ANGIOTENSIN-II FORMATION IN THE INTACT HUMAN HEART - PREDOMINANCE OF THE ANGIOTENSIN-CONVERTING ENZYME PATHWAY

It has been proposed that the contribution of myocardial tissue angiot ensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to A ng II formation in the human heart. To examine angiotensin II formatio n in the intact human heart, we administered intracoronary I-123-label ed angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients, The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides b y HPLC, was 0.415+/-0.104 (n = 5, mean+/-SD). Enalaprilat reduced frac tional conversion by 89%, to a value of 0.044+/-0.053 (n = 4, P = 0.00 2), In a separate study of explanted hearts, a newly developed in vitr o Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized le ft ventricular membrane preparations from failing hearts was 49.6+/-5. 3 fmol I-125-Ang II formed per minute per milligram of protein (n = 8, +/-SE), and 35.9+/-4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08), In the presence of 1 mu M enalaprilat, ACE activity was reduced by 85%, to 7.3+/-1.4 fmol/min/mg in the failing group and to 4 .6+/-1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE.