Genetic models provide unique insight into angiotensin and bradykinin peptides in the extravascular compartment of the heart in vivo.

1. There is continuing uncertainty about the tissue compartments where angiotensin and bradykinin peptide formation occurs. Mice with angiotensin-converting enzyme (ACE) expression targeted to the cardiomyocyte membrane provide a unique experimental model to detect ACE substrates in the extravascular compartment of the heart in vivo. 2. Angiotensin (Ang) I and II, bradykinin-(1-7) and bradykinin-(1-9) were measured in blood and cardiac ventricles of wild-type (WT) mice, mice with a non-functional somatic ACE gene promoter (KO), mice homozygous (8/8) and heterozygous (1/8) for cardiomyocyte-targeted ACE expression and a non-functional somatic ACE gene promoter, and mice heterozygous for cardiomyocyte-targeted ACE expression and heterozygous for the WT ACE allele (WT/8). 3. Cardiac AngII levels of 8/8, 1/8, WT/8 and WT mice were higher than KO levels. Cardiac AngII levels in 8/8 and 1/8 mice were also higher than WT levels, but the levels in WT/8 mice were similar to WT levels. Cardiac bradykinin-(1-9) levels of WT, but not 8/8 mice, were lower than in KO mice, whereas bradykinin-(1-7) levels in 8/8 mice were lower than in KO mice. 4. We conclude that AngI and bradykinin-(1-7) are present in the cardiac extravascular compartment of mice lacking vascular ACE and that extravascular ACE produces AngII and metabolises bradykinin-(1-7) in this compartment. The data suggest that the vascular compartment is the main site of AngI and bradykinin-(1-9) formation and metabolism and that vascular ACE may limit AngI entry to the extravascular compartment of WT mice.