Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production.
BACKGROUND
It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens.


RESULTS
To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg x kg(-1) x d(-1)) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation.


CONCLUSIONS
Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.
Wassmann
Sven
S
Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, Homburg/Saar, Germany.
Laufs
Ulrich
U
Stamenkovic
Djordje
D
Linz
Wolfgang
W
Stasch
Johannes-Peter
JP
Ahlbory
Katja
K
Rösen
Renate
R
Böhm
Michael
M
Nickenig
Georg
G
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D046508:Culture Techniques; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D017382:Reactive Oxygen Species; D020845:Selective Estrogen Receptor Modulators; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases