title: Late sodium current and intracellular ionic homeostasis in acute ischemia.
abstract: Blockade of the late Na+current (INaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in INaLduring 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 INaLblockade. The results indicate that INaLwas enhanced during ISC in spite of changes in action potential (AP) contour; INaLsignificantly contributed to Nacytrise, but only marginally to Cacytrise. The impact of INaLon Cacytwas 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 Cacytand decreased Nacyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Nacytincrement. Thus, a robust Ca2+source, other than sNCX and including mitochondria, contributed to Cacytduring ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Cacytaccumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) INaLis enhanced during ISC, when the effect of Nacyton mitochondrial Ca2+transport may substantially contribute to INaLimpact on Cacyt; (3) RAN may act mostly, but not exclusively, through INaLblockade during ISC.
authors.affiliation: Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Ronchi
authors.affiliation: Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Torre
authors.affiliation: Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rizzetto
authors.affiliation: Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bernardi
authors.affiliation: Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.affiliation: Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy. antonio.zaza@unimib.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium
keywords: Acute ischemia; Ca2+ homeostasis; Late sodium current; Mitochondria; Na+ homeostasis; Ranolazine