Endothelins are peptides with receptors and effects in many body organs.[1][2][3] Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.[1][4]

Endothelin family
1EDN human endothelin1 02.png
OPM superfamily147
OPM protein3cmh
Endothelin 1
NCBI gene1906
Other data
LocusChr. 6 p23-p24
Endothelin 2
NCBI gene1907
Other data
LocusChr. 1 p34
Endothelin 3
Other data
LocusChr. 20 q13.2-q13.3

Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelins are implicated in vascular diseases of several organ systems, including the heart, lungs, kidneys, and brain.[5][6] As of 2018, endothelins remain under extensive basic and clinical research to define their roles in several organ systems.[1][7][8][9]


Endothelins derived the name from their isolation in cultured endothelial cells.[1][10]


There are three isoforms of the peptide (identified as ET-1, -2, -3), each encoded by a separate gene, with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC.[1][11]

The human genes for endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3) are located on chromosomes 6, 1, and 20, respectively.[2]

Mechanism of action and functionEdit

Endothelin functions through activation of two G protein-coupled receptors, endothelinA and endothelinB receptor (ETA and ETB, respectively).[2] These two subtypes of endothelin receptor are distinguished in the laboratory by the order of their affinity for the three endothelin peptides: the ETA receptor is selective for ET-1, whereas the ETB receptor has the same affinity for all three ET peptides.[2] The two types of ET receptor are distributed across diverse cells and organs, but with different levels of expression and activity, indicating a multiple-organ ET system.[2]

Endothelin-1 is the most powerful endogenous chemical affecting vascular tone across organ systems.[2][12] Secretion of endothelin-1 from the vascular endothelium signals vasoconstriction and influences local cellular growth and survival.[12] ET-1 has been implicated in the development and progression of several cardiovascular diseases, such as atherosclerosis and hypertension.[12] Endothelin also has roles in mitogenesis, cell survival, angiogenesis, bone growth, nociceptor function, and cancer onset mechanisms.[2] Clinically, anti-ET drugs are used to treat pulmonary arterial hypertension.[2][12]

Physiological effectsEdit

Endothelins are the most potent vasoconstrictors known.[1][13] Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentan, sitaxentan or ambrisentan.[1]

Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the three pituitary lobes[14] which display increased metabolic activity when exposed to ET-1 in the blood or ventricular system.[15]

ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.[16] The ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release.[16]

The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction.[17]

Clinical significanceEdit

The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems.[1] Among numerous diseases potentially occurring from endothelin dysregulation are:

In insulin resistance the high levels of blood insulin results in increased production and activity of ET-1, which promotes vasoconstriction and elevates blood pressure.[21]

ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.[22]

In preliminary research, injection of endothelin-1 into a lateral cerebral ventricle was shown to potently stimulate glucose metabolism in specified interconnected circuits of the brain, and to induce convulsions, indicating its potential for diverse neural effects in conditions such as epilepsy.[23] Receptors for endothelin-1 exist in brain neurons, indicating a potential role in neural functions.[2]


Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788.[10] An ETA-selective antagonist, ambrisentan was approved for treatment of pulmonary arterial hypertension in 2007, followed by a more selective ETA antagonist, sitaxentan, which was later withdrawn due to potentially lethal effects in the liver.[1] Bosentan was a precursor to macitentan, which was approved in 2013.[1]


  1. ^ a b c d e f g h i j k Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, et al. (April 2016). "Endothelin". Pharmacological Reviews. 68 (2): 357–418. doi:10.1124/pr.115.011833. PMC 4815360. PMID 26956245.
  2. ^ a b c d e f g h i j k l Kawanabe Y, Nauli SM (January 2011). "Endothelin". Cellular and Molecular Life Sciences. 68 (2): 195–203. doi:10.1007/s00018-010-0518-0. PMC 3141212. PMID 20848158.
  3. ^ Kedzierski RM, Yanagisawa M (2001). "Endothelin system: the double-edged sword in health and disease". Annual Review of Pharmacology and Toxicology. 41: 851–76. doi:10.1146/annurev.pharmtox.41.1.851. PMID 11264479.
  4. ^ Maguire JJ, Davenport AP (December 2014). "Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12". British Journal of Pharmacology. 171 (24): 5555–72. doi:10.1111/bph.12874. PMC 4290702. PMID 25131455.
  5. ^ Agapitov AV, Haynes WG (March 2002). "Role of endothelin in cardiovascular disease". Journal of the Renin-Angiotensin-Aldosterone System. 3 (1): 1–15. doi:10.3317/jraas.2002.001. PMID 11984741. S2CID 11382836.
  6. ^ Schinelli S (2006). "Pharmacology and physiopathology of the brain endothelin system: an overview". Current Medicinal Chemistry. 13 (6): 627–38. doi:10.2174/092986706776055652. PMID 16529555.
  7. ^ Kuang HY, Wu YH, Yi QJ, Tian J, Wu C, Shou WN, Lu TW (March 2018). "The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis". Medicine. 97 (10): e0075. doi:10.1097/MD.0000000000010075. PMC 5882424. PMID 29517668.
  8. ^ Iljazi A, Ayata C, Ashina M, Hougaard A (March 2018). "The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review". Current Pain and Headache Reports. 22 (4): 27. doi:10.1007/s11916-018-0682-8. PMID 29557064. S2CID 35440852.
  9. ^ Lu YP, Hasan AA, Zeng S, Hocher B (2017). "Plasma ET-1 Concentrations Are Elevated in Pregnant Women with Hypertension -Meta-Analysis of Clinical Studies". Kidney & Blood Pressure Research. 42 (4): 654–663. doi:10.1159/000482004. PMID 29212079.
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  14. ^ Lange M, Pagotto U, Renner U, Arzberger T, Oeckler R, Stalla GK (May 2002). "The role of endothelins in the regulation of pituitary function". Experimental and Clinical Endocrinology & Diabetes. 110 (3): 103–12. doi:10.1055/s-2002-29086. PMID 12012269.
  15. ^ Gross PM, Wainman DS, Espinosa FJ (August 1991). "Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1". Endocrinology. 129 (2): 1110–2. doi:10.1210/endo-129-2-1110. PMID 1855455.
  16. ^ a b Böhm F, Pernow J (October 2007). "The importance of endothelin-1 for vascular dysfunction in cardiovascular disease". Cardiovascular Research. 76 (1): 8–18. doi:10.1016/j.cardiores.2007.06.004. PMID 17617392. S2CID 16753650.
  17. ^ Kakutani M, Masaki T, Sawamura T (January 2000). "A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1". Proceedings of the National Academy of Sciences of the United States of America. 97 (1): 360–4. Bibcode:2000PNAS...97..360K. doi:10.1016/j.biochi.2016.10.010. PMC 26668. PMID 10618423.
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