nitric oxide as a unique bioactive signaling messenger in physiology and pathophysiology speaker:...
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Nitric Oxide as a Unique Nitric Oxide as a Unique Bioactive Signaling Messenger Bioactive Signaling Messenger
in Physiology and in Physiology and
PathophysiologyPathophysiology
Speaker: Dr. R. A. Siddique
B.V.Sc., M.V.Sc., PhD Scholar
Division of Animal Biochemistry
National Dairy Research Institute, Karnal
INDIA , 132001
E-mail- [email protected]
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Background InformationBackground Information
Prior to 1990: An air pollutantPrior to 1990: An air pollutant Named “Molecule of the Year” by Science magazine in 1992Named “Molecule of the Year” by Science magazine in 1992
Robert Furchgott, Louis J Ignore, Ferid Murad:Robert Furchgott, Louis J Ignore, Ferid Murad: Nobel Prize 1998Nobel Prize 1998 Properties of NO:Properties of NO:• Small water and lipid soluble gasSmall water and lipid soluble gas• Gaseous free radicalGaseous free radical
Three interchangeable forms:Three interchangeable forms: NO: Nitric OxideNO: Nitric Oxide NONO++: Nitrosonium cation: Nitrosonium cation NONO- - : Nitroxyl Radical: Nitroxyl Radical
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NO: Unique messenger and play important role in following NO: Unique messenger and play important role in following functions:functions:
Neuronal signalingNeuronal signaling
Penile erectionPenile erection
Cardiovascular homeostasisCardiovascular homeostasis
Decompensation in atherogenesis Decompensation in atherogenesis
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CVS also affected by NO production and regulate:CVS also affected by NO production and regulate:
Cardiovascular motor toneCardiovascular motor tone
Modulation of myocardial contractilityModulation of myocardial contractility
Inhibition of platelet activation aggregation and adhesion Inhibition of platelet activation aggregation and adhesion
Source of NO in CVS: eNOSSource of NO in CVS: eNOS Inhibition of chronic NO synthesis neurogenic and Inhibition of chronic NO synthesis neurogenic and
arterial hypertension Myocardial fibrosisarterial hypertension Myocardial fibrosis
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Interaction of NO with Free RadicalsInteraction of NO with Free Radicals
Free radicals-unpaired electron –paramagneticFree radicals-unpaired electron –paramagnetic
Free radical formed by gaining an additional electron. NO radical Free radical formed by gaining an additional electron. NO radical can react with peroxyl radical (ROcan react with peroxyl radical (RO22),hydroxyl radical (OH),hydroxyl radical (OH..) and NO) and NO- -
to produce peroxinitrite, nitrous acid and nitrous oxide respectively.to produce peroxinitrite, nitrous acid and nitrous oxide respectively.
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Synthesis of Nitric Acid
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Contd…
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Contd…
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Contd..
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Contd…
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Nitric Oxide SignalingNitric Oxide Signaling
Enzyme Enzyme
GeneGene No. ofNo. ofexonsexons
No. ofNo. ofresiduesresidues
Subcellular Subcellular locationlocation
RegulationRegulation
nNOSnNOS NOS1NOS1 2929 1429-1429-14331433
Mainly Mainly soluble soluble (brain);(brain);
CaCa2+2+/Ca/CaMM
iNOSiNOS NOS2NOS2 2727 1144-1144-11531153
Mainly Mainly solublesoluble
CaCa2+2+ independentindependent
eNOSeNOS NOS3NOS3 2626 1203-1203-12051205
MainlyMainlyparticulateparticulate
CaCa2+2+/CaM/CaM
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Neuronal Nitric OxideSynthase (nNOS)
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Epithelial Nitric Oxide Synthase (eNOS)
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Inducible Nitric Oxide Synthase (iNOS)
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Mechanism of Action of NOMechanism of Action of NO
Various stimuli 5’- HTAcetylcholineThrombinCalcium ionophore A23187Arachidonic AcidChanges in AP &ES
NO Release
Platelet antiaggregation &Vasorelaxation effect
Prostacyclin
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Contd…Contd… NO
NO bind to Fe 2+ haem group of Guanylyl Cyclase
Active Guanylate Cyclase
Increased cGMP
Increased intracellular Ca 2+
Relaxes muscle
Dilating the vessel &lowering B.P.
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Physiology of Nitric oxidePhysiology of Nitric oxide
• NO play important role :NO play important role :
• Penile erectionPenile erection • Lung vasodilatationLung vasodilatation
• Physiological stimuli for generation of NO are not fully understood, Physiological stimuli for generation of NO are not fully understood, but pulsatile flow and shear forces may be the main determinant.but pulsatile flow and shear forces may be the main determinant.
• In biological system NO is not stored and diffuses freely to its site of In biological system NO is not stored and diffuses freely to its site of action where it bind covalently to its effectors (taction where it bind covalently to its effectors (t1/21/2=3-5 second)=3-5 second)
• In coronary artery disease, basal level of NO as well as stimulated In coronary artery disease, basal level of NO as well as stimulated release of NO reducedrelease of NO reduced
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Cond….Cond….
NO inhibitor of platelet activation
Alteration in formation of NO
Vasoconstriction, Platelet adhesion and Aggregation
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Contd…Contd…
Isosorbide dinitrate
NITRIC OXIDE
Reduced Platelet deposition & Increased survival time in patients with peripheral vascular disease
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The generation of NO in CVS dependent on constant vasodilation.The generation of NO in CVS dependent on constant vasodilation.
