title: A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels.
abstract: Since the discovery of endothelium-dependent vasodilation, vascular endothelium has been recognized as an important functional unit contributing to the regulation of vascular tonus. Recent purification, structure determination and molecular cloning of a novel peptidergic vasoconstrictor, endothelin, from the culture supernatant of porcine aortic endothelial cells has further substantiated this concept. Starting from a large quantity of serum-fee endothelial cell-conditioned medium, endothelin was purified to homogeneity after three steps of high performance liquid chromatography by collecting active fractions and constricting porcine coronary artery strips. A peptide sequence analysis showed that endothelin was a previously unknown 21-residue peptide with two intrachain disulphide bonds. The EC50 of endothelin for contraction of porcine coronary artery was 4.0 x 10(-10) mol/l, indicating that endothelin is one of the most potent vasoconstrictors known. The pharmacological and structural properties of endothelin suggest that the peptide acts by activating voltage-dependent Ca2+ channels in vascular smooth muscle cells. Cloning and sequence analysis of complementary (c)DNA encoding porcine and human endothelin precursors showed that endothelin was produced de novo in endothelial cells from an approximately 200-residue prepropeptide through an unusual proteolytic processing by a putative 'endothelin-converting enzyme'. Northern blot analysis showed that preproendothelin messenger (m)RNA was expressed not only in cultured endothelial cells but also in fresh intimal tissue from porcine aorta, and that mRNA can be induced markedly in response to several vasoactive agents in cultured endothelial cells, suggesting the existence of a novel endothelium-mediated cardiovascular control system.
authors.affiliation: Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Goto
authors.forename: T
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D016232:Endothelins; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology / Q000502:physiology*; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D016232:Endothelins; D010455:Peptides; D014662:Vasoconstrictor Agents