Late sodium current and intracellular ionic homeostasis in acute ischemia.

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