Inhibitory activities of metal chelators on endothelin-converting enzyme. II. In vivo studies.
The effects of metal chelators on endothelin (ET)-converting enzyme (ECE) activity in vivo were examined. Three compounds, (2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ)), which inhibited ECE in in vitro studies, exhibited inhibitory activity towards big ET-1-induced sudden death in mice, while EDTA did not. Similar results were obtained in big ET-1-induced hypertension. Big ET-1-induced hemoconcentration was inhibited by pretreatment with 8-MQ or EDTA but not with DMP or TDT. The elevation of immunoreactive ET-1 (IR-ET-1) in plasma after administration of big ET-1 was inhibited by pretreatment with the three compounds but not by EDTA. On the other hand, no chelator inhibited the elevation of IR-ET-1 in lung tissue after injection of big ET-1. Taking into consideration the in vitro results, more selective chelating activity of the compounds towards Zn2+ rather than Ca2+ and Mg2+ may contribute to the inhibition of big ET-1-induced responses in vivo. The ET-1 formation involved in big ET-1-induced hemoconcentration may have different physiological characteristics from that involved in big ET-1-induced sudden death or hypertension.
Ashizawa
N
N
Pharmaceutical Research Laboratories, Sapporo Breweries Limited, Shizuoka, Japan.
Okumura
H
H
Kobayashi
F
F
Aotsuka
T
T
Asakura
R
R
Arai
K
K
Ashikawa
N
N
Matsuura
A
A
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D003645:Death, Sudden; D004112:Dimercaprol / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D006020:Glycopeptides / Q000494:pharmacology; D006400:Hematocrit; D008168:Lung / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011498:Protein Precursors / Q000008:administration & dosage / Q000633:toxicity; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology
D002614:Chelating Agents; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D011804:Quinolines; D004112:Dimercaprol; D014050:Toluene; C087618:8-mercaptoquinoline; D004492:Edetic Acid; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon; C004848:dithiol