SlideShare a Scribd company logo
1 of 40
Presented by –
ROHIT BISHT
(M. pharma Pharmacology
I.S. F. College of pharmacy
, Moga,Punjab
ENDOTHELIUM
ENDOTHELIUM
 The endothelium is the thin layer of cells that lines the interior
surface of Blood vessels and lymphatic vessels forming an
interface between circulating blood and lymph in the lumen
and the rest of the vessel wall.
 The cells that form the endothelium are called endothelial
cells.
 Endothelial cells in direct contact with blood are called
vascular endothelial cells where as those in direct contact with
lymph are known as lymphatic endothelial cells.
• Endothelial cells release substances acting directly on
vascular smooth muscle cells, causing either contraction
or relaxation.
• In 1980 Furchgott & Zawadzki first described endothelium-
dependent relaxation of the blood vessels by acetylcholine.
 Further studies in 1984 revealed that other factors such as
bradykinin, histamine and 5-hydroxytryptamine release
endothelium derived relaxing factor (EDRF), which can
modulate vessel tone.
 In 1987 Furchgott proposed that EDRF might be nitric oxide
(NO) based on a study of the transient relaxations of
endothelium-denuded rings of rabbit aorta to „acidified‟
inorganic nitrite (NO-) solutions and the observations that
superoxide dismutase (SOD, which removes O2
-) protected
EDRF.
ENDOTHELIUM DERIVED RELAXING FACTOR
• In 1988 Palmer et al could detect NO production both
biologically and chemically by chemiluminescence. The following
year in 1989 the enzyme responsible for NO production, NO
synthase, was discovered and NO pathway was proposed.
• Neuronal and humoral mediators, e.g. Ach, adrenaline
, noradrenaline , histamine ,5-HT, ATP, adenosine, substance P
, arginine vasopressin (AT/VP), bradykinin, thrombin and Ca++ -
ionophore A 23187 , VEGF , insulin, angiotensin , TNF-α, IL-6
, arginase , asymmetric dimethylarginine
(ADMA), dimethylarginine dimethylaminohydrolase (DDAH), etc.
acting in their corresponding receptors or cellular structures can
affect production and release of NO.
NITRIC OXIDE
 A chemical compound with formula NO is a free radical gas.
 It is first identified as endothelial derived releasing factor(E D
R F ).
 At high concentration , fight against infectious organism and
cancer cell.
 At lower concentration helps in regulating the circulatory
and central nervous system.
 Nitric oxide differs from other neurotransmitter and
hormones in a way that it is not regulated by
storage, release , or targeted degradation.
 No does not require receptor for its action when
synthesized immediately utilized.
 Ca++ clamudulin complex is necessary for nitric oxide
synthesis.
The structure and nature of Nitric
Oxide
 Nitric oxide is a di atomic 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.
N O
Synthesis of Nitric Oxide
 Nitric oxide is synthesized from L-arginine.
 This reaction is catalyzed by nitric oxide synthase, a
1,2,9,4 amino acid enzyme.
COO-
C
(CH2)3
NH
C
H2N
H
NH2+
+H3N
Arginine
NOS
NADPH
+ O2
NAD+
COO-
C
(CH2)3
NH
C
H+H3N
N
+
H2N
H
OH
N-w-Hydroxyarginine
COO-
C
(CH2)3
NH
H+H3N + NO
NOS
C
O NH2
Citrulline
Release & m/a of No-
Intracellular mechanism:
 When nitric oxide forms in large parts because superoxide
anion has a height affinity for No.
 Superoxide anion reduces No bioavailability.
 Nitric oxide also binds to the heme moiety of hemoglobin
and heme moiety of enzyme gunayl cyclase , which is
found in smooth muscle cell and most other cells of body.
 When NO formed by vascular endothelium it rapidly
diffuses into the blood where it binds to hemoglobin &
subsequently broken down.
 It also diffuses into vascular smooth muscle cells adjacent to
the endothelium where it binds to & activate gunyl cyclase .
This enzyme catalyse the dephosprylation of GTP to cGMP
which serve as a second messenger for many important cellular
function , particular for signaling smooth muscle contraction.
 cGMP induces smooth muscle relaxation by multiple
mechanism including-
 increased intracellular cGMP which inhibit ca++ entry into the
cell and decrease intracellular ca++ concentration.
 activates k+ channel which leads to hyper polarization &
relaxation .
• Stimulates a cGMP dependent protein kinase that activates
myosin light chain phosphate (MLCK) the enzyme that
dephosphorylate myosin light chain leads to smooth muscle
relaxation
Types of NOS
 NOS I or n NOS
 Central and peripheral neuronal cells, brain, spinal cord, platelets.
 Ca++ dependent, used for neuronal communication
 Constitutive
 NOS II or I NOS
 Most nucleated cells, particularly macrophages
 Independent of intracellular Ca++ and its regulation depend upon de novo
synthesis.
 Inducible in presence of inflammatory cytokines, bacterial liposaccharides.
 NOS III or e NOS
 Present on Vascular endothelial cells and neuronal cells
 Ca+2 dependent
 Vascular regulation
NOS
Constitutive
Inducible
 Nitric Oxide in the human body has many uses which are best
summarized under five categories.
 NO in the nervous system
 NO in the circulatory system
 NO in the muscular system
 NO in the immune system
 NO in the digestive system
 No in the reproductive system
 NO in the gene toxicity
 No in the apoptosis
14
Role of nitric oxide
 NO is a signaling molecule, but not necessarily a neurotransmitter.
 NO signals inhibition of smooth muscle contraction, adaptive
relaxation, and localized vasodilation.
 n nos action in C N S have been associated with pain perception in
spinal cord level.
 NO diffuses out of the cells making it vescular storage in vesicles and
release by exocytosis
 NO does not bind to surface receptors, but instead exits
cytoplasm, enters the target cell, and binds with intracellular guanyl
cyclase
 Present in presynaptic terminal
15
Nitric oxide in the Nervous system
 NO serves in the body as a neurotransmitter, but there are
definite differences.
Role in Neurodegenerative disease
 Implicated in :- Alzheimer disease
Parkinson disease
Huntington disease
Amyotrophic leteral sclerosis
All are related to the excessive release of NO & glutamate
both.
But in Parkinson's disease Glial cells produce excessive levels of nitric
oxide, which may be neurotoxic for a sub population of dopaminergic
neurons, especially those not expressing NADPH- diaphorase activity.
The presence of glial cells expressing nitric oxide synthase in the
substantia nigra of patients with Parkinson's disease represents a
consequence of dopaminergic neuronal loss.
 Play a role in long term memory
 As a retrograde messenger that facilitates long term potentiation
of neurons (memory)
 Synthesis mechanism involve Ca2+/Calmodulin
activates NOS-I
activates Guanyl cyclase
cycle of nerve action potentials
catalyzes cGMP production
Nitric oxide in the circulatory system
 NO serves as a vasodilator
 Released in response to high blood flow rate and signaling
molecules (Ach and bradykinin)
 Highly localized and effects are brief
 If NO synthesis is inhibited, blood pressure increases
 NO aids in gas exchange between hemoglobin and cells
 Hemoglobin is a vasoconstrictor, Fe scavenges NO
 NO is protected by cysteine group when O2 binds to
hemoglobin.
 During O2 delivery, NO locally dilates blood vessels to aid
in gas exchange
Nitric oxide in the Muscular system
 NO was originally 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
 This causes guanyl cyclase to produce cGMP
 A rise in cGMP causes Ca2+ pumps to be activated, thus
reducing Ca2+ concentration in the cell
 This causes muscle relaxation
Role in Blood vessels
Role in the Immune system
 NOS II catalyzes synthesis of NO used in host defense
reactions
 Activation of NOS II is independent of Ca2+ in the cell
