(Hypertension. 1998;31:362.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Metabolism of Angiotensin-(1–7) by Angiotensin-Converting Enzyme
From the Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
Correspondence to Mark C. Chappell, Hypertension Center, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1095. E-mail mchappel{at}bgsm.edu
Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1–7) [Ang-(1–7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1–7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1–7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1–7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of 125I-Ang-(1–7). The primary product of 125I-Ang-(1–7) metabolism was identified as Ang-(1–5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1–7) to the pentapeptide Ang-(1–5). The ACE inhibitors lisinopril and enalaprilat (1 µmol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1–5) and did not yield other metabolic products. Ang-(1–5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1–7) by ACE revealed a substrate affinity of 0.81 µmol/L and maximal velocity of 0.65 µmols min-1 mg-1. The calculated turnover constant for the peptide was 1.8 sec-1 with a catalytic efficiency (Kcat/Km) of 2200 sec-1mmol/L-1. These findings suggest that increased levels of Ang-(1–7) following ACE inhibition may due, in part, to decreased metabolism of the peptide.
Key Words: angiotensin-converting enzyme • dipeptidyl carboxypeptidase • Ang-(1–7) • Ang-(1–5) • lisinopril • enalaprilat
Abbreviations: ACE = angiotensin converting enzyme • Ang = angiotensin • DNFB = 1-fluro-2,4-dinitroflurobenzene • DTT = dithiothreitiol • EDTA = ethylene diaminetetraacetic acid • HPLC = high performance liquid chromatography • kcat = catalytic constant • kcat/Km = specificity constant • Ki = inhibitory constant • Km = affinity constant • SHR = spontaneously hypertensive rat • Vmax = maximal velocity • WKY = Wistar-Kyoto • ZPP = Z-prolyl prolinal
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