Hypertension, Vol 20, 89-95, Copyright © 1992 by American Heart Association
ZA Abassi, JE Tate, E Golomb and HR Keiser
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.
ARTICLES
Role of neutral endopeptidase in the metabolism of endothelin
Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
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