 Synthesis of NO happens in most nucleated
cells, particularly macrophages.
 NO is a potent inhibitor of viral replication.
 NO is a bactericidal 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.
Role In the Digestive system
 NO is used 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.
Role In the Reproductive system:
Nos localized in pelvic nerve neuron innervating the
corpora cavrinosa and the neuronal plexuses of the
adventitial layer of the penile arteries – proven most
effective for erectyl dysfunction.
 No and its derivatives produced in inflamed tissue
contribute to the carcinogenesis process due to direct
or indirect DNA damage.
Direct DNA damage: DNA deamination , peroxynitrite
induced adult formation single strand break in the
DNA
Indirect DNA damage: interaction of NO reactive
species with other molecule like amines , thioles
, lipids.
-NO after reaction with O2/superoxide forms
genotoxicity .
Role In Genotoxicity:
Role in wound healing & tissue repair
No is powerful stimulator of cell division maturation
and differentiation . Necessary mediator of neuro
vascularization i.e. angiogenesis and lymph ducts to
nourish the healing of tissue.
Role in Apoptosis
 Nitric oxide and its reaction products either promotes or
prevent apoptosis .
Pro-apoptosis effect of NO- induction of apoptosis by NO
resulting in the accumulation of tumor suppressor protein
p-53.
Anti-apoptotic effect of NO- some studies suggest that
endogenous I Nos expression or exposure to low dose of
NO donors inhibits apoptosis.
Role in Inflammation
NO has shown to act as a mediator of inflammatory
processes. This process has enhanced the effect of
cyclooxygenases and stimulates the production of pro-
inflammatory eicosanoids.
PROSTACYCLINE
 Prostacyclin (or PGI2) is a prostaglandin member of the
family of lipid molecules known as eicosanoids. It inhibits
platelet activation and is also an effective vasodilator.
 In 1960s, ,Professor John Vane, began to explore the role
of prostaglandins in anaphylaxis and respiratory diseases. Sir
John discovered that aspirin and other oral anti-inflammatory
drugs work by inhibiting the synthesis of prostaglandins.
 Sir John and a team had identified a lipid mediator they called
“PG-X,” which inhibits platelet aggregation. PG-X, which later
would become known as prostacyclin, is 30 times more potent
than any other then-known anti-aggregatory agent.
E D H F :
 In blood vessels Endothelium-Derived Hyperpolarizing
Factor or EDHF is proposed to be a substance or
electrical signal that is generated or synthesized in and
released from the endothelium; its action is to
hyperpolarise vascular smooth muscle cells, causing these
cells to relax, thus allowing the blood vessel to expand in
diameter.
Both a vascular endothelial cytochrome P450 (CYP450)
product of arachidonic acid metabolism and the potassium
ion (K+) have been identified as endothelium-derived
hyperpolarizing factors (EDHFs) in animal vascular
tissues.
Pathways Of EDHF:-
There are two general pathways that explain EDHF:-
 1. Diffusible factors are endothelium-derived
substances that are able to pass through internal elastic
layer (IEL), reach underlying vascular smooth muscle
cells at a concentration sufficient to activate ion
channels , and initiate smooth muscle
hyperpolarisation and relaxation.
 2. Contact-mediated mechanisms bestow endothelial
hyperpolarisation that passively spreads to the smooth
muscle through inter cellular coupling and therefore
EDHF is considered as a solely electrical event.
Although the phenomenon of EDHF has been observed and reported
in scientific literature, to date the chemical identity of the factor(s)
has not been determined.
1) In some cases, members of a class of arachidonic acid
derivatives, the epoxyeicosatrienoic acids (EETs), have been
found to mediate the vasodilatation. These compounds are formed
by epoxidation of any one of four double bonds of the
arachidonic acid carbon backbone by cytochrome p450
epoxygenase enzymes.
Structure of Arachidonic acid
2) In addition, in some cases hydrogen peroxide has
been suggested to function as an EDHF in some
vascular beds; although the validity of this
observation is debated. because the H2O2 candidacy
is questioned by the fact that it may have an
inhibitory action on K+ channels, at least, in some
vascular beds.
3) It Has been suggested that EDHF is Potassium Ions
(K+) as the activation of endothelial K-Ca+ channels
causes an efflux of K+ from endothelial cells towards
the extracellular space.
 An increase in extracellular K+ has been shown to
activate an ouabain -sensitive electrogenic Na+–K+-
ATPase followed by hyperpolarization and smooth
muscle cell relaxation.
 However the involvement of K+ ions into EDHF-
mediated relaxation does not necessarily involve the
activation Na+–K+-ATPase channels. It is more likely
that K+ ions and gap junctions can be involved in
EDHF-mediated relaxation simultaneously, and may
also act synergistically.
 4. An alternative explanation for the EDHF
phenomenon is that direct intercellular
communication via gap junctions allows passive
spread of agonist-induced endothelial
hyperpolarization through the vessel wall. In some
arteries, eicosanoids and K+ ions may themselves
initiate a conducted endothelial
hyperpolarization, thus suggesting that electro tonic
signalling may represent a general mechanism through
which the endothelium participates in the regulation
of vascular tone.
INTERACTION B/W NO,EDHF AND
PROSTACYCLIN:-
 The three main mediators of endothelial vasodilator
function, NO, prostacyclin, and EDHF appear not to be
mutually exclusive and act synergistically in a complex
manner to maintain the health of the vasculature .
 In arteries, NO is the predominant endothelium-derived
vasodilator but has relatively less prominent contribution
in the resistance vessels of the microcirculation where
EDHF appears to predominate.
 NO may inhibit EDHF responses as some studies could
only demonstrate. EDHF responses once NO production
had been inhibited.
Pharmacological inhibitors Targets Comments
Apamin S KCa
+ Highly specific
Charybdotoxin IKCa
+-BKCa
+ Can inhibit some Kv channels
Iberiotoxin
B KCa
+ Highly specific
Tetraethylammonium SKCa
+-IKCa
+-BKCa
+ Inhibit other K+channels at
>10−2)m
Tetraethybutylammonium S KCa
+-I KCa
+-B KCa
+ Inhibit other K+channels at
>10−2m
BaCl2 KIR
+ —
Ouabain Na+/K+ ATPase
Can affect gap junction
activity at >10−4m
KCL K+ currents
Dilates at >10−2m through KIR
+
and Na+/K+ ATPase activation
18 α-glycyrrhetic acid Gap junctions
Possesses nonjunctional
effects on membrane currents
Connexin mimetic peptides Gap junctions Highly specific
Catalase Hydrogen peroxide —
EDHF IN DISEASES
 Experimental evidence indicates that a shift away from NO-
mediated endothelium-dependent relaxation toward EDHF
dependent relaxation occurs in disease states.
 Alteration of EDHF-mediated responses has been reported with
aging, hypertension, atherosclerosis, hypercholesterolemia, heart
failure, angioplasty, eclampsia, diabetes.
EDHF in Hypertension
• Evidence suggests that CYP expression and EET generation are
increased in hypertension and in hypercholesterolemia.
• Polymorphisms within CYP epoxygenases being associated with
an enhanced risk of developing coronary artery disease and
hypertension.
EDHF in diabetes
EDHF-mediated responses are depressed in some models
of type I and type II diabetes with the exception of murine
models.
EDHF in hypercholesterolemia
 In hypercholesterolemia, it has been observed that there is
significant contribution of KCa+ channel activation and a
lower Nitric Oxide release with acetylcholine.
Demonstrated level of E D R F‟s-
Nitric oxide

