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) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with phosphoramidon. When ET-1 was exogenously added to the perfusate, phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the phosphoramidon-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 endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
Fujita
K
K
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.
Matsumura
Y
Y
Kita
S
S
Hisaki
K
K
Takaoka
M
M
Morimoto
S
S
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D016232:Endothelins; D006020:Glycopeptides; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon