Two endothelin receptor subtypes have been isolated and identified, endothelin A receptor(ETA) and endothelin B receptor (ETB), and are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family (GPCRA) which stimulate multiple effectors via several types of G protein. ETA and ETB receptors are both widely distributed, ETA receptors are mainly located on vascular smooth muscle cells, whereas ETB receptors are present on endothelial cells lining the vessel wall. Endothelin receptors have also been found in the brain.
Endothelin is a bioactive substance composed of 21 amino acids, which is produced by endothelin precursor after enzymolysis. Endothelin was first found to be synthesized in the endothelial cells, and it has very significant vasoconstriction activity and promotes vascular smooth muscle constriction and neuroendocrine. In addition to its strong vasoconstriction, it has been found to have properties of inducing angiogenesis, differentiation, promoting mitosis and cell-like growth factors in recent years. Evidence is emerging that endothelin is involved in the development of many kinds of cancers because of its remarkable role in promoting mitosis and cell growth factor. Endothelin was found to induce angiogenesis in cancer tissue. In mammals, the endothelin family comprises three endogenous isoforms, namely ET-1, ET-2, and ET-3. The biological activity of these three isomerases is different. ET-1 is the most potent whereas ET-3 is the weakest. Endothelin plays an important role in many physiological systems in mammals, such as the gastrointestinal tract, the central nervous system, the respiratory system, the cardiovascular system, and the urinary and reproductive systems. Correspondingly, endothelin is involved in the development of a variety of diseases by binding to endothelin receptors, such as , hypertension, congestive heart failure, atherosclerosis and subarachnoid hemorrhage. Endothelin receptor belongs to G protein-coupled rhodopsin-type receptor superfamily, the size of 45~50 KDa, characterized with seven transmembrane domain. In particular, transmembrane domain 2 and 5 have been proven that they play an important role in selective combination with ligand subtypes. The endothelin receptor has so far been found to contain three homologous isomers, namely ETA, ETB and ETC. But only ETA and ETB are found in mammals and humans. ETC is found in many species, but does not exist in human tissues and is activated by a specific combination with ET-3. ETA distributes on placenta, atrium, kidney smooth muscle, aortic, cerebrovascular and lung, and it mediates cell proliferation and vascular contraction. ETB distributes on the central choroid plexus epithelial cells, glomerular endothelium, ventricle, lung and placenta, mediating vasodilation. ETC distributes on tubular epithelial cells in renal outer medulla.
Recent reviews and meta-analyses of experimental and clinical data obtained with endothelin receptor blockade confirmed that endothelin receptor antagonists are associated with significant decreases in blood pressure in essential hypertension but also in resistant hypertension. In addition, endothelin receptor antagonists induce significant 30-40% decreases in albuminuria in patients with diabetic nephropathy when they are administered on top of blockers of the renin-angiotensin system. Since the development of bosentan, numerous selective and non-selective antagonists of ETA and ETB receptors have been developed for research or clinical purposes. Today, three endothelin receptor antagonists are on the market to treat pulmonary hypertension (bosentan, macitentan, and ambrisentan). and diabetic nephropathy, and a study with zibotentan, a selective ETA receptor antagonist, is carried out by the London University College, in patients with renal disease due to scleroderma. Sparsentan, an orally active, dual-acting angiotensin type 1 receptor blocker and highly selective ETA receptor antagonist, is also under investigation for the treatment of primary focal segmental glomerulosclerosis (FSGS). Only one new endothelin receptor antagonist is still investigated for the treatment of hypertension, i.e., aprocitentan, the active metabolite of macitentan.
1. Michel Burnier. Update on Endothelin Receptor Antagonists in Hypertension. Current Hypertension Reports .2018, 20(6): 51.
2. Davenport AP. International Union of Pharmacology. XXIX.Update on Endothelin Receptor Nomenclature. Pharmacol Rev, 2002, 54(2):219-226.
3. Nasser SA, EI-Mas MM. Endothelin ETA receptor antagonism in cardiovascular disease. Eur J Pharmacol. 2014, 737:210-213.
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