Downloaded 33 times
Uploaded byMohammad Elshawwa MD
Seminar0
Nitric oxide (NO) is involved in many physiological processes as a signaling molecule. It is synthesized endogenously through nitric oxide synthase enzymes and was named "Molecule of the Year" in 1992. NO regulates processes in the cardiovascular, respiratory, nervous, reproductive, immune, muscular and digestive systems. It acts as a vasodilator, neurotransmitter, and promotes smooth muscle relaxation. While NO has many beneficial functions, excessive amounts can also be toxic.
More Related Content
Seminar0
- 1. NITRIC OXIDE Dr. KANIMOZHI.S 1ST YEAR-MD PHYSIOLOGY
- 2. Prior to1990: An air pollutant Named “Molecule of the Year” by Science magazine in 1992 Robert Furchgott, Louis J Ignore, Ferid Murad got Nobel Prize in 1998 Furchgott IgnarroMurad
- 3. Nitric oxide(NO) is an endogenous messenger molecule that is extensively involved in the physiologic regulation of different tissues in the human body First described in 1979 as a potent relaxant of peripheral vascular smooth muscle Serves different functions depending on body system. i.e. neurotransmitter, vasodilator, bactericide etc
- 4. The structure andnature of NitricThe structure and nature of Nitric OxideOxide Nitric oxide is a 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 or reacted within a few seconds The natural form is a gas
- 5. Synthesis of Nitricoxide
- 6. Common chemical reactionsof nitric oxide
- 7. Interaction of NOwith free radicals Free radical formed by gaining an additional electron NO radical can react with peroxyl radical (RO2),hydroxyl radical (OH. ) and NO- to produce peroxinitrite, nitrous acid and nitrous oxide respectively.
- 8. NO NO bind toFe 2+ haem group of Guanylyl Cyclase Active Guanylate Cyclase Increased cGMP decreased intracellular Ca 2+ Relaxes muscle Dilating the vessel & lowering B.P.
- 9. Production of NO Thereare many organic nitrates and they can release NO through enzymatic or non- enzymatic reactions and have been used for a long time to relieve angina pectoris The organic nitrites produce NO which can react with thiols to give RSNO that can transport it where it is needed
- 10. Other importantclasses of NO donors are the diazetinedioxides, Furoxans, C-nitoso compound, Oxatriazole-5-imines One other possibility is to connect a NO- donor to known drugs. This can reduce the toxicity of the drug and add other effects connected to the NO-releasing capacity. eg NO aspirin
- 11.
- 12. Detection of NOand its derivatives classical method is colorimetric and fluorimetric griess system other methods are ESR and chemiluminescence
- 13.
- 14. NOS I (nNos) Central and peripheral neuronal cells Ca+2 dependent, used for neuronal communication NOS II (iNos) Most nucleated cells, particularly macrophages Independent of intracellular Ca+2 Inducible in presence of inflammatory cytokines NOS III (eNos) Vascular endothelial cells Ca+2 dependent Vascular regulation Types of NOS
- 15. Nitric Oxide inthe human body has many uses which are best summarized under following categories NO in the cardiovascular system NO in the respiratory system NO in the nervous system NO in reproductive system NO in the immune system NO in the muscular system NO in the digestive system NO in the kidneys
- 16. Cardiovascular system Endothelial cellsexpress eNOS, that is sensitive to Ca++ , as well as iNOS , that is Ca++ insensitive The largest bulk of NO within the cardiovascular system is produced by NOS III Main stimuli that activate the biosynthesis of NO by endothelium is blood flow
- 17. Arg NO GTP cGMP 5)NO binds to Guanylyl cyclase Relaxation of smooth muscle NO Smooth muscle cell blood vessel wall 4) NO diffuses across membranes 2) ACh binds to receptors on endothelial cells 3) Activate NO synthase 1) Stimulated nerve releases Acetylcholine(ACh) at Nerve terminal Nitric Oxide Signaling
- 18. Cells in cardiovasculartree synthesizing NO platelets (eNOS, iNOS) smooth muscle cells (iNOS) macrophages (iNOS) neutrophils (iNOS) cardiomyocytes (eNOS)
- 19. NO and platelets Plateletsand their progenitors contain a constitutive NOS identical to endothelial NOS and produce and release NO upon activation Platelet-derived NO inhibits P-selectin and GPIIb/IIIa expression in stimulated platelets Antiplatelet effects of NO include the inhibition of 12-lipoxygenase and cyclooxygenase-2. platelet recruitment and aggregation is inhibited by platelet-derived NO,thus preventing thrombosis
- 20. NO as atherapeutic agent in cvs diseases Direct NO donors Indirect NO donors Compounds that stimulate endogenous NO biosynthesis NO-ASA
- 21. NO-ASA (Nitroaspirin) Nitroaspirin hasbeen shown to exert a wider antiplatelet action as compared with aspirin In addition to the effects of aspirin other actions are: Antiproliferative action on SMC Prevents platelets induced pulmonary thromboembolism
- 22. Exerts tissue protectiveeffects in focal spontaneous ischemia in hypertensives Prevents restenosis and atherogenesis in aged and hypercholesterolemic individuals Prevents gastric toxicity
- 23. Respiratory system The gasis primarily produced in the lungs by cells in the airways (eg, epithelial cells in the lungs, endothelial cells in vessels, and neurons) NO promotes bronchodilation by directly relaxing the smooth muscles in the airway. Its produced continuously by the overlying airway epithelium NO may also play a critical role in ventilation- perfusion coupling in the lung
- 24. Role of NOin lung pathology Bronchial asthma Primary pulmonary hypertension Smoking Acute respiratory distress syndrome Persistent pulmonary hypertension in newborn High altitude pulmonary oedema
- 25. Inhalational nitric oxide NOis a potent vasodilator of vascular smooth muscle and when delivered by the inhalational route is a selective pulmonary vasodilator. Mechanism of Action Diffuses rapidly from alveolus to pulmonary vascular smooth muscle
- 26. Stimulates guanylate cyclaseactivity which increases the concentration of cyclic GMP which causes vasodilation Selectively reverses acute pulmonary vasoconstriction caused by hypoxia or thromboxane Rapidly inactivated by forming methemoglobin therefore does not cause systemic hypotension
- 27. Dosing of NO Continuousinhalational agent given through inspiratory limb of the breathing circuit Serum half-life is 3-4 seconds Theoretical effective range: 6-80 ppm Verify inhaled concentration of NO by using inline chemiluminescence
- 28.
