title: Genetic models provide unique insight into angiotensin and bradykinin peptides in the extravascular compartment of the heart in vivo.
abstract: 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.
authors: St Vincent's Institute of Medical Research, Department of Medicine, University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia. dcampbell@svi.edu.au
authors: Duncan J
authors: DJ
authors: Campbell
authors: Hong D
authors: HD
authors: Xiao
authors: Sebastien
authors: S
authors: Fuchs
authors: Kenneth E
authors: KE
authors: Bernstein
mesh_terms: D000809:Angiotensins / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001920:Bradykinin / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D003331:Coronary Vessels / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D000809:Angiotensins; D010446:Peptide Fragments; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin