Effects of Neutral Endopeptidase Inhibition in the Rat Remnant Kidney Model

Abstract

The orally active neutral metalloendopeptidase (NEP) inhibitor SCH34826 was given by oral gavage in a dose of 90 mg/kg twice daily for 3 days to rats with subtotal nephrectomy (n = 7) and effects were compared to a placebo group receiving phosphate buffer (n = 5). Inhibition of neutral endopeptidase in the remnant kidney was measured by in vitro autoradiography using the specific radioligand [¹²⁵I]–SCH 47896. Treatment with the NEP inhibitor SCH34826 caused a 60% reduction in the neutral endopeptidase radioligand–binding site density in the kidneys of the SCH34826–treated animals compared to the placebo group (81.6±3.7 versus 214.5±4.2 dpm/mm², p<0.01). This was associated with a marked increase in urinary atrial natriuretic peptide (ANP) from 3,930±295 to 9,094±1,089 pg/24 h in the SCH34826–treated group (p<0.01). Concomitantly there was a transient increase in natriuresis in the SCH34826–treated group [baseline 2.03±0.55 to 3.77±0.58 mmol/24 h on treatment day 1 (p = 0.02) and 2.58±0.19 mmol/24 h on treatment day 3 (p = 0.09)] which was not observed in the placebo group. Urinary protein excretion, glomerular filtration rate (determined by ^99mTc–DTPA clearance), systemic blood pressure, plasma ANP concentration and urinary cyclic GMP excretion were not changed by SCH34826 treatment. These results suggest that oral administration of the NEP inhibitor SCH34826 inhibits renal neutral endopeptidase, increases urinary ANP and modulates natriuresis without alteration of systemic blood pressure, plasma ANP and renin level, glomerular filtration or protein excretion.