University of Pittsburgh, School of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA.
J Physiol. 2011 Mar 1;589(Pt 5):1061-80. doi: 10.1113/jphysiol.2010.203398. Epub 2011 Jan 4.
Female rabbit hearts are more susceptible to torsade de pointes (TdP) in acquired long QT type 2 than males, in-part due to higher L-type Ca2+ current (ICa,L) at the base of the heart. In principle, higher Ca2+ influx via ICa,L should be balanced by higher efflux, perhaps mediated by parallel sex differences of sodium-calcium exchange (NCX) current (INCX). We now show that NCX1, like Cav1.2α, is greater at the base of female than male left ventricular epicardium and greater at the base than at the apex in both sexes. In voltage-clamp studies, inward (0, +20 mV, P < 0.04) and outward (-80, -60, -40, -20 mV, P < 0.01) INCX densities were significantly higher (1.5-2 fold) in female base compared to apex and male (base and apex) myocytes. Myocytes were incubated ±17β-oestradiol (E2 = 1 nm) and INCX was measured on days 0, 1, 2 and 3. Inward and outward INCX decreased over 2 days in female base myocytes becoming similar to INCX at the apex. E2 incubation (24 h) increased NCX1 (50%) and INCX (∼3-fold at 60 mV) in female base but not endocardium, apex or in male base myocytes. INCX upregulation by E2 was blunted by an oestrogen receptor (ER) antagonist (fulvestrant, 1 μm), and inhibition of transcription (actinomycin D, 5 μg ml-1) or translation (cycloheximide, 20 μg ml-1). Dofetilide (an IKr blocker) induced early afterdepolarizations (EADs) in female base myocytes cultured for 1 day if incubated with E2, but not without E2 or with E2+KB-R4973 (an INCX inhibitor), E2+fulvestrant or E2 with apex myocytes. Thus, E2 upregulates NCX1 by a genomic mechanism mediated by ERs, and de novo mRNA and protein biosynthesis, in a sex- and region-dependent manner which contributes to the enhanced propensity to EADs and TdP in female hearts.
雌性兔子的心脏比雄性更容易发生获得性长 QT 型 2 扭转型室性心动过速（TdP），部分原因是心脏底部的 L 型钙电流（ICa,L）较高。原则上，通过 ICa,L 增加的 Ca2+内流应该通过更高的流出来平衡，这种流出可能是由钠钙交换（NCX）电流（INCX）的平行性别差异介导的。我们现在表明，NCX1 与 Cav1.2α 一样，在雌性左心室心外膜的底部比雄性多，在两性中均在底部比在顶部多。在电压钳研究中，内向（0、+20 mV，P < 0.04）和外向（-80、-60、-40、-20 mV，P < 0.01）INCX 密度在雌性底部比顶部和雄性（底部和顶部）心肌细胞显著更高（1.5-2 倍）。心肌细胞孵育±17β-雌二醇（E2 = 1 nm），并在第 0、1、2 和 3 天测量 INCX。在雌性底部心肌细胞中，内向和外向的 INCX 在 2 天内下降，变得与顶部的 INCX 相似。E2 孵育（24 h）增加了雌性底部心肌细胞中的 NCX1（50%）和 INCX（在 60 mV 时增加约 3 倍），但不在心内膜、顶部或雄性底部心肌细胞中。E2 对 INCX 的上调作用被雌激素受体（ER）拮抗剂（氟维司群，1 μm）、转录抑制（放线菌素 D，5 μg ml-1）或翻译抑制（环己酰亚胺，20 μg ml-1）所阻断。多非利特（一种 IKr 阻滞剂）在孵育 E2 的情况下，在雌性底部心肌细胞培养 1 天后诱导早期后除极（EAD），但如果没有 E2 或与 E2+KB-R4973（一种 INCX 抑制剂）、E2+氟维司群或与顶部心肌细胞的 E2 一起，不会诱导 EAD。因此，E2 通过雌激素受体介导的基因组机制上调 NCX1，并通过新的 mRNA 和蛋白质生物合成，以性别和区域依赖的方式，增加雌性心脏中 EAD 和 TdP 的易感性。
