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- Dr. Chandini
- Moderator: Dr. Princy Pallatty
 Introduction
 Discovery
 Synthesis
 Signalling mechanisms
 Inactivation
 Effects of NO
 Potentiation of NO synthesis
 Inhibition of NO synthesis
 Side effects
 Summary
 Nitric oxide is a gaseous signalling molecule
- readily diffuses across cell membranes
- regulates a wide range of physiologic & pathophysiologic
processes (CV, inflammatory & neuronal)
 Endogenous activator of soluble Guanylyl cyclase,
↓
Cyclic GMP (cGMP),
‘second messenger’
• 1772: 1st identified as a gas by Joseph Priestly.
(atmospheric pollutant)
• 1980s: Nitroglycerin given for patients with angina.
(MOA not known)
Robert Furchgott investigated vasorelaxants (Ach)
 relaxation of blood vessels only occurred if luminal
endothelial cells were present & intact.
↓
Endothelial Derived Relaxing Factor (EDRF)
• 1977: Ferid Murad investigated how nitroglycerin works
 releases NO  relaxation of smooth muscle cells
• 1986: Louis Ignarro – identified EDRF.
• Comparison of biochemical & pharmacological properties
of EDRF & NO
 NO - major bioactive component of EDRF.
Nobel prize - 1998
 by NO synthase isoenzymes:
3 types –
nNOS eNOS iNOS
Neurons Endothelium Macrophages
cardiac myocytes Neutrophils
airway epithelium fibroblasts
platelets vascular smooth
muscle cells
Constitutive forms
Heme
THB
FAD
• nNOS & eNOS – activated
by calcium-calmodulin.
• Factors ↑ eNOS activity
- shear stress
(physiological)
- Protein kinase A-
mediated phosphorylation.
(eg. Β2 agonists)
- tyrosine kinase activation
(eg. Insulin)
• Protein kinase C ↓ eNOS
activity
iNOS
• Not regulated by Ca.
• Inflammatory mediators (IFN-ϒ)
↓
activation of iNOS gene
↓
accumulation of iNOS
↓
↑ synthesis of NO.
• Inhibited by glucocorticoids & cytokines (transforming
growth factor-β.)
1. Metalloproteins –
• NO interacts with metals, esp iron in heme.
• Interaction with other metalloproteins  Cytotoxic effects.
Eg.
- NO inhibits citric acid cycle enzyme aconitase and
electron transport chain protein cytochrome oxidase.
- Inhibition of heme-containing cytochrome P450
enzymes (inflammatory liver disease.)
2. Thiols –
• NO reacts with thiols ( –SH group)  Nitrosothiols.
‘S-nitrosylation’
- Major targets : H-ras, (regulator of cell proliferation)
• Glutathione can also be S-nitrosylated
 S-nitrosoglutathione.
- endogenous stabilized form of NO, or
- as carrier of NO.
Vascular glutathione ↓ in diabetes mellitus &
atherosclerosis  ↓ S-nitrosoglutathione
 ↑ incidence of CV complications.
3. Tyrosine nitration –
• Addition of nitrate to tyrosines.
• Marker of excessive NO production
• NO + superoxide  Peroxynitrite (ONOO–),
 DNA damage, tyrosine nitration,
& oxidation of cysteine to disulfides.
• Enzymes involved in superoxide formation
- ↑ in inflammatory and degenerative diseases,
 ↑ peroxynitrite levels.
• Intracellular glutathione - scavenges peroxynitrite,
protective.
NO
NO + HbO  NO3
−
+ Hb
2NO + O2  N2O4
NO + O2
−
 ONOO−
Exhaled
via lungs
S-nitrosylation
of Hb
↓
Carries NO in
circulation
1. Vascular effects –
 Maintains vascular smooth muscle tone and BP.
 Endothelium-dependent vasodilators
(acetylcholine and bradykinin),
↓
↑ intracellular Ca2+ levels in endothelial cells,
↓
NO synthesis
1) NO  vascular smooth muscle  vasorelaxation.
(Mutant mice lacking eNOS gene - hypertensive,
2) Also has antithrombotic effects –
Both endothelial cells & platelets contain eNOS,
NO-cGMP pathway
inhibits platelet activation.
Endothelial dysfunction  ↓ in NO generation
 ↑ risk of abnormal platelet function & thrombosis.
3) Protective against atherosclerosis
Mech:
a) Inhibition of proliferation & migration of vascular smooth
muscle cells.
b) ↓ endothelial adhesion of monocytes & leukocytes
(d/t inhibition of expression of adhesion molecules)
c) As anti-oxidant - ↓ formation of foam cells in vessel wall.
d) ↓ endothelial cell permeability to lipoproteins
* Animals treated with eNOS inhibitors  ↑ atherosclerosis
2. Septic shock –
• Bacterial endotoxins + cytokines (TNF-α)
↓
Synthesis of
iNOS
↓
Exaggerated hypotension
↓
Shock (& death)
• Reversed by iNOS inhibitors (but no overall improvement in
survival in G –ve sepsis)
macrophages,
neutrophils, T cells,
hepatocytes,
smooth muscle cells,
endothelial cells
3. Infection & Inflammation –
• NO has both beneficial and detrimental roles.
• Inflammatory mediators (TNF & IL-1)
↓
Induction of iNOS in leukocytes,
↓
NO synthesis (+ ONOO−) - important microbicide.
Vasodilation Activates COX-2 Other mech
Acute inflammation
• Both acute & chronic inflammatory conditions –
prolonged or excessive NO production
 exacerbate tissue injury.
