PHOSPHORAMIDON ATTENUATES BIG ENDOTHELIN-1-INDUCED VASOCONSTRICTION IN CANINE STOMACH

We compared the effects of endothelin-1 and its precursor, big endothe lin-1, on vascular resistance of a blood-perfused ex vivo stomach segm ent of chloralose-anesthetized dogs. In separate groups of dogs, endot helin-1 or big endothelin-1 was infused intraarterially directly to th e gastric segment. Endothelin-1 caused statistically significant dose- related increases in gastric vascular resistance at final blood concen trations of 0.15-10 nM. Although each dose was given for only 5 min, e ndothelin-1 at concentrations >0.6 nM caused sustained responses with vascular resistance remaining above control values for similar to 45-9 0 min. In contrast, however, big endothelin-1 caused a small but stati stically significant vasoconstriction only at the highest concentratio n (10 nM). In other experiments, using 15-min peptide infusions, we fo und that pretreatment with phosphoramidon, an inhibitor of endothelin- converting enzyme, markedly reduced response to big endothelin-1 but n ot to endothelin-1. Our results demonstrate that endothelin-1, but not big endothelin-1, is a potent vasoconstrictor of the canine gastric m icrocirculation. In addition, it appears that big endothelin-1 is degr aded to endothelin-1 in the stomach by a phosphoramidon-sensitive meta lloproteinase.