ANGIOTENSIN-II FORMATION IN THE HUMAN HEART - AN ACE OR NON-ACE-MEDIATED PATHWAY

The enzymatic pathways for local angiotensin II (Ang II) formation in the heart have been studied both in vivo and in vitro, but the results of these experiments have been discrepant. Thus, the experiments in v ivo with intact hearts, both in humans and in animal models, have uneq uivocally demonstrated that the major Ang II-forming enzyme is angiote nsin-converting enzyme (ACE). In contrast, the experiments in vitro wi th both human or animal heart preparations, have unequivocally demonst rated that the major Ang II-forming enzyme is chymase, a mast cell-der ived chymotrypsin-like serine protease. The in vitro approach, however , seems to involve several pitfalls, which tend to overestimate the co ntribution of chymase as compared to that of ACE. It seems evident tha t in vivo the chymase-mediated Ang II formation is subjected to local inhibition, a fact that has been overlooked in most of the studies per formed in vitro. Accordingly, human chymase, even in its natural form as a protease-proteoglycan complex, is highly sensitive to the proteas e inhibitors naturally present in the interstitial fluid (IF). We foun d that if human heart tissue preparations are incubated in vitro in th e presence of IF, the chymase-mediated Ang II formation is almost tota lly suppressed. As the heart interstitium is constantly bathed by IF w ith its protease inhibitors in concentrations sufficiently high to ens ure efficient inhibition of this enzyme, the protease inhibitor-mediat ed suppression of chymase should also be effective in vivo. Thus, the local production of Ang II in the human heart appears to be regulated by ACE rather than by chymase.