Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen.

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.