Effects of neutral endopeptidase inhibition in the rat remnant kidney model

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 gr oup receiving phosphate buffer (n = 5). Inhibition of neutral endopeptidase in the remnant kidney was measured by in vitro autoradiography using the s pecific radioligand [I-125]-SCH 47896. Treatment with the NEP inhibitor SCH 34826 caused a 60% reduction in the neutral endopeptidase radioligand-bindi ng 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/mm(2), p<0.01). This w as 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 gro up (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 Tc-99m-DTPA clearance) , systemic blood pressure, plasma ANP concentration and urinary cyclic GMP excretion were not changed by SCH34826 treatment. These results suggest tha t oral administration of the NEP inhibitor SCH34826 inhibits renal neutral endopeptidase, increases urinary ANP and modulates natriuresis without alte ration of systemic blood pressure, plasma ANP and renin level, glomerular f iltration or protein excretion.