• Eg. psoriasis lesions, airway epithelium in asthma, &
inflammatory bowel lesions
- ↑ levels of NO and iNOS,
Persistent iNOS induction  disease pathogenesis.
• Thus inhibition of NO pathway - beneficial effect
4. CNS –
• NO – important role as NT
• Not stored
• Induced at postsynaptic sites in neurons:
activation of NMDA receptors,
↓
Ca2+ influx and activation of nNOS.
• Excessive NO synthesis  excitotoxic neuronal death in
several neurologic diseases
(stroke, ALS & Parkinson’s disease)
• NOS inhibitors - ↓ neuronal damage.
5. PNS –
• Nonadrenergic, noncholinergic (NANC) neurons (GIT &
reproductive tracts)
• NO (NANC neurons)  relaxation of the smooth muscle
in the corpora cavernosa
↓
penile erection
• Phosphodiesterase (PDE5) breakdown of cGMP
PDE-5Is  ↑ NO signalling
(sildenafil, tadalafil etc) - Erectile dysfunction
GI effects –
• Protective effect.
• Preclinical studies –
- maintain gastric mucosal integrity (inhibiting gastric
acid secretion & ↑ gastric blood flow)
- inhibits leukocyte adherence to endothelium,
- repair NSAID-induced damage.
• Epidemiological studies –
use of NO-donating agents with
NSAIDs (CINODs) 
↓ risk for GI bleeding.
• Large conc  deleterious effects.
6. Respiratory disorders –
• NO inhalation  dilates pulmonary vessels,
↓
↓ pulmonary vascular resistance & ↓ pul artery pressure.
 also improves oxygenation
(by ↓ ventilation-perfusion mismatch)
- administered to newborns with hypoxic resp failure
• also shown to ↑ cardio-pul functions in adults with PAH.
• PDE-5Is  vasodilation & marked ↓ in pul HTN
7. In cancer –
• Dichotomous effect.
Pro cancer –
• Angiogenesis
• Invasion
• Metastasis
• apoptosis of macrophages
Anti cancer –
• Cytotoxic
• Supresses cellular
respiration
• Apoptotic
• Inhibits viral replication
• Various cancers where NO is implicated –
- Breast Ca
- Cervical Ca
- Brain tumors
- Lung Ca
- Gastric Ca
- Head & neck Ca
• NO  biphasic response.
exploited therapeutically (pre-clinical models)
 slow tumor growth,
↑ efficacy of both chemo- & radio Rx.
 Replacement Rx with NO donors
 Dietary supplementation with L-arginine
 Antioxidants - ↓ reactive O2 species
 Drugs that restore endothelial function in patients with
metabolic risk factors for vascular disease
- ACE inhibitors, statins, insulin, oestrogens
 β2-adrenoceptor agonists & related drugs
↓
activates L-arginine/NO pathway
 PDE inhibition  potentiate NO actions
(PDE degrade cGMP)
Eg. PDE-5Is (sildenafil)
↓
prolong NO-induced cGMP elevation
 Release NO or related species
- used clinically to elicit smooth muscle relaxation.
 Different classes -
1) Organic nitrates
2) Organic nitrites
3) Sodium nitroprusside
1. Organic nitrates –
• Nitroglycerin  dilates veins and coronary arteries
↓
↓ preload (‘antianginal effect’)
metabolized to NO - by mitochondrial aldehyde reductase,
(venous smooth muscle)
• Others – isosorbide mono/dinitrate
• less significant effects on aggregation of platelets
• Rapid tolerance during continuous administration.
( d/t generation of reactive oxygen species)
2. Organic nitrites –
• Eg. Amyl nitrite
• Arterial vasodilators
• No rapid tolerance seen
• Amyl nitrite (abuse potential)
+
PDE-5Is
↓
Lethal hypotension
Therefore replaced by nitroglycerin
3. Sodium nitroprusside –
• Dilates both arterioles & venules
• Used for rapid pressure ↓ in arterial hypertension.
• Sodium nitroprusside
5 CN− + NO
Light/chemicals/enzymes
4. NO gas –
• Inhalation of NO  ↓ pul artery pressure
↑ lung perfusion
• Uses –
1) PAH
2) Acute hypoxemia
3) CPR
• Short-term improvements in pulmonary function
• N2O3 & methemoglobin levels monitored during inhaled
NO Rx.
Inhibitor Mechanism
NGmonomethyl-L-arginine
(L-NMMA)
Non-selective, competitive
inhibitor
- binds arginine-binding site
in NOSNG-nitro-L arginine
methyl ester (L-NAME)
ADMA
Inhibitor Mechanism
N-iminoethyl-L-
lysine,
Glucocorticoids.
Selective iNOS
inhibitor
Rx of inflammatory
conditions
(asthma)
7-Nitroindazole,
S-methyl-L-
thiocitrulline
Selective nNOS
inhibitor
Neurodegenerative
conditions
NO Feedback
inhibition
FEEDBACK INHIBITION
 L-arginine/ NO pathway – imp role in disease pathogenesis
 Evidence: Following indirect approaches –
1) Analysing nitrate &/or cGMP in urine
2) Administer [15N]-arginine & use mass spectrometry
(to measure the enrichment of 15N over naturally abundant
[14N]-nitrate in urine)
3) Measuring NO in exhaled air
4) Measuring effects of NOS inhibitors (e.g. L-NMMA)
5) Comparing responses to endothelium-dependent agonists
(e.g. acetylcholine)
& endothelium-independent agonists (e.g.nitroprusside)
6) Measuring responses to ↑ blood flow (‘flowmediated
dilatation’), - largely mediated by NO
7) Studying histochemical appearances & pharmacological
responses in vitro of tissue obtained at operation
(e.g. coronary artery surgery).
