In-vitro and in-vivo inhibition of rat neutral endopeptidase and angiotensin converting enzyme with the vasopeptidase inhibitor gemopatrilat.

Abstract

OBJECTIVES:

Vasopeptidase inhibitors are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The aim of this study was to characterize in-vitro and in-vivo inhibition of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat.

DESIGN AND METHODS:

In-vitro NEP and ACE inhibition was studied by radioinhibitory binding assay using rat renal membranes and the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatrilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or received oral gemopatrilat (3, 10 mg/kg) and were killed at time points 1, 2, 4, 8, 18, 24 and 48 h (n = 4 per time point).

RESULTS:

Gemopatrilat caused a concentration-dependent displacement of specific radioligands from renal membrane NEP (IC50 305 +/- 5.4 nmol/I) and ACE (IC50 3.6 +/- 0.02 nmol/). In the dose-response study gemopatrilat (1, 3 and 10 mg/kg) caused significant inhibition of plasma ACE (P< 0.01), and renal ACE and NEP (3, 10 mg/kg, P < 0.01). In the time course experiment, gemopatrilat (10 mg/kg) increased plasma renin activity for 8 h (P< 0.01) and inhibited plasma ACE (P< 0.05), renal NEP (P< 0.01) and renal ACE (P< 0.05) for 48 h.

CONCLUSIONS:

Gemopatrilat is a potent in-vitro vasopeptidase inhibitor that also causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose. The data suggest that gemopatrilat may be a useful addition to existing vasopeptidase inhibitors in the treatment of cardiovascular disease.

• Authors: R A Hubner, E Kubota, D J Casley, C I Johnston, L M Burrell
• Journal: Journal of hypertension (J Hypertens) Vol. 19 Issue 5 Pg. 941-6 (May 2001) ISSN: 0263-6352 [Print] England
• PMID: 11393678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Dipeptides
• Enzyme Inhibitors
• Iodine Radioisotopes
• Iodobenzenes
• Protease Inhibitors
• L-proline, N2-((1S)-1-carboxy-3-phenylpropyl)-N6-((4-hydroxyphenyl)iminomethyl)-L-lysyl-
• RB 104
• gamma-Aminobutyric Acid
• Neprilysin

Topics

• Administration, Oral
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Binding, Competitive
• Dipeptides (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• In Vitro Techniques
• Iodine Radioisotopes
• Iodobenzenes (metabolism)
• Male
• Neprilysin (antagonists & inhibitors)
• Protease Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Time Factors
• gamma-Aminobutyric Acid (analogs & derivatives, metabolism)