Role of neutral endopeptidase in the metabolism of endothelin

Abstract

Endothelin is a potent vasoconstrictor produced by endothelial cells. Although endothelin has been studied extensively, little is known about its metabolism in vivo. Neutral endopeptidase EC.3.4.24.11 is reported to degrade endothelin in vitro. Therefore, we studied the effect of neutral endopeptidase inhibition by SQ29,072 on plasma levels and urinary excretion of endogenous and exogenous endothelin. Injection of 30 or 60 mg/kg SQ29,072 into anesthetized rats increased the urinary excretion of endothelin nearly 14-fold. The response was maximal during the first 30 minutes of collection and lasted for 90 minutes. The larger dose of inhibitor caused a 37-43% increase (p less than or equal to 0.05) in the plasma concentration of endothelin. Only 0.20 +/- 0.04% of the total radioactivity injected as 125I-endothelin (1 microCi; 1,308 pg) into normal rats was recovered in the urine within 30 minutes. Urinary radioactivity increased to 0.54-0.63% (p less than or equal to 0.05) of the total infused in rats pretreated with SQ29,072. Chromatographic analysis of radioactivity in the urine revealed that intact endothelin accounted for only 6-9% of the total counts in control rats but 50-56% in rats pretreated with the inhibitor. We also studied the effects of another inhibitor of neutral endopeptidase, SQ28,063, on the distribution of radioactivity in the urine, kidney, and lung of rats injected with 125I-endothelin. SQ28,063 increased urinary excretion of labeled endothelin and increased total radioactivity accumulated in the lung and kidney from 157 and 105 pg to 234 and 157 pg, respectively. Intact endothelin accounted for 90% or more of the accumulated counts in both tissues. These results indicate that 1) little circulating endothelin is cleared into the urine, 2) endothelin in the urine is likely of renal origin, and 3) neutral endopeptidase EC.3.4.24.11 plays a major role in the inactivation of endothelin.