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Current theories posit that women have a reduced ��repolarization reserve�� due to reduced potassium currents resulting in longer http://www.selleckchem.com/products/lee011.html QT and greater repolarization delays. We proposed an alternative mechanism of ?higher calcium currents in women which would likewise prolong QT intervals, delay repolarization while increasing the force of contractions and intracellular calcium load. Here, we show that physiological concentrations of oestrogen increase the calcium current only in cells from the base of the heart, by increasing messenger RNA and proteins levels that encode for the calcium current. Moreover, oestrogen acts by interacting with oestrogen receptors (ER)�� but not ER�� which may explain why hormone replacement therapy increases the risk of arrhythmia and offers a possible protective solution of using an oestrogen mimetic that selectively binds to ER��. Abstract? In type-2 long QT (LQT2), adult women and adolescent boys have a higher risk of lethal arrhythmias, called Torsades de pointes (TdP), compared to the opposite sex. In rabbit hearts, similar sex- and age-dependent TdP risks were attributed to higher expression levels of L-type Ca2+ channels and Na+�CCa2+ exchanger, at the base of the female epicardium. Here, the effects of oestrogen and progesterone are investigated to elucidate the mechanisms whereby?ICa,L density http://www.selleckchem.com/products/bmn-673.html is upregulated in adult female rabbit hearts.?ICa,L density was measured by the whole-cell patch-clamp technique on days 0�C3 in cardiomyocytes isolated from the base and apex of adult female epicardium. Peak?ICa,L was 28% higher at the base than apex (P? http://www.selleck.cn/products/AZD6244.html 5 nm) but not the ��- (DPN, 5 nm) subtype oestrogen receptor (ER��/ER��) upregulated?ICa,L like E2. Western blots detected similar levels of ER�� and ER�� in male and female hearts at the base and apex. E2 increased Cav1.2�� (immunocytochemistry) and mRNA (RT-PCR) levels but did not change?ICa,L kinetics.?ICa,L upregulation by E2 was suppressed by the ER antagonist ICI 182,780 (10 ��m) or by inhibition of transcription (actinomycin D, 4 ��m) or protein biosynthesis (cycloheximide, 70 ��m). Therefore, E2 upregulates?ICa,L by a regional genomic mechanism involving ER�� which is a known determinant of sex differences in TdP risk in LQT2.