Cardioprotective actions of KC 12291 II. Delaying Na+ overload in ischemia improves cardiac function and energy status in reperfusion

Abstract

The novel blocker of voltage-gated Na⁺ channels KC 12291 (1-(5-phenyl-1,2,4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl] amino] propane hydrochloride) delays myocardial Na⁺ overload in ischemia. To test whether KC 12291 displays cardioprotective properties in the intact heart, cardiac function, energy status and intracellular pH (³¹P NMR) as well as ion homeostasis (²³Na NMR) were investigated during low-flow ischemia (100 µl/min for 36 min) followed by reperfusion. In the well-oxygenated, isolated perfused guinea pig heart, KC 12291 (1 µM) had no effect on left ventricular developed pressure (LVDP; 54±19 mmHg). KC 12291 delayed the onset and decreased the extent of ischemic contracture and markedly improved the recovery of LVDP in reperfusion [39±14 mmHg (n=4) vs 2±2 mmHg in controls (n=5)]. KC 12291 did not influence the rapid drop in phosphocreatine (PCr) following onset of ischemia but attenuated the decline in ATP. It also diminished the ischemia-induced fall in intracellular pH [6.39±0.2 (n=6) vs 6.18±0.20 in controls (n=6)]. In reperfusion, KC 12291 remarkably enhanced the recovery of PCr (84.8±9.6% vs 51.1±8.8% of baseline) and ATP (38.2±12.9% vs 23.7±9.3% of baseline). It also accelerated the recovery of intracellular pH. KC 12291 not only reduced the extent of ischemia-induced Na⁺ overload, but also enhanced Na⁺ recovery. It is concluded that KC 12291 delays contracture and reduces ATP depletion and acidosis in ischemia, and markedly improves the functional, energetic and ionic recovery in reperfusion. Blocking voltage-gated Na⁺ channels in ischemia to delay Na⁺ overload may thus constitute a promising therapeutic approach for cardioprotection.