Pharmacological Profiles of Aspergillomarasmines as Endothelin Converting Enzyme Inhibitors

The Japanese Journal of Pharmacology

Mayumi Takahashi¹  Akihiro Matsuura¹  Rieko Asakura¹  Koshi Arai¹  Nami Ashikawa¹  Fujio Kobayashi¹  Hiroshi Okumura¹  Naoki Ashizawa¹ 

[1] Pharmaceutical Research Laboratories, Sapporo Breweries, Ltd.

关键词: Aspergillomarasmine;    Endothelin-1;    Big endothelin-1;    Endothelin converting enzyme;    EDTA;   

DOI  :  10.1254/jjp.63.187

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(17)Cited-By(8)Aspergillomarasmine-A and -B (AM-A and -B), which were isolated from the cultured broth of an unidentified fungus N877, showed apparent inhibition against endothelin-converting enzyme (ECE) from bovine endothelial cells as measured by the formation of endothelin-1 (ET-1) converted from big endothelin-1 (bET-1), with IC50 values of 3.4 and 2.5 μM for AM-A and -B, respectively. EDTA also inhibited ECE (IC50=1.1 μM), but the inhibitions by AM-A, AM-B and EDTA were each abolished by the addition of 10 μM Zn2+ to the reaction mixture. In mice, AM-A and -B dose-dependently (10-50 mg/kg, i.v.) caused significant prolongation of the latency to sudden death induced by i.v. bET-1 (25 nmol/kg), but not that by ET-1 (5 nmol/kg), accompanied by a decrease in plasma immunoreactive ET-1 formation, while EDTA (24 mg/kg) failed to do so. In mice, the LD50 value of AM-A was calculated to be 159.8 mg/kg, i.v., which was much larger than that of EDTA (28.5 mg/kg, i.v.), indicating the low toxicity of AM-A. AM-A (30 mg/kg, i.v.) also suppressed bET-1-induced hemoconcentration and hypertension in mice and rats, respectively. These findings suggest that although ECE inhibition by AM-A was mainly attributable to its chelating activity, it showed apparent in vivo activities due to ECE inhibition with low toxicity.

【 授权许可】

Unknown