 All these methods have limitations.
 L-arginine/ NO pathway  New therapeutic approaches
1) Hematological: Methemoglobinemia
2) CV: Hypotension
3) Respiratory: dyspnoea, stridor
4) Renal: Hematuria
5) Metabolic: Hyperglycemia
6) Others: withdrawal,
sepsis,
cellulitis,
chest discomfort,
dizziness
 Nitric oxide (NO) is synthesised from L-arginine &
molecular O2 by Nitric oxide synthase (NOS).
 3 isoforms: nNOS,
eNOS,
iNOS - Ca2+ independent
Constitutive forms
(Ca2+ - dependent)
 Signalling mechanisms –
1) Metalloproteins -
Soluble guanylyl cyclase: main target
2) S-nitrosylation (thiols)
3) Tyrosine nitration
 Inactivation:
Reaction with - haem,
O2,
O2
−
 In host immune response, acute & chronic inflammatory
conditions.
 Both ↑/↓ production  disease.
 NO donors (e.g. nitroprusside & organic
nitrovasodilators) are well established
 Type V phosphodiesterase inhibitors (e.g. sildenafil,
tadalafil) potentiate the action of NO
- used to treat erectile dysfunction
 Therapeutic uses (NO/NO donors) –
1) Cardio-vascular:
Angina, HTN
2) Respiratory:
a) Neonatal hypoxic resp failure
b) PAH
3) GIT:
NSAID-induced gastric damage – CINODs
(COX-inhibiting, NO-donating)
4) Erectile dysfunction: PDE-5Is
5) Heart & lung surgery
6) Sickle cell disease
7) Potential anti-cancer agent
- refractory cancers
- chemo-/radio-/immune-sensitizer
- eg. NTG
8) NO supplements –
muscle gain, enhanced stamina and vigor.
1) Basic & clinical pharmacology – Katzung & Trevor
2) Rang & Dale’s Pharmacology
3) The pharmacological basis of therapeutics – Goodman &
Gilman

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Nitric oxide

  • 1. - Dr. Chandini - Moderator: Dr. Princy Pallatty
  • 2.  Introduction  Discovery  Synthesis  Signalling mechanisms  Inactivation  Effects of NO  Potentiation of NO synthesis  Inhibition of NO synthesis  Side effects  Summary
  • 3.  Nitric oxide is a gaseous signalling molecule - readily diffuses across cell membranes - regulates a wide range of physiologic & pathophysiologic processes (CV, inflammatory & neuronal)  Endogenous activator of soluble Guanylyl cyclase, ↓ Cyclic GMP (cGMP), ‘second messenger’
  • 4. • 1772: 1st identified as a gas by Joseph Priestly. (atmospheric pollutant) • 1980s: Nitroglycerin given for patients with angina. (MOA not known) Robert Furchgott investigated vasorelaxants (Ach)  relaxation of blood vessels only occurred if luminal endothelial cells were present & intact. ↓ Endothelial Derived Relaxing Factor (EDRF)
  • 5. • 1977: Ferid Murad investigated how nitroglycerin works  releases NO  relaxation of smooth muscle cells • 1986: Louis Ignarro – identified EDRF. • Comparison of biochemical & pharmacological properties of EDRF & NO  NO - major bioactive component of EDRF.
  • 7.  by NO synthase isoenzymes: 3 types – nNOS eNOS iNOS Neurons Endothelium Macrophages cardiac myocytes Neutrophils airway epithelium fibroblasts platelets vascular smooth muscle cells Constitutive forms
  • 9. • nNOS & eNOS – activated by calcium-calmodulin. • Factors ↑ eNOS activity - shear stress (physiological) - Protein kinase A- mediated phosphorylation. (eg. Β2 agonists) - tyrosine kinase activation (eg. Insulin) • Protein kinase C ↓ eNOS activity
  • 10. iNOS • Not regulated by Ca. • Inflammatory mediators (IFN-ϒ) ↓ activation of iNOS gene ↓ accumulation of iNOS ↓ ↑ synthesis of NO. • Inhibited by glucocorticoids & cytokines (transforming growth factor-β.)
  • 11.
  • 12. 1. Metalloproteins – • NO interacts with metals, esp iron in heme.
  • 13. • Interaction with other metalloproteins  Cytotoxic effects. Eg. - NO inhibits citric acid cycle enzyme aconitase and electron transport chain protein cytochrome oxidase. - Inhibition of heme-containing cytochrome P450 enzymes (inflammatory liver disease.)
  • 14. 2. Thiols – • NO reacts with thiols ( –SH group)  Nitrosothiols. ‘S-nitrosylation’ - Major targets : H-ras, (regulator of cell proliferation) • Glutathione can also be S-nitrosylated  S-nitrosoglutathione. - endogenous stabilized form of NO, or - as carrier of NO. Vascular glutathione ↓ in diabetes mellitus & atherosclerosis  ↓ S-nitrosoglutathione  ↑ incidence of CV complications.
  • 15. 3. Tyrosine nitration – • Addition of nitrate to tyrosines. • Marker of excessive NO production • NO + superoxide  Peroxynitrite (ONOO–),  DNA damage, tyrosine nitration, & oxidation of cysteine to disulfides. • Enzymes involved in superoxide formation - ↑ in inflammatory and degenerative diseases,  ↑ peroxynitrite levels. • Intracellular glutathione - scavenges peroxynitrite, protective.
