METABOLISM OF ENDOTHELIN-1 AND BIG ENDOTHELIN-1 BY RECOMBINANT NEUTRAL ENDOPEPTIDASE EC.3.4.24.11

1 Inhibitors of neutral endopeptidase EC.3.4.24.11 (NEP) have been shown to attenuate the hypertensive effect of big-endothelin-1 (BET-1) in rats. To determine whether NEP converts BET-1 to endothelin-1 (ET-1), the effect of a recombinant NEP (rNEP) on BET-1 and on ET-1 was assessed in vitro. 2 Incubation of [I-125]-ET-1 with 1 mug ml-1 of rNEP resulted in degradation of the peptide within minutes. Increase in the amount of rNEP to 10 mug ml-1 led to total cleavage of [I-125]-ET-1 within seconds. 3 Phosphoramidon (10 muM) or SQ-28,603 (100 muM) totally suppressed the degradation of [I-125]-ET-1 by rNEP. 4 The degradation of [I-125]-BET-1 by either 1 or 10 mug ml-1 of rNEP was much slower than that of [I-125]-ET-1. Again, both phosphoramidon and SQ 28,603 protected the peptide from degradation. 5 Intact [I-125]-ET-1 was not observed when [I-125]-BET-1 was incubated with rNEP. 6 These data show that neutral endopeptidase EC.3.4.24.11 is not an endothelin convertin enzyme.