Vascular structure and oxidative stress in salt-loaded spontaneously hypertensive rats: effects of losartan and atenolol.
BACKGROUND
Renin-angiotensin system (RAS) modulation by high dietary sodium may contribute to salt-induced hypertension, oxidative stress, and target organ damage. We investigated whether angiotensin II (Ang-II) type 1 (AT1)-receptor blockade (losartan) could protect the aorta and renal arteries from combined hypertension- and high dietary salt-related oxidative stress.


METHODS
Spontaneously hypertensive rats (3-month-old, n = 10/group) received tap water (SHR), water containing 1.5% NaCl (SHR+S), 1.5% NaCl and 30 mg losartan/kg/day (SHR+S+L), or 50 mg atenolol/kg/day (SHR+S+A). Atenolol was used for comparison. Ten Wistar-Kyoto rats (WKY) were controls. Systolic blood pressure (SBP) was determined by tail plethysmography. After 5 months of treatment, vascular remodeling and oxidative stress (superoxide production and NAD(P)H-oxidase activity (chemiluminescence), malondialdehyde (MDA) content (high-performance liquid chromatography), endothelial nitric oxide synthase (eNOS) activity [(14)C-arginine to (14)C citrulline], CuZn-SOD activity (spectrophotometry)) were studied.


RESULTS
In SHR, salt-loading significantly aggravated hypertension, urinary protein excretion, intraparenchymal renal artery (IPRArt) perivascular fibrosis, aortic and renal artery oxidative stress, and induced endothelial cell loss in IPRArts. In salt-loaded SHR, 5-month losartan and atenolol treatments similarly reduced SBP, but only losartan significantly prevented (i) urinary protein excretion increase, (ii) or attenuated hypertension-related vascular remodeling, (iii) aortic MDA accumulation, (iv) renal artery eNOS activity lowering, and (v) aortic and renal artery superoxide dismutase (SOD) activity reduction. In SHR+S, the contributions to aortic superoxide production were as follows: uncoupled eNOS > xanthine oxidase (XO) > NAD(P)H oxidase.


CONCLUSIONS
In this salt-sensitive genetic hypertension model, losartan protects from hypertension- and high dietary salt-related vascular oxidative stress, exceeding the benefits of BP reduction. Also, during salt overload, BP-independent factors contribute to vascular remodeling, at least part of which derive from AT1-receptor activation.
de Cavanagh
Elena M V
EM
Center of Arterial Hypertension, Cardiology Department, Austral University Hospital, Pilar, Argentina.
Ferder
León F
LF
Ferder
Marcelo D
MD
Stella
Inés Y
IY
Toblli
Jorge E
JE
Inserra
Felipe
F
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001262:Atenolol / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012077:Renal Artery / Q000187:drug effects / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D017673:Sodium Chloride, Dietary; D013481:Superoxides; D008315:Malondialdehyde; D001262:Atenolol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019808:Losartan