Metabolic Pathways for Ion Homeostasis and Persistent Na+ Current

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ATP supply in heart cells is preserved by a number of different mechanisms to maintain a constant level of ATP concentration. ADP, phosphocreatine, inorganic phosphate, and cAMP-activated kinases are effectively involved in ATP supply in abnormal conditions such as ischemia. Intracellular Na+ and Ca2+ concentrations in the heart cells are maintained at low levels through the operation of ion transport across the plasma membrane, such as Na+–K+ pumps, as well as Na+–Ca2+, and Na+–H+ exchangers. The activity of the latter two exchanger mechanisms depends on their expression levels and the concentration gradients of Na+ and Ca2+ across the membrane. These exchangers may interact, and both are strongly regulated by intracellular Na+, which is maintained by the Na+–K+ pump, utilizing ATP as an energy source. The mitochondria and the sarcoplasmic reticulum are the organelles responsible for intracellular Ca2+ stores and release sites for maintaining very low cytoplasmic concentration of Ca2+. Ischemia disrupts the delicate interactions of these transport mechanisms. This may cause intracellular Na+ and Ca2+ accumulation, which can cause decreased contractility and electrical instability. Further, a persistent (noninactivating) Na+ current may be enhanced during ischemia, and this can contribute to action potential prolongation, and the development of early afterdepolarizations. The Na+ influx via the persistent Na+ current may induce further Na+ and Ca2+ accumulation in the cells.

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