PHOSPHORAMIDON-SENSITIVE CONVERSION OF BIG ENDOTHELIN-1 AND DEGRADATION OF ENDOTHELIN-1 IN RAT-KIDNEY

We investigated the intrarenal conversion of big endothelin-1 (ET-1) t o ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentr ation-dependent increase in perfusion pressure, and the presser molar potency of the peptide was 50-fold less than that of ET-1. The big ET- 1 (2x10(-8) mol/L)induced presser action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal ti ssues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, s ignificantly suppressed the big ET-1-induced presser action and the ac cumulation of immunoreactive endothelin in renal tissues. On the other hand, phosphoramidon slightly but significantly sustained the ET-1-in duced presser effect. The effect of kelatorphan (10(-4) mol/L), a spec ific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pre sser effect was the same as that seen with phosphoramidon. When ET-1 w as exogenously added to the perfusate, phosphoramidon or kelatorphan s ignificantly increased the immunoreactive endothelin levels in renal t issues after perfusion, without affecting the disappearance rate of im munoreactive endothelin from the perfusate. Therefore, the phosphorami don-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral e ndopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels i n renal tissues but not in the perfusate can account for the functiona l conversion of big ET-1 to ET-1 and for the local proteolytic degrada tion of ET-1 in the kidney.