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 microM) at 37 degrees 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.