MECHANISMS OF INTRACELLULAR MAGNESIUM MAINTENANCE IN CARDIAC MYOCYTES UNDER HYPOXIC CONDITIONS

Abstract

Objective : Cardiac hypoxia-reoxygenation reduces the intracellular magnesium concentration. During hypoxia, an increase in the extracellular magnesium concentration inhibits the decrease in the cardiac intracellular magnesium concentration and protects the heart effectively;however, the underlying mechanisms remain unclear. We hypothesizedthat the influx of ionized magnesium (Mg²⁺) from the extracellular high-Mg²⁺ space into the intracellular space facilitates the recovery of cardiac function. Therefore, we examined the relationship between cardiac function and intracellular magnesium. Materials and Methods : Male Sprague-Dawley rats were sacrificed and the heart of each rat was quickly excisedto establish Langendorff perfusion. After the stabilization period, isoproterenol (iso) was appliedto the hearts, which decreases [Mg²⁺] _i, and was then washedout. After the washout of iso, we examinedthe relationship between cardiac function andcard iac total magnesium content. On the other hand, we studied the [Mg²⁺] _i dynamics under hypoxic conditions with or without transient receptor potential melastatin 7 (TRPM7) inhibitors and under iso-applied conditions using mag-fura2/ AM fluorometry with isolatedrat ventricular myocytes. Results : In the Langendorff perfused rat heart model, the washout of iso resulted in the depression of cardiac function and decrease in the cardiac total magnesium content. Application of iso with a high extracellular Mg2+ concentration improved the recovery of cardiac function and prevented the decline in the cardiac total magnesium content. In isolated cardiac myocytes, [Mg²⁺] _i was only slightly increased by the high extracellular Mg²⁺ concentration under aerobic conditions. However, under hypoxic conditions, a high extracellular Mg²⁺ concentration increased [Mg²⁺] _i substantially. In addition, this increase in [Mg²⁺] _i was suppressedby TRPM7 inhibitors. Conclusions : We demonstrated that a decrease in cardiac total magnesium content due to hypoxia or iso application depresses cardiac contractile function. The depression of cardiac function by the decrease in the cardiac total magnesium content improved because of the high extracellular concentration of Mg2+. This mechanism suggestedthe possibility of an increase in [Mg²⁺] _i by influx from the extracellular high-Mg²⁺ space via TRPM7.