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We have previously reported increased intracardiac angiotensin II (ANG II) levels in a dog model of volume overload hypertrophy produced by percutaneous chordal rupture of the mitral valve. Whether the increase in ANG II is mediated by angiotensin converting enzyme (ACE) and/or heart chymase is unknown. Magnetic resonance imaging and high-fidelity pressure monitoring were performed on 8 adult mongrel dogs before and 5 months after causing mitral regurgitation (MR). Left ventricular (LV) end-diastolic volume increased from 58 ± 13 [SD] to 102 ± 35 ml (p l 0.001), as did end-systolic volume (33 ± 10 to 47 ± 18 ml, p l 0.001). LV mass increased in all dogs from 82 ± 22 to 112 ± 25 grams (p l 0.001) and the LV mass/end-diastolic volume ratio decreased significantly from 1.63 ± 0.20 to 1.17 ± 0.23 gm/ml (p l 0.001). ANG II levels were significantly higher in the midwall of the left ventricle in mitral regurgitation hearts than in normal controls (85 ± 39 vs. 27 ± 16 pg/gm, p l 0.01) and ANG II correlated with LV end-diastolic wall stress (r = 0.75, P l 0.05). ACE activity increased in MR hearts compared to controls (1.22 ± 0.46 vs. 3.55 ± 1.39 mUnits/gm, p l 0.05) and chymase activity was also in MR hearts compared to controls (9.42 ± 4.6 vs. 19.81 ± 8.93 nmol/gm/min, p l 0.05). These results demonstrate significant elevation of intracardiac ANG II levels associated with increasing diastolic stress and increasing intracardiac ACE and chymase activity. The parallel responses of ACE and chymase activity in response to volume overload of the dog heart suggest that the increased ANG II levels in this model are generated by ACE and chymase. Further studies using selective inhibitors of these enzymes are needed to establish an etiologic relationship between increased ACE activity and left ventricular remodeling in this model.