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Title: Inhibition of neutral endopeptidase, the degradative enzyme for natriuretic peptides, in rat kidney after oral SCH 42495.
Austin Authors: Burrell, Louise M ;Farina, N K;Risvanis, John;Woollard, D;Casely, D;Johnston, Colin I
Affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia
Issue Date: 1-Jul-1997
Publication information: Clinical Science 1997; 93(1): 43-50
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.
Gov't Doc #: 9279202
Journal: Clinical Science
Type: Journal Article
Subjects: Administration, Oral
Atrial Natriuretic Factor.metabolism
Binding, Competitive
Dose-Response Relationship, Drug
Iodine Radioisotopes.diagnostic use
Iodobenzenes.administration & dosage.pharmacology
Kidney.drug effects.enzymology
Methionine.administration & dosage.analogs & derivatives.pharmacology
Neprilysin.antagonists & inhibitors
Peptidyl-Dipeptidase A.blood
Prodrugs.administration & dosage.pharmacology
Rats, Sprague-Dawley
Time Factors
gamma-Aminobutyric Acid.administration & dosage.analogs & derivatives.pharmacology
Appears in Collections:Journal articles

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