REGULATION OF LOCAL ANGIOTENSIN-II FORMATION IN THE HUMAN HEART IN THE PRESENCE OF INTERSTITIAL FLUID - INHIBITION OF CHYMASE BY PROTEASE INHIBITORS OF INTERSTITIAL FLUID AND OF ANGIOTENSIN-CONVERTING ENZYME BY ANG-(1-9) FORMED BY HEART CARBOXYPEPTIDASE A-LIKE ACTIVITY

Background Data from in vitro studies suggest that both chymase and AC E contribute to the local generation of angiotensin (Ang) II in the he art. 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 occurrin g protease inhibitors. Methods and Results Ang I was incubated with he art homogenate in the presence of IF. IF obtained from human skin cont ained substantial amounts of protease inhibitors and ACE activity, the concentration of alpha(1)-antitrypsin being 35% and the activity of A CE 24% of the corresponding serum values. When heart homogenate was in cubated with Ang I, three enzymes were responsible for its metabolism: heart chymase and heart ACE converted Ang I to Ang II, and heart carb oxypeptidase A (CPA)-like activity degraded Ang I to Ang-(1-9). Incuba tion 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 activit y 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 An g-(1-9) formed. Conclusions The present experimental study defines two novel inhibitory mechanisms of Ang II formation in the human heart in terstitium. Heart chymase-mediated Ang II formation is strongly inhibi ted by the natural protease inhibitors present in the IF. Similarly, b oth heart ACE- and IF ACE-mediated Ang II formation appear to be inhib ited by the endogenous inhibitor Ang-(1-9) formed by heart CPA-like ac tivity. These inhibitory mechanisms provide additional information abo ut how the Ang II concentration in the heart interstitium may be contr olled.