THE EFFECTS OF ENDOTHELIN PEPTIDES IN THE RABBIT ISOLATED-PERFUSED KIDNEY

1. Endothelin-1 (21-amino acids) and pre-pro endothelin-1 (39-amino ac ids) produced a concentration-dependent increase in perfusion pressure when infused through the renal artery of rabbit isolated perfused kid ney. Addition of phosphoramidon to the medium caused a potentiation in the vasoconstrictor response to endothelin-1 and greatly, but not com pletely, inhibited vasoconstriction induced by pre-pro-endothelin-1. 2 . Addition of indomethacin to the medium did not alter the vasoconstri ctor effects of the peptides. 3. Methylene blue in the medium caused a highly significant potentiation in the vasoconstrictor response to en dothelin-1. 4. A short-term infusion of endothelin-1 through the renal artery elicited a decrease in urine flow which returned to control le vels after perfusing the kidney with Krebs buffer, but prolonged infus ion of the peptide produced an irreversible increase in urine flow. 5. Phosphoramidon, methylene blue and indomethacin failed to alter the e ffect of endothelin-1 on urine how. 6. From these results it was concl uded that phosphoramidon-sensitive endothelin-converting enzyme, proba bly localized in microvasculature of the kidney, can convert pre-pro-e ndothelin-1 to endothelin-1 which is responsible for the vasoconstrict or effect of pre-pro-endothelin-1 in addition to its possible direct v asoconstrictor effect on kidney vasculature. Moreover, the endothelin- 1 degradating enzyme in kidney should be a phosphoramidon-sensitive me talloproteinase(s). The results also indicated the release of EDRF but not prostanoids by endothelin-peptides in the rabbit isolated perfuse d kidney.