More Related Content

What's hot (20)

Nitric oxide
Nitric oxideNitric oxide
Nitric oxide
 
nitric oxide
nitric oxidenitric oxide
nitric oxide
 
Role of nitric oxide in pathology
Role of nitric oxide in pathologyRole of nitric oxide in pathology
Role of nitric oxide in pathology
 
EICOSANOIDS
EICOSANOIDSEICOSANOIDS
EICOSANOIDS
 
Eicosanoids
EicosanoidsEicosanoids
Eicosanoids
 
Nitric oxide
Nitric oxideNitric oxide
Nitric oxide
 
prostaglandinsPG leukotrienesLT thromboxinesTX
prostaglandinsPG  leukotrienesLT thromboxinesTXprostaglandinsPG  leukotrienesLT thromboxinesTX
prostaglandinsPG leukotrienesLT thromboxinesTX
 
Nitric oxide
Nitric oxideNitric oxide
Nitric oxide
 
PROSTAGLANDINS
PROSTAGLANDINSPROSTAGLANDINS
PROSTAGLANDINS
 
Nitric oxide and its role in therapeutics
Nitric oxide and its role in therapeuticsNitric oxide and its role in therapeutics
Nitric oxide and its role in therapeutics
 
Glucose receptors1
Glucose receptors1Glucose receptors1
Glucose receptors1
 
Endothelin
EndothelinEndothelin
Endothelin
 
Ion channels
Ion channelsIon channels
Ion channels
 
Eicosanoids
EicosanoidsEicosanoids
Eicosanoids
 
Serotonin.dr.asa
Serotonin.dr.asaSerotonin.dr.asa
Serotonin.dr.asa
 
Mechanism of action of insulin
Mechanism of action of insulin Mechanism of action of insulin
Mechanism of action of insulin
 
Enzyme and coenzyme
Enzyme and coenzymeEnzyme and coenzyme
Enzyme and coenzyme
 
Endothelin ppt
Endothelin ppt Endothelin ppt
Endothelin ppt
 
(Eicosanoids) Prostaglandins, leucotrienes, and platelet activating factors
(Eicosanoids) Prostaglandins, leucotrienes, and platelet activating factors(Eicosanoids) Prostaglandins, leucotrienes, and platelet activating factors
(Eicosanoids) Prostaglandins, leucotrienes, and platelet activating factors
 
Antihypertensives | Classes of Drugs | Baro Receptor
Antihypertensives | Classes of Drugs | Baro ReceptorAntihypertensives | Classes of Drugs | Baro Receptor
Antihypertensives | Classes of Drugs | Baro Receptor
 

Viewers also liked

Viewers also liked (15)

ANTI-TB AND ANTI LEPROTIC DRUGS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR.
ANTI-TB AND ANTI LEPROTIC DRUGS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR.ANTI-TB AND ANTI LEPROTIC DRUGS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR.
ANTI-TB AND ANTI LEPROTIC DRUGS [MEDICINAL CHEMISTRY] BY P.RAVISANKAR.
 
