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

Abstract

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. . 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 þ -free solution. Moreover, tamoxifen triggered extracellular Ca 2 þ -dependent increases in endothelial [Ca 2 þ ] 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 þ -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 [Ca 2 þ ] i in endothelial cells; an effect abolished by ICI 182,780. NO activates Na þ /K þ -ATPase in vascular smooth muscle, leading to relaxation. These results suggest that tamoxifen is able to modulate eNOS phosphorylation directly.

Dilation of Epicardial Coronary Arteries by the G Protein-Coupled Estrogen Receptor Agonists G-1 and ICI 182,780

“…The present study confirms that acute vasodilation mediated by G-1 is endothelium-and NO-dependent [16,17] , and extends these previous findings for the coronary circulation, in which -in contrast to the rat aorta -both NO and endothelium-dependent hyperpolarization play a role [7,37] . The present findings are also in line with studies using the selective ER modulator tamoxifen, another GPER agonist [11] , reporting acute vasodilation of rabbit and porcine coronary arteries through endothelium-and NO-dependent mechanisms [22,38] .…”

“…We [6,21] and others [8,9,22,23] have previously used porcine coronary arteries as a model of human coronary arteries because of high anatomic and physiological similarities [24] . The present study, using G-1 and ICI 182,780 as GPER agonists, was set out to investigate whether GPER activation directly or indirectly regulates epicardial coronary artery tone, and to determine whether effects are affected by concomitant blockade of ER ␣ and ER ␤ .…”

Transient ST-segment elevation in lead aVR associated with tako-tsubo cardiomyopathy

“…Estrogen deprivation (natural or iatrogenic) impairs endothelial function and microcirculation via decreased expression of endothelial nitric oxide synthase (eNOS) and the subsequent reduction in nitric oxide (NO) bioavailability [8,9]. In the presented postmenopausal woman, chronic treatment with tamoxifen, a selective estrogen-receptor modulator (SERM) with strong anti-estrogenic activity, might additionally disturb coronary microcirculation [10,11]. However, recently published clinical and animal studies showed that tamoxifen improves endothelial function mostly due to enhancing NO release and reduction of plasma lipid and homocysteine levels [10,11].…”

“…In the presented postmenopausal woman, chronic treatment with tamoxifen, a selective estrogen-receptor modulator (SERM) with strong anti-estrogenic activity, might additionally disturb coronary microcirculation [10,11]. However, recently published clinical and animal studies showed that tamoxifen improves endothelial function mostly due to enhancing NO release and reduction of plasma lipid and homocysteine levels [10,11].…”

Tamoxifen and Its Metabolites Cause Acute Vasorelaxation of Aortic Rings by Inducing Vasodilator Prostanoid Synthesis

“…For example, Tam enhances flow-mediated dilation in humans under regular treatment with this drug. 2,3 Moreover, Tam acutely relaxes rabbit coronary rings [4][5][6] and mesenteric vascular bed from rats. 7 Although the vascular effects of Tam have been studied, there is little information with respect to the metabolites of Tam, which have variable effects.…”