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

1. Endothelin-1 (21-amino acids) and pre-pro endothelin-1 (39-amino acids) produced a concentration-dependent increase in perfusion pressure when infused through the renal artery of rabbit isolated perfused kidney. Addition of phosphoramidon to the medium caused a potentiation in the vasoconstrictor response to endothelin-1 and greatly, but not completely, inhibited vasoconstriction induced by pre-pro-endothelin-1. 2. Addition of indomethacin to the medium did not alter the vasoconstrictor effects of the peptides. 3. Methylene blue in the medium caused a highly significant potentiation in the vasoconstrictor response to endothelin-1. 4. A short-term infusion of endothelin-1 through the renal artery elicited a decrease in urine flow which returned to control levels after perfusing the kidney with Krebs buffer, but prolonged infusion of the peptide produced an irreversible increase in urine flow. 5. Phosphoramidon, methylene blue and indomethacin failed to alter the effect of endothelin-1 on urine how. 6. From these results it was concluded that phosphoramidon-sensitive endothelin-converting enzyme, probably localized in microvasculature of the kidney, can convert pre-pro-endothelin-1 to endothelin-1 which is responsible for the vasoconstrictor effect of pre-pro-endothelin-1 in addition to its possible direct vasoconstrictor effect on kidney vasculature. Moreover, the endothelin-1 degradating enzyme in kidney should be a phosphoramidon-sensitive metalloproteinase(s). The results also indicated the release of EDRF but not prostanoids by endothelin-peptides in the rabbit isolated perfused kidney.