Modulation of Iron Uptake in Heart by L-Type Ca 2+ Channel Modifiers

Abstract

Abstract —Heart failure is the leading cause of mortality in patients with transfusional iron (Fe) overload in which myocardial iron uptake ensues via a transferrin-independent process. We examined the ability of L-type Ca 2+ channel modifiers to alter Fe 2+ uptake by isolated rat hearts and ventricular myocytes. Perfusion of rat hearts with 100 nmol/L 59 Fe 2+ and 5 mmol/L ascorbate resulted in specific 59 Fe 2+ uptake of 20.4±1.9 ng of Fe per gram dry wt. Abolishing myocardial electrical excitability with 20 mmol/L KCl reduced specific 59 Fe 2+ uptake by 60±7% ( P <0.01), which suggested that a component of myocardial Fe 2+ uptake depends on membrane voltage. Accordingly, 59 Fe 2+ uptake was inhibited by 10 μmol/L nifedipine (45±12%, P <0.02) and 100 μmol/L Cd 2+ (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 ( 59 Fe 3+ ) was significantly lower (1.4±0.3 ng Fe per gram dry wt; P <0.001) compared with divalent iron. These data suggest that a component of Fe 2+ uptake into heart occurs via the L-type Ca 2+ channel in myocytes. To investigate this further, the effects of Fe 2+ on cardiac myocyte L-type Ca 2+ currents were measured. In the absence of Ca 2+ , noninactivating nitrendipine-sensitive Fe 2+ currents were recorded with 15 mmol/L [Fe 2+ ] o . Low concentrations of Fe 2+ enhanced Ca 2+ current amplitude and slowed inactivation rates, which was consistent with Fe 2+ entry into the cell, whereas higher Fe 2+ levels caused dose-dependent decreases in peak current. Fe 3+ had no effect on current amplitude or decay. Combined, our data suggest that myocardial Fe 2+ uptake occurs via L-type Ca 2+ channels and that blockade of these channels might be useful in the treatment of patients with excessive serum iron levels.