Therapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activation

Yau Chi Chan, Fung Ping Leung, Wing Tak Wong, Xiao Yu Tian, Lai Ming Yung, Chi Wai Lau, Suk Ying Tsang, Xiaoqiang Yao, Zhen Yu Chen, Yu Huang

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Objective-: Selective estrogen receptor modulators (SERMs) inhibit constriction of mammalian conduit arteries. However, it is unknown whether SERMs at therapeutically achievable concentrations could reduce vascular tone in resistance arteries. The present study aimed to examine roles of Ca influx in endothelium and endothelial nitric oxide synthase (eNOS) activation in dilatations induced by raloxifene, a second-generation SERM in myogenically active arteries.Methods and results-: Small mesenteric arteries from Sprague-Dawley rats were isolated and mounted in a pressure myograph for measurement of changes in vessel diameter. [Ca]i images on native endothelial cells of intact arteries were determined by the fluorescence imaging technique, and phosphorylation of eNOS was assayed by Western blotting. Raloxifene (0.3 to 10 nmol/L) produced dilatations on established steady myogenic constriction. Female rat arteries dilated significantly more in response to raloxifene than male arteries. Raloxifene-induced dilatations of female arteries were blunted by N-nitro-l-arginine methyl ester but unaffected by 1400W, charybdotoxin plus apamin, wortmannin, or LY294002. Raloxifene (3 nmol/L) triggered rises in endothelial cell [Ca]i and increased eNOS phosphorylation at Ser1177. Both effects were greater in arteries from female rats than in arteries from male rats. Increases in endothelial cell [Ca]i and in eNOS phosphorylation were prevented by removal of extracellular Ca ions. Finally, ICI 182,780 did not affect the raloxifene-stimulated rise in endothelial cell [Ca]i, eNOS phosphorylation, and vasodilatations. Chronic raloxifene treatment reduced myogenic constriction in arteries from female but not male rats. Conclusion-: Raloxifene at therapeutically relevant concentrations inhibits myogenic constriction by an NO-dependent mechanism that causally involves the elevated [Ca]i in endothelial cells and subsequent eNOS activation. Raloxifene dilates resistance arteries more effectively in female rats, indicating its significant gender-related action on endothelial cells in microcirculation.

Original languageEnglish (US)
Pages (from-to)992-999
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number5
StatePublished - May 2010


  • Endothelial nitric oxide synthase
  • Mesenteric artery
  • Myogenic tone
  • Raloxifene
  • Selective estrogen receptor modulator

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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