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


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).


CONCLUSIONS
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.
Wei
Shao-Kui
SK
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Hanlon
Stephen U
SU
Haigney
Mark C P
MC
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology*; D000318:Adrenergic beta-Agonists / Q000493:pharmacokinetics*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015994:Incidence; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000493:pharmacokinetics; D008274:Magnesium / Q000378:metabolism* / Q000493:pharmacokinetics*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism; D013552:Swine
D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D019831:Sodium-Calcium Exchanger; D008274:Magnesium; D007545:Isoproterenol