title: Inhibitory activities of metal chelators on endothelin-converting enzyme. I. In vitro studies.
abstract: The effects of various metal chelators on endothelin (ET)-converting enzyme (ECE) activity were examined in vitro. Three chelators, 2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ), were found to dose-dependently inhibit ECE activity, but this inhibition was much weaker compared with EDTA. In the presence of Zn2+, the inhibitory activity of all these compounds, including EDTA, was abolished. The addition of Ca2+ and Mg2+ markedly attenuated the inhibitory activity of EDTA, but the other three chelators were still able to inhibit ECE. ECE, once inactivated by EDTA or 8-MQ, was reactivated by the addition of divalent cations such as Zn2+ and Mn2+. These compounds also inhibited angiotensin-converting enzyme activity in a manner similar to the inhibition exhibited towards ECE. Chelate-titration indicated that DMP, TDT and 8-MQ chelate Zn2+ but not Ca2+ and Mg2+. These results suggest that the ECE inhibition exhibited by these compounds is mainly attributable to their chelating activities. The metal-selective chelating activity by DMP, TDT and 8-MQ may contribute to the retention of ECE inhibition in the presence of Ca2+ and Mg2+.
authors.affiliation: Pharmaceutical Research Laboratories, Sapporo Breweries Limited, Shizuoka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ashizawa
authors.forename: H
authors.initials: H
authors.lastname: Okumura
authors.forename: F
authors.initials: F
authors.lastname: Kobayashi
authors.forename: T
authors.initials: T
authors.lastname: Aotsuka
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: R
authors.initials: R
authors.lastname: Asakura
authors.forename: K
authors.initials: K
authors.lastname: Arai
authors.forename: A
authors.initials: A
authors.lastname: Matsuura
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D008274:Magnesium / Q000494:pharmacology; D008666:Metalloendopeptidases; D011804:Quinolines / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002614:Chelating Agents; D011804:Quinolines; D014050:Toluene; C087618:8-mercaptoquinoline; D004492:Edetic Acid; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D008274:Magnesium; D002118:Calcium; C004848:dithiol