Endothelin-1 (ET-1) is a vasoactive peptide containing 21 amino acids, which was first isolated from the cultured porcine aortic endothelial cell fluid by Yanagisswa et al at 1988. At present, there are three kinds of heteromorphisms, ET-1, ET-2 and ET-3, found in organisms. All of these three endothelins have vasoconstriction effects, but there are some differences in gene location, tissue expression and binding to receptors. Particularly, ET-1 is mainly expressed on chromosome 6p in endothelial cells and its release quantity and rate depends on the gene transcription rate affected by activators and inhibitors. The ET-1 gene encodes a 203-amino acid precursor peptide, which is then decomposed into a smaller 38-amino acid peptide by amino acid invertase, and finally forms a 21-amino acid ET-1 by further transformation of endothelin converting enzyme.
Endothelin-1 is characterized by binding to ETA receptors and mediating smooth muscle cell-dependent vasoconstriction. A study of ETA receptors and mixed receptors of ETA and ETB shows that drug antagonists can effectively control high salt or laboratory hypertensions induced by angiotensin, and protect target organs, suggesting that ET-1 may be involved in the pathogenesis of hypertension. An experiment conducted on rats and its result showed that ET-1 induces the proliferation and phenotypic transformation of vascular smooth muscle cell through its specific receptor pathway, which may be related to the expression of regulatory gene HRG-1 and gene SM22 α.
Currently, ET-1 is considered as the most powerful vasoconstrictor produced by vascular endothelium, which plays a vital role cardiovascular regulation and pathophysiology. Except the function of constricting blood vessels, it also promotes the production of inflammation. In addition to its effects on cardiovascular, urinary, respiratory, digestive, neurological, reproductive, endocrine and other systems, it also exhibits a greatly important role in ophthalmologic blinding diseases. For example, ET-1 in eyes is mainly distributed in the choroid. It has a relation with cataract development, increased intraocular pressure of glaucoma and optic nerve damage.
Pharmacokinetics and metabolism
Research reports believe that the endothelial ETB-receptors are involved with the clearance of ET-1 from the circulation by internalizing the receptor complex once ET-1 has bound. The lung removes ET-1 from the circulation owing to the high surface area of pulmonary blood vessels, and the removal rate is estimated to be 50% as the blood passes across the lung. This may explain why circulating levels of ET-1 are kept at very low levels (in the picomolar range) and why most of the ET-1 released by the endothelium is directed towards to the underlying smooth muscle cells.
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