Late sodium current and intracellular ionic homeostasis in acute ischemia

Blockade of the late Na+ current (INaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in INaL during acute ischemia and their effect on intracellular milieu is missing. INaL, cytosolic Na+ and Ca2+ activities (Nacyt, Cacyt) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to INaL blockade. The results indicate that INaL was enhanced during ISC in spite of changes in action potential (AP) contour; INaL significantly contributed to Nacyt rise, but only marginally to Cacyt rise. The impact of INaL on Cacyt was markedly enhanced by blockade of the sarcolemmal(s) Na+/Ca2+ exchanger (NCX) and was due to the presence of (Na+-sensitive) Ca2+ efflux through mitochondrial NCX (mNCX). sNCX blockade increased Cacyt and decreased Nacyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Nacyt increment. Thus, a robust Ca2+ source, other than sNCX and including mitochondria, contributed to Cacyt during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Cacyt accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) INaL is enhanced during ISC, when the effect of Nacyt on mitochondrial Ca2+ transport may substantially contribute to INaL impact on Cacyt; (3) RAN may act mostly, but not exclusively, through INaL blockade during ISC.