GTN (Glycerine trinitrate) = VasodilatorGTN (Glycerine trinitrate) = Vasodilator
Pharmacological Role of NO
Nitrovasodilators & No
Activation of sGC
cGMP in smooth muscle
Protein Phosphorylation with smooth muscle relaxation
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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
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NO in Ischemic myocardium:NO in Ischemic myocardium:
ACE inhibitor
Inhibition in degradation of Bradykinin
Accumulation of Bradykinin and NO
Prevent coronary Vasoconstriction
Increase in coronary blood flow
1.Stimulation of Bradykinin
Receptor
2. Inhibit Kininase II
Reduced Degdn. Of Bradykinin
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Contd…Contd…
Kitakaze Kitakaze et alet al.(2000) ACE I attenuate both reversible and .(2000) ACE I attenuate both reversible and irreversible myocardial cellular injury via bradykinin/ NO- dependentirreversible myocardial cellular injury via bradykinin/ NO- dependent
mannermanner
ACE I, enalaprilat, improves transmural myocardial perfusion at rest ACE I, enalaprilat, improves transmural myocardial perfusion at rest and after stress and restore impaired sub endothelial coronary flow and after stress and restore impaired sub endothelial coronary flow and vasodilator reserve .and vasodilator reserve .
The effect of Enalaprilat is bradykinin and NO dependent.The effect of Enalaprilat is bradykinin and NO dependent.
ACE I increase Bradykinin and NO:ACE I increase Bradykinin and NO:
Potent cardio protectionPotent cardio protection
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Role of NO in Role of NO in HypertensionHypertension
In hypertension, morphological vascular alteration affecting In hypertension, morphological vascular alteration affecting • EndotheliumEndothelium• IntimaIntima• Vascular smooth muscleVascular smooth muscle Abnormalities of endothelial cells-- vascular resistance – Abnormalities of endothelial cells-- vascular resistance –
increase in Arterial Pressure.increase in Arterial Pressure. Endothelium produce contracting substances:Endothelium produce contracting substances:• O O 2- 2-
• Thromboxane AThromboxane A22
• Endothelin-1(Peptide)Endothelin-1(Peptide) Endothelin-1: Potent vasoconstrictor Endothelin-1: Potent vasoconstrictor
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Contd…Contd…
Increase in endothelin plasma conc. observed in patients with Increase in endothelin plasma conc. observed in patients with primary hypertension compared to normal.primary hypertension compared to normal.
Mitogenic activation described in hypertension is induced by :Mitogenic activation described in hypertension is induced by : Increase in sympathetic activityIncrease in sympathetic activity Release of vasoactive agents such as endothelin, Release of vasoactive agents such as endothelin, Angiotensin II, PGAngiotensin II, PG Basal formation of NO decreased in Hypertension.Basal formation of NO decreased in Hypertension. Recently Das,U. N. (2004), the overall role of NO and ORecently Das,U. N. (2004), the overall role of NO and O2 2 (super (super
oxide anion ) in hypertension oxide anion ) in hypertension Patient with hypertension have elevated conc. Of super oxide Patient with hypertension have elevated conc. Of super oxide
anion , Hanion , H22OO2 2 ,Lipid peroxides, endothelin, with simultaneous ,Lipid peroxides, endothelin, with simultaneous decrease in eNO, SOD, Vit E and LCPUFAs.decrease in eNO, SOD, Vit E and LCPUFAs.
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Nitroglycerine was used for many years to treat"angina" (chest pain) due to reduced blood flowin heart arteries without any knowledge of mechanism
Lumen diameter increases and resistance to blood flow decreases
Heart ("coronary") artery
NO
N
O O
O
N
O O
O
N
O O
O
C C C
H H H H H H
N-O
Nitroglycerine
We now know nitroglycerine does not act directly but is degraded to NO
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Role of NO in ReproductionRole of NO in Reproduction
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Contd…
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ConclusionConclusion
NO is a universal messenger moleculeNO is a universal messenger molecule It is involved in a wide variety of pathophysiogical and biochemical It is involved in a wide variety of pathophysiogical and biochemical
reactions.reactions. In summary NO is involved in regulation of B.P., prevention of In summary NO is involved in regulation of B.P., prevention of
aggregation and adhesion of platelets, promotion of penile erection.aggregation and adhesion of platelets, promotion of penile erection. Other way to increase active concentration of endogenous NO such Other way to increase active concentration of endogenous NO such
as by prolonging its half life of duration of its actions.as by prolonging its half life of duration of its actions. NO donating compounds can be used as replacement therapy to NO donating compounds can be used as replacement therapy to
treat its impaired productiontreat its impaired production NO also as therapeutic potential for Ischemic CVS diseases, NO also as therapeutic potential for Ischemic CVS diseases,
pulmonary hypertension associated with cardiac and respiratory pulmonary hypertension associated with cardiac and respiratory diseases.diseases.
They are far from ideal because of the associated side effect mainly They are far from ideal because of the associated side effect mainly due to the catabolism of NO into NO2due to the catabolism of NO into NO2
Therefore a technology to regulate in vivo synthesis of NO by Therefore a technology to regulate in vivo synthesis of NO by genetic manipulation would be a welcome move.genetic manipulation would be a welcome move.
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