Structure-activity relationships of endothelin: importance of the C-terminal moiety.
The vasoconstrictor activities of various forms of derivatives of endothelin (ET) were characterized in vitro by measuring the contraction of porcine coronary artery strips. The removal of the C-terminal Trp21 reduced the molar potency of the peptide by nearly 3 orders of magnitude. The removal of amino acid residues from the C-terminus of ET(1-20) further attenuated the activity. Replacement of Trp21 with D-Trp, reduction and carboxamidomethylation of the four Cys residues, or cleavage at Lys9 by lysyl endopeptidase all lowered the potency approximately 200 fold. While both native ET and [D-Trp21]ET induced a very slow and sustained vasoconstriction, the other derivatives of ET listed above showed a much more rapid kinetics of vasoconstriction. These results indicate that the C-terminal Trp of ET is especially important for the potent and extremely long-lasting vasoconstrictor activity characteristic to ET.
Kimura
S
S
Department of Biochemistry, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan.
Kasuya
Y
Y
Sawamura
T
T
Shinmi
O
O
Sugita
Y
Y
Yanagisawa
M
M
Goto
K
K
Masaki
T
T
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016232:Endothelins; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010455:Peptides / Q000032:analysis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014662:Vasoconstrictor Agents / Q000032:analysis* / Q000494:pharmacology
D016232:Endothelins; D010455:Peptides; D014662:Vasoconstrictor Agents