title: Modulation of iron uptake in heart by L-type Ca2+ channel modifiers: possible implications in iron overload.
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 micromol/L nifedipine (45+/-12%, P<0.02) and 100 micromol/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.
authors.affiliation: Departments of Physiology and Medicine, University of Toronto and The Toronto Hospital, Toronto, Ontario, Canada.
authors.forename: R G
authors.initials: RG
authors.lastname: Tsushima
authors.forename: A D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: R A
authors.initials: RA
authors.lastname: Bouchard
authors.forename: G Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: P P
authors.initials: PP
authors.lastname: Liu
authors.forename: P H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D007501:Iron; D009543:Nifedipine; D007545:Isoproterenol