Pharmacological profiles of aspergillomarasmines as endothelin converting enzyme inhibitors.
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 microM for AM-A and -B, respectively. EDTA also inhibited ECE (IC50 = 1.1 microM), but the inhibitions by AM-A, AM-B and EDTA were each abolished by the addition of 10 microM 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.
Matsuura
A
A
Pharmaceutical Research Laboratories, Sapporo Breweries, Ltd., Shizuoka, Japan.
Okumura
H
H
Asakura
R
R
Ashizawa
N
N
Takahashi
M
M
Kobayashi
F
F
Ashikawa
N
N
Arai
K
K
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002417:Cattle; D004492:Edetic Acid / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000097:blood / Q000187:drug effects / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D006020:Glycopeptides / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley
D016232:Endothelins; D006020:Glycopeptides; D001224:Aspartic Acid; C085297:aspergillomarasmine B; C069862:aspergillomarasmine A; D004492:Edetic Acid; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon