Raloxifene enhances nitric oxide release in rat aorta via increasing endothelial nitric oxide mRNA expression.
We report the modulatory effects of chronic oral LY139481 (raloxifene) on basal release of nitric oxide (NO) and mRNA levels of endothelial NO synthase (eNOS) in rat thoracic aorta. Constrictor dose-response curves to phenylephrine were generated before and after pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Aortic segments were obtained from four groups of rats gavaged orally for 21 days: (i) ovariectomized, (ii) sham, (iii) ovariectomized estradiol-treated, and (iv) ovariectomized raloxifene-treated. Intact aortic rings from sham rats and ovariectomized rats receiving raloxifene and estrogen showed a greater potentiation of the phenylephrine responses after L-NAME. Semi-quantitative reverse transcription-polymerase chain reaction indicated a gender-based difference in eNOS mRNA expression in thoracic aorta. Moreover, we demonstrated that eNOS mRNA expression in the upper thoracic aorta was significantly higher in treatment groups. These results show that chronically administered raloxifene is exerting a potentially important vasculo-protective effect by stimulating eNOS expression.
Rahimian
Roshanak
R
The Vancouver Vascular Biology Research Center, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
Dubé
Gregory P
GP
Toma
Warda
W
Dos Santos
Nancy
N
McManus
Bruce M
BM
van Breemen
Cornelis
C
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D020847:Estrogen Receptor Modulators; D004967:Estrogens; D012333:RNA, Messenger; D010656:Phenylephrine; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000109:Acetylcholine