Evidence for angiotensin-converting enzyme- and chymase-mediated angiotensin II formation in the interstitial fluid space of the dog heart in vivo

Background-We have previously demonstrated that angiotensin II (Ang II) lev els in the interstitial fluid (ISF) space of the heart are higher than in t he blood plasma and do not change after systemic infusion of Ang I. In this study, we assess the enzymatic mechanisms (chymase versus ACE) by which An g II is generated in the ISF space of the dog heart in vivo. Methods and Results-Cardiac microdialysis probes were implanted in the left ventricular (LV) myocardium (3 to 4 probes per dog) of 12 anesthetized ope n-chest normal dogs. ISF Ang I and II levels were measured at baseline and during ISF infusion of Ang I (15 mu mol/L, n=12), Ang I+the ACE inhibitor c aptopril (cap) (2.5 mmol/L, n=4), Ang I+the chymase inhibitor chymostatin ( chy) (1 mmol/L, n=4), and Ang I+cap+chy (n=4). ISF infusion of Ang I increa sed ISF Ang II levels 100-fold (P<0.01), whereas aortic and coronary sinus plasma Ang I and II levels were unaffected and were 100-fold lower than ISF levels. Compared with ISF infusion of Ang I alone, Ang I+cap (n=4) produce d a greater reduction in ISF Ang II levels than did Ang I+chy (n=4) (71% ve rsus 43%, P<0.01), whereas Ang I+cap+chy produced a 100% decrease in ISF An g II levels. Conclusions-This study demonstrates for the first time a very high capacity for conversion of Ang I to Ang II mediated by both ACE and chymase in the ISF space of the dog heart in vivo.