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 125I-MK351A and the NEP inhibitor radioligand 125I-RB104 in rats that received oral omapatrilat (40 mg·day-1·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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September 2003
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Research Article|
September 01 2003
Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat
Eiji KUBOTA;
Eiji KUBOTA
1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
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Rachael G. DEAN;
Rachael G. DEAN
1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
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Richard A. HUBNER;
Richard A. HUBNER
1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
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David J. CASLEY;
David J. CASLEY
1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
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Colin I. JOHNSTON;
Colin I. JOHNSTON
1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
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Louise M. BURRELL
1Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Road, Heidelberg, Victoria 3084, Australia
Correspondence: Associate Professor Louise M. Burrell (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
March 17 2003
Revision Received:
May 02 2003
Accepted:
May 12 2003
Accepted Manuscript online:
May 12 2003
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2003 The Biochemical Society
2003
Clin Sci (Lond) (2003) 105 (3): 339–345.
Article history
Received:
March 17 2003
Revision Received:
May 02 2003
Accepted:
May 12 2003
Accepted Manuscript online:
May 12 2003
Citation
Eiji KUBOTA, Rachael G. DEAN, Richard A. HUBNER, David J. CASLEY, Colin I. JOHNSTON, Louise M. BURRELL; Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat. Clin Sci (Lond) 1 September 2003; 105 (3): 339–345. doi: https://doi.org/10.1042/CS20030097
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