Phosphoramidon, a metalloproteinase inhibitor, suppresses the secretion of endothelin-1 from cultured endothelial cells by inhibiting a big endothelin-1 converting enzyme.
Time-dependent secretion of immunoreactive-endothelin (IR-ET) from cultured porcine aortic endothelial cells was markedly suppressed by phosphoramidon is due to proteinase inhibitor. Analysis of the culture supernatant with or without phosphoramidon by reverse-phase high performance liquid chromatography confirmed that the suppression of IR-ET secretion by phosphoramidon is due to a decreae in secretion of endothelin-1-like materials. The secretion of the C-terminal fragment (CTF, 22-39)-like materials of big ET-1 was also decreased by phosphoramidon, whereas there was an increased secretion of big ET-1-like materials. These data strongly suggest that phosphoramidon suppresses the secretion of ET-1 from cultured endothelial cells by inhibiting the conversion of big ET-1 to ET-1. It is most likely that phosphoramidon-sensitive metalloproteinase is responsible for the processing of big ET-1 in vascular endothelial cells.
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.
R
R
Ikegawa
Y
Y
Matsumura
Y
Y
Tsukahara
M
M
Takaoka
S
S
Morimoto
D000818:Animals; D001013:Aorta, Thoracic; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D010450:Endopeptidases / Q000494:pharmacology*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D006020:Glycopeptides / Q000494:pharmacology*; D008666:Metalloendopeptidases; D010452:Peptide Biosynthesis; D010455:Peptides / Q000302:isolation & purification; D011480:Protease Inhibitors / Q000494:pharmacology*; D013552:Swine
D016232:Endothelins; D006020:Glycopeptides; D010455:Peptides; D011480:Protease Inhibitors; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon