Comparison of a Vasopeptidase Inhibitor with Neutral Endopeptidase and Angiotensin-Converting Enzyme Inhibitors on Bradykinin Metabolism in the Rat Coronary Bed

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Abstract
The in vitro effects of omapatrilat, a dual vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), on exogenous bradykinin metabolism after a single passage through the coronary bed were compared with that of a NEP inhibitor (retrothiorphan, 25 n M), an ACE inhibitor (enalaprilat, 130 n M), and omapatrilat (25 n M). Bradykinin and inhibitors were infused into isolated Langendorff rat hearts perfused at 1 ml/min followed by reperfusion at 10 ml/min. Residual bradykinin was quantified in the coronary effluent by enzyme-linked immunosorbent assay to calculate bradykinin recovery and its kinetic parameters (Vmax/Km). Bradykinin degradation rate at 1 ml/min was 4.56 ± 0.39 1/min per gram without inhibitors and was significantly reduced to 2.57 ± 0.19 1/min per gram in the presence of enalaprilat, to 2.97 ± 0.38 1/min per gram with retrothiorphan, to 1.82 ± 0.17 1/min per gram with both enalaprilat and retrothiorphan, and to 1.14 ± 0.35 1/min per gram with omapatrilat. In a second set of experiments, the effect of a 14-day treatment of rats with either ACE inhibitors (enalapril, quinapril, and ramipril), a NEP inhibitor (candoxatril), or omapatrilat on exogenous bradykinin metabolism was studied in Langendorff perfused hearts isolated from these long-term treated rats. In untreated rats, bradykinin degradation at a coronary perfusion of 1 ml/min was 4.35 ± 0.41 1/min per gram. This value was reduced by 30% for the NEP inhibitor, by 50% for all ACE inhibitors, and by 75% for omapatrilat. All inhibitors administered either short term or long term significantly reduced bradykinin degradation during a single passage through the coronary bed. However, omapatrilat administration resulted in the greatest protection from bradykinin breakdown than ACE or NEP inhibitors alone.