Tamoxifen dilates porcine coronary arteries: roles for nitric oxide and ouabain-sensitive mechanisms.
OBJECTIVE
Experiments were designed to determine the mechanism of the relaxation induced by tamoxifen in porcine coronary arteries at the tissue, cellular and molecular levels.


METHODS
Porcine left circumflex coronary arteries were isolated and isometric tension was measured. [Ca2+]i in native endothelial cells of intact arteries was determined by a calcium fluorescence imaging technique and eNOS ser1177 phosphorylation was assayed by Western blotting.


RESULTS
Tamoxifen induced an endothelium-dependent relaxation that was antagonized by ICI 182,780 and abolished by NG-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadizolo[4,3-a]quinoxalin-1-one (ODQ). L-Arginine reversed the effect of L-NAME while indomethacin was without effect. Tamoxifen-induced relaxation was attenuated by charybdotoxin (CTX) plus apamin, ouabain or by incubation in a K+ -free solution. Moreover, tamoxifen triggered extracellular Ca2+ -dependent increases in endothelial [Ca2+]i and this effect was abolished by ICI 182,780. Endothelium-independent relaxation to sodium nitroprusside was also inhibited by ouabain or in a K+ -free solution. Furthermore, tamoxifen increased endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177 and ICI 182,780 prevented this effect.


CONCLUSIONS
The present results suggest that tamoxifen mainly induces endothelium-dependent relaxation and that endothelial nitric oxide (NO) is the primary mediator of this effect. NO-dependent responses may result from elevated [Ca2+]i in endothelial cells; an effect abolished by ICI 182,780. NO activates Na+/K+ -ATPase in vascular smooth muscle, leading to relaxation. These results suggest that tamoxifen is able to modulate eNOS phosphorylation directly.
Leung
H S
HS
Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
Yung
L M
LM
Leung
F P
FP
Yao
X
X
Chen
Z Y
ZY
Ko
W H
WH
Laher
I
I
Huang
Y
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology*; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013552:Swine; D013629:Tamoxifen / Q000494:pharmacology*
D016166:Free Radical Scavengers; D026902:Potassium Channel Blockers; D013629:Tamoxifen; D009599:Nitroprusside; D003609:Dactinomycin; D009569:Nitric Oxide; D004958:Estradiol; D010042:Ouabain; D003513:Cycloheximide; D052250:Nitric Oxide Synthase Type III; D002118:Calcium