Calcium Overload Blockade in Neurons and Cardiomyocytes

Abstract

An important role in cell death following an ischemic insult has been attributed to Ca²⁺, although the mechanisms by which altered Ca²⁺ homeostasis induces cell injury are poorly understood. A good insight into the factors responsible for abnormal Ca2⁺ load in brain and heart cells is critical for the development of pharmacological agents that afford protection during ischemia. It is generally assumed that the depletion of ATP during ischemia triggers an impairment of ion homeostasis. Intracellular Ca²⁺ increases to a concentration which might exceed the equilibrium between influx and extrusion or sequestration capacities. This situation imposes a heavy burden on the already compromised energy household and eventually might be the cause of cell death. In addition to Ca^2+. transients, Na⁺ transients are considered to play a crucial role in the development of ischemic cell damage and Na⁺ overload might precede excessive Ca²⁺-influx. Factors liberated during ischemia and reperfusion (e.g., reactive 0₂ species, lysophosphatides) are known to impair the inactivation kinetics of the Na⁺ channel causing excessive Na⁺-entry. The resulting Na⁺-overload may then drive the Na /Ca²⁺ -exchanger in the direction of Ca²⁺-overload. Moreover, altered Na⁺ channels may directly contribute to Ca²⁺-overload by carrying Ca²+ in addition to Na+.