Modulation of iron uptake in heart by L-type Ca2+ channel modifiers - Possible implications in iron overload

Heart failure is the leading cause of mortality in patients with transfusio nal iron (Fe) overload in which myocardial iron uptake ensues via a transfe rrin-independent process. We examined the ability of L-type Ca2+ channel mo difiers to alter Fe2+ uptake by isolated rat hearts and ventricular myocyte s. Perfusion of rat hearts with 100 nmol/L Fe-59(2+) and 5 mmol/L ascorbate resulted in specific Fe-59(2+) uptake of 20.4+/-1.9 ng of Fe per gram dry wt. Abolishing myocardial electrical excitability with 20 mmol/L KCI reduce d specific Fe-59(2+) uptake by 60+/-7% (P<0.01), which suggested that a com ponent of myocardial Fe2+ uptake depends on membrane voltage. Accordingly, Fe-59(2+) uptake was inhibited by 10 mu mol/L nifedipine (45+/-12%, P<0.02) and 100 mu mol/L Cd2+ (86+/-3%; P<0.001) while being augmented by 100 nmol /L Bay K 8644 (61+/-18%, P<0.01) or 100 nmol/L isoproterenol (40+/-12%, P<0 .05), By contrast, uptake of 100 nmol/L ferric iron (Fe-59(3+)) was signifi cantly lower (1.4+/-0.3 ng Fe per gram dry wt; P<0.001) compared with dival ent iron. These data suggest that a component of Fe2+ uptake into heart occ urs via the L-type Ca2+ channel in myocytes. To investigate this further, t he effects of Fe2+ on cardiac myocyte L-type Ca2+ currents were measured. I n the absence of Ca2+, noninactivating nitrendipine-sensitive Fe2+ currents were recorded with 15 mmol/L [Fe2+](o). Low concentrations of Fe2+ enhance d Ca2+ current amplitude and slowed inactivation rates, which was consisten t with Fe2+ entry into the cell, whereas higher Fe2+ levels caused dose-dep endent decreases in peak current. Fe3+ had no effect on current amplitude o r decay. Combined, our data suggest that myocardial Fe2+ uptake occurs via L-type Ca2+ channels and that blockade of these channels might be useful in the treatment of patients with excessive serum iron levels.