High angiotensin II state without cardiac remodeling (Bartter's and Gitelman's syndromes): are angiotensin II type 2 receptors involved?
OBJECTIVE
While Angiotensin II (Ang II) is a major factor in the development of cardiomyocyte hypertrophy and a pivotal role for Ang II signals via ERK1/2 has been identified, mechanism(s) responsible are still unclear. As Bartter's and Gitelman's syndrome patients (BS/GS) have increased Ang II, and yet normo/hypotension, hyporesponsiveness to pressors and blunted Ang II signaling via type 1 receptors (AT1R), this study assesses BS/GS's left ventricular (LV) mass and structure as well as Ang II induced ERK1/2 phosphorylation compared with essential hypertensive patients (EH) and normotensive healthy subjects (C) to gain insight into Ang II mediated processes.


METHODS
Indices of cardiac hypertrophy were determined by M-mode, two-dimensional echo Doppler and ERK phosphorylation by Western blot.


RESULTS
None of BS/GS exhibited LV remodelling; LV mass, LV end-diastolic volume and mass/volume ratio were unchanged vs C (60+/-14 g/m2 vs 64+/-12, 64+/-12 ml/m2 vs 60+/-8 and 0.95+/-0.2 vs 1.0+/-0.2, respectively) and reduced vs EH (119+/-15, p<0.001, 78+/-9, p<0.05 and 1.52+/-0.15, p<0.01). Despite BS/GS's higher plasma renin activity and aldosterone and unchanged level of AT1R, Ang II induced ERK1/2 phosphorylation was reduced vs both C and EH: 0.64 d.u.+/-0.08 vs 0.90+/-0.06 in C, p<0.006, and vs 1.45+/-0.07 in EH, p<0.001.


CONCLUSIONS
The data point to a direct cardioremodeling role for Ang II and support a role of Ang II type 2 receptor (AT2R) signaling as involved in the lack of cardiovascular remodeling in BS/GS. However, further studies using more direct approaches to demonstrate the effects of AT2R signaling must be pursued.
Calò
L A
LA
Department of Clinical and Experimental Medicine, Clinica Medica 4, Cagliari, Italy. renzcalo@unipd.it
Montisci
R
R
Scognamiglio
R
R
Davis
P A
PA
Pagnin
E
E
Schiavo
S
S
Mormino
P
P
Semplicini
A
A
Palatini
P
P
D'Angelo
A
A
Pessina
A C
AC
D000293:Adolescent; D000328:Adult; D000450:Aldosterone / Q000097:blood; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D001477:Bartter Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D053579:Gitelman Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation / Q000187:drug effects; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012083:Renin / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D014463:Ultrasonography
D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D000450:Aldosterone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012083:Renin