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 enzy me (ACE) inhibitors results from their protective effects on cardiac bradyk inin (BK) metabolism, the purpose of this study was to define the metabolis m of BK in normal and failing human hearts and to compare the effect of oma patrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits bo th neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exog enous 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 (omapa trilat, 61 nM) with left ventricular membranes prepared from normal donor h earts (n = 7), and hearts from patients with an ischemic (n = 11) or dilate d (n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (19 9 +/- 60, 224 +/- 108, and 283 +/- 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat signi ficantly increased the half-life of BK (P < .01), but the effect was simila r for the three kinds of tissues (297 +/- 104, 267 +/- 157, and 407 +/- 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat o n the kinetic parameter of BK (478 +/- 210, 544 +/- 249, and 811 +/- 349 s, respectively) was greater than that of the ACE inhibitor (P < .01). Moreov er, omapatrilat had a more important potentiating effect with DCM than norm al 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 he art membranes. Omapatrilat, a VPI, has a greater protective effect on BK me tabolism than that of a pure ACE inhibitor. Thus, inhibition of both ACE an d NEP with omapatrilat could be more cardioprotective than ACE inhibition a lone.