. Pulmonary toxicityat increases levels of NO Meth Haemoglobinemia Immune system: macrophage induced cytotoxicity TOXICITY 41
- 42. Over production:mediator of inflammation Neuron: long term potentiation cytotoxicity resulting from N-Methyl D-Aspartate (NMDA) and NANC transmission 42
- 43. NCX 320- dual acting compound releasing nitric oxide (NO) and ibuprofen, significant therapeutic effects in mouse model of muscular dystrophy NO-donors and NOS-inhibitors - effective, safe, and inexpensive drugs to regulate and steer various functions in female reproductive life RECENT ADVANCES 43
- 44. Preventing possiblylethal pregnancy complications such as preeclampsia Peroxisome Proliferator-Activated Receptor γ Ligands (prostaglandin J2 (15d-PGJ2) - Increase Release of Nitric Oxide From Endothelial Cells 44
- 45. Novel NOdonor drugs 3 major drug classes Diazeniumdiolates S-nitrosothiols Mesoionic oxatriazoles 45
- 46. Hybrid NOdonor drugs: Recent development in NO donor drug - hybridization of NO donor moieties with currently available cardiovascular drugs The first example of such a compound was S-nitrosocaptopril (SNOCap) SNOCap combines NO donor properties with an inhibitory effect on angiotensin converting enzyme (ACE) 46
- 47. Similarly, furoxan- calcium antagonists retained their ability to bind to and inhibit Ca2+ channels, as well as to cause vasodilatation 47
- 48. NO isa miraculous molecule, with innumerable effects on various parts of the human body Studying its role has greatly help in our understand of vascular physiology A great many drugs being used wide spread all across the globe act through NO activation Recent advances in studyding NO and its properties has helped us to understand vascular, smooth muscle relaxation to great depths 48 CONCLUSION
- 49. Goodman andGilman’s, local anaesthetics and therapeutic gases, chapter 19, the pharmacological basis of therapeutics, 12th edition, 561 Bertram G. Katzung, vasodilators, chapter 12, Basic and Clinical Pharmacology, 13th edition, 194 H. Sharma, Vasoactive peptides and nitric oxide, chapter 17, principles of pharmacology, 2nd edition, 238 Stuart-Smith K. Demystified, Nitric oxide [Internet]. PubMed Central (PMC). 2017 [cited 18 January 2017]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1187271/ De Oliveira GA e. Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers. - PubMed - NCBI [Internet]. Ncbi.nlm.nih.gov. 2017 [cited 18 January 2017]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27494631 REFERENCES 49
- 50.