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

Objectives Vasopeptidase inhibitors are single molecules that simultaneousl y inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (AC E), The aim of this study was to characterize in-vitro and in-vivo inhibiti on of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat, Design and methods In-vitro NEP and ACE inhibition was studied by radioinhi bitory binding assay using rat renal membranes and the specific NEP inhibit or radioligand I-125-RB104 and the specific ACE inhibitor radioligand I-125 -MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatr ilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or receive d 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 speci fic radioligands from renal membrane NEP (IC(50)305 +/- 5.4 nmol/l) and ACE (IC50 3.6 +/- 0.02 nmol/l), In the dose-response study gemopatrilat (1,3 a nd 10 mg/kg) caused significant inhibition of plasma ACE (P < 0.01), and re nal ACE and NEP (3, 10 mg/kg, P < 0.01). In the time course experiment, gem opatrilat (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 usef ul addition to existing vasopeptidase inhibitors in the treatment of cardio vascular disease. I Hypertens 19: 941-946 (C) 2001 Lippincott Williams & Wi lkins.