Late sodium current and intracellular ionic homeostasis in acute ischemia

Blockade of the late Na⁺ current (I _NaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in I _NaL during acute ischemia and their effect on intracellular milieu is missing. I _NaL, cytosolic Na⁺ and Ca²⁺ activities (Na_cyt, Ca_cyt) 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 I _NaL blockade. The results indicate that I _NaL was enhanced during ISC in spite of changes in action potential (AP) contour; I _NaL significantly contributed to Na_cyt rise, but only marginally to Ca_cyt rise. The impact of I _NaL on Ca_cyt 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 Ca_cyt and decreased Na_cyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Na_cyt increment. Thus, a robust Ca²⁺ source, other than sNCX and including mitochondria, contributed to Ca_cyt during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Ca_cyt accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) I _NaL is enhanced during ISC, when the effect of Na_cyt on mitochondrial Ca²⁺ transport may substantially contribute to I _NaL impact on Ca_cyt; (3) RAN may act mostly, but not exclusively, through I _NaL blockade during ISC.