  • 16. NO NO + HbO  NO3 − + Hb 2NO + O2  N2O4 NO + O2 −  ONOO− Exhaled via lungs S-nitrosylation of Hb ↓ Carries NO in circulation
  • 17. 1. Vascular effects –  Maintains vascular smooth muscle tone and BP.  Endothelium-dependent vasodilators (acetylcholine and bradykinin), ↓ ↑ intracellular Ca2+ levels in endothelial cells, ↓ NO synthesis
  • 18. 1) NO  vascular smooth muscle  vasorelaxation. (Mutant mice lacking eNOS gene - hypertensive, 2) Also has antithrombotic effects – Both endothelial cells & platelets contain eNOS, NO-cGMP pathway inhibits platelet activation. Endothelial dysfunction  ↓ in NO generation  ↑ risk of abnormal platelet function & thrombosis.
  • 19. 3) Protective against atherosclerosis Mech: a) Inhibition of proliferation & migration of vascular smooth muscle cells. b) ↓ endothelial adhesion of monocytes & leukocytes (d/t inhibition of expression of adhesion molecules) c) As anti-oxidant - ↓ formation of foam cells in vessel wall. d) ↓ endothelial cell permeability to lipoproteins * Animals treated with eNOS inhibitors  ↑ atherosclerosis
  • 20. 2. Septic shock – • Bacterial endotoxins + cytokines (TNF-α) ↓ Synthesis of iNOS ↓ Exaggerated hypotension ↓ Shock (& death) • Reversed by iNOS inhibitors (but no overall improvement in survival in G –ve sepsis) macrophages, neutrophils, T cells, hepatocytes, smooth muscle cells, endothelial cells
  • 21. 3. Infection & Inflammation – • NO has both beneficial and detrimental roles. • Inflammatory mediators (TNF & IL-1) ↓ Induction of iNOS in leukocytes, ↓ NO synthesis (+ ONOO−) - important microbicide. Vasodilation Activates COX-2 Other mech Acute inflammation
  • 22. • Both acute & chronic inflammatory conditions – prolonged or excessive NO production  exacerbate tissue injury. • Eg. psoriasis lesions, airway epithelium in asthma, & inflammatory bowel lesions - ↑ levels of NO and iNOS, Persistent iNOS induction  disease pathogenesis. • Thus inhibition of NO pathway - beneficial effect
  • 23. 4. CNS – • NO – important role as NT • Not stored • Induced at postsynaptic sites in neurons: activation of NMDA receptors, ↓ Ca2+ influx and activation of nNOS. • Excessive NO synthesis  excitotoxic neuronal death in several neurologic diseases (stroke, ALS & Parkinson’s disease) • NOS inhibitors - ↓ neuronal damage.
  • 24. 5. PNS – • Nonadrenergic, noncholinergic (NANC) neurons (GIT & reproductive tracts) • NO (NANC neurons)  relaxation of the smooth muscle in the corpora cavernosa ↓ penile erection • Phosphodiesterase (PDE5) breakdown of cGMP PDE-5Is  ↑ NO signalling (sildenafil, tadalafil etc) - Erectile dysfunction
  • 25. GI effects – • Protective effect. • Preclinical studies – - maintain gastric mucosal integrity (inhibiting gastric acid secretion & ↑ gastric blood flow) - inhibits leukocyte adherence to endothelium, - repair NSAID-induced damage. • Epidemiological studies – use of NO-donating agents with NSAIDs (CINODs)  ↓ risk for GI bleeding. • Large conc  deleterious effects.
  • 26. 6. Respiratory disorders – • NO inhalation  dilates pulmonary vessels, ↓ ↓ pulmonary vascular resistance & ↓ pul artery pressure.  also improves oxygenation (by ↓ ventilation-perfusion mismatch) - administered to newborns with hypoxic resp failure • also shown to ↑ cardio-pul functions in adults with PAH. • PDE-5Is  vasodilation & marked ↓ in pul HTN
  • 27. 7. In cancer – • Dichotomous effect. Pro cancer – • Angiogenesis • Invasion • Metastasis • apoptosis of macrophages Anti cancer – • Cytotoxic • Supresses cellular respiration • Apoptotic • Inhibits viral replication
  • 28. • Various cancers where NO is implicated – - Breast Ca - Cervical Ca - Brain tumors - Lung Ca - Gastric Ca - Head & neck Ca • NO  biphasic response. exploited therapeutically (pre-clinical models)  slow tumor growth, ↑ efficacy of both chemo- & radio Rx.
  • 29.  Replacement Rx with NO donors  Dietary supplementation with L-arginine  Antioxidants - ↓ reactive O2 species  Drugs that restore endothelial function in patients with metabolic risk factors for vascular disease - ACE inhibitors, statins, insulin, oestrogens
  • 30.  β2-adrenoceptor agonists & related drugs ↓ activates L-arginine/NO pathway  PDE inhibition  potentiate NO actions (PDE degrade cGMP) Eg. PDE-5Is (sildenafil) ↓ prolong NO-induced cGMP elevation
  • 31.  Release NO or related species - used clinically to elicit smooth muscle relaxation.  Different classes - 1) Organic nitrates 2) Organic nitrites 3) Sodium nitroprusside
  • 32. 1. Organic nitrates – • Nitroglycerin  dilates veins and coronary arteries ↓ ↓ preload (‘antianginal effect’) metabolized to NO - by mitochondrial aldehyde reductase, (venous smooth muscle) • Others – isosorbide mono/dinitrate • less significant effects on aggregation of platelets • Rapid tolerance during continuous administration. ( d/t generation of reactive oxygen species)
  • 33. 2. Organic nitrites – • Eg. Amyl nitrite • Arterial vasodilators • No rapid tolerance seen • Amyl nitrite (abuse potential) + PDE-5Is ↓ Lethal hypotension Therefore replaced by nitroglycerin
  • 34. 3. Sodium nitroprusside – • Dilates both arterioles & venules • Used for rapid pressure ↓ in arterial hypertension. • Sodium nitroprusside 5 CN− + NO Light/chemicals/enzymes
  • 35. 4. NO gas – • Inhalation of NO  ↓ pul artery pressure ↑ lung perfusion • Uses – 1) PAH 2) Acute hypoxemia 3) CPR • Short-term improvements in pulmonary function • N2O3 & methemoglobin levels monitored during inhaled NO Rx.
