Regulation of Local Angiotensin II Formation in the Human Heart in the Presence of Interstitial Fluid

Abstract

Background Data from in vitro studies suggest that both chymase and ACE contribute to the local generation of angiotensin (Ang) II in the heart. The enzyme kinetics under in vivo conditions are unclear. We thus studied the generation of Ang II by cardiac tissue in the presence of interstitial fluid (IF) that contains a variety of naturally occurring protease inhibitors. Methods and Results Ang I was incubated with heart homogenate in the presence of IF. IF obtained from human skin contained substantial amounts of protease inhibitors and ACE activity, the concentration of α 1 -antitrypsin being 35% and the activity of ACE 24% of the corresponding serum values. When heart homogenate was incubated with Ang I, three enzymes were responsible for its metabolism: heart chymase and heart ACE converted Ang I to Ang II, and heart carboxypeptidase A (CPA)–like activity degraded Ang I to Ang-(1-9). Incubation of heart homogenate in the presence of IF led to practically full inhibition of heart chymase–mediated Ang II formation by the natural protease inhibitors present in IF. In contrast, heart CPA–like activity was not blocked, as reflected by the continued generation of Ang-(1-9). In addition, both heart ACE– and IF ACE–mediated Ang II formation were strongly inhibited. This inhibition was shown to be due to the Ang-(1-9) formed. Conclusions The present experimental study defines two novel inhibitory mechanisms of Ang II formation in the human heart interstitium. Heart chymase–mediated Ang II formation is strongly inhibited by the natural protease inhibitors present in the IF. Similarly, both heart ACE– and IF ACE–mediated Ang II formation appear to be inhibited by the endogenous inhibitor Ang-(1-9) formed by heart CPA–like activity. These inhibitory mechanisms provide additional information about how the Ang II concentration in the heart interstitium may be controlled.