Effects of Late Sodium Current (INAL) Blockade during Acute Myocardial Ischemia

Abstract

Background: Ischemia ischaracterized by an overproduction of toxic metabolites well-known enhancers of the late sodium current (INaL). Ranolazine (RAN), a blocker of INaL, improves recovery during reperfusion. However, during ischemia diastolic potential depolarization might limit INa recruiting; thus, whether INaL is actually enhanced during acute ischemia is still unknown.Aim: To test the functional contribution of INaL in a cellular model of acute ischemia.Methods: Rat ventricular myocytes were exposed for 7 min to a (normoxic) ischemia-mimic solution (ISC); to evaluate the role of INaL, RAN (10μM) or TTX (1μM) were added throughout the protocol. INaL was isolated as TTX (1μM)-sensitive current during action potentials (APs) elicited at 1Hz. Cell shortening, cytosolic Na+ (Nai) and Ca2+ (Cai) were monitored in field-stimulated myocytes (1Hz). The sarcolemma (s) and mitochondrial (m) Na+/Ca2+exchanger (NCX) were blocked by SEA-0400 (1μM) and CGP37157 (1μM) respectively.Results: During ISC, loss of contraction was followed by partial recovery. While APs persisted throughout ISC, diastolic potential markedly depolarized and AP upstroke velocity decreased. In spite of this, ISC induced INaL enhancement, which was completely prevented by RAN. ISC increased Nai and Cai, which were partially prevented by RAN; TTX affected ISC-induced Nai enhancement only. SEA-0400 boosted cytosolic Cai and sarcoplasmic reticulum (SR) Ca2+content during ISC. SEA-0400 effects were sharply curtailed by RAN and partially prevented by TTX. CGP37157 prevented RAN effects during sNCX blockade.Conclusion: During ISC, INaL increased in spite of AP changes and contributed to Nai increment. Unexpectedly, sNCX blockade unrevealed RAN and TTX effects on Cai. These results suggest Na+-dependent, but sNCX-independent Ca2+ accumulation mechanisms during acute ischemia. Indeed, mNCX appears to be involved in the INaL induced cytosolic Ca2+ accumulation.