4. VASOACTIVE PEPTIDES
DEFINATION – Something influencing
tone and calibre of blood vessels.
Any group of circulating substances that
regulates vascular tone , causing either
vasodilatation or vasoconstriction
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5. VASOACTIVE PEPTIDES INCLUDES
-vasoconstrictors
-vasodilators
-VASOCONSTRICTORS-an agent that causes narrowing of the
blood vessels . Also called so vasopressors EX.angiotensin-2,
vasopressin, endothelins, neuropeptide-Y and urotensin
-VASODILATORS- an agent that causes
dilation of the blood vessels EX. bradykinin and
related kinins , natriuretic peptides ,VIP ,substance P ,
neurotensine, NO(nitric oxide) etc
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6. ENDOTHELINS
Endothelin is a very potent vasoconstrictor
peptide derived from the endothelial cells of
vasculature.
Its was first isolated , characterised, and
cloned in procaine aortic endothelial cells
It is a peptide made up of 20 amino acids and
molecular weight about 2492 Daltons.
It have free carboxyl and amino terminal . It
has two disulphide bonds.
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7. Endothelin is secreted in vascular smooth
muscles cells, renal tubular epithelial cells,
glomerular mesangial cells , glial cells ,
macrophages, mast cells, primary pitutary
cells etc.
Endothelin acts functionally opposite to
nitric oxide. while endothelin is a
endothelium derived vasoconstrictor , NO
is a potent endothelium derived
vasodilator
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9. BIOSYNTHESIS OF
ENDOTHELINS
There are three isoforms (identified
as ET-1, -2, -3) with varying regions
of expression and binding to at least
three known ET1, ET2, and ET3.
Primarily ET1
present in brain & kidney
also present in vascular
endothelium
13. Endothelin receptors are classified into :-
ENDOTHELIN RECEPTOR type-A
ENDOTHELIN RECEPTOR type-B
CLASSIFICATION OF ENDOTHELIN RECEPTORS.
14. • ENDOTHELIN RECEPTOR TYPE-A
ETA
• ENDOTHELIN RECEPTOR TYPE-B
ETB1
ETB2
SUBTYPES OF ENDOTHELIN RECEPTORS OF
TYPE-A AND TYPE-B
15. Endothelin receptor type-A are located on
vascular smooth muscle
cells,brain,lungs,kidney and adrenal gland.
Endothelin receptors type-B are located on
endothelial cells lining the vessel wall.
Endothelin receptors have also been found in
the brain,e.g:- cerebral cortex,cerebellum
and glial cells.
LOCATION OF ENDOTHELIN RECEPTORS
16.
17. Both ETA and ETB receptor subtypes are G-protein
coupled receptors.
ETA RESPONSE:-
As shown in figure,the signal transduction
mechanisms include:-
opening of Ca2+ channels through phospholipase
C/IP3 pathway
increase in intracellular Ca2+
results in vasoconstriction
SIGNAL TRANSDUCTION MECHANISM OF
ENDOTHELIN RECEPTORS
18. ETB response:-
An activation of phospholipase A2(which
produce PGI2) and of nitric oxide synthase
leading to vasodilation.
ETA and ETB response:-
Activation of protein kinase-c through
phospholipase C/DAG parhway,leading to
mitogenesis and also being leading to
vasoconstriction.
ETB RESPONSE AND ETA AND ETB RESPONSE
19. ETA is a subtype for vasoconstriction,these
receptors are found in smooth muscles tissue of
blood vessels,and binding of endothelin to ETA
increases vasoconstriction and the retention of
sodium,leading yo increased in blood pressure.
ETB1 mediates vasodilation, when endothelin
binds to ETB1 receptors,this leads to the release
of nitric oxide (also called endothelium-derived
relaxing factor),natriuresis and diuresis and
mechanism that lowers blood pressure.
PHYSIOLOGICAL FUNCTIONS OF ENDOTHELIN
RECEPTORS.
20. ETB2 mediates vasoconstriction.
ET receptors are also found in the nervous
system where they may mediate
neurotransmission and vascular functions.
21.
22. ENDOTHELIN 1 :-
selective agonists for ETB receptors
ENDOTHELIN 2:-
potent vasoconstricor from vascular
endothelium cells,displays similar selectivity for
ETA and ETB receptors.
ENDOTHELIN 3:-
vasoconstrictor from vascular endothelial
cells,preffered agonists for ETB receptors.
AGONISTS OF ENDOTHELIN RECEPTORS
24. Many selective as well as non-selective
antagonists have been developed.
SELECTIVE ETA receptor antagonists.
• SITAXSENTAN
AMBRISETAN
these drugs are currently under trails.
SELECTIVE ETB receptor antagonists.
IRL-1038
ANTAGONISTS OF ENDOTHELIN RECEPTORS.
25. NON SELECTIVE ANTAGONISTS:-
• Bosentan
this drug is active both I.V and orally,blocks
both ETA and ETB.
OTHER ANTAGONIST:-
• Phosphoramidon.
it acts by inhibiting endothelin converting
enzyme so, the inhibition of formation of
endothelin-1 occurs.
26. ADVERSE EFFECTS
ET receptor antagonists include fall in blood
pressure
Tachycardia
Oedema
Headache
Gastric upset