Sulfonamides(1)
Sulfonamides(1)Sulfonamides(1)
Sulfonamides(1)
 
Sulphonamide
SulphonamideSulphonamide
Sulphonamide
 
Neurotransmitters
NeurotransmittersNeurotransmitters
Neurotransmitters
 
Anti tubercular drugs
Anti tubercular drugsAnti tubercular drugs
Anti tubercular drugs
 
GABA
GABAGABA
GABA
 
Neuropeptide Y
Neuropeptide YNeuropeptide Y
Neuropeptide Y
 
Neurosteroids and neuropeptides
Neurosteroids and neuropeptidesNeurosteroids and neuropeptides
Neurosteroids and neuropeptides
 
Neuropeptides 2014
Neuropeptides 2014 Neuropeptides 2014
Neuropeptides 2014
 
Glycine
GlycineGlycine
Glycine
 
Gaba
Gaba Gaba
Gaba
 
neurotransmitter gaba
neurotransmitter gabaneurotransmitter gaba
neurotransmitter gaba
 
Neuropeptides
NeuropeptidesNeuropeptides
Neuropeptides
 
Gaba
GabaGaba
Gaba
 
Neurotransmitters
NeurotransmittersNeurotransmitters
Neurotransmitters
 

Similar to Nitric oxide

No and co final by syed kashifpptx
No and co final by syed kashifpptxNo and co final by syed kashifpptx
No and co final by syed kashifpptxshaffain
 
Nitric oxide .pdfckjgcgchfcfhxcfhcfhchfch
Nitric oxide .pdfckjgcgchfcfhxcfhcfhchfchNitric oxide .pdfckjgcgchfcfhxcfhcfhchfch
Nitric oxide .pdfckjgcgchfcfhxcfhcfhchfchSriRam071
 
Role of nitric oxide in cell signaling
Role of nitric oxide in cell signalingRole of nitric oxide in cell signaling
Role of nitric oxide in cell signalingGamitKinjal
 
Endothelial Dysfunction Y O U S R Y Y Yeasured
Endothelial  Dysfunction   Y O U S R Y Y YeasuredEndothelial  Dysfunction   Y O U S R Y Y Yeasured
Endothelial Dysfunction Y O U S R Y Y YeasuredM.YOUSRY Abdel-Mawla
 
Yousry Endothelial Vs Erectile Dysfunction
Yousry Endothelial Vs Erectile DysfunctionYousry Endothelial Vs Erectile Dysfunction
Yousry Endothelial Vs Erectile Dysfunctionguest5a246c
 
Biochemistry of nitric oxide
Biochemistry of nitric oxideBiochemistry of nitric oxide
Biochemistry of nitric oxideDr.M.Prasad Naidu
 
Nitric oxide and its role in reproduction
Nitric oxide and its role in reproductionNitric oxide and its role in reproduction
Nitric oxide and its role in reproductiondavid sonwani
 
blood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjh
blood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjhblood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjh
blood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjhSriRam071
 
Key pointsmedicalsciencesataglance
Key pointsmedicalsciencesataglanceKey pointsmedicalsciencesataglance
Key pointsmedicalsciencesataglanceElsa von Licy
 
Noradrenergc transmission
Noradrenergc transmissionNoradrenergc transmission
Noradrenergc transmissionamitgajjar85
 
Noradrenergc transmission
Noradrenergc transmissionNoradrenergc transmission
Noradrenergc transmissionamitgajjar85
 
Atherosclerosis.pdfjgkgjcgjcghcfhchggkguc
Atherosclerosis.pdfjgkgjcgjcghcfhchggkgucAtherosclerosis.pdfjgkgjcgjcghcfhchggkguc
Atherosclerosis.pdfjgkgjcgjcghcfhchggkgucSriRam071
 
Types of receptors pharmacology
Types of receptors pharmacologyTypes of receptors pharmacology
Types of receptors pharmacologyWasiem El-Helaly
 
Arachidonic acid metabolites ppt pdf
Arachidonic acid metabolites ppt pdfArachidonic acid metabolites ppt pdf
Arachidonic acid metabolites ppt pdfmohammadazizi31
 
NITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptx
NITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptxNITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptx
NITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptxDrMadanChandraDas
 

Similar to Nitric oxide (20)

Nitric oxide
Nitric oxideNitric oxide
Nitric oxide
 
No and co final by syed kashifpptx
No and co final by syed kashifpptxNo and co final by syed kashifpptx
No and co final by syed kashifpptx
 
Seminar0
Seminar0Seminar0
Seminar0
 
Nitric oxide .pdfckjgcgchfcfhxcfhcfhchfch
Nitric oxide .pdfckjgcgchfcfhxcfhcfhchfchNitric oxide .pdfckjgcgchfcfhxcfhcfhchfch
Nitric oxide .pdfckjgcgchfcfhxcfhcfhchfch
 
Role of nitric oxide in cell signaling
Role of nitric oxide in cell signalingRole of nitric oxide in cell signaling
Role of nitric oxide in cell signaling
 
Leptin and Nitric Oxide
Leptin and Nitric OxideLeptin and Nitric Oxide
Leptin and Nitric Oxide
 
Endothelial Dysfunction Y O U S R Y Y Yeasured
Endothelial  Dysfunction   Y O U S R Y Y YeasuredEndothelial  Dysfunction   Y O U S R Y Y Yeasured
Endothelial Dysfunction Y O U S R Y Y Yeasured
 
Yousry Endothelial Vs Erectile Dysfunction
Yousry Endothelial Vs Erectile DysfunctionYousry Endothelial Vs Erectile Dysfunction
Yousry Endothelial Vs Erectile Dysfunction
 
Endothelium derived factors
Endothelium derived factorsEndothelium derived factors
Endothelium derived factors
 
Biochemistry of nitric oxide
Biochemistry of nitric oxideBiochemistry of nitric oxide
Biochemistry of nitric oxide
 
Nitric oxide and its role in reproduction
Nitric oxide and its role in reproductionNitric oxide and its role in reproduction
Nitric oxide and its role in reproduction
 
blood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjh
blood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjhblood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjh
blood vesels.pdfutdjxjfxhfxfgxgfxgfcgfcfhcjh
 
Key pointsmedicalsciencesataglance
Key pointsmedicalsciencesataglanceKey pointsmedicalsciencesataglance
Key pointsmedicalsciencesataglance
 
