Acute and chronic neutral endopeptidase inhibition and the natriuretic response to acute volume expansion.
Neutral endopeptidase inhibition (NEPI) provides a potential avenue to modulate the actions of atrial natriuretic peptide (ANP). We tested the hypothesis that acute and chronic NEPI increased the renal responses at baseline and after acute volume expansion in rats. ANP plasma levels and cGMP excretion were significantly increased with acute NEPI by SQ 28.603, whereas chronic inhibition with SCH 34826 did not lead to any changes. The ratio of cGMP excretion per plasma ANP, however, was significantly increased (6.2 +/- 0.9) by chronic treatment with SCH 34826 compared to chronic vehicle treatment (4.2 +/- 0.7) indicating an activated renal ANP receptor system. Baseline diuresis and natriuresis were enhanced with acute but not with chronic treatment. After acute volume expansion, ANP increased five-fold with acute NEPI, whereas it only increased about 70% in chronically inhibited rats. The natriuretic (497 +/- 62 vs. 329 +/- 42 micromol/60 min with vehicle, P < 0.05) and diuretic responses were significantly enhanced with chronic treatment. Together with an increased cGMP/ANP ratio, these data suggest that chronic activation of the renal ANP system after long-term NEPI facilitated the excretion of an acute volume load. These findings may have therapeutic implications in patients with chronic sodium retention.
Scheuermann
M
M
Franz-Volhard-Klinik, Max-Delbrück-Center for Molecular Medicine, Charité, Humboldt-University of Berlin, Germany.
Dietz
R
R
Willenbrock
R
R
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood*; D004231:Diuresis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics; D007668:Kidney / Q000187:drug effects; D008297:Male; D009318:Natriuresis; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; C065359:SQ 28603; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP; D000409:Alanine