Beta-adrenergic stimulation of pig myocytes with decreased cytosolic free magnesium prolongs the action potential and enhances triggered activity

Introduction: Heart failure results in chronic beta-adrenergic stimulation, repolarization lability, and arrhythmias associated with early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). Having described a significant reduction in intracellular free magnesium ([Mg²⁺]_i) in experimental heart failure, we asked whether a reduction in [Mg²⁺]_i would delay repolarization or facilitate EADs and/or DADs. Methods and Results: Left ventricular myocytes were isolated from Yorkshire swine. Cytosolic free [Mg²⁺] was set at 0.12 mM (LoMg) or 1.2 mM (HiMg) through pipette dialysis. Action potentials (AP), Ca current (I_Ca), and sodium/calcium exchange current (I_NCX) were measured in the presence or absence of isoproterenol (2 μM) at 37°C. Under basal conditions (0.1-Hz stimulation, 2 mM external [Ca²⁺]), reducing [Mg²⁺]_i had no effect on AP duration and I_Ca but did significantly enhance I_NCX. In contrast, during superfusion with isoproterenol, reduced [Mg²⁺]_i caused a significant increase in AP duration at both 50% and 90% repolarization (APD₅₀ and APD₉₀) compared with HiMg (P < 0.05). LoMg cells manifested a high incidence of triggered activities, including spontaneous AP, EADs, and DADs (83.3% in LoMg, n = 12 vs 38.3% in HiMg, n = 13; P < 0.05). I_Ca and I_NCX were significantly increased in LoMg cells compared with HiMg cells (P < 0.05). Conclusion: Decreased cytosolic free magnesium prolongs AP duration and increases the incidence of triggered activity during beta-adrenergic stimulation. These effects may be due to increased I_Ca and I_NCX in the presence of reduced intracellular [Mg²⁺]. A magnesium-dependent increase in triggered activity coupled with delayed repolarization during beta-adrenergic stimulation could contribute to the arrhythmogenic substrate in heart failure.