Noradrenergc transmission
Noradrenergc transmissionNoradrenergc transmission
Noradrenergc transmission
 
Noradrenergc transmission
Noradrenergc transmissionNoradrenergc transmission
Noradrenergc transmission
 
Atherosclerosis.pdfjgkgjcgjcghcfhchggkguc
Atherosclerosis.pdfjgkgjcgjcghcfhchggkgucAtherosclerosis.pdfjgkgjcgjcghcfhchggkguc
Atherosclerosis.pdfjgkgjcgjcghcfhchggkguc
 
Types of receptors pharmacology
Types of receptors pharmacologyTypes of receptors pharmacology
Types of receptors pharmacology
 
Arachidonic acid metabolites ppt pdf
Arachidonic acid metabolites ppt pdfArachidonic acid metabolites ppt pdf
Arachidonic acid metabolites ppt pdf
 
NITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptx
NITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptxNITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptx
NITRIC OXIDE AND VASOACTIVE PEPTIDE SIGNAL MOLECULE.pptx
 
Cell surface receptors and signalling molecules
Cell surface receptors and signalling moleculesCell surface receptors and signalling molecules
Cell surface receptors and signalling molecules
 

Recently uploaded

Oppenheimer Film Discussion for Philosophy and Film
Oppenheimer Film Discussion for Philosophy and FilmOppenheimer Film Discussion for Philosophy and Film
Oppenheimer Film Discussion for Philosophy and FilmStan Meyer
 
Daily Lesson Plan in Mathematics Quarter 4
Daily Lesson Plan in Mathematics Quarter 4Daily Lesson Plan in Mathematics Quarter 4
Daily Lesson Plan in Mathematics Quarter 4JOYLYNSAMANIEGO
 
Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)
Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)
Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)lakshayb543
 
Q-Factor HISPOL Quiz-6th April 2024, Quiz Club NITW
Q-Factor HISPOL Quiz-6th April 2024, Quiz Club NITWQ-Factor HISPOL Quiz-6th April 2024, Quiz Club NITW
Q-Factor HISPOL Quiz-6th April 2024, Quiz Club NITWQuiz Club NITW
 
Team Lead Succeed – Helping you and your team achieve high-performance teamwo...
Team Lead Succeed – Helping you and your team achieve high-performance teamwo...Team Lead Succeed – Helping you and your team achieve high-performance teamwo...
Team Lead Succeed – Helping you and your team achieve high-performance teamwo...Association for Project Management
 
Grade Three -ELLNA-REVIEWER-ENGLISH.pptx
Grade Three -ELLNA-REVIEWER-ENGLISH.pptxGrade Three -ELLNA-REVIEWER-ENGLISH.pptx
Grade Three -ELLNA-REVIEWER-ENGLISH.pptxkarenfajardo43
 
Measures of Position DECILES for ungrouped data
Measures of Position DECILES for ungrouped dataMeasures of Position DECILES for ungrouped data
Measures of Position DECILES for ungrouped dataBabyAnnMotar
 
MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptx
MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptxMULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptx
MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptxAnupkumar Sharma
 
Narcotic and Non Narcotic Analgesic..pdf
Narcotic and Non Narcotic Analgesic..pdfNarcotic and Non Narcotic Analgesic..pdf
Narcotic and Non Narcotic Analgesic..pdfPrerana Jadhav
 
4.16.24 Poverty and Precarity--Desmond.pptx
4.16.24 Poverty and Precarity--Desmond.pptx4.16.24 Poverty and Precarity--Desmond.pptx
4.16.24 Poverty and Precarity--Desmond.pptxmary850239
 
week 1 cookery 8 fourth - quarter .pptx
week 1 cookery 8  fourth  -  quarter .pptxweek 1 cookery 8  fourth  -  quarter .pptx
week 1 cookery 8 fourth - quarter .pptxJonalynLegaspi2
 
Using Grammatical Signals Suitable to Patterns of Idea Development
Using Grammatical Signals Suitable to Patterns of Idea DevelopmentUsing Grammatical Signals Suitable to Patterns of Idea Development
Using Grammatical Signals Suitable to Patterns of Idea Developmentchesterberbo7
 
INTRODUCTION TO CATHOLIC CHRISTOLOGY.pptx
INTRODUCTION TO CATHOLIC CHRISTOLOGY.pptxINTRODUCTION TO CATHOLIC CHRISTOLOGY.pptx
INTRODUCTION TO CATHOLIC CHRISTOLOGY.pptxHumphrey A Beña
 
Influencing policy (training slides from Fast Track Impact)
Influencing policy (training slides from Fast Track Impact)Influencing policy (training slides from Fast Track Impact)
Influencing policy (training slides from Fast Track Impact)Mark Reed
 
MS4 level being good citizen -imperative- (1) (1).pdf
MS4 level   being good citizen -imperative- (1) (1).pdfMS4 level   being good citizen -imperative- (1) (1).pdf
MS4 level being good citizen -imperative- (1) (1).pdfMr Bounab Samir
 
Textual Evidence in Reading and Writing of SHS
Textual Evidence in Reading and Writing of SHSTextual Evidence in Reading and Writing of SHS
Textual Evidence in Reading and Writing of SHSMae Pangan
 
Transaction Management in Database Management System
Transaction Management in Database Management SystemTransaction Management in Database Management System
Transaction Management in Database Management SystemChristalin Nelson
 

Recently uploaded (20)

Oppenheimer Film Discussion for Philosophy and Film
Oppenheimer Film Discussion for Philosophy and FilmOppenheimer Film Discussion for Philosophy and Film
Oppenheimer Film Discussion for Philosophy and Film
 
Daily Lesson Plan in Mathematics Quarter 4
Daily Lesson Plan in Mathematics Quarter 4Daily Lesson Plan in Mathematics Quarter 4
Daily Lesson Plan in Mathematics Quarter 4
 
Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)
Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)
Visit to a blind student's school🧑‍🦯🧑‍🦯(community medicine)
 
Q-Factor HISPOL Quiz-6th April 2024, Quiz Club NITW
Q-Factor HISPOL Quiz-6th April 2024, Quiz Club NITWQ-Factor HISPOL Quiz-6th April 2024, Quiz Club NITW
Q-Factor HISPOL Quiz-6th April 2024, Quiz Club NITW
 
Team Lead Succeed – Helping you and your team achieve high-performance teamwo...
Team Lead Succeed – Helping you and your team achieve high-performance teamwo...Team Lead Succeed – Helping you and your team achieve high-performance teamwo...
Team Lead Succeed – Helping you and your team achieve high-performance teamwo...
 
