Endothelins are peptides with receptors and effects in many body organs.
Endothelins are 21-amino acid vasoconstriction produced primarily in the endothelium having a key role in smooth muscle. Endothelins are implicated in vascular diseases of several organ systems, including the heart, lungs, kidneys, and brain.
Etymology
Endothelins derived the name from their isolation in cultured .
Isoforms
There are three 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.
The human for endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3) are located on 6, 1, and 20, respectively.[
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Mechanism of action and function
Endothelin functions through activation of two G protein-coupled receptors, endothelinA and endothelinB receptor (ETA and ETB, respectively).[ 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.][ 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.][ Most endothelin receptors in the human cerebral cortex (~90%) are of the ETB subtype.]
Endothelin-1 is the most powerful endogenous chemical affecting vascular tone across organ systems.[ ET-1 has been implicated in the development and progression of several cardiovascular diseases, such as atherosclerosis and hypertension.][ Endothelin also has roles in mitogenesis, cell survival, angiogenesis, bone growth, nociceptor function, and cancer onset mechanisms.][ Clinically, anti-ET drugs are used to treat pulmonary arterial hypertension.][
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Endothelin-2 differs from endothelin-1 by two amino acids, and sometimes has the same affinity as endothelin-1 for ETA and ETB receptors. Studies have shown that endothelin-2 plays a significant role in ovarian physiology and could impact the pathophysiology of heart failure, immunology, and cancer.[
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Physiological effects
Endothelins are the most potent vasoconstrictors known.[
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Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types.[ Endothelin receptors are present in the three pituitary gland]
ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.
The binding of to the endothelium receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction.
Clinical significance
The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems.[ Among numerous diseases potentially occurring from endothelin dysregulation are:
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several types of cancer
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Cerebrum vasospasm following subarachnoid hemorrhage
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arterial hypertension, pulmonary hypertension, and other cardiovascular disorders
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pain mediation
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cardiac hypertrophy and heart failure
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Dengue haemorrhagic fever
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Type II diabetes
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some cases of Hirschsprung disease
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.
ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.
In preliminary research, injection of endothelin-1 into a lateral cerebral ventricle was shown to potently stimulate metabolism in specified interconnected circuits of the brain, and to induce , indicating its potential for diverse neural effects in conditions such as epilepsy.[
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Antagonists
Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788.[ Bosentan was a precursor to macitentan, which was approved in 2013.][
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