Seminar on Endothelin Receptors

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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

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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

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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.

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Endothelin receptors are classified in to:

Endothelin receptor type-A

Endothelin receptor type-B

Classification Of Endothelin Receptors

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Endothelin receptor type-A

ETA

Endothelin receptor type-B

ETB1

ETB2

Subtypes

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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

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Figure no -1Actions of endothelin-1 through its receptors.

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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

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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

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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

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ETB2 mediates vasoconstriction

ET receptor are also found in the nervous system where they may mediate neurotransmission and vascular functions.

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Figure no -2: characteristic features of endothelin receptors.13

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

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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+

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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

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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.

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Fall in BP

Tachycardia

Headache

Gastric upset

Teratogenic effects

Adverse Effects Of Endothelin Antagonists

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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

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THANK YOU

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