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) levels in the interstitial fluid (ISF) space of the heart are higher than in the 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 Ang 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 open-chest normal dogs. ISF Ang I and II levels were measured at baseline and during ISF infusion of Ang I (15 micromol/L, n=12), Ang I+the ACE inhibitor captopril (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 increased 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) produced a greater reduction in ISF Ang II levels than did Ang I+chy (n=4) (71% versus 43%, P<0.01), whereas Ang I+cap+chy produced a 100% decrease in ISF Ang 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.