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JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat.
Clinical Science (1979-) 2003 September
Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study characterized the tissue distributions of ACE and NEP, and assessed the effects of the vasopeptidase inhibitor omapatrilat on ACE and NEP in rat tissues. In vivo ACE and NEP inhibition was studied by in vitro autoradiography and using the ACE inhibitor radioligand (125)I-MK351A and the NEP inhibitor radioligand (125)I-RB104 in rats that received oral omapatrilat (40 mg x day(-1) x kg(-1)) for 3 days. In vitro autoradiography was used to examine the distribution of ACE and NEP in the kidney, aorta, heart, adrenal gland, lung, intestine, liver, spleen and brain, and to assess enzyme inhibition after oral omapatrilat. Omapatrilat inhibited plasma ACE and increased plasma renin activity (P <0.01). Tissue ACE was inhibited by 70-95% (P <0.01), except in the brain, where ACE was not inhibited. NEP was inhibited by 87% in the kidney and by 20-40% in atria, aorta, adrenal gland, lung, liver and intestine; it was not inhibited in the brain, the ventricle or the spleen. Omapatrilat is a potent vasopeptidase inhibitor that significantly inhibits tissue ACE and NEP, with the degree of inhibition varying according to the enzyme and the tissue under assessment. The degree and site of tissue enzyme inhibition by vasopeptidase inhibitors may be relevant to end-organ protection as well as to the side-effect profiles of these agents.
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