Endothelin

protein
Name = Endothelin 2


width =
caption =
Symbol = EDN2
AltSymbols =
ATC_prefix=
ATC_suffix=
ATC_supplemental=
CAS_number=
CAS_supplemental=
DrugBank=
EntrezGene = 1907
HGNCid =3177
OMIM = 131241
PDB =
RefSeq = NM_001956
UniProt = P20800
ECnumber =
Chromosome = 1
Arm = p
Band = 34
LocusSupplementaryData = protein
Name = Endothelin 3


width =
caption =
Symbol = EDN3
AltSymbols =
ATC_prefix=
ATC_suffix=
ATC_supplemental=
CAS_number=
CAS_supplemental=
DrugBank=
EntrezGene =
HGNCid =3178
OMIM = 131242
PDB =
RefSeq = NM_000114
UniProt = P14138
ECnumber =
Chromosome = 20
Arm = q
Band = 13.2
LocusSupplementaryData = -q13.3

Endothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure (hypertension) and heart disease.

Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Among the strongest vasoconstrictors known, endothelins are implicated in vascular diseases of several organ systems, including the heart, general circulation and brain [ [http://www.ncbi.nlm.nih.gov/pubmed/11984741 Agapitov AV, Haynes WG. Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2002 Mar;3(1):1-15.] ] [ [http://www.ncbi.nlm.nih.gov/pubmed/16529555 Schinelli S. Pharmacology and physiopathology of the brain endothelin system: an overview. Curr Med Chem. 2006;13(6):627-38.] ] .

Isoforms and organ distribution

There are three isoforms (identified as ET-1, -2, -3) with varying regions of expression and two key receptor types, ET_A and ET_B [ [http://www.ncbi.nlm.nih.gov/pubmed/17200683 Hynynen MM, Khalil RA. The vascular endothelin system in hypertension--recent patents and discoveries. Recent Patents Cardiovasc Drug Discov. 2006 Jan;1(1):95-108.] ] .
* ET_A receptors are found in the smooth muscle tissue of blood vessels, and binding of endothelin to ET_A increases vasoconstriction (contraction of the blood vessel walls) and the retention of sodium, leading to increased blood pressure.
* ET_B is primarily located on the endothelial cells that line the interior of the blood vessels. When endothelin binds to ET_B receptors, this leads to the release of nitric oxide (also called "NO" or endothelium-derived relaxing factor), natriuresis and diuresis (the production and elimination of urine) and mechanisms that lower blood pressure.
*Both types of ET receptor are found in the nervous system where they may mediate neurotransmission and vascular functions [ [http://www.ncbi.nlm.nih.gov/pubmed/9239759 Barnes K, Turner AJ. The endothelin system and endothelin-converting enzyme in the brain: molecular and cellular studies. Neurochem Res. 1997 Aug;22(8):1033-40.] ] .

Brain and nerves

Widely distributed in the body, receptors for endothelin are present in blood vessels and cells of the brain, choroid plexus and peripheral nerves. When applied directly to the brain of rats in picomolar quantities as an experimental model of stroke, endothelin-1 caused severe metabolic stimulation and seizures with substantial decreases in blood flow to the same brain regions, both effects mediated by calcium channels [ [http://www.ncbi.nlm.nih.gov/pubmed/1331845 Gross PM, Zochodne DW, Wainman DS, Ho LT, Espinosa FJ, Weaver DF. Intraventricular endothelin-1 uncouples the blood flow: metabolism relationship in periventricular structures of the rat brain: involvement of L-type calcium channels. Neuropeptides. 1992 Jul;22(3):155-65.] ] . A similar strong vasoconstrictor action of endothelin-1 was demonstrated in a peripheral neuropathy model in rats [ [http://www.ncbi.nlm.nih.gov/pubmed/1481904 Zochodne DW, Ho LT, Gross PM. Acute endoneurial ischemia induced by epineurial endothelin in the rat sciatic nerve. Am J Physiol. 1992 Dec;263(6 Pt 2):H1806-10.] ] .

Examples of physiological interaction

In a healthy individual, a delicate balance between vasoconstriction and vasodilation is maintained by endothelin and other vasoconstrictors on the one hand and nitric oxide, prostacyclin and other vasodilators on the other.

Overproduction of endothelin in the lungs may cause pulmonary hypertension, which can sometimes be treated by the use of an endothelin receptor antagonist, such as bosentan, sitaxentan or ambrisentan. The latter drug selectively blocks endothelin A receptors, decreasing the vasoconstrictive actions and allowing for increased beneficial effects of endothelin B stimulation, such as nitric oxide production. The precise effects of endothelin B receptor activation depends on the type of cells involved.

Disease involvement

The ubiquitous distribution of endothelin peptides and receptors implicates its involvement in a wide variety of physiological and pathological processes in the body. Among numerous diseases potentially occurring from endothelin dysregulation are

* several types of cancer [ [http://www.ncbi.nlm.nih.gov/pubmed/18325824 Bagnato A, Rosanò L. The endothelin axis in cancer. Int J Biochem Cell Biol. 2008;40(8):1443-51.] ]
* cerebral vasospasm following subarachnoid hemorrhage [ [http://www.ncbi.nlm.nih.gov/pubmed/17479073 Macdonald RL, Pluta RM, Zhang JH. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol. 2007 May;3(5):256-63.] ]
* arterial hypertension and other cardiovascular disorders [ [http://www.ncbi.nlm.nih.gov/pubmed/11984741 Agapitov AV, Haynes WG. Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst. 2002 Mar;3(1):1-15.] ]
* pain mediation [ [http://www.ncbi.nlm.nih.gov/pubmed/15664691 Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M. Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice. Neuroscience. 2005;130(2):349-58.] ]

References

External links

* [http://www.endothelinscience.com/ Endothelin science (Actelion Pharmaceuticals)]
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