Simvastatin and losartan enhance nitric oxide and reduce oxidative stress in salt-induced hypertension.
BACKGROUND
The renin-angiotensin-aldosterone system and oxidative stress play a major role in the pathogenesis of hypertension.


METHODS
We examined the effects of simvastatin, an HMG-CoA inhibitor, and losartan, an angiotensin type 1 receptor antagonist, in Dahl rats fed a high salt diet (8% NaCl), and treated with either simvastatin (3 mg/kg/d), losartan (10 mg/kg/d), or their combination using the drinking water as vehicle, for 3 weeks. Mean blood pressure (MAP) was measured by tail-cuff plethysmography. Plasma levels of nitric oxide (NO) and prostanoids, as well as plasma and tissue angiotensin II (Ang II) and aldosterone (ALDO) were analyzed by enzyme immunoassay. Renal and aortic superoxide production was determined by fluorescence spectrometry. Vascular reactivity of second-order mesenteric arteries was assessed in vitro.


RESULTS
Simvastatin, losartan, and the drug combination attenuated the salt-induced increase in MAP. Plasma NO was elevated by simvastatin, losartan, and the combination, whereas plasma thromboxane was reduced by losartan. Simvastatin, losartan, and the combination reduced renal Ang II, but only the combination reduced cardiac Ang II. Heart and renal ALDO were reduced by simvastatin, losartan, and the combination. Aortic and renal NADPH-dependent superoxide production was reduced by simvastatin, losartan, and the combination. The response to acetylcholine, in mesenteric arteries preconstricted with norepinephrine, was greater in the losartan group.


CONCLUSIONS
Thus, treatment with simvastatin and losartan lowered oxidative stress and improved endothelial function. Simvastatin significantly reduced the effect of losartan on vascular reactivity in mesenteric arteries, suggesting that their combination may be contraindicated.
Bayorh
Mohamed A
MA
Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA. bayorh@msm.edu
Ganafa
Agaba A
AA
Eatman
Danita
D
Walton
Marcus
M
Feuerstein
Giora Z
GZ
D000109:Acetylcholine / Q000494:pharmacology; D000450:Aldosterone / Q000097:blood / Q000378:metabolism; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004359:Drug Therapy, Combination; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000097:blood*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011453:Prostaglandins / Q000097:blood; D051381:Rats; D020303:Rats, Inbred Dahl; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013481:Superoxides / Q000378:metabolism; D013928:Thromboxane A2 / Q000097:blood; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011453:Prostaglandins; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D000450:Aldosterone; D013928:Thromboxane A2; D019821:Simvastatin; D019808:Losartan; D000109:Acetylcholine