Pravastatin enhances beneficial effects of olmesartan on vascular injury of salt-sensitive hypertensive rats, via pleiotropic effects.
OBJECTIVE
This work was undertaken to investigate comparative effect of AT1 receptor blocker (ARB), 3-hydroxy-3-methylglutaryl (HMG) coenzymeA (CoA) reductase inhibitor (statin), and their combination on vascular injury of salt-sensitive hypertension.


RESULTS
Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were treated with (1) vehicle, (2) hydralazine (5 mg/kg/d), (3) olmesartan (0.5 mg/kg/d), (4) pravastatin (100 mg/kg/d), and (5) combined olmesartan and pravastatin for 4 weeks. Olmesartan or pravastatin significantly and comparably improved vascular endothelium-dependent relaxation to acetylcholine, coronary arterial remodeling, and eNOS activity of DS rats. Olmesartan prevented vascular eNOS dimer disruption or the downregulation of dihydrofolate reductase (DHFR) more than pravastatin, whereas Akt phosphorylation was enhanced by pravastatin but not olmesartan, indicating differential pleiotropic effects between olmesartan and pravastatin. Add-on pravastatin significantly enhanced the improvement of vascular endothelial dysfunction and remodeling by olmesartan in DS rats. Moreover, pravastatin enhanced the increase in eNOS activity by olmesartan, being associated with additive effects of pravastatin on phosphorylation of Akt and eNOS.


CONCLUSIONS
Olmesartan and pravastatin exerted beneficial vascular effects in salt-sensitive hypertension, via differential pleiotropic effects. Pravastatin enhanced vascular protective effects of olmesartan. Thus, the combination of ARB with statin may be the potential therapeutic strategy for vascular diseases of salt-sensitive hypertension.
Yamamoto
Eiichiro
E
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Yamashita
Takuro
T
Tanaka
Tomoko
T
Kataoka
Keiichiro
K
Tokutomi
Yoshiko
Y
Lai
Zhong-Fang
ZF
Dong
Yi-Fei
YF
Matsuba
Shinji
S
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013777:Tetrazoles / Q000494:pharmacology*; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D009569:Nitric Oxide; C437965:olmesartan; D017035:Pravastatin