Cardiac phenotype and angiotensin II levels in AT1a, AT1b, and AT2 receptor single, double, and triple knockouts.
OBJECTIVE
Our aim was to determine the contribution of the three angiotensin (Ang) II receptor subtypes (AT(1a), AT(1b), AT(2)) to coronary responsiveness, cardiac histopathology, and tissue Ang II levels using mice deficient for one, two, or all three Ang II receptors.


RESULTS
Hearts of knockout mice and their wild-type controls were collected for histochemistry or perfused according to Langendorff, and kidneys were removed to measure tissue Ang II. Ang II dose-dependently decreased coronary flow (CF) and left ventricular systolic pressure (LVSP), and these effects were absent in all genotypes deficient for AT(1a), independently of AT(1b) and AT(2). The deletion of Ang II receptors had an effect neither on the morphology of medium-sized vessels in the heart nor on the development of fibrosis. However, the lack of both AT(1) subtypes was associated with atrophic changes in the myocardium, a reduced CF and a reduced LVSP. AT(1a) deletion alone, independently of the presence or absence of AT(1b) and/or AT(2), reduced renal Ang II by 50% despite a five-fold rise of plasma Ang II. AT(1b) deletion, on top of AT(1a) deletion (but not alone), further decreased tissue Ang II, while increasing plasma Ang II. In mice deficient for all three Ang II receptors, renal Ang II was located only extracellularly.


CONCLUSIONS
The lack of both AT(1) subtypes led to a baseline reduction of CF and LVSP, and the effects of Ang II on CF and LVSP were found to be exclusively mediated via AT(1a). The lack of AT(1a) or AT(1b) does not influence the development or maintenance of normal cardiac morphology, whereas deficiency for both receptors led to atrophic changes in the heart. Renal Ang II levels largely depend on AT(1) binding of extracellularly generated Ang II, and in the absence of all three Ang II receptors, renal Ang II is only located extracellularly.
van Esch
Joep H M
JH
Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Gembardt
Florian
F
Sterner-Kock
Anja
A
Heringer-Walther
Silvia
S
Le
Thu H
TH
Lassner
Dirk
D
Stijnen
Theo
T
Coffman
Thomas M
TM
Schultheiss
Heinz-Peter
HP
Danser
A H Jan
AH
Walther
Thomas
T
D000804:Angiotensin II / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001284:Atrophy; D003326:Coronary Circulation; D005355:Fibrosis; D005838:Genotype; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010477:Perfusion; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency* / Q000235:genetics; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
C544066:Agtr1a protein, mouse; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain