Involvement of oxidative stress in the profibrotic action of aldosterone. Interaction wtih the renin-angiotension system.
BACKGROUND
The aim of this study was to investigate the involvement of angiotensin II and oxidative stress on cardiovascular damage induced by chronic subcutaneous aldosterone infusion in the absence of salt loading.


METHODS
Sprague-Dawley rats were infused with d-aldosterone (0.75 microg/h subcutaneously) for 6 weeks. Blood pressure was measured with the tail-cuff method. Small arteries were investigated on a pressurized myograph. Cardiovascular and renal collagen was evaluated by Sirius red staining. Systemic oxidant excess was measured with plasma 8-isoprostane by ELISA and by measurement of thiobarbituric acid-reactive substances. Vascular reactive oxygen species were studied using hydroethidine and NADPH-generated superoxide anion measured by lucigenin chemiluminescence.


RESULTS
After 6 weeks of treatment, systolic blood pressure was significantly increased in aldosterone-infused rats (170+/-8 v 123+/-2 mm Hg in controls, P < .05). Progression of hypertension was partially prevented by co-administration of losartan (AT1 receptor blocker) or tempol (superoxide dismutase mimetic): 140+/-4 and 149+/-6 mm Hg, respectively, P < .05 versus the aldosterone group. Aldosterone induced renal but not cardiac hypertrophy, which was not prevented by losartan or by tempol. Moreover, losartan and tempol failed to prevent vascular hypertrophy of resistance mesenteric vessels. However, losartan (0.77%+/-0.05%) and tempol (0.65%+/-0.10%) prevented cardiac fibrosis in the midmyocardium in the aldosterone group (1.03%+/-0.12% v 0.68%+/-0.07% positive staining per area in control, P < .05). In the kidney, collagen accumulation of aldosterone-infused rats was also significantly decreased by losartan (-77%) and tempol (-60%). Similar effects were obtained on aortic fibrosis. Aldosterone increased serum 8-isoprostane levels.This increase was blunted by losartan and tempol. Losartan and tempol totally prevented vascular, cardiac, and renal increase of NADPH-induced superoxide production stimulated by aldosterone.


CONCLUSIONS
Our data suggest that the profibrotic but not the hypertrophic action of aldosterone are mediated at least in part by reactive oxygen species generation and involve an interaction with the renin-angiotensin system.
Iglarz
Marc
M
Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
Touyz
Rhian M
RM
Viel
Emilie C
EC
Amiri
Farhad
F
Schiffrin
Ernesto L
EL
D000450:Aldosterone / Q000008:administration & dosage*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D000975:Antioxidants / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004699:Endocardium / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005355:Fibrosis; D007261:Infusions, Intra-Arterial; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D008955:Models, Cardiovascular; D009249:NADP / Q000187:drug effects / Q000378:metabolism; D009599:Nitroprusside / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects*; D010496:Pericardium / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013113:Spin Labels; D013599:Systole / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage
D000959:Antihypertensive Agents; D000975:Antioxidants; D015415:Biomarkers; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D017392:Thiobarbituric Acid Reactive Substances; D014665:Vasodilator Agents; D009599:Nitroprusside; D000450:Aldosterone; D009249:NADP; D019808:Losartan; C001803:tempol