  • 36. Inhibitor Mechanism NGmonomethyl-L-arginine (L-NMMA) Non-selective, competitive inhibitor - binds arginine-binding site in NOSNG-nitro-L arginine methyl ester (L-NAME) ADMA
  • 37. Inhibitor Mechanism N-iminoethyl-L- lysine, Glucocorticoids. Selective iNOS inhibitor Rx of inflammatory conditions (asthma) 7-Nitroindazole, S-methyl-L- thiocitrulline Selective nNOS inhibitor Neurodegenerative conditions NO Feedback inhibition
  • 39.  L-arginine/ NO pathway – imp role in disease pathogenesis  Evidence: Following indirect approaches – 1) Analysing nitrate &/or cGMP in urine 2) Administer [15N]-arginine & use mass spectrometry (to measure the enrichment of 15N over naturally abundant [14N]-nitrate in urine)
  • 40. 3) Measuring NO in exhaled air 4) Measuring effects of NOS inhibitors (e.g. L-NMMA) 5) Comparing responses to endothelium-dependent agonists (e.g. acetylcholine) & endothelium-independent agonists (e.g.nitroprusside) 6) Measuring responses to ↑ blood flow (‘flowmediated dilatation’), - largely mediated by NO
  • 41. 7) Studying histochemical appearances & pharmacological responses in vitro of tissue obtained at operation (e.g. coronary artery surgery).  All these methods have limitations.  L-arginine/ NO pathway  New therapeutic approaches
  • 42. 1) Hematological: Methemoglobinemia 2) CV: Hypotension 3) Respiratory: dyspnoea, stridor 4) Renal: Hematuria 5) Metabolic: Hyperglycemia 6) Others: withdrawal, sepsis, cellulitis, chest discomfort, dizziness
  • 43.  Nitric oxide (NO) is synthesised from L-arginine & molecular O2 by Nitric oxide synthase (NOS).  3 isoforms: nNOS, eNOS, iNOS - Ca2+ independent Constitutive forms (Ca2+ - dependent)
  • 44.  Signalling mechanisms – 1) Metalloproteins - Soluble guanylyl cyclase: main target 2) S-nitrosylation (thiols) 3) Tyrosine nitration  Inactivation: Reaction with - haem, O2, O2 −
  • 45.
  • 46.  In host immune response, acute & chronic inflammatory conditions.  Both ↑/↓ production  disease.  NO donors (e.g. nitroprusside & organic nitrovasodilators) are well established  Type V phosphodiesterase inhibitors (e.g. sildenafil, tadalafil) potentiate the action of NO - used to treat erectile dysfunction
  • 47.  Therapeutic uses (NO/NO donors) – 1) Cardio-vascular: Angina, HTN 2) Respiratory: a) Neonatal hypoxic resp failure b) PAH 3) GIT: NSAID-induced gastric damage – CINODs (COX-inhibiting, NO-donating)
  • 48. 4) Erectile dysfunction: PDE-5Is 5) Heart & lung surgery 6) Sickle cell disease 7) Potential anti-cancer agent - refractory cancers - chemo-/radio-/immune-sensitizer - eg. NTG
  • 49. 8) NO supplements – muscle gain, enhanced stamina and vigor.
  • 50. 1) Basic & clinical pharmacology – Katzung & Trevor 2) Rang & Dale’s Pharmacology 3) The pharmacological basis of therapeutics – Goodman & Gilman

Editor's Notes

  1. Nitric oxide is a gaseous signaling molecule that readily diffuses across cell membranes & regulates a wide range of physiologic & pathophysiologic processes including CV, inflammatory & neuronal functions. (NO should not be confused with nitrous oxide, an anesthetic gas, nor with nitrogen dioxide, a toxic pulmonary irritant gas.)  NO is the endogenous activator  of soluble guanylyl cyclase, leading to the formation of  cyclic GMP (cGMP), an important ‘second messenger’
  2. …of endogenously generated NO Nitric oxide was first identified as a gas by Joseph Priestly in 1772. For much of the time since this discovery nitric oxide, or NO, has been thought of simply as an atmospheric pollutant. In the 1980's researchers were investigating how blood vessels dilate (or relax).  (At the time drugs such as nitroglycerin were given to patients for heart conditions like angina in order to promote vasodilation and reduce blood pressure, but no-one knew how these drugs worked). In 1980 Robert Furchgott investigated the role of a drug called acetylcholine on vasodilation and found that relaxation of blood vessels only occurred if luminal endothelial cells covering smooth muscles of vessel wall were present & intact. Robert Furchgott and his group found that without the endothelial cells the smooth muscle cells were not able to cause vasodilation. This suggested that there was some kind of factor produced by the endothelial cells that was required for relaxation of the blood vessels. This factor was termed Endothelial Derived Relaxing Factor or EDRF 
  3. Independently, in 1977 Ferid Murad was investigating how nitroglycerin works and discovered that it can release nitric oxide which in turn was able to cause relaxation of smooth muscle cells The pieces of the puzzle were finally put together in 1986 when Louis Ignarroidentified EDRF. Comparison of the biochemical & pharmacological properties of EDRF & NO provided the initial evidence that NO is the major bioactive component of EDRF.
