1. Ruchita Bhavsar
ENDOTHELIN
The endothelins (ETs) belong to a family of potent vasoconstrictor
peptides that were first isolated in 1988.
They appear to be produced and active in almost all tissues, and have
been found in abundance, for example, in brain, lung, kidney, intestine,
adrenal gland, thyroid, parathyroid, uterus, placenta, amnion, and ovary.
DISCOVERY :-
• Hickey et al Described A Vasoconstrictor Factor In 1985.
• This Was Identified As Endothelin, A 21 Residue Peptide By
Yanagisava et al In 1988.
• It was first isolated, characterized and cloned in procine aortic
endothelial cells.
STRUCTURE :
• Endothelin is composed of 21 amino acid peptide.
• It has a molecular weight of 2492 daltons.
• Free carboxyl and amino terminal
• It has two intramolecular disulfide bonds .
• It is present in many mammalian animals.
SYNTHESIS :-
• The biosynthesis of ET occurs via proteolytic processing of
preprohormones.
2. • The preproendothelin, a polypeptide consisting of about 200 amino
acids, undergoes proteolytic cleavage to form a 38 to 39 amino-
acid peptide known as “big ET.”
• ET-l is then formed by the action of a putative endopeptidase,
termed endothelin converting enzyme (ECE), which is inhibited by
phosphoramidon.
• Big ET-l is at least 100 fold less active than ET-l in constricting
isolated vascular preparations and in displacing the binding of ET-l
from its receptor.
• The conversion of big ET-l to ET-l is, therefore, a crucial step in the
formation of the biologically active peptide; consequently,
inhibition of ECE has been viewed as a route by which the biological
effects of endogenous ET could be suppressed.
3. ISOFORM :-
DISTRIBUTION :-
ET-1 ET-2 ET-3
Endothelial cell
Cardiac myocytes
Pancreatic islets
Kidney
Intestine
Ovary
Brain
Lungs
Intestine
Adrenal gland
RECEPTOR SUBTYPES :-
❖ Two type of ET receptor are present ETA and ETB
❖ Both are G-Protein Coupled Receptor
Receptors Affinity Pharmacological response
ETA ET-1= ET-2 > ET-3 Vasoconstriction
Bronchoconstriction
Aldosterone secretion
ETB ET-1 = ET-2 = ET-3 Vasodilation
Inhibition of ex vivo platelet
aggregation
4. MECHANISM :-
Both ETA and ETB subtypes are G-protein coupled receptor.
ETA response
Opening of Ca+2
channels through Phospholipase C / IP3 pathway
Increase in intracellular Ca+2
Vasoconstriction
ETB response
Activation of phospholipase A2
Nitric oxide synthetase
Vasodilation
5. Function :-
Endothelin-1 is a paracrine mediator rather than a circulating hormone,
although it stimulates secretion of several hormones
Endothelins have several other possible functions, including roles in:
• Release of various hormones, including atrial natriuretic peptide,
aldosterone, adrenaline, and hypothalamic and pituitary hormones
• Natriuresis and diuresis via actions of collecting duct-derived ET-1
on ETB receptors on tubular epithelial cells
• Thyroglobulin synthesis (the concentration of ET-1 in thyroid
follicles is extremely high)
• Control of uteroplacental blood flow (ET-1 is present in very high
concentrations in amniotic fluid)
• Renal and cerebral vasospasm
• Development of the cardiorespiratory systems (if the ET-1 gene is
disrupted in mice, pharyngeal arch tissues develop abnormally and
homozygotes die of respiratory failure at birth), and ET receptor
antagonists are teratogenic, causing cardiorespiratory
developmental disorders.
6. ENDOTHELIN ANTAGONIST :-
• Non-seective antagonist
o Bosentan
o Tezosentan
• Selective ET-A antagonist
o Ambrisentan
o Atrasentan
o Darusentan
o Sitaxentan
o Zibotentan
o BQ-123
• Selective ET-B antagonist
o IRL-1038
USE OF ENDOTHELIN RECEPTOR ANTAGONISTS :-
ENDOTHELIN RECEPTOR DISORDERS :-
1. HIRSCHSPRUNG'S DISEASE (HSCR)
▪ A missense mutation of the endothelin-B receptor gene
results in multigenic hirschsprung's disease.
▪ It is characterized by an absence of enteric ganglia in the
distal colon and a failure of innervation in the gastrointestinal
tract.
2. SHAH-WAARDENBURG SYNDROME
▪ Shah-Waardenburg syndrome is a rare autosomal recessive
condition that occasionally has been ascribed to mutations of
the endothelin-receptor B gene.
Ruchita Bhavsar
Pumonary
Hypertention
Congestive
Heart Failure
Coronary
Artery
Disease
