**5. Changes in the ionic cellular equilibrium (Figure 3)**

Ischemia induces a profound disturbance of the ionic homeostasis of a cell. The two major changes are the loss of ionic transmembrane gradients, which causes membrane depolariza‐ tion, and increased intracellular sodium ([Na+ ]i ), which is responsible for inducing a rise in the intracellular calcium ([Ca2+]i ) levels, leading to cellular edema.

Cellular depolarization occurs very rapidly after the onset of ischemia, and these mecha‐ nisms are not fully understood. However, it is recognized that both the inhibition of the Na + /K+ -ATPase and the opening of ATP-dependent K+ channels play a crucial role. Cellular de‐ polarization is characterized by a negative outgoing current and a decrease in the extracellu‐ lar concentrations of Na+ , Cl and Ca2+, as well as an increase in the extracellular concentration of K+ . Progressive depolarization of the cell also promotes prolonged activa‐ tion of voltage-dependent sodium channels. [29]

The accumulation of sodium in the cytosol is multifactorial. Acidosis stimulates Na+ /H+ ex‐ changers to purge cellular H+ , which results in increased intracellular Na+ .[32]-[34] This net movement of Na+ is accompanied by osmotic water movement. Moreover, inhibition of the Na+ /K+ -ATPase due to a lack of ATP prevents the removal of excess intracellular Na+ . The high intracellular concentration of Na+ affects the function of other membrane transporters, such as the Na+ /Ca2+ antiporter, an accelerator. This allows the extrusion of sodium from the cell at the expense of an intracellular accumulation of Ca2+. The massive entry of calcium in‐ to the cell disrupts the mechanisms that regulate its intracellular concentration and induces the release of calcium from the intracellular endoplasmic reticulum stores.[35] The lack of ATP prevents calcium excretion into the interstitium and its sequestration in the endoplas‐ mic reticulum. The accumulation of cytosolic calcium induces degradation of membrane phospholipids and cytoskeletal proteins, alters the both the calcium affinity and the efficien‐ cy of proteins involved in contractility, activates nitric oxide synthase (NOS) and proteases such as calpains and caspases, promotes the production of free radicals and alters the terti‐ ary structure of enzymes such as xanthine dehydrogenase, which is converted to xanthine oxidase. [36]-[38]
