Abstract
Objective: Acute ischemia is associated with rapidly decreasing contractility and Ca2+-transients. Diastolic intracellular Ca2+, however, only mildly increases until development of contracture. The purpose of this study was to investigate whether changes of cellular calcium handling during the early phase of ischemia are associated with active sarcolemmal calcium transport. Methods: Changes of extracellular concentration of calcium ([Ca2+]o) and tetramethylammonium ([TMA+]o), to estimate extracellular space, were simultaneously measured with ion-specific electrodes in the globally ischemic rat heart. The magnitude and direction of sarcolemmal calcium transport were calculated from [Ca2]ocorrected for changed extracellular water content. Energy dependence of sarcolemmal calcium transport was investigated by application of iodoaceticacid (IAA) to inhibit anaerobic glycolysis, and the involvement of the sarcoplasmic reticulum (SR) was studied by application of thapsigargin. The effect of anoxia and thapsigargin on cytosolic and SR calcium was studied in isolated myocytes with the fluorescent indicator indo-1. Results: [Ca2+]oincreased and extracellular space gradually decreased in the ischemic intact heart. During the first 7 min, the increase of [Ca2+]owas associated with net outward transport of calcium. Subsequently, net re-uptake occurred. IAA completely abolished outward transport and influx was accelerated and enhanced. Application of thapsigargin attenuated outward transport. In electrically-stimulated myocytes, anoxia caused little change of diastolic calcium and depletion of SR. Thapsigargin reduced both calcium transient amplitude and SR calcium without affecting diastolic calcium. During three successive short episodes of ischemia/reperfusion (preconditioning), outward transport of calcium progressively decreased. Conclusion: During the early phase of global ischemia, energy dependent transport of calcium to the extracellular space occurs. At least part of this calcium originates from SR. During the later stage of ischemia, re-uptake of calcium occurs, which is associated with development of contracture.
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