Tamoxifen dilates porcine coronary arteries: roles for nitric oxide and ouabain‐sensitive mechanisms

Background and purpose:

Experiments were designed to determine the mechanism of the relaxation induced by tamoxifen in porcine coronary arteries at the tissue, cellular and molecular levels.

Experimental approach:

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.

Key results:

Tamoxifen induced an endothelium‐dependent relaxation that was antagonized by ICI 182,780 and abolished by N^G‐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 and Implications:

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.

DOI: 10.1038/sj.bjp.0706921

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