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.