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- Title
Therapeutic concentrations of raloxifene augment nitric oxide-dependent coronary artery dilatation in vitro.
- Authors
Leung, F. P.; Yung, L. M.; Leung, H. S.; Au, C. L.; Yao, X.; Vanhoutte, P. M.; Laher, I.; Huang, Y.
- Abstract
Background and purpose:Raloxifene improves cardiovascular function. This study examines the hypothesis that therapeutic concentrations of raloxifene augment endothelium-dependent relaxation via up-regulation of eNOS expression and activity in porcine coronary arteries.Experimental approach:Isometric tension was measured in rings from isolated arteries. Intracellular Ca2 concentrations ([Ca2 ]i) in arterial endothelial cells were detected by Ca2 fluorescence imaging. Phosphorylation of eNOS at Ser-1177 was assayed by Western blot analysis.Key results:In arterial rings pre-contracted with 9,11-dideoxy-11α,9α-epoxy-methano-prostaglandin F2α (U46619), treatment with raloxifene (1-3 nM) augmented bradykinin- or substance P-induced relaxation and this effect was antagonized by ICI 182,780, an estrogen receptor antagonist. The enhanced relaxation was abolished in rings treated with inhibitors of nitric oxide/cyclic GMP-dependent dilation, NG-nitro-L-arginine methyl ester (L-NAME) plus 1H-[1,2,4]oxadizolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, effects of raloxifene were unaffected after inhibition of endothelium-derived hyperpolarizing factors by charybdotoxin plus apamin. Raloxifene (3 nM) did not influence endothelium-independent relaxation to sodium nitroprusside. 17ß-Estradiol (3-10 nM) also enhanced bradykinin-induced relaxation, which was inhibited by ICI 182,780. Treatment with raloxifene (3 nM) did not affect bradykinin-stimulated rise in endothelial cell [Ca2 ]i. Raloxifene, 17ß-estradiol, and bradykinin increased eNOS phosphorylation at Ser-1177 and ICI 182,780 prevented effects of raloxifene or 17ß-estradiol but not that of bradykinin. Raloxifene had neither additive nor antagonistic effects on 17ß-estradiol-induced eNOS phosphorylation.Conclusions and implications:Raloxifene in therapeutically relevant concentrations augmented endothelial function in porcine coronary arteries in vitro through ICI 182,780-sensitive mechanisms that were associated with increased phosphorylation of eNOS but independent of changes in endothelial cell [Ca2 ]i.British Journal of Pharmacology (2007) 152, 223–229; doi:10.1038/sj.bjp.0707387; published online 9 July 2007
- Subjects
CARDIOVASCULAR system; CORONARY arteries; BRITISH Journal of Pharmacology (Periodical); RALOXIFENE; PHOSPHORYLATION
- Publication
British Journal of Pharmacology, 2007, Vol 152, Issue 2, p223
- ISSN
0007-1188
- Publication type
Academic Journal
- DOI
10.1038/sj.bjp.0707387