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Protective Effect of Omapatrilat, a Vasopeptidase Inhibitor, on the Metabolism of Bradykinin in Normal and Failing Human Hearts
Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and failing human hearts and to compare the effect of oma...
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Published in: | The Journal of pharmacology and experimental therapeutics 2000-11, Vol.295 (2), p.621-626 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective
effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and
failing human hearts and to compare the effect of omapatrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits
both neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exogenous BK at a nanomolar concentration was incubated
alone, in the presence of an ACE inhibitor (ramiprilat, 36 nM), or in the presence of a VPI (omapatrilat, 61 nM) with left
ventricular membranes prepared from normal donor hearts ( n = 7), and hearts from patients with an ischemic ( n = 11) or dilated ( n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (199 ± 60, 224 ± 108, and 283 ± 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat significantly increased
the half-life of BK ( P < .01), but the effect was similar for the three kinds of tissues (297 ± 104, 267 ± 157, and 407 ± 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat on the kinetic parameter of BK (478 ± 210, 544 ± 249, and 811 ± 349
s, respectively) was greater than that of the ACE inhibitor ( P < .01). Moreover, omapatrilat had a more important potentiating effect with DCM than normal heart membranes ( P < .05). These results show that not only ACE but also and mainly NEP play an important role in the degradation of BK in human
heart membranes. Omapatrilat, a VPI, has a greater protective effect on BK metabolism than that of a pure ACE inhibitor. Thus,
inhibition of both ACE and NEP with omapatrilat could be more cardioprotective than ACE inhibition alone. |
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ISSN: | 0022-3565 1521-0103 |