757-2 Angiotensin II Formation in the Intact Human Heart: Predominance of the Angiotensin Converting Enzyme Pathway

Abstract

It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the heart is low compared to non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. Accordingly, we developed a method to quantify ACE and non-ACEmediated conversion of angiotensin I (Ang I) to Ang II across the myocardial circulation in human subjects. Using an intracoronary(lC) infusion of 123|-Ang I before and during an IC infusion of enalaprilat, we measured the fractional conversion of Ang I to Ang II in coronary sinus blood samples by taking the ratio of the labeled Ang II activity to the sum of activity corresponding to labeled Ang I and Ang II after peptide extraction and separation by HPLC (activity ratio method). Results obtained from this method were confirmed by combined HPLC/RIA of both labeled and unlabeled Ang I and Ang II (RIA method). The initial experience has been obtained in orthotopic heart transplant recipients with normal cardiac function and coronary anatomy. After a six minute IC infusion of 123|Ang I, fractional conversion of Ang I to Ang II was 0.44 ± 0.141, and 0.43 ± 0.084 (n = 4, mean ± SD) as determined, respectively, by the activity ratio and RIA methods. IC enalaprilat (0.01 mg/min for five minutes) reduced fractional conversion to 0.046 ± 0.065 (activity ratio method) or 0.033 ± 0.012 (RIA method) (n = 3, P = 0.014).Download : Download high-res image (61KB)Download : Download full-size image 1) Ang II formation can be measured in the intact human heart; 2) ACE mediates 90% of Ang I to Ang II conversion across the myocardial circulation.