  4. For their role in this discovery Furchgott, Murad and Ignarro were awarded the Nobel Prize for Medicine or Physiology in 1998.
  5. Synthesis, signalling mechanisms & inactivation NO, is a highly reactive signaling molecule that is made by any of three closely related NO synthase (NOS, EC 1.14.13.49) isoenzymes,. These enzymes, neuronal NOS (nNOS or NOS-1), macrophage or inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3), despite their names, are each expressed in a wide variety of cell types.
  6. These NOS isoforms generate NO from the amino acid l-arginine (usually present in excess in endothelial cell  cytoplasm) in an O2- and NADPH-dependent reaction (Figure 19–1). This enzymatic reaction involves enzyme-bound cofactors, including heme, tetrahydrobiopterin, and flavin adenine dinucleotide (FAD).
  7. In the case of nNOS and eNOS, NO synthesis is triggered by agents and processes that increase cytosolic calcium concentrations. (e.g.  acetylcholine, bradykinin, substance P)  Cytosolic calcium forms complexes with calmodulin, an abundant calciumbinding protein, which then binds and activates eNOS and nNOS. eNOS – One important physiological stimulus controlling endothelial NO synthesis in resistance vessels is believed to be  shear stress. This is sensed by endothelial mechanoreceptors. and transduced via a serine–threonine protein kinase  called  Akt.  Agonists  that  increase  cAMP  in  endothelial  cells  (e.g.  β2-adrenoceptor  agonists)  also  increase  eNOS  activity,  but  via  protein  kinase  A-mediated  phosphorylation,2 whereas protein kinase C reduces eNOS activity  by  phosphorylating  residues  in  the  calmodulin-binding  domain,  thereby  reducing  the  binding  of  calmodulin.  Insulin increases eNOS activity via tyrosine kinase activation 
  8. iNOS – On the other hand, iNOS is not regulated by calcium ,  activity of  iNOS is effectively independent of [Ca2+]i, being fully activated even at the low values of [Ca2+]i present under resting  conditions. inflammatory mediators  notably interferon-γ, (the antiviral effect  of which can be explained by this action) induce the transcriptional activation of the iNOS gene, resulting in accumulation of iNOS and increased synthesis of NO.  Induction of iNOS is inhibited by glucocorticoids  and  by  several  cytokines,  including  transforming  growth factor-β. 
  9. Signaling Mechanisms NO mediates its effects by covalent modification of proteins. There are three major targets of NO –
  10. 1. Metalloproteins— NO interacts with metals, especially iron in heme. The major target of NO is soluble guanylyl cyclase (sGC), a heme-containing enzyme that generates cyclic guanosine monophosphate (cGMP). NO binds to the heme in sGC, resulting in enzyme activation and elevation in intracellular cGMP levels. cGMP activates protein kinase G (PKG), which phosphorylates specific proteins. In blood vessels, this process results in phosphorylation of proteins that lead to reduced cytosolic calcium levels and subsequently reduced contraction of vascular smooth muscle. (pic) Regulation of vasorelaxation by endothelial-derived nitric oxide (NO). Endogenous vasodilators, eg, acetylcholine and bradykinin, cause calcium (Ca2+) efflux from the endoplasmic reticulum in the luminal endothelial cells into the cytoplasm. Calcium binds to calmodulin (CaM), which activates endothelial NO synthase (eNOS), resulting in NO synthesis from l-arginine. NO diffuses into smooth muscle cells, where it activates soluble guanylyl cyclase and cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphosphate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx, and inhibition of calcium-dependent muscle contraction. * cGMP signaling is terminated by phosphodiesterases, which convert cGMP to GMP
  11. In some cases, Interaction of NO with other metalloproteins mediates some of the cytotoxic effects of NO associated. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease.
  12. 2. Thiols— NO reacts with thiols (compounds containing the –SH group) to form nitrosothiols. This posttranslational modification, termed S-nitrosylation. S-nitrosylation can alter the function, stability, or localization of target proteins. Major targets of S-nitrosylation include H-ras, a regulator of cell proliferation that is activated by S-nitrosylation, Glutathione can also be S-nitrosylated under physiologic conditions to generate S-nitrosoglutathione. S-nitrosoglutathione may serve as an endogenous stabilized form of NO or as a carrier of NO. Vascular glutathione is decreased in diabetes mellitus and atherosclerosis, and the resulting deficiency of S-nitrosoglutathione may account for the increased incidence of cardiovascular complications in these conditions.
  13. 3. Tyrosine nitration— NO undergoes both oxidative and reductive reactions, resulting in a variety of oxides of nitrogen that can not only nitrosylate thiols but also add nitrate to tyrosines. Detection of tyrosine nitration in tissue is often used as a marker of excessive NO production, although a direct causal role of tyrosine nitration in the pathogenesis of any disease has not been definitively established. NO reacts very efficiently with superoxide to form peroxynitrite (ONOO–), a highly reactive oxidant that leads to DNA damage, nitration of tyrosine, and oxidation of cysteine to disulfides or to various sulfur oxides. Enzymes involved in superoxide formation (as well as NO synthesis) is increased in numerous inflammatory and degenerative diseases, resulting in an increase in peroxynitrite levels. intracellular levels of glutathione, which can protect against tissue damage by scavenging peroxynitrite.
  14. Inactivation – NO is highly labile due to its rapid reaction with metals, O2, and reactive oxygen species. NO can react with heme and hemoproteins, including oxyhemoglobin, which oxidizes NO to nitrate. Haem has an affinity for NO > 10,000 times greater than  for oxygen. The reaction of NO with hemoglobin may also lead to S-nitrosylation of hemoglobin, resulting in transport of NO throughout the vasculature. NO is also inactivated by reaction with O2 to form nitrogen dioxide. As noted, NO reacts with superoxide, which results in the formation of the highly reactive oxidizing species, peroxynitrite. Scavengers of superoxide anion such as superoxide dismutase may protect NO, enhancing its potency and prolonging its duration of action. small amounts of NO produced in the lung escape degradation  and  can  be  detected  in  exhaled  air.
  15. Vascular effects – NO has a significant effect on vascular smooth muscle tone and blood pressure. Numerous endothelium-dependent vasodilators, such as acetylcholine and bradykinin, act by increasing intracellular calcium levels in endothelial cells, leading to the synthesis of NO.
  16. NO diffuses to vascular smooth muscle leading to vasorelaxation. (Mutant mice that lack the  gene coding for eNOS are hypertensive, consistent with a  role for NO biosynthesis in the physiological control of  blood pressure) Apart from being a vasodilator and regulating blood pressure, NO also has antithrombotic effects. Both endothelial cells and platelets contain eNOS, which acts via an NO-cGMP pathway to inhibit platelet activation, an initiator of thrombus formation. Thus, in diseases associated with endothelial dysfunction, the associated decrease in NO generation leads to an increased propensity for abnormal platelet function and thrombosis.
  17. 3) NO also protects against atherogenesis. A major antiatherogenic mechanism of NO involves the inhibition of proliferation and migration of vascular smooth muscle cells. In animal models, myointimal proliferation following angioplasty can be blocked by NO donors, by NOS gene transfer, and by NO inhalation. NO reduces endothelial adhesion of monocytes and leukocytes, which are early steps in the development of atheromatous plaques. This effect is due to the inhibitory effect of NO on the expression of adhesion molecules on the endothelial surface. In addition, NO may act as an antioxidant, blocking the oxidation of low-density lipoproteins and thus preventing or reducing the formation of foam cells in the vascular wall. Plaque formation is also affected by NO-dependent reduction in endothelial cell permeability to lipoproteins. The importance of eNOS in cardiovascular disease is supported by experiments showing increased atherosclerosis in animals treated with eNOS inhibitors. * Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, and hypertension, are associated with decreased endothelial NO production, and thus enhance atherogenesis.
  18. 2. Septic shock – Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-α and other cytokines induce synthesis of iNOS in macrophages, neutrophils, and T cells, as well as hepatocytes, smooth muscle cells, endothelial cells, and fibroblasts. This widespread generation of NO results in exaggerated hypotension, shock, and, in some cases, death. This hypotension is reduced or reversed by NOS inhibitors in humans as well as in animal models. A similar reversal of hypotension is produced by compounds that prevent the action of NO, such as the sGC inhibitor methylene blue. despite the ability of NOS inhibitors to ameliorate hypotension in sepsis, there is no overall improvement in survival in patients with gram-negative sepsis treated with NOS inhibitors. * The absence of benefit may reflect the inability of the NOS inhibitors used in these trials to differentiate between NOS isoforms,
  19. 3. Infection & Inflammation – The generation of NO has both beneficial and detrimental roles in the host immune response and in inflammation. The host response to infection or injury - release of inflammatory mediators, such as tumor necrosis factor and interleukin-1. This leads to induction of iNOS in leukocytes, The NO that is produced, along with peroxynitrite that forms from its interaction with superoxide, is an important microbicide. When challenged with foreign antigens, Th1 cells (see Chapter 55) respond by synthesizing NO, NO also stimulates the synthesis of inflammatory prostaglandins by activating cyclooxygenase isoenzyme 2 (COX-2). Through its effects on COX-2, its direct vasodilatory effects, and other mechanisms, NO generated during inflammation contributes to the erythema, vascular permeability, and subsequent edema associated with acute inflammation.
  20. in both acute and chronic inflammatory conditions, prolonged or excessive NO production may exacerbate tissue injury. Indeed, psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of NO and iNOS, suggesting that persistent iNOS induction may contribute to disease pathogenesis. Thus, inhibition of the NO pathway may have a beneficial effect on a variety of acute and chronic inflammatory diseases.
  21. 4. CNS – NO has an important role in the central nervous system as a neurotransmitter (see Chapter 21). Unlike classic transmitters, NO is not stored, but rather is synthesized on demand and immediately diffuses to neighboring cells. NO synthesis is induced at postsynaptic sites in neurons, most commonly upon activation of the NMDA subtype of glutamate receptor, which results in calcium influx and activation of nNOS. excessive NO synthesis is linked to excitotoxic neuronal death in several neurologic diseases, including stroke, amyotrophic lateral sclerosis, and Parkinson’s disease, therapy with NOS inhibitors may reduce neuronal damage in these conditions. * However, clinical trials have not clearly supported the benefit of NOS inhibition, which may reflect nonselectivity of the inhibitors, resulting in inhibition of the beneficial effects of eNOS.
  22. 5. The PNS – Nonadrenergic, noncholinergic (NANC) neurons are widely distributed in peripheral tissues, especially the gastrointestinal and reproductive tracts. Penile erection is thought to be caused by the release of NO from NANC neurons; NO promotes relaxation of the smooth muscle in the corpora cavernosa— the initiating factor in penile erection—and inhibitors of NOS have been shown to prevent erection in rats. An established approach in treating erectile dysfunction is to enhance the effect of NO signaling by inhibiting the breakdown of cGMP by the phosphodiesterase (PDE isoform 5) present in the smooth muscle of the corpora cavernosa with drugs such as sildenafil, tadalafil, and vardenafil.
  23. Nitric oxide (NO) is known to have a protective effect on the gastrointestinal tract.  In preclinical studies NO was shown to help maintain gastric mucosal integrity by inhibiting gastric acid secretion & increasing gastric blood flow , to inhibit leukocyte adherence to the endothelium, and to repair NSAID-induced damage. In addition, epidemiologic studies have shown that the use of NO-donating agents with NSAIDs or aspirin resulted in reduced risk for gastrointestinal bleeding. Although prostaglandins and NO are required for normal gastrointestinal function, there is also some evidence that a large excess of these compounds may have deleterious effects on the gastrointestinal tract.
  24. 6. Respiratory disorders – NO is administered by inhalation to newborns with hypoxic respiratory failure associated with pulmonary hypertension. NO inhalation dilates pulmonary vessels, resulting in decreased pulmonary vascular resistance and reduced pulmonary artery pressure. Inhaled NO also improves oxygenation by reducing mismatch of ventilation and perfusion in the lung. Inhaled NO has also been shown to improve cardiopulmonary function in adult patients with pulmonary artery hypertension. Due to the enrichment of PDE-5 in pulmonary vascular beds, PDE-5 inhibitors such as sildenafil and tadalafil induce vasodilation and marked reductions in pulmonary hypertension.
  25. NO has been reported to exert dichotomous effects within the multistage model of cancer (Tables 1 and ​and2).2). NO plays an important role in tumor progression by modulates different cancer-related events including angiogenesis, apoptosis, cell cycle, invasion, and metastasis [8] (Table 1). In contrast to tumor promoting effects, NO has also been reported to have tumoricidal effects
  26. NO may exert a biphasic response, such that when NO levels go beyond a critical concentration that would be suitable for tumor growth and survival, growth arrest and/or apoptotic pathways are initiated. These characteristics of NO have been exploited therapeutically with impressive effects in pre-clinical models of cancer to slow tumor growth and to enhance the efficacy of both chemotherapy and radiotherapy  Transfer of NOS-encoding cDNA sequences into cancer cells for gene therapy. Alternative mechanisms for NO delivery would be the use of NO releasing drugs or NO donors. 
  27. Several means whereby the L-arginine/NO pathway could  be enhanced are under investigation.  is that, by potentiating NO, they will  prevent atherosclerosis or its thrombotic complications or  have other beneficial effects attributed to NO. Possibilities  include:
  28. NO donors, which release NO or related NO species, are used clinically to elicit smooth muscle relaxation. Different classes of NO donors have differing biologic properties,
  29. Kz - 332
  30. The primary strategy to reduce NO generation in cells is to use NOS inhibitors. can inhibit NO synthesis or action by several mechanisms. The majority of these inhibitors are arginine analogs compete with arginine  for  NOS.  Several  such  compounds,  for  example  NGmonomethyl-L-arginine  (L-NMMA)  and  NG-nitro-Larginine  methyl  ester  (L-NAME),  have  proved  of  great value as experimental tools. ADMA  (see above), is approximately equipotent with L-NMMA. present in human plasma and is excreted in urine.  increased in people with hypercholesterolaemia.
  31. There is therapeutic interest in selective inhibitors of different isoforms of NOS. Selective inhibitors of iNOS - N-iminoethyl-L-lysine have potential for the treatment of inflammatory and other conditions in which iNOS  has been implicated (e.g. asthma).  7-Nitroindazole selectively inhibits nNOS, the mechanism of selectivity being  uncertain. S-methyl-L-thiocitrulline is a potent and selective inhibitor of human nNOS – useful in neurodegenerative conditions. Glucocorticoids inhibit biosynthesis of inducible (but   not constitutive) nitric oxide synthase (NOS). NO itself – feed back inhibition.
  32.  ADMA is also eliminated  by  metabolism  to  a  mixture  of  citrulline  and  methylamine  by  dimethylarginine dimethylamino hydrolase  (DDAH), an enzyme.  Inhibition of DDAH by NO causes feedback inhibition of the  L-arginine/NO pathway by allowing cytoplasmic accumulation of ADMA. Conversely, activation of DDAH could  potentiate the L-arginine/NO pathway;
  33. N 2 O 3 & methemoglobin levels monitored during inhaled NO Rx.
  34. Inhaled nitric oxide is the medication of choice for treatment of pulmonary hypertension and hypoxemia following cardiopulmonary bypass (29) or the use of a ventricular assist device (30), for mitral valve replacement (31), coronary artery bypass graft (32), heart or lung transplantation. NO improves blood flow to organs & tissues in SCD by vasodilation. Eg. The role of nitro-glycerine as a chemo-sensitizing agent   NO can act as a novel potential therapeutic agent in patients with refractory cancer by sensitizing tumor cells to chemotherapy, radiotherapy or immunotherapy. Nevertheless, further validation and experimental/clinical trials are required to develop NO based strategies for cancer prevention and treatment.
  35. Nitric oxide supplements can help in quick muscle gain and enhanced stamina and vigor. These supplements will also increase the physical strength and endurance. promote blood flow and helps to supply nutrients throughout the body, majorly to the muscles.