Grade Three -ELLNA-REVIEWER-ENGLISH.pptx
Grade Three -ELLNA-REVIEWER-ENGLISH.pptxGrade Three -ELLNA-REVIEWER-ENGLISH.pptx
Grade Three -ELLNA-REVIEWER-ENGLISH.pptx
 
prashanth updated resume 2024 for Teaching Profession
prashanth updated resume 2024 for Teaching Professionprashanth updated resume 2024 for Teaching Profession
prashanth updated resume 2024 for Teaching Profession
 
Measures of Position DECILES for ungrouped data
Measures of Position DECILES for ungrouped dataMeasures of Position DECILES for ungrouped data
Measures of Position DECILES for ungrouped data
 
Mattingly "AI & Prompt Design: Large Language Models"
Mattingly "AI & Prompt Design: Large Language Models"Mattingly "AI & Prompt Design: Large Language Models"
Mattingly "AI & Prompt Design: Large Language Models"
 
MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptx
MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptxMULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptx
MULTIDISCIPLINRY NATURE OF THE ENVIRONMENTAL STUDIES.pptx
 
Narcotic and Non Narcotic Analgesic..pdf
Narcotic and Non Narcotic Analgesic..pdfNarcotic and Non Narcotic Analgesic..pdf
Narcotic and Non Narcotic Analgesic..pdf
 
4.16.24 Poverty and Precarity--Desmond.pptx
4.16.24 Poverty and Precarity--Desmond.pptx4.16.24 Poverty and Precarity--Desmond.pptx
4.16.24 Poverty and Precarity--Desmond.pptx
 
week 1 cookery 8 fourth - quarter .pptx
week 1 cookery 8  fourth  -  quarter .pptxweek 1 cookery 8  fourth  -  quarter .pptx
week 1 cookery 8 fourth - quarter .pptx
 
Using Grammatical Signals Suitable to Patterns of Idea Development
Using Grammatical Signals Suitable to Patterns of Idea DevelopmentUsing Grammatical Signals Suitable to Patterns of Idea Development
Using Grammatical Signals Suitable to Patterns of Idea Development
 
INTRODUCTION TO CATHOLIC CHRISTOLOGY.pptx
INTRODUCTION TO CATHOLIC CHRISTOLOGY.pptxINTRODUCTION TO CATHOLIC CHRISTOLOGY.pptx
INTRODUCTION TO CATHOLIC CHRISTOLOGY.pptx
 
Influencing policy (training slides from Fast Track Impact)
Influencing policy (training slides from Fast Track Impact)Influencing policy (training slides from Fast Track Impact)
Influencing policy (training slides from Fast Track Impact)
 
MS4 level being good citizen -imperative- (1) (1).pdf
MS4 level   being good citizen -imperative- (1) (1).pdfMS4 level   being good citizen -imperative- (1) (1).pdf
MS4 level being good citizen -imperative- (1) (1).pdf
 
Textual Evidence in Reading and Writing of SHS
Textual Evidence in Reading and Writing of SHSTextual Evidence in Reading and Writing of SHS
Textual Evidence in Reading and Writing of SHS
 
INCLUSIVE EDUCATION PRACTICES FOR TEACHERS AND TRAINERS.pptx
INCLUSIVE EDUCATION PRACTICES FOR TEACHERS AND TRAINERS.pptxINCLUSIVE EDUCATION PRACTICES FOR TEACHERS AND TRAINERS.pptx
INCLUSIVE EDUCATION PRACTICES FOR TEACHERS AND TRAINERS.pptx
 
Transaction Management in Database Management System
Transaction Management in Database Management SystemTransaction Management in Database Management System
Transaction Management in Database Management System
 

Nitric oxide

  • 1. Presented by – ROHIT BISHT (M. pharma Pharmacology I.S. F. College of pharmacy , Moga,Punjab
  • 3. ENDOTHELIUM  The endothelium is the thin layer of cells that lines the interior surface of Blood vessels and lymphatic vessels forming an interface between circulating blood and lymph in the lumen and the rest of the vessel wall.  The cells that form the endothelium are called endothelial cells.  Endothelial cells in direct contact with blood are called vascular endothelial cells where as those in direct contact with lymph are known as lymphatic endothelial cells.
  • 4. • Endothelial cells release substances acting directly on vascular smooth muscle cells, causing either contraction or relaxation.
  • 5. • In 1980 Furchgott & Zawadzki first described endothelium- dependent relaxation of the blood vessels by acetylcholine.  Further studies in 1984 revealed that other factors such as bradykinin, histamine and 5-hydroxytryptamine release endothelium derived relaxing factor (EDRF), which can modulate vessel tone.  In 1987 Furchgott proposed that EDRF might be nitric oxide (NO) based on a study of the transient relaxations of endothelium-denuded rings of rabbit aorta to „acidified‟ inorganic nitrite (NO-) solutions and the observations that superoxide dismutase (SOD, which removes O2 -) protected EDRF. ENDOTHELIUM DERIVED RELAXING FACTOR
  • 6. • In 1988 Palmer et al could detect NO production both biologically and chemically by chemiluminescence. The following year in 1989 the enzyme responsible for NO production, NO synthase, was discovered and NO pathway was proposed. • Neuronal and humoral mediators, e.g. Ach, adrenaline , noradrenaline , histamine ,5-HT, ATP, adenosine, substance P , arginine vasopressin (AT/VP), bradykinin, thrombin and Ca++ - ionophore A 23187 , VEGF , insulin, angiotensin , TNF-α, IL-6 , arginase , asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), etc. acting in their corresponding receptors or cellular structures can affect production and release of NO.
  • 7. NITRIC OXIDE  A chemical compound with formula NO is a free radical gas.  It is first identified as endothelial derived releasing factor(E D R F ).  At high concentration , fight against infectious organism and cancer cell.  At lower concentration helps in regulating the circulatory and central nervous system.  Nitric oxide differs from other neurotransmitter and hormones in a way that it is not regulated by storage, release , or targeted degradation.  No does not require receptor for its action when synthesized immediately utilized.  Ca++ clamudulin complex is necessary for nitric oxide synthesis.
  • 8. The structure and nature of Nitric Oxide  Nitric oxide is a di atomic 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. N O
  • 9. Synthesis of Nitric Oxide  Nitric oxide is synthesized from L-arginine.  This reaction is catalyzed by nitric oxide synthase, a 1,2,9,4 amino acid enzyme. COO- C (CH2)3 NH C H2N H NH2+ +H3N Arginine NOS NADPH + O2 NAD+ COO- C (CH2)3 NH C H+H3N N + H2N H OH N-w-Hydroxyarginine COO- C (CH2)3 NH H+H3N + NO NOS C O NH2 Citrulline
  • 10. Release & m/a of No-
  • 11. Intracellular mechanism:  When nitric oxide forms in large parts because superoxide anion has a height affinity for No.  Superoxide anion reduces No bioavailability.  Nitric oxide also binds to the heme moiety of hemoglobin and heme moiety of enzyme gunayl cyclase , which is found in smooth muscle cell and most other cells of body.  When NO formed by vascular endothelium it rapidly diffuses into the blood where it binds to hemoglobin & subsequently broken down.
  • 12.  It also diffuses into vascular smooth muscle cells adjacent to the endothelium where it binds to & activate gunyl cyclase . This enzyme catalyse the dephosprylation of GTP to cGMP which serve as a second messenger for many important cellular function , particular for signaling smooth muscle contraction.  cGMP induces smooth muscle relaxation by multiple mechanism including-  increased intracellular cGMP which inhibit ca++ entry into the cell and decrease intracellular ca++ concentration.  activates k+ channel which leads to hyper polarization & relaxation . • Stimulates a cGMP dependent protein kinase that activates myosin light chain phosphate (MLCK) the enzyme that dephosphorylate myosin light chain leads to smooth muscle relaxation
  • 13. Types of NOS  NOS I or n NOS  Central and peripheral neuronal cells, brain, spinal cord, platelets.  Ca++ dependent, used for neuronal communication  Constitutive  NOS II or I NOS  Most nucleated cells, particularly macrophages  Independent of intracellular Ca++ and its regulation depend upon de novo synthesis.  Inducible in presence of inflammatory cytokines, bacterial liposaccharides.  NOS III or e NOS  Present on Vascular endothelial cells and neuronal cells  Ca+2 dependent  Vascular regulation NOS Constitutive Inducible
  • 14.  Nitric Oxide in the human body has many uses which are best summarized under five categories.  NO in the nervous system  NO in the circulatory system  NO in the muscular system  NO in the immune system  NO in the digestive system  No in the reproductive system  NO in the gene toxicity  No in the apoptosis 14 Role of nitric oxide
  • 15.  NO is a signaling molecule, but not necessarily a neurotransmitter.  NO signals inhibition of smooth muscle contraction, adaptive relaxation, and localized vasodilation.  n nos action in C N S have been associated with pain perception in spinal cord level.  NO diffuses out of the cells making it vescular storage in vesicles and release by exocytosis  NO does not bind to surface receptors, but instead exits cytoplasm, enters the target cell, and binds with intracellular guanyl cyclase  Present in presynaptic terminal 15 Nitric oxide in the Nervous system  NO serves in the body as a neurotransmitter, but there are definite differences.
  • 16. Role in Neurodegenerative disease  Implicated in :- Alzheimer disease Parkinson disease Huntington disease Amyotrophic leteral sclerosis All are related to the excessive release of NO & glutamate both. But in Parkinson's disease Glial cells produce excessive levels of nitric oxide, which may be neurotoxic for a sub population of dopaminergic neurons, especially those not expressing NADPH- diaphorase activity. The presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represents a consequence of dopaminergic neuronal loss.
  • 17.  Play a role in long term memory  As a retrograde messenger that facilitates long term potentiation of neurons (memory)  Synthesis mechanism involve Ca2+/Calmodulin activates NOS-I activates Guanyl cyclase cycle of nerve action potentials catalyzes cGMP production
  • 18. Nitric oxide in the circulatory system  NO serves as a vasodilator  Released in response to high blood flow rate and signaling molecules (Ach and bradykinin)  Highly localized and effects are brief  If NO synthesis is inhibited, blood pressure increases  NO aids in gas exchange between hemoglobin and cells  Hemoglobin is a vasoconstrictor, Fe scavenges NO  NO is protected by cysteine group when O2 binds to hemoglobin.  During O2 delivery, NO locally dilates blood vessels to aid in gas exchange
  • 19. Nitric oxide in the Muscular system  NO was originally 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  This causes guanyl cyclase to produce cGMP  A rise in cGMP causes Ca2+ pumps to be activated, thus reducing Ca2+ concentration in the cell  This causes muscle relaxation
  • 20. Role in Blood vessels
