Sch-34826

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 <sup>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.

We examined the effects of brief exposure to weak 60 Hz extremely low frequency (ELF) magnetic fields and opioid systems on spatial behavior and learning in reproductive adult male and female deer mice, Peromyscus maniculatus. Sex differences were evident in spatial performance, with male deer mice displaying significantly better performance than female mice in the Morris water maze, whereby animals had to acquire and retain the location of a submerged hidden platform. Brief (maximum 5 min) exposure to weak (100 microT) 60 Hz magnetic fields during task acquisition significantly improved female performance, eliminating the sex differences in acquisition. The opiate antagonist, naltrexone, also improved female acquisition, though significantly less than the magnetic fields. These facilitatory effects involved alterations of "non-spatial" (task familiarization and reduction of related anxiety/aversive related behaviors) and possibly "spatial" aspects of the task. Enhancement of enkephalin activity with the enkephalinase inhibitor, SCH 34826, significantly reduced task performance by male deer mice. Both naltrexone and the 60 Hz magnetic fields attenuated the enkephalin mediated reductions of spatial performance. These findings indicate that brief exposure to 60 Hz magnetic fields can enhance water maze task acquisition by deer mice and suggest that these facilitatory effects on spatial performance involve alterations in opioid activity.