endothelin ppt
TRANSCRIPT
Seminar on Endothelin Receptors
1
Prepared by-
Kunj M. Patel,
M. Pharm ,sem-1
Roll no - 01
Guided by-
Dr. N. N. Shah,A. R. College of Pharmacy &G. H. Patel Institute of Pharmacy, V. V. Nagar
Introduction
Classification of endothelin receptors
Location of endothelin receptors
Signal transduction mechanism of endothelin receptors
Physiological functions of endothelin receptors
Agonists of endothelin receptors
Antagonists of endothelin receptors
Adverse effects of endothelin receptor antagonists
References
Contents
2
Endothelin is a very potent vasoconstrictor peptide derived from the endothelial cells of vasculature.
After the discovery of the endothelium-derived relaxing factor, a contracting factor was isolated from bovine aortic and pulmonary endothelium. Its gene sequence was identified in 1987, and it was named endothelin (ET).
ET is a family of four 21-amino acid peptides, i.e., ET-1, ET-2, ET-3 and ET-4 (vasoactive intestinal constrictor).
Introduction
3
ET-1 is a potent vasoconstrictor.
In addition to their cardiovascular effects, ETs are involved in embryonic development, bronchoconstriction, prostate growth, carcinogenesis, and gastrointestinal and endocrine function.
Continue…...
4
Endothelin receptors are classified in to:
Endothelin receptor type-A
Endothelin receptor type-B
Classification Of Endothelin Receptors
5
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
7
Both ET𝐴and 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
9
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 pathway .
leading to mitogenesis and also leading
to vasoconstriction.
ETB Response And ETA And ETB
Response
10
ETA is a subtype for vasoconstriction These receptors are found in the smooth muscle tissue of blood vessels, and binding of endothelin to ETA increases vasoconstriction and the retention of sodium, leading to increased 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 mechanisms that lower blood pressure.
Physiological Functions Of Endothelin Receptors
11
ETB2 mediates vasoconstriction
ET receptor are also found in the nervous system where they may mediate neurotransmission and vascular functions.
Continue…..
12
Endothelin 1:-
Selective agonist for ETB receptors.
Endothelin 2:-
Potent vasoconstrictor from vascular
endothelial cells; displays similar selectivity for
ETA and ETB receptors
Agonists Of Endothelin Receptors
14
Endothelin 3:-
Vasoconstrictor from vascular endothelial cells; preferred agonist for ETB receptors.
Sarafotoxin:-
ETB agonist; toxin with strong vasoconstrictor activity
ETA agonist; increases intracellular Ca2+
Continue…..
15
Many selective as well as non- selective antagonists have been developed.
Selective ETA receptor antagonists
• sitaxsentan
• ambrisetan
these drugs are currently under trials.
Selective ETB receptor antagonists
• IRL-1038
Antagonists Of Endothelin receptors
16
Non selective antagonists
• Bosentan
this drug is active both I.V. and orally . blocks both ETA and ETB.
Other antagonists
• Phosphoramidon
it acts by inhibiting endothelin converting enzyme so, the inhibition of formation of endothelin -1 occurs.
Continue…..
17
Fall in BP
Tachycardia
Headache
Gastric upset
Teratogenic effects
Adverse Effects Of Endothelin Antagonists
18
1. Sharma H.L., sharma K.K., “principles of pharmacology”, Paras medical publisher, New Delhi, 2nd edition, 2011, page no:242-244
2. http://circ.ahajournals.org/content/102/19/2434.full
3. http://www.ebi.ac.uk/interpro/entry/IPR000499
4. http://en.wikipedia.org/wiki/Endothelin_receptor_type_A
5. http://en.wikipedia.org/wiki/Endothelin_receptor_antagonist
6. http://en.wikipedia.org/wiki/Endothelin_receptor
7. http://www.sigmaaldrich.com/life-science/biochemicals/biochemical-products.html?TablePage=111029074
8. http://www.pharmacorama.com/en/Sections/Angiotensin_6.php
9. http://www.cvpharmacology.com/vasodilator/ETblockers.htm
10. http://en.wikipedia.org/wiki/Endothelin_receptor_type_B
References
19