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(Circulation Research. 1999;84:1302-1309.)
© 1999 American Heart Association, Inc.

Original Contributions

Modulation of Iron Uptake in Heart by L-Type Ca²⁺ Channel Modifiers

Possible Implications in Iron Overload

Robert G. Tsushima, Alan D. Wickenden, Ron A. Bouchard, Gavin Y. Oudit, Peter P. Liu, Peter H. Backx

From the Departments of Physiology and Medicine, University of Toronto and The Toronto Hospital, Toronto, Ontario, Canada.

Correspondence to Dr Peter H. Backx, Department of Medicine, The Toronto Hospital, CCRW 3-802, 101 College St, Toronto, Ontario M5G 2C4, Canada. E-mail p.backx{at}utoronto.ca

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 Ca²⁺ channel modifiers to alter Fe²⁺ uptake by isolated rat hearts and ventricular myocytes. Perfusion of rat hearts with 100 nmol/L ⁵⁹Fe²⁺ and 5 mmol/L ascorbate resulted in specific ⁵⁹Fe²⁺ uptake of 20.4±1.9 ng of Fe per gram dry wt. Abolishing myocardial electrical excitability with 20 mmol/L KCl reduced specific ⁵⁹Fe²⁺ uptake by 60±7% (P<0.01), which suggested that a component of myocardial Fe²⁺ uptake depends on membrane voltage. Accordingly, ⁵⁹Fe²⁺ uptake was inhibited by 10 µmol/L nifedipine (45±12%, P<0.02) and 100 µmol/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 (⁵⁹Fe³⁺) 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 Fe²⁺ uptake into heart occurs via the L-type Ca²⁺ channel in myocytes. To investigate this further, the effects of Fe²⁺ on cardiac myocyte L-type Ca²⁺ currents were measured. In the absence of Ca²⁺, noninactivating nitrendipine-sensitive Fe²⁺ currents were recorded with 15 mmol/L [Fe²⁺]_o. Low concentrations of Fe²⁺ enhanced Ca²⁺ current amplitude and slowed inactivation rates, which was consistent with Fe²⁺ entry into the cell, whereas higher Fe²⁺ levels caused dose-dependent decreases in peak current. Fe³⁺ had no effect on current amplitude or 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.

Key Words: iron overload • channels • heart failure • permeability • Ca²⁺

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