title: Inhibition of neutral endopeptidase, the degradative enzyme for natriuretic peptides, in rat kidney after oral SCH 42495.
abstract: 1. Inhibition of neutral endopeptidase (NEP), the degradative enzyme for atrial natriuretic peptide, was studied in vitro and in vivo using a previously characterized NEP inhibitor radioligand, 125I-labelled RB104. 2. SCH 42354, the active di-acid of the ethylester prodrug, SCH 42495, caused a concentration-dependent displacement of 125I-labelled RB104 from rat renal NEP. The concentration of SCH 42354 that displaced 50% of radioligand bound to the enzyme NEP (IC50) was 3.3 +/- 0.1 nmol/l (mean +/- SEM). Enalaprilat, an angiotensin converting enzyme inhibitor, did not displace 125I-labelled RB104 in concentrations up to 10 mumol/l. 3. In adult normotensive Sprague-Dawley rats, oral SCH 42495 (3-300 mg/kg) caused significant inhibition of renal NEP (P < 0.001). SCH 42495 had no effect on renal or plasma angiotensin converting enzyme activity, but high-dose SCH 42495 (300 mg/kg) caused a significant increase in plasma renin activity (P < 0.01). 4. In a time course study, oral SCH 42495 (30 mg/kg) caused rapid (within 30 min) and significant inhibition of renal NEP for up to 48 h (P < 0.001). No changes in plasma atrial natriuretic peptide or plasma angiotensin converting enzyme activity were seen. 5. These data provide evidence that short-term administration of the NEP inhibitor SCH 42495 results in inhibition of renal NEP and does not inhibit the circulating or the tissue renin-angiotensin system. The NEP inhibitor radioligand 125I-labelled RB104, is a useful tool to study tissue NEP inhibition after administration of NEP inhibitors.
authors.affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Burrell
authors.forename: N
authors.initials: N
authors.lastname: Farina
authors.forename: J
authors.initials: J
authors.lastname: Risvanis
authors.forename: D
authors.initials: D
authors.lastname: Woollard
authors.forename: D
authors.initials: D
authors.lastname: Casely
authors.forename: C I
authors.initials: CI
authors.lastname: Johnston
mesh_terms: D000284:Administration, Oral; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005260:Female; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D011355:Prodrugs; C075662:RB 104; C086374:CGS 26129; D005680:gamma-Aminobutyric Acid; D009320:Atrial Natriuretic Factor; D008715:Methionine; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin