17β-Estradiol Inhibits Ca 2+ Influx and Ca 2+ Release Induced by Thromboxane A 2 in Porcine Coronary Artery

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Abstract
Background We wished to investigate the possible mechanism of the protective effect of estrogen replacement on coronary atherosclerosis observed in postmenopausal women. Methods and Results Cytosolic Ca 2+ concentration ([Ca 2+ ] i ) and contraction were measured simultaneously in fura 2–loaded porcine coronary arterial strips stimulated by the thromboxane A 2 analogue U46619 and high-K + depolarization in the presence and absence of 17β-estradiol. Pretreatment with 17β-estradiol (30 nmol/L to 30 μmol/L) inhibited the sustained elevation of [Ca 2+ ] i and the sustained contraction induced by 300 nmol/L U46619. Higher concentrations of 17β-estradiol (1 to 100 μmol/L) also inhibited the U46619-induced transient increase in [Ca 2+ ] i and contraction in the absence of extracellular Ca 2+ . In the strips precontracted by 90 mmol/L K + , 17β-estradiol (30 μmol/L) inhibited the increases in [Ca 2+ ] i and contraction to resting levels. In contrast, 30 μmol/L 17β-estradiol only partially inhibited the U46619-induced sustained contraction, despite complete inhibition of the sustained increase in [Ca 2+ ] i . Verapamil (10 μmol/L) also strongly inhibited the sustained increase in [Ca 2+ ] i induced by 300 nmol/L U46619, with a partial inhibition of the U46619-induced sustained contraction. A subsequent addition of 30 μmol/L 17β-estradiol did not show an additional inhibitory effect on either the [Ca 2+ ] i or the tension after the addition of verapamil. 17β-Estradiol (10 μmol/L) also inhibited the increase in [Ca 2+ ] i and the contraction induced by cumulative addition of Ca 2+ in the strips pretreated with 90 mmol/L K + . However, 17β-estradiol did not change the slope of the [Ca 2+ ] i -tension curves. 17β-Estradiol (10 μmol/L) had no effect on the levels of cAMP and cGMP in the coronary strips. Conclusions 17β-Estradiol inhibits the contraction of coronary vascular smooth muscle mainly by inhibiting Ca 2+ influx without changing Ca 2+ sensitivity of contractile elements. The Ca 2+ channel blocker–like action of 17β-estradiol may explain at least a part of the antiatherosclerotic effect of estrogen.