Neutral endopeptidase inhibition increases the urinary excretion and plasma levels of endothelin

Abstract

The pathway for removal of the circulating potent vasoconstrictor peptide, endothelin (ET), is unclear. To determine the contribution of neutral endopeptidase (NEP) to ET metabolism, urinary excretion (U ETV) and plasma levels of ET (P ET) were measured after infusion of the NEP inhibitor (NEP-I), SQ 29,072 (30 mg/kg [n = 10] and 60 mg/kg [n = 6]), in anesthetized Munich Wistar rats. Both doses significantly increased U ETV at 30, 60, and 90 minutes; the maximal effect was obtained 30 minutes after infusion, and the response was longer in rats pretreated with the higher dose of the inhibitor. P ET increased 36% and 55% ( P ≤ .05) at 30 and 120 minutes after injection of the larger dose of SQ 29,072. We also studied the effect of NEP-I on the excretion of exogenous ET after the infusion of 125I-ET (1 μCi) in rats pretreated with either NEP-I or vehicle. In rats treated with the lower dose of the inhibitor, urinary radioactivity increased 2.1- and 1.5-fold ( P ≤ .05 v control) after 30 and 60 minutes, respectively. After the higher dose of NEP-I, urinary radioactivity increased 2.7- and 1.7-fold ( P ≤ .05). The distribution of the urinary radioactivity as defined by high-performance liquid chromatography (HPLC) showed that intact labeled ET accounts for only 6% to 9% of the total counts recovered in urine from control rats, while the remainder was either free iodine or other products of hydrolysis. Intact ET increased significantly in urine from rats pretreated with NEP-I, to 50% to 56% of total radioactivity in urine. These results demonstrate that the inhibition of NEP increases the urinary excretion and plasma levels of ET, and that NEP plays an important role in the metabolism of ET.