The novel inhibitor of the reverse mode of the Na⁺/Ca²⁺ exchanger (NCE) KB-R7943 (KB) was tested in isolated rat cardiomyocytes exposed to 80 min of simulated ischemia [substrate-free anoxia, extracellular pH (pH_o) of 6.4] and 15 min of reoxygenation (pH_o 7.4). At pH_o 6.4, 20 µmol/l KB was required for complete inhibition of the reverse mode of NCE. Treatment with 20 µmol/l KB only during anoxia did not influence the onset of rigor contracture and intracellular pH (pH_i) (monitored with 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein) but significantly reduced the cytosolic accumulation of Ca²⁺ (monitored with fura 2) and Na⁺ (monitored with sodium-binding benzofuran isophthalate). During reoxygenation, cardiomyocytes developed hypercontracture. This was significantly reduced by anoxic KB treatment. To investigate this protection against reoxygenation-induced injury in the whole heart, we exposed Langendorff-perfused rat hearts to 110 min of anoxia (pH_o 6.4) and 50 min of reoxygenation (pH_o 7.4). Application of 20 µmol/l KB during anoxia significantly reduced the reoxygenation-induced enzyme release. We conclude that KB offers significant protection of cardiomyocytes against Ca²⁺ and Na⁺ overload during anoxia and hypercontracture or enzyme release on reoxygenation.

calcium overload; sodium overload; reoxygenation injury; cardiomyocytes; heart

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