Metabolic Pathways for Ion Homeostasis and Persistent Na⁺ Current

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 Ca(2+) 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(+)-Ca(2+), and Na(+)-H(+) exchangers. The activity of the latter two exchanger mechanisms depends on their expression levels and the concentration gradients of Na(+) and Ca(2+) 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 Ca(2+) stores and release sites for maintaining very low cytoplasmic concentration of Ca(2+). Ischemia disrupts the delicate interactions of these transport mechanisms. This may cause intracellular Na(+) and Ca(2+) 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 Ca(2+) accumulation in the cells.