Angiotensin-(1-7) formation in the intact human heart - In vivo dependence on angiotensin II as substrate

Background-Several enzymes that hydrolyze angiotensin I (Ang I) and Ang II to Ang-(1-7) have been identified, but their relative importance in the intact human heart is not known. Methods and Results-Intracoronary (IC) I-123-Ang I was administered to 4 heart transplantation recipients. Arterial and coronary sinus (CS) samples were taken before and after coadministration of IC enalaprilat. I-123-Ang metabolites were separated by high-pressure liquid chromatography, and I-123-Ang-(1-7) and I-123-Ang II were quantified across the myocardial circulation. I-123-Ang II formation (as measured by fractional conversion) at steady state was 0.43+/-0.05 and was reduced to 0.042+/-0.02 after IC enalaprilat (P<0.01). The fractional conversion of I-123-Ang-(1-7) was 0.198 +/- 0.032 but was reduced to 0.06 +/- 0.01 during IC enalaprilat (P<0.01). Net Ang II production at steady state was 2720+/-704 pg/min. Ang-(1-7) production was 3489+/-768 pg/min. After IC enalaprilat, Ang II production fell to 436+/-66.8 pg/min (P<0.05 versus Ang II production). After suppression of Ang II production with enalaprilat, there was net uptake of Ang-(1-7): -289 +/- 144 pg/min (P<0.05). Conclusions-Ang-(1-7) was formed in the intact human myocardial circulation and was decreased when Ang II formation was suppressed. These data indicate that the major pathway for Ang-(1-7) generation in the intact human heart was dependent on substrate availability of Ang II. Ang-(1-7)-forming enzymes that demonstrate substrate preference for Ang II are likely to play an important role in the regulation of Ang-(1-7) formation in the intact human heart.