Phosphoramidon attenuates big endothelin-1-induced vasoconstriction in canine stomach.
We compared the effects of endothelin-1 and its precursor, big endothelin-1, on vascular resistance of a blood-perfused ex vivo stomach segment of chloralose-anesthetized dogs. In separate groups of dogs, endothelin-1 or big endothelin-1 was infused intra-arterially directly to the gastric segment. Endothelin-1 caused statistically significant dose-related increases in gastric vascular resistance at final blood concentrations of 0.15-10 nM. Although each dose was given for only 5 min, endothelin-1 at concentrations > 0.6 nM caused sustained responses with vascular resistance remaining above control values for approximately 45-90 min. In contrast, however, big endothelin-1 caused a small but statistically significant vasoconstriction only at the highest concentration (10 nM). In other experiments, using 15-min peptide infusions, we found that pretreatment with phosphoramidon, an inhibitor of endothelin-converting enzyme, markedly reduced response to big endothelin-1 but not to endothelin-1. Our results demonstrate that endothelin-1, but not big endothelin-1, is a potent vasoconstrictor of the canine gastric microcirculation. In addition, it appears that big endothelin-1 is degraded to endothelin-1 in the stomach by a phosphoramidon-sensitive metalloproteinase.
Wood
J G
JG
Department of Surgery, University of Kansas Medical Center, Kansas City 66160.
Yan
Z Y
ZY
Davis
J M
JM
Cheung
L Y
LY
D000818:Animals; D004285:Dogs; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D008297:Male; D011498:Protein Precursors / Q000494:pharmacology*; D013270:Stomach / Q000098:blood supply / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; C008890:phosphoramidon