  • 21. Role in the Immune system  NOS II catalyzes synthesis of NO used in host defense reactions  Activation of NOS II is independent of Ca2+ in the cell  Synthesis of NO happens in most nucleated cells, particularly macrophages.  NO is a potent inhibitor of viral replication.  NO is a bactericidal 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.
  • 22. Role In the Digestive system  NO is used 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. Role In the Reproductive system: Nos localized in pelvic nerve neuron innervating the corpora cavrinosa and the neuronal plexuses of the adventitial layer of the penile arteries – proven most effective for erectyl dysfunction.
  • 23.  No and its derivatives produced in inflamed tissue contribute to the carcinogenesis process due to direct or indirect DNA damage. Direct DNA damage: DNA deamination , peroxynitrite induced adult formation single strand break in the DNA Indirect DNA damage: interaction of NO reactive species with other molecule like amines , thioles , lipids. -NO after reaction with O2/superoxide forms genotoxicity . Role In Genotoxicity:
  • 24. Role in wound healing & tissue repair No is powerful stimulator of cell division maturation and differentiation . Necessary mediator of neuro vascularization i.e. angiogenesis and lymph ducts to nourish the healing of tissue. Role in Apoptosis  Nitric oxide and its reaction products either promotes or prevent apoptosis . Pro-apoptosis effect of NO- induction of apoptosis by NO resulting in the accumulation of tumor suppressor protein p-53. Anti-apoptotic effect of NO- some studies suggest that endogenous I Nos expression or exposure to low dose of NO donors inhibits apoptosis.
  • 25. Role in Inflammation NO has shown to act as a mediator of inflammatory processes. This process has enhanced the effect of cyclooxygenases and stimulates the production of pro- inflammatory eicosanoids.
  • 26. PROSTACYCLINE  Prostacyclin (or PGI2) is a prostaglandin member of the family of lipid molecules known as eicosanoids. It inhibits platelet activation and is also an effective vasodilator.  In 1960s, ,Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Sir John discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of prostaglandins.  Sir John and a team had identified a lipid mediator they called “PG-X,” which inhibits platelet aggregation. PG-X, which later would become known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent.
  • 27.
  • 28. E D H F :  In blood vessels Endothelium-Derived Hyperpolarizing Factor or EDHF is proposed to be a substance or electrical signal that is generated or synthesized in and released from the endothelium; its action is to hyperpolarise vascular smooth muscle cells, causing these cells to relax, thus allowing the blood vessel to expand in diameter. Both a vascular endothelial cytochrome P450 (CYP450) product of arachidonic acid metabolism and the potassium ion (K+) have been identified as endothelium-derived hyperpolarizing factors (EDHFs) in animal vascular tissues.
  • 29. Pathways Of EDHF:- There are two general pathways that explain EDHF:-  1. Diffusible factors are endothelium-derived substances that are able to pass through internal elastic layer (IEL), reach underlying vascular smooth muscle cells at a concentration sufficient to activate ion channels , and initiate smooth muscle hyperpolarisation and relaxation.  2. Contact-mediated mechanisms bestow endothelial hyperpolarisation that passively spreads to the smooth muscle through inter cellular coupling and therefore EDHF is considered as a solely electrical event.
  • 30. Although the phenomenon of EDHF has been observed and reported in scientific literature, to date the chemical identity of the factor(s) has not been determined. 1) In some cases, members of a class of arachidonic acid derivatives, the epoxyeicosatrienoic acids (EETs), have been found to mediate the vasodilatation. These compounds are formed by epoxidation of any one of four double bonds of the arachidonic acid carbon backbone by cytochrome p450 epoxygenase enzymes. Structure of Arachidonic acid
  • 31. 2) In addition, in some cases hydrogen peroxide has been suggested to function as an EDHF in some vascular beds; although the validity of this observation is debated. because the H2O2 candidacy is questioned by the fact that it may have an inhibitory action on K+ channels, at least, in some vascular beds. 3) It Has been suggested that EDHF is Potassium Ions (K+) as the activation of endothelial K-Ca+ channels causes an efflux of K+ from endothelial cells towards the extracellular space.
  • 32.  An increase in extracellular K+ has been shown to activate an ouabain -sensitive electrogenic Na+–K+- ATPase followed by hyperpolarization and smooth muscle cell relaxation.  However the involvement of K+ ions into EDHF- mediated relaxation does not necessarily involve the activation Na+–K+-ATPase channels. It is more likely that K+ ions and gap junctions can be involved in EDHF-mediated relaxation simultaneously, and may also act synergistically.
  • 33.  4. An alternative explanation for the EDHF phenomenon is that direct intercellular communication via gap junctions allows passive spread of agonist-induced endothelial hyperpolarization through the vessel wall. In some arteries, eicosanoids and K+ ions may themselves initiate a conducted endothelial hyperpolarization, thus suggesting that electro tonic signalling may represent a general mechanism through which the endothelium participates in the regulation of vascular tone.
  • 34.
  • 35. INTERACTION B/W NO,EDHF AND PROSTACYCLIN:-  The three main mediators of endothelial vasodilator function, NO, prostacyclin, and EDHF appear not to be mutually exclusive and act synergistically in a complex manner to maintain the health of the vasculature .  In arteries, NO is the predominant endothelium-derived vasodilator but has relatively less prominent contribution in the resistance vessels of the microcirculation where EDHF appears to predominate.  NO may inhibit EDHF responses as some studies could only demonstrate. EDHF responses once NO production had been inhibited.
  • 36. Pharmacological inhibitors Targets Comments Apamin S KCa + Highly specific Charybdotoxin IKCa +-BKCa + Can inhibit some Kv channels Iberiotoxin B KCa + Highly specific Tetraethylammonium SKCa +-IKCa +-BKCa + Inhibit other K+channels at >10−2)m Tetraethybutylammonium S KCa +-I KCa +-B KCa + Inhibit other K+channels at >10−2m BaCl2 KIR + — Ouabain Na+/K+ ATPase Can affect gap junction activity at >10−4m KCL K+ currents Dilates at >10−2m through KIR + and Na+/K+ ATPase activation 18 α-glycyrrhetic acid Gap junctions Possesses nonjunctional effects on membrane currents Connexin mimetic peptides Gap junctions Highly specific Catalase Hydrogen peroxide —
  • 37. EDHF IN DISEASES  Experimental evidence indicates that a shift away from NO- mediated endothelium-dependent relaxation toward EDHF dependent relaxation occurs in disease states.  Alteration of EDHF-mediated responses has been reported with aging, hypertension, atherosclerosis, hypercholesterolemia, heart failure, angioplasty, eclampsia, diabetes. EDHF in Hypertension • Evidence suggests that CYP expression and EET generation are increased in hypertension and in hypercholesterolemia. • Polymorphisms within CYP epoxygenases being associated with an enhanced risk of developing coronary artery disease and hypertension.
  • 38. EDHF in diabetes EDHF-mediated responses are depressed in some models of type I and type II diabetes with the exception of murine models. EDHF in hypercholesterolemia  In hypercholesterolemia, it has been observed that there is significant contribution of KCa+ channel activation and a lower Nitric Oxide release with acetylcholine.
  • 39. Demonstrated level of E D R F‟s-