Ashizawa N, Okumura H, Kobayashi F, Aotsuka T, Asakura R, Arai K, Ashikawa N, Matsuura A
Pharmaceutical Research Laboratories, Sapporo Breweries Limited, Shizuoka, Japan.
Biol Pharm Bull. 1994 Feb;17(2):212-6. doi: 10.1248/bpb.17.212.
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.
研究了金属螯合剂对体内内皮素（ET）转换酶（ECE）活性的影响。三种在体外研究中抑制ECE的化合物，即2,3-二巯基-1-丙醇（DMP）、甲苯-3,4-二硫醇（TDT）和8-巯基喹啉（8-MQ），对大内皮素-1（big ET-1）诱导的小鼠猝死表现出抑制活性，而乙二胺四乙酸（EDTA）则没有。在big ET-1诱导的高血压实验中也得到了类似结果。8-MQ或EDTA预处理可抑制big ET-1诱导的血液浓缩，而DMP或TDT则不能。三种化合物预处理可抑制big ET-1给药后血浆中免疫反应性ET-1（IR-ET-1）的升高，而EDTA则不能。另一方面，注射big ET-1后，没有一种螯合剂能抑制肺组织中IR-ET-1的升高。考虑到体外实验结果，这些化合物对锌离子（Zn2+）而非钙离子（Ca2+）和镁离子（Mg2+）具有更高的选择性螯合活性，这可能有助于抑制体内big ET-1诱导的反应。big ET-1诱导的血液浓缩过程中涉及的ET-1生成可能具有与big ET-1诱导的猝死或高血压过程中不同的生理特征。
