R 56865 exerts cardioprotective properties independent of the intracellular Na(+)-overload in the guinea pig heart.

Reducing intracellular Na(+)-accumulation during ischemia exerts cardioprotective effects in reperfusion in a variety of models. Since slowly-inactivating Na(+)-channels may contribute to Na(+)-influx in ischemia, we investigated whether the ischemia-protective properties of R 56865, an inhibitor of slowly inactivating Na(+)-channels, are mediated by inhibition of the ischemic Na(+)-overload. Monitoring intracellular Na(+) (Na(+)(i)) by (23)Na-NMR-spectroscopy revealed a continuous rise of Na(+)(i) during ischemia in the isolated perfused guinea pig heart. Within 30 and 60 min of ischemia, respectively, Na(+)(i) had risen 2.6+/-0.2- and 4.4+/-0.2-fold compared to baseline ( n=6). R 56865 (1 microM) did not influence the time course of the Na(+)(i)-accumulation at any point of the ischemic period. R 56865, however, showed marked cardioprotective properties: in the reperfusion period the agent markedly improved the restoration of left ventricular developed pressure (29.1+/-6.8 mm Hg vs. 2.4+/-2.0 mm Hg), ATP (2.8+/-0.3 mM vs. 1.7+/-0.6 mM) and phosphocreatine (10.9+/-2.2 mM vs. 6.8+/-1.1 mM), furthermore contracture development was reduced. The present study strongly suggests slowly-inactivating Na(+)-channels being at best a minor port of Na(+)-entry in the ischemic guinea pig heart. It clearly demonstrates that the potent cardioprotective properties of R 56865 are unrelated to intracellular sodium homeostasis.