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Nidhi Patel 36Mihir devdhara 37

Nupur desai 38Nirav Panchal 39

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ENDOTHELINS

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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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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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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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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

ENDOTHELINSBiosynthesis, release and distribution

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

Metalloproteinase metalloprotease, is any

protease enzyme whose catalytic mechanism involves a metal.

Prepro-ETBIG-ET

ET1

ECEendothelin-converting enzyme (ECE)

Growth factorCytokinesAngiotensin IIVesopressinHypoxia

Nitric oxideProstaglandinAtrial naturic peptide

ETA Receptor ETB Receptor

Endothelin receptors are classified into :-

ENDOTHELIN RECEPTOR type-A ENDOTHELIN RECEPTOR type-B

CLASSIFICATION OF ENDOTHELIN RECEPTORS.

• ENDOTHELIN RECEPTOR TYPE-A ETA

• ENDOTHELIN RECEPTOR TYPE-B ETB1

ETB2

SUBTYPES OF ENDOTHELIN RECEPTORS OF TYPE-A AND TYPE-B

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

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

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

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.

ETB2 mediates vasoconstriction. ET receptors are also found in the

nervous system where they may mediate neurotransmission and vascular functions.

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

SARAFOTOXIN:- ETB agonists,toxin with strong vasoconstrictor activity. ETA agonists,increases intracellular Ca2+.

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.

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.

ADVERSE EFFECTS ET receptor antagonists include fall in

blood pressure Tachycardia Oedema Headache Gastric upset