CARDIOPROTECTIVE ACTIONS OF KC-12291 - II - DELAYING NA-FUNCTION AND ENERGY STATUS IN REPERFUSION( OVERLOAD IN ISCHEMIA IMPROVES CARDIAC)

The novel blocker of voltage-gated Na+ channels KC 12291 opyl)-3-[N-me thyl-N-[2-(3,4-dimethoxyphenyl)ethyl] amino] propane hydrochloride) de lays myocardial Na+ overload in ischemia. To test whether KC 12291 dis plays cardioprotective properties in the intact heart, cardiac functio n, energy status and intracellular pH (P-31 NMR) as well as ion homeos tasis (Na-23 NMR) were investigated during low-flow ischemia (100 mu l /min for 36 min) followed by reperfusion. In the well-oxygenated, isol ated perfused guinea pig heart, KC 12291 (1 mu M) had no effect on lef t ventricular developed pressure (LVDP; 54+/-19 mmHg). KC 12291 delaye d the onset and decreased the extent of ischemic contracture and marke dly improved the recovery of LVDP in reperfusion [39+/-14 mmHg (n=4) v s 2+/-2 mmHg in controls (n=5)]. KC 12291 did not influence the rapid drop in phosphocreatine (PCr) following onset of ischemia but attenuat ed 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+ overloa d, bur also enhanced Na+ recovery.It is concluded that KC 12291 delays contracture and reduces ATP depletion and acidosis in ischemia, and m arkedly improves the functional, energetic and ionic recovery in reper fusion. Blocking voltage-gated Na+ channels in ischemia to delay Na+ o verload may thus constitute a promising therapeutic approach for cardi oprotection.