In vitro and in vivo activity of chymotrypsin-activated big endothelin (porcine 1-40).
We investigated whether big endothelin (porcine 1-40) had contractile activity in isolated rat aorta or pressor activity when injected intravenously into the anesthetized rat. When isolated rat aorta was exposed to a 100 nM concentration of big endothelin, 4.8% of a maximal KCl contraction was observed, compared to 131% of KClmax when paired aortic rings were exposed to an equivalent concentration of synthetic endothelin. Likewise, big endothelin had very weak pressor activity when injected intravenously into anesthetized, ganglion-blocked rats at 10 nmol/kg. When big endothelin was incubated with chymotrypsin, native endothelin and other peptide fragments were formed. Chymotrypsin-treated big endothelin produced an endothelin-like contraction when applied to isolated rat aortic rings, and a characteristic endothelin-like effect on blood pressure in vivo. Our results indicate that the biological activity of endothelin could be effectively blocked by inhibiting the enzyme which converts big endothelin to endothelin.
McMahon
E G
EG
Searle Research and Development, Washington University School of Medicine, Department of Pharmacology, St. Louis, Missouri 63110.
Fok
K F
KF
Moore
W M
WM
Smith
C E
CE
Siegel
N R
NR
Trapani
A J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta; D001794:Blood Pressure / Q000187:drug effects; D002918:Chymotrypsin; D016232:Endothelins; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D010455:Peptides; D002918:Chymotrypsin