Cardioprotective effects of KB-R7943:: a novel inhibitor of the reverse mode of Na+/Ca2+ exchanger

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,) of 6.4] and 15 min of reoxygenation (pH(o) 7.4). At pH(o) 6.4, 20 mu mol/l KB was required for complete inhibition of the reverse mode of NCE. Treatment with 20 mu mol/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, 6.4) and 50 min of reoxygenation (pH, 7.4). Application of 20 mu mol/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.