Objectives: Recent studies in homogenized hearts suggest that chymase rather than angiotensin converting enzyme (ACE) is responsible for cardiac angiotensin I to angiotensin II conversion. We investigated in intact rat hearts whether (i) enzymes other than ACE contribute to angiotensin I to angiotensin II conversion and (ii) the localization (endothelial/extra-endothelial) of converting enzymes. Design and Methods: We used a modified version of the rat Langendorff heart, allowing separate collection of coronary effluent and interstitial fluid. Hearts were perfused with angiotensin I (arterial concentration 5-10 pmol/ml) under control conditions, in the presence of captopril (1 μmol/l) or after endothelium removal with 0.2% triton X-100. Endothelium removal was verified as the absence of a coronary vasodilator response to 10 nmol bradykinin. Angiotensin I and angiotensin II were measured in coronary effluent and interstitial fluid with sensitive radioimmunoassays. Results: In control hearts, 45% of arterial angiotensin I was metabolized during coronary passage, partly through conversion to angiotensin II. At steady-state, the angiotensin I concentration in interstitial fluid was three to four-fold lower than in coronary effluent, while the angiotensin II concentrations in both fluids were similar. Captopril and endothelium removal did not affect coronary angiotensin I extraction, but increased the interstitial fluid levels of angiotensin I two- and three-fold, respectively, thereby demonstrating that metabolism (by ACE) as well as the physical presence of the endothelium normally prevent arterial angiotensin I from reaching similar levels in coronary effluent and interstitial fluid. Captopril, but not endothelium removal, greatly reduced the angiotensin II levels in coronary effluent and interstitial fluid. With the ACE inhibitor, the angiotensin II/I ratios in coronary effluent and interstitial fluid were 83 and 93% lower, while after endothelium removal, the ratios were 33 and 71% lower. Conclusions: In the intact rat heart, ACE is the main contributor to angiotensin I to angiotensin II conversion, both in the coronary vascular bed and the interstitium. Cardiac ACE is not limited to the coronary vascular endothelium.

Angiotensin, Angiotensin converting enzyme inhibitors, Chymase, Coronary circulation, Interstitial space
dx.doi.org/10.1097/00004872-200105000-00017, hdl.handle.net/1765/63340
Journal of Hypertension
Department of Pharmacology

de Lannoy, L.M, Schuijt, M.P, Saxena, P.R, Schalekamp, M.A.D.H, & Danser, A.H.J. (2001). Angiotensin converting enzyme is the main contributor to angiotensin I-II conversion in the interstitium of the isolated perfused rat heart. Journal of Hypertension, 19(5), 959–965. doi:10.1097/00004872-200105000-00017