- 29. Treatment 100% O2 methyleneblue exchange transfusion hyperbaric oxygen
- 31. Nervous system NO isa signaling molecule, also acts as a retrograde neurotransmitter NO signals inhibition of smooth muscle contraction, adaptive relaxation, and localized vasodilation Nitric oxide believed to play a role in long term potentiation in hippocampus
- 33. Difference between NOand other NT NO is synthesized on demand Not stored in vesicles Rather than exocytosis it simply diffuses between nerve terminals NO does not bind to surface receptors, but instead exits cytoplasm, enters the target cell, and binds with intracellular guanylyl cyclase
- 34. In the adrenalgland, nNOS occurs in discrete ganglion cells and fibers in the medulla, Splanchnic nerve stimulation augments both blood flow and catecholamine secretion from the adrenal medulla In blood vessels, besides localizations in the endothelium, nNOS occurs in autonomic nerves in the outer, adventitial layers of various large blood vessels
- 35. nNOS neurons occurin the myenteric plexus throughout the gastrointestinal pathway. Depolarization of myenteric plexus neurons is associated with relaxation of the smooth muscle associated with peristalsis
- 36. Reproductive system Nitric oxide(NO) plays a crucial role in reproduction at every level in the organism In the brain, it activates the release of luteinizing hormone-releasing hormone (LHRH) The axons of the LHRH neurons project to the mating centers in the brain stem and by afferent pathways evoke the lordosis reflex in females
- 37. In males, thereis activation of NOergic terminals that release NO in the corpora cavernosa penis to induce erection by generation of cyclic guanosine monophosphate (cGMP) NO also activates the release of LHRH which reaches the pituitary and activates the release of gonadotropins by activating neural NO synthase (nNOS) in the pituitary gland In the gonad, NO plays an important role in inducing ovulation and in the reproductive tract, it relaxes uterine muscle via cGMP
- 40. Immune system NOS IIcatalyzes synthesis of NO used in host defense reactions Activation of NOS II is independent of Ca+2 in the cell Synthesis of NO happens in most nucleated cells, particularly macrophages NO is a potent inhibitor of viral replication
- 41. NO is abactericidal agent NO is created from the nitrates extracted from food near the gums This kills bacteria in the mouth that may be harmful to the body
- 42. Digestive system NO isused in adaptive relaxation NO promotes the stretching of the stomach in response to filling When the stomach gets full, stretch receptors trigger smooth muscle relaxation through NO releasing neurons
- 43. Muscular system NO wasorginally called EDRF (endothelium derived relaxation factor) NO signals inhibition of smooth muscle contraction Ca+2 is released from the vascular lumen activating NOS NO is synthesized from NOS III in vascular endothelial cells
- 44. This causes guanylylcyclase to produce cGMP A rise in cGMP causes Ca2+ pumps to be activated, thus reducing Ca2+ concentration in the cell This causes muscle relaxation
- 45. Role of NOin kidneys plays a major role in renal vascular biology in terms of anti-thrombotic anti-inflammatory antiproliferative antioxidative effect
- 46. Functions of NOin kidneys Renal macrovascular and microvascular dilatation (afferent > efferent) Regulation of mitochondrial respiration Modulation renal medullary blood flow Stimulation of fluid, sodium and HCO3 reabsorption in the proximal tubule
- 47. Inhibition ofNa+ , Cl- and HCO3 reabsorption in the mTALH Inhibition of Na+ conductance in the CCD Inhibition of H+ -ATPase in CCD
- 48. Excessive release ofNO causes Neurotoxicity (stroke and neurodegenerative diseases) Hypotension in septic shock Reperfusion injury Carcinogenesis
- 49. Conclusion NO is auniversal messenger molecule It is involved in a wide variety of pathophysiogical and biochemical reactions. In summary NO is involved in regulation of B.P., prevention of aggregation and adhesion of platelets, promotion of penile erection. Other way to increase active concentration of endogenous NO such as by prolonging its half life of duration of its actions
- 50. NO donating compoundscan be used as replacement therapy to treat its impaired production NO also as therapeutic potential for Ischemic CVS diseases, pulmonary hypertension associated with cardiac and respiratory diseases They are far from ideal because of the associated side effect mainly due to the catabolism of NO into NO2 Therefore a technology to regulate in vivo synthesis of NO by genetic manipulation would be a welcome move