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]
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 function
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] Most endothelin receptors in the human cerebral cortex (~90%) are of the ETB subtype.[12]
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.[12]
Endothelins have involvement in cardiovascular function, fluid-electrolytehomeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the three pituitary lobes[15] which display increased metabolic activity when exposed to ET-1 in the blood or ventricular system.[16]
ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.[17] 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.[17]
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.[22]
ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.[23]
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.[24] Receptors for endothelin-1 exist in brain neurons, indicating a potential role in neural functions.[2]
Antagonists
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]
^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. PMID11264479.
^Schinelli S (2006). "Pharmacology and physiopathology of the brain endothelin system: an overview". Current Medicinal Chemistry. 13 (6): 627–38. doi:10.2174/092986706776055652. PMID16529555.
^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. PMID29557064. S2CID35440852.
^Boron WF, Boulpaep EL (2009). Medical physiology a cellular and molecular approach (2nd International ed.). Philadelphia, PA: Saunders/Elsevier. p. 480. ISBN978-1-4377-2017-4.
^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. PMID12012269.
^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. PMID1855455.
^Bagnato A, Rosanò L (2008). "The endothelin axis in cancer". The International Journal of Biochemistry & Cell Biology. 40 (8): 1443–51. doi:10.1016/j.biocel.2008.01.022. PMID18325824.
^Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M (2005). "Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice". Neuroscience. 130 (2): 349–58. doi:10.1016/j.neuroscience.2004.09.036. PMID15664691. S2CID23517779.
^Potenza MA, Addabbo F, Montagnani M (September 2009). "Vascular actions of insulin with implications for endothelial dysfunction". American Journal of Physiology. Endocrinology and Metabolism. 297 (3): E568-77. doi:10.1152/ajpendo.00297.2009. PMID19491294.
