K. Fujita et al., PHOSPHORAMIDON-SENSITIVE CONVERSION OF BIG ENDOTHELIN-1 AND DEGRADATION OF ENDOTHELIN-1 IN RAT-KIDNEY, Hypertension, 24(2), 1